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  • 301.
    Popova, Svetlana N
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sooman, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Subtyping of gliomas of various WHO grades by the application of immunohistochemistry2014In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 64, no 3, p. 365-379Article in journal (Refereed)
    Abstract [en]

    Aims

    In 2010, four subtypes (classical, proneural, mesenchymal, and neural) of glioblastoma multiforme (GBM) were defined by molecular genetic analyses. The objective of this study was to assess whether gliomas, independently of the type and grade, could be subdivided into protein-based subtypes.

    Methods and results

    A tissue microarray (TMA) approach was applied to incorporate tissue samples of low-grade and high-grade gliomas into five TMAs. High expression levels of epidermal growth factor receptor (EGFR), CD44, c-MER proto-oncogene tyrosine kinase (MERTK), platelet-derived growth factor receptor α, p53, oligodendrocyte transcription factor 2 (OLIG2) and isocitrate dehydrogenase 1 with the R132H mutation were assessed using immunohistochemistry (IHC). Glioma could be subdivided into four subtypes by IHC. The majority of the low-grade gliomas were of the proneural subtype, i.e. high p53 expression (63% of grade II). The classical subtype, with high EGFR and low p53 expression, was most common in GBMs (39%), followed by the proneural (29%) and mesenchymal (with high CD44 and MERTK expression) (29%) subtypes, a frequency that is in line with previously published data based on molecular genetics.

    Conclusions

    Assessment of the expression of the five proteins EGFR, CD44, MERTK, p53 and OLIG2 is sufficient for subtyping gliomas, and can be recommended for implementation in clinical practice for both low-grade and high-grade gliomas.

  • 302. Poveda, A.
    et al.
    Vergote, I.
    Tjulandin, S.
    Kong, B.
    Roy, M.
    Chan, S.
    Filipczyk-Cisarz, E.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kaye, S. B.
    Colombo, N.
    Lebedinsky, C.
    Parekh, T.
    Gomez, J.
    Park, Y. C.
    Alfaro, V.
    Monk, B. J.
    Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial2011In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 22, no 1, p. 39-48Article in journal (Refereed)
    Abstract [en]

    Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6-12 months platinum-free interval (PFI)] is unclear. Patients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup. Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45-0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43-0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months). Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6-12 months).

  • 303.
    Påhlman, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Role of radiotherapy2008In: International Handbook of Colorectal Cancer / [ed] Jim Cassidy, Euromed Commincations Ltd , 2008, p. 57-70Chapter in book (Other academic)
  • 304.
    Quartino, Angelica L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Characterization of Endogenous G-CSF and the Inverse Correlation to Chemotherapy-Induced Neutropenia in Patients with Breast Cancer Using Population Modeling2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 12, p. 3390-3403Article in journal (Refereed)
    Abstract [en]

    Neutropenia is a severe adverse-event of chemotherapeutics. Neutrophils (ANC) are mainly regulated by granulocyte colony stimulating factor (G-CSF). The aim was to characterize the dynamics between endogenous G-CSF and ANC over time following chemotherapy. Endogenous G-CSF and ANC were monitored in forty-nine breast cancer patients treated with sequential adjuvant 5-fluorouracil-epirubicin-cyclophosphamide and docetaxel. During treatment courses ANC was transiently decreased and was reflected in an endogenous G-CSF increase, which was well described by a semi-mechanistic model including control mechanisms; when G-CSF concentrations increased the proliferation rate increased and the bone maturation time reduced for ANC. Subsequently, ANC in the circulation increased leading to increased elimination of G-CSF. Additionally, a non-specific elimination for G-CSF was quantified. The ANC-dependent elimination contributed to 97% at baseline and 49% at an ANC of 0.1 center dot 10(9)/L to the total G-CSF elimination. The integrated G-CSF-myelosuppression model captured the initial rise in endogenous G-CSF following chemotherapy-induced neutropenia and the return to baseline of G-CSF and ANC. The model supported the self-regulatory properties of the system and may be a useful tool for further characterization of the biological system and in optimization of chemotherapy treatment.

  • 305. Quentmeier, H.
    et al.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Dirks, W. G.
    Ehrentraut, S.
    Geffers, R.
    MacLeod, R. A. F.
    Nagel, S.
    Romani, J.
    Scherr, M.
    Zaborski, M.
    Drexler, H. G.
    U-2932: two clones in one cell line, a tool for the study of clonal evolution2013In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 5, p. 1155-1164Article in journal (Refereed)
    Abstract [en]

    Genetic heterogeneity is common in tumors, explicable by the development of subclones with distinct genetic and epigenetic alterations. We describe an in vitro model for cancer heterogeneity, comprising the diffuse large B-cell lymphoma cell line U-2932 which expresses two sets of cell surface markers representing twin populations flow-sorted by CD20 vs CD38 expression. U-2932 populations were traced to subclones of the original tumor with clone-specific immunoglobulin IgV(H)4-39 hypermutation patterns. BCL6 was overexpressed in one subpopulation (R1), MYC in the other (R2), both clones overexpressed BCL2. According to the combined results of immunoglobulin hypermutation and cytogenetic analysis, R1 and R2 derive from a mother clone with genomic BCL2 amplification, which acquired secondary rearrangements leading to the overexpression of BCL6 (R1) or MYC (R2). Some 200 genes were differentially expressed in R1/R2 microarrays including transcriptional targets of the aberrantly expressed oncogenes. Other genes were regulated by epigenetic means as shown by DNA methylation analysis. Ectopic expression of BCL6 in R2 variously modulated new candidate target genes, confirming dual silencing and activating functions. In summary, stable retention of genetically distinct subclones in U-2932 models tumor heterogeneity in vitro permitting functional analysis of oncogenes against a syngenic background.

  • 306.
    Qvarnström, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Jan
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Oncol, Gothenburg, Sweden..
    Hermansson, Ingegerd
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Oncol, Gothenburg, Sweden..
    Book, Majlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Karl-Axel
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Radiophys, Gothenburg, Sweden..
    Turesson, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Double strand break induction and kinetics indicate preserved hypersensitivity in keratinocytes to subtherapeutic doses for 7 weeks of radiotherapy2017In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 122, no 1, p. 163-169Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Previously we reported that hyper-radiosensitivity (HRS) was evidenced by quantifying DNA double strand break (DSB) foci in epidermis biopsies collected after delivering radio therapeutic one and five dose fractions. The aim of this study was to determine whether HRS was preserved throughout a 7-week radiotherapy treatment, and also to examine the rate of foci decline and foci persistence between dose fractions.

    Materials and methods: 42 patients with prostate cancer received 7-week fractionated radiotherapy treatment (RT) with daily dose fractions of 0.05-1.10 Gy to the skin. Before RT, and at several times throughout treatment, skin biopsies (n = 452) were collected at 30 min, and 2, 3, 24, and 72 h after dose fractions. DSB-foci markers, gamma H2AX and 53BP1, were labelled in epidermal keratinocytes with immunofluorescence and immunohistochemical staining. Foci were counted both with digital image analysis and manually.

    Results: HRS in keratinocytes was evidenced by the dose-response relationships of DSB foci, observed throughout the treatment course, independent of sampling time and quantification method. Foci observed at 24 h after dose fractions indicated considerable DSB persistence. Accordingly, foci significantly accumulated after 5 consecutive dose fractions. For doses below 0.3 Gy, persistent foci could be observed even at 72 h after damage induction. A comparison of gamma H2AX and 53BP1 quantifications in double-stained biopsies showed similar HRS dose-response relationships.

    Conclusions: These results represented the first evidence of preserved HRS, assessed by gamma H2AX- and 53BP1-labelled DSB foci, throughout a 7-week treatment course with daily repeated subtherapeutic dose fractions.

  • 307.
    Qvarnström, O. Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Tran, Thuy A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Effects of affinity on binding of HER2-targeting Affibody molecules: Model experiments in breast cancer spheroids2011In: International Journal of Oncology, ISSN 1019-6439, Vol. 39, no 2, p. 353-359Article in journal (Refereed)
    Abstract [en]

    Binding of a targeting agent in tumor tissue is influenced by many factors such as molecular weight, charge and affinity of the targeting agent and vascularization of the tumor. In this study, we analyzed tumor cell binding of three HER2-specific and radiolabeled Affibody molecules with different affinities. The Affibody molecules had affinities in the range of 0.12-3.8 nM. Cellular binding was analyzed, after 2 h of incubation, in tumor spheroids composed of BT474 breast cancer cells, which highly express HER2. Binding was, due to the binding-site barrier,limited to the outer 15 +/- 5 mu m rim of the spheroids, independent of affinity when the concentration of the substances was low. When the concentration was high, the binding site barrier was overcome and the binding occurred approximately 35 +/- 5 mu m into the spheroids for the two high affinity substances and 50 +/- 5 mu m for the low affinity substance. The lower affinity might allow for penetration into deeper regions due to less firm binding. We conclude that there is a binding site barrier within tumor spheroids which can be overcome by increased concentration of substance and modified by affinity.

  • 308. Qvortrup, C.
    et al.
    Cvancarova, M.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pfeiffer, P.
    Sorbye, H.
    Age dependent increase in median and long-term survival in 29 628 metastatic colorectal cancer (mcrc) scandinavian patients during the past two decades2012In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, no S9, p. 188-188Article in journal (Other academic)
  • 309. Racadot, S.
    et al.
    Hammel, P.
    Chibaudel, B.
    Goldstein, D.
    Spry, N.
    Van Laethem, J.
    Van Houtte, P.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gubanski, M.
    Huguet, F.
    Dummy Run in the Phase III LAP07 Pancreatic Cancer Trial: First Evaluation of Quality of Radiation Therapy Planning2012In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 84, no 3, p. S322-S322Article in journal (Other academic)
  • 310.
    Radu, Calin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Optimising Radiotherapy in Rectal Cancer Patients2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rectal cancer is the eight most common cancer diagnosis in Sweden in both men and women, with almost 2000 new cases per year. Radiotherapy, which is an important treatment modality for rectal cancer, has evolved during the past decades. Diagnostic tools have also improved, allowing better staging and offering information used to make well-founded decisions in multidisciplinary team conferences.

    In a retrospective study (n=46) with locally advanced rectal cancer (LARC) patients, unfit for chemoradiotherapy, patients were treated with short-course radiotherapy. Delayed surgery was done when possible. Radical surgery was possible in 89% of the patients who underwent surgery (80%). Grade IV diarrhoea affected three elderly patients. Target radiation volume should be reduced in elderly or metastatic patients.

    In a prospective study (n=68) with LARC patients, magnetic resonance imaging (MRI) and 2-18F-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) were used to determine if FDG-PET could provide extra treatment information. Information from FDG-PET changed the stage of 10 patients. Delineation with FDG-PET generally resulted in smaller target volumes than MRI only.

    Seven of the most advanced LARC patients in the above cohort were used for a methodological study to determine if dose escalation to peripheral, non-resectable regions was feasible. Simultaneous integrated boost plans with photons and protons were evaluated. While toxicity was acceptable in five patients with both protons and photons, two patients with very large tumours had unacceptable risk for intestinal toxicity regardless of modality.

    In the interim analysis of the Stockholm III Trial (n=303, studying radiotherapy-fractionation and timing of surgery in relation to radiotherapy) compliance was acceptable and severe acute toxicity was infrequent, irrespective of fractionation. Short-course radiotherapy with immediate surgery tended to give more postoperative complications, but only if surgery was delayed more than 10 days after the start of radiotherapy.

    Quality-of-life in the Stockholm III Trial was studied before, during and shortly after treatment using the EORTC QLQ-C30 and CR38 questionnaires. Surgery accounted for more adverse effects than radiotherapy in all groups. Postoperatively, the poorest quality-of-life was seen in patients given short-course radiotherapy followed by immediate surgery. No postoperative differences were seen between the two groups with delayed surgery.

    List of papers
    1. Short-course preoperative radiotherapy with delayed surgery in rectal cancer: a retrospective study
    Open this publication in new window or tab >>Short-course preoperative radiotherapy with delayed surgery in rectal cancer: a retrospective study
    2008 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 87, no 3, p. 343-9Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: In the most advanced, non-resectable primary rectal cancers, conventional long-course radiotherapy (RT) (1.8-2Gyx25-28), frequently combined with chemotherapy, has been used since tumour regression is needed in order to allow a radical (R0) resection. In Uppsala, short-course 5x5Gy with planned delayed surgery has been used in patients with contraindications to long-course RT (+/-chemotherapy). The aim is to describe our experience of using this approach in patients not eligible for standard treatment. PATIENTS AND METHODS: During 2002 and 2005, 46 patients with non-resectable rectal cancer (+/-synchronous distant metastases) were treated with 5x5Gy and delayed surgery if possible. The clinical records were retrospectively evaluated. The first group (A) had no metastases (T4NXM0), whereas the other two groups (B+C) had metastases (T4NXM1). In group (B), the patients had predominantly loco-regional disease and were not candidates for combination chemotherapy (high age, co-morbidities), and in group (C) up-front combination chemotherapy was given, with the intention to have surgery of both the primary and the secondaries if sufficient regression at both sites were seen. RESULTS: The patients in the first two groups (A+B) were old (median 79 and 76 years, respectively), and had several co-morbidities. In group (C), median age was 63 years. The 5x5Gy RT was well tolerated by most patients, but grade IV diarrhoea was recorded in three elderly patients. One patient in the group (C) died from neutropenic fever. Many patients were reported to have less local symptoms after the treatment given. Delayed surgery was performed in all but nine patients. Radical surgery (R0+R1) was performed in 22 (92%) (group A), 4 (44%) (group B), and 6 (46%) (group C) patients, respectively. A pCR was seen in four patients (two in group A and two in group C). No postoperative deaths occurred. CONCLUSIONS: Considering the very high age and presence of co-morbidity, the 5x5Gy schedule is well tolerated. Further, considering the very advanced local stage, the schedule has considerable anti-tumour activity and can result in radical surgery in a high proportion of patients.

    Keywords
    Rectal cancer, Radiotheraphy, Non-resectable, 5 ×5 Gy, Delay surgery
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98972 (URN)10.1016/j.radonc.2007.11.025 (DOI)000257631700007 ()18093674 (PubMedID)
    Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2017-12-13Bibliographically approved
    2. Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT: a prospective study
    Open this publication in new window or tab >>Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT: a prospective study
    Show others...
    2011 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 81, no 4, p. e439-e445Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE:

    Accurate delineation of target volumes is important to maximize radiation dose to the tumor and minimize it to nontumor tissue. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities in rectal cancer. The aim was to explore whether functional imaging with F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), combined with CT (FDG-PET/CT) gives additional information to standard pretreatment evaluation and changes the shape and size of the gross tumor volume (GTV).

    METHODS AND MATERIALS:

    From 2007 to 2009, 77 consecutive patients with locally advanced rectal cancer were prospectively screened for inclusion in the study at two university hospitals in Sweden, and 68 patients were eligible. Standard GTV was delineated using information from clinical examination, CT, and MRI (GTV-MRI). Thereafter, a GTV-PET was defined in the fused PET-CT, and the target volume delineations were compared for total volume, overlap, and mismatch. Pathologic uptake suspect of metastases was also registered.

    RESULTS:

    The median volume of GTV-MRI was larger than that of GTV-PET: 111 cm3 vs. 87 cm3 (p < 0.001). In many cases, the GTV-MRI contained the GTV defined on the PET/CT images as subvolumes, but when a GTV total was calculated after the addition of GTV-PET to GTV-MRI, the volume increased, with median 11% (range, 0.5–72%). New lesions were seen in 15% of the patients for whom PET/CT was used.

    CONCLUSIONS:

    FDG-PET/CT facilitates and adds important information to the standard delineation procedure of locally advanced rectal cancer, mostly resulting in a smaller GTV, but a larger total GTV using the union of GTV-MRI and GTV-PET. New lesions were sometimes seen, potentially changing the treatment strategy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-169858 (URN)10.1016/j.ijrobp.2011.03.031 (DOI)000309412300031 ()21641122 (PubMedID)
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2017-12-07Bibliographically approved
    3. Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients
    Open this publication in new window or tab >>Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-172407 (URN)
    Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01
    4. Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Open this publication in new window or tab >>Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-172410 (URN)
    Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01
    5. Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Open this publication in new window or tab >>Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-172410 (URN)
    Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01
  • 311.
    Radu, Calin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pettersson, David
    Departments of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm.
    Martling, Anna
    Departments of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancerManuscript (preprint) (Other academic)
  • 312.
    Radu, Calin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Norrlid, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Braendengen, Morten
    Department of Oncology, Oslo University Hospital, Oslo, Norway.
    Hansson, Karl
    Department of Diagnostic Radiology, Karolinska University Hospital Solna and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm.
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patientsManuscript (preprint) (Other academic)
  • 313.
    Radu, Calin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Norrlid, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Braendengen, Morten
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, Oslo University Hospital, Oslo, Norway.
    Hansson, Karl
    Department of Diagnostic Radiology, Karolinska University Hospital, Solna, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 3, p. 528-537Article in journal (Refereed)
    Abstract [en]

    Background and Purpose.

    Few studies have explored the potential clinical advantages of dose escalation and integrated boosts for patients with non-resectable locally advanced rectal cancer. The possibility of escalating dose to non-resectable regions in these patients was the aim of this study.

    Patients and methods.

    Seven patients with locally very advanced rectal tumours (sacrum overgrowth or growth into pelvic side walls) were evaluated. Intensity modulated photon and pencil beam scanning proton plans with simultaneously integrated boosts (45 Gy to elective lymph nodes, 50 Gy to tumour and 62.5 Gy to boost area in 25 fractions) were compared.

    Results.

    Target coverage was achieved with both photon and proton plans. Estimated risks of acute side effects put the two patients with the largest tumours at unacceptable risk for intestinal toxicity, regardless of modality. The remaining five patients had beneficial sparing of dose to the small intestine with protons.

    Conclusions.

    Adding boost to areas where rectal tumours infiltrate adjacent non-resectable organs is an attractive option which appears possible using both photon and proton irradiation. Proton plans reduced dose to organs at risk. Integrated peripheral boosts should be considered more frequently in these very advanced tumours.

  • 314.
    Rasmussen, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kultima, Hanna Göransson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity2011In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 10, p. R108-Article in journal (Refereed)
    Abstract [en]

    We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors.

  • 315. Reizenstein, Johan A
    et al.
    Holmberg, Lars
    Regional Cancer Centre, Uppsala, Sweden.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Linder, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lödén, Britta
    Holmqvist, Marit
    Regional Cancer Centre, Uppsala, Sweden.
    Hellström, Karin
    von Beckerath, Mattias
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergström, Stefan N
    Time trends in T3 to T4 laryngeal cancer: a population-based long-term analysis2014In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 36, no 12, p. 1727-1731Article in journal (Refereed)
    Abstract [en]

    Background:

    A decline in laryngectomies and survival in laryngeal cancer has been reported, especially among advanced tumors.

    Methods:

    Out of 1058 patients with laryngeal cancer diagnosed 1978-2007 in the Uppsala-Örebro-region in Sweden 263 T3-4 tumors treated with curative intent were studied retrospectively. Two time periods were defined, 1978-1992 and 1993-2007.

    Results:

    Glottic tumors decreased constituting 68.6% of cases 1978-1992 and 47.9% 1993-2007. Laryngectomy was performed in 38.8% and in 34.5% in the corresponding time periods. The use of laryngectomy was not strongly prognostic. A decline in overall survival over time could only be identified for the first year of follow-up. Chemotherapy was only used in a minority of cases.

    Conclusion:

    The marked decrease of glottic site may mark a shift in etiology. Laryngectomy was not strongly associated with improved survival. The absence of improved survival calls for intensified research.

  • 316.
    Rexhepaj, Elton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergman, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Uhlen, Mathias
    Gallagher, William M.
    Lundberg, Emma
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Texture Based Pattern Recognition Approach to Distinguish Melanoma from Non-Melanoma Cells in Histopathological Tissue Microarray Sections2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e62070-Article in journal (Refereed)
    Abstract [en]

    Aims: Immunohistochemistry is a routine practice in clinical cancer diagnostics and also an established technology for tissue-based research regarding biomarker discovery efforts. Tedious manual assessment of immunohistochemically stained tissue needs to be fully automated to take full advantage of the potential for high throughput analyses enabled by tissue microarrays and digital pathology. Such automated tools also need to be reproducible for different experimental conditions and biomarker targets. In this study we present a novel supervised melanoma specific pattern recognition approach that is fully automated and quantitative. Methods and Results: Melanoma samples were immunostained for the melanocyte specific target, Melan-A. Images representing immunostained melanoma tissue were then digitally processed to segment regions of interest, highlighting Melan-A positive and negative areas. Color deconvolution was applied to each region of interest to separate the channel containing the immunohistochemistry signal from the hematoxylin counterstaining channel. A support vector machine melanoma classification model was learned from a discovery melanoma patient cohort (n = 264) and subsequently validated on an independent cohort of melanoma patient tissue sample images (n = 157). Conclusion: Here we propose a novel method that takes advantage of utilizing an immuhistochemical marker highlighting melanocytes to fully automate the learning of a general melanoma cell classification model. The presented method can be applied on any protein of interest and thus provides a tool for quantification of immunohistochemistry-based protein expression in melanoma.

  • 317.
    Rodriguez, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rehn, S M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Rickard S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundström, J C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Glimelius, Bengt L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    CT in malignancy grading and prognostic prediction of non-Hodgkin's lymphoma1999In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 40, no 2, p. 191-197Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    The presence of tumor inhomogeneities in MR images of non-Hodgkin's lymphoma (NHL) provides information about malignancy grade and prognosis. The aim of this study was to determine whether CT images are also informative in these respects.

    MATERIAL AND METHODS:

    Sixty-three CT examinations in patients with NHL (32 high-grade and 31 low-grade tumors) were reviewed retrospectively by two senior radiologists. The tumor patterns were classified subjectively as homogeneous, slightly inhomogeneous or severely inhomogeneous and their relations to malignancy grade, clinical characteristics and prognosis were determined.

    RESULTS:

    Sixteen out of 17 patients with a severely inhomogeneous tumor pattern had high-grade NHL tumors while 21 out of 29 patients with a homogeneous tumor appearance had low-grade NHL tumors. Among chemotherapy-treated patients, those with the highest degree of inhomogeneity had a significantly worse prognosis (9 out of 11 patients died). This relationship was not found in patients treated with radiotherapy.

    CONCLUSION:

    A severely inhomogeneous tumor pattern on CT images was found to be associated with a high malignancy grade in NHL. This CT pattern was also compatible with a poor prognosis in patients treated with chemotherapy.

  • 318.
    Rodriguez, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundín, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rehn, Suzanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    [18F] FDG PET in gastric non-Hodgkin's lymphoma1997In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 36, no 6, p. 577-584Article in journal (Refereed)
    Abstract [en]

    The possibility of using [18F] FDG PET for assessment of tumor extension in primary gastric non-Hodgkin's lymphoma (NHL) was studied in 8 patients (6 high-grade and 2 low-grade, one of the MALT type) and in a control group of 7 patients (5 patients with NHL without clinical signs of gastric involvement, 1 patient with NHL and benign gastric ulcer and 1 patient with adenocarcinoma of the stomach). All patients with gastric NHL and the two with benign gastric ulcer and adenocarcinoma, respectively, underwent endoscopy including multiple biopsies for histopathological diagnosis. All patients with high-grade and one of the two with low-grade NHL and the patient with adenocarcinoma displayed high gastric uptake of [18F] FDG corresponding to the pathological findings at endoscopy and/or CT. No pathological tracer uptake was seen in the patient with low-grade gastric NHL of the MALT type. In 6/8 patients with gastric NHL, [18F] FDG PET demonstrated larger tumor extension in the stomach than was found at endoscopy, and there was high tracer uptake in the stomach in two patients who were evaluated as normal on CT. [18F] FDG PET correctly excluded gastric NHL in the patient with a benign gastric ulcer and in the patients with NHL without clinical signs of gastric involvement. Although the experience is as yet limited, [18F] FDG PET affords a novel possibility for evaluation of gastric NHL and would seem valuable as a complement to endoscopy and CT in selected patients, where the technique can yield additional information decisive for the choice of therapy.

  • 319.
    Rodriguez, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rehn, Suzanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Predicting malignancy grade with PET in non-Hodgkin's lymphoma1995In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 36, no 10, p. 1790-1796Article in journal (Refereed)
    Abstract [en]

    Our goal was to determine whether PET with 11C-methionine and/or 18FDG could predict malignancy grade in non-Hodgkin's lymphoma (NHL).

    METHODS:

    Twenty-three patients with high-grade, low-grade or transformed low-grade NHL were investigated. Standardized uptake values (SUV), transport rate and mass influx values were calculated both for the whole tumor [mean regions of interest, (ROI)] and for the tumor area with the highest levels of activity, comprising four contiguous pixels within each tumor and designated as a hot spot.

    RESULTS:

    Both 11C-methionine and 18FDG detected all tumors. In addition, 18FDG discriminated between high- and low-grade NHL, whereas 11C-methionine did not. With 18FDG, three transformed low-grade NHLs behaved in an intermediate manner. All quantitative uptake values correlated well with each other for both tracers, except for the mean ROI SUV and transport rate of 11C-methionine. Quantifications of mean ROI uptake and hot spots were strongly correlated.

    CONCLUSION:

    The results of this study together with previous findings from other studies indicate that 18FDG but not 11C-methionine can predict malignancy grade in NHL. Further studies with a larger series of patients are needed.

  • 320. Rollven, Erik
    et al.
    Holm, Torbjorn
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lorinc, Esther
    Blomqvist, Lennart
    Potentials of high resolution magnetic resonance imaging versus computed tomography for preoperative local staging of colon cancer2013In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 54, no 7, p. 722-730Article in journal (Refereed)
    Abstract [en]

    Background: Preoperative identification of locally advanced colon cancer is of importance in order toproperly plan treatment. Purpose: To study high resolution T2-weighted magnetic resonance imaging (MRI) versus computed tomography (CT) for preoperative staging of colon cancer with surgery and histopathology as reference standard. Material and Methods: Twenty-eight patients with a total of 29 tumors were included. Patients were examined on a 1.5 T MR unit using a phased array body coil. T2 turbo spin-echo high resolution sequences were obtained in a coronal, transverse, and perpendicular plane to the long axis of the colon at the site of the tumor. Contrast-enhanced CT was performed using a protocol for metastasis staging. The examinations were independently evaluated by two gastrointestinal radiologists using criteria adapted to imaging for prediction of T-stage, N-stage, and extramural venous invasion. Based on the T-stage, tumors were divided in to locally advanced (T3cd-T4) and not locally advanced (T1-T3ab). Surgical and histopathological findings served as reference standard. Results: Using MRI, T-stage, N-stage, and extramural venous invasion were correctly predicted for each observer in 90% and 93%, 72% and 69%, and 82% and 78% of cases, respectively. With CT the corresponding results were 79% and 76%, 72% and 72%, 78% and 67%. For MRI inter-observer agreements (Kappa statistics) were 0.79, 0.10, and 0.76. For CT the corresponding results were 0.64, 0.66, and 0.22. Conclusion: Patients with locally advanced colon cancer, defined as tumor stage T3cd-T4, can be identified by both high resolution MRI and CT, even when CT is performed with a metastasis staging protocol. MRI may have an advantage, due to its high soft tissue discrimination, to identify certain prognostic factors such as T-stage and extramural venous invasion.

  • 321. Ronquist-Nii, Yuko
    et al.
    Eksborg, Staffan
    Axelson, Magnus
    Harmenberg, Johan
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Beck, Olof
    Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography-tandem mass spectrometry2011In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 879, no 5-6, p. 326-334Article in journal (Refereed)
    Abstract [en]

    A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of the new anticancer agent picropodophyllin (AXL1717) and its isomer podophyllotoxin levels in human serum has been developed. Monitoring of hexylamine adducts rather than proton adducts was used to optimize sensitivity. The chromatography system was an Acquity BEN C18, 2.1 mm x 50 mm 1.7 mu m column with gradient elution (mobile phase A: 2.5 mM hexylamine and 5 mM formic acid in Milli-Qwater and mobile phase B: methanol). The retention times were 1.4 min for picropodophyllin, 1.5 min for podophyllotoxin and 1.9 min for internal standard deoxypodophyllotoxin. The isomers were base-line separated. The analytes were detected after electrospray ionization in positive mode with selected reaction monitoring (SRM) with ion transitions m/z 516 --> 102 for picropodophyllin and podophyllotoxin and m/z 500 --> 102 for internal standard. The sample preparation was protein precipitation with acetonitrile (1:3) containing internal standard followed by dilution of the supernatant with mobile phase A (1:1). The limit of quantification (LOQ) was 0.01 mu mol/L for picropodophyllin and podophyllotoxin. The limit of detection (LOD) at 3 times the signal to noise (S/N) was estimated below 0.001 mu mol/L for picropodophyllin and podophyllotoxin. The quantification range of the method was between 0.01 mu mol/L and 5 mu mol/L for both isomers. The accuracy was within +/-15% of the theoretical value for both picropodophyllin and podophyllotoxin and inter-assay precision did not exceed +/-15%, except for the 0.016 mu mol/L level of podophyllotoxin, which was 18%. The selectivity of the method was verified by analysis of two different product ions for each analyte and by analysis for interference of seven different batches of blank human serum. The combined recovery and matrix effects were about 83% for picropodophyllin and podophyllotoxin. The new LC-MS/MS method showed sufficient sensitivity and selectivity for determination of picropodophyllin and its isomer podophyllotoxin levels in human serum from subjects receiving therapeutic doses of AXL1717.

  • 322. Rosell, J.
    et al.
    Nordenskjöld, B.
    Bengtsson, N-O
    Fornander, T.
    Hatschek, T.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Malmström, P-O
    Wallgren, A.
    Stål, O.
    Carstensen, J.
    Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 6, p. 899-902Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tamoxifen has been associated with an increased risk of stroke. There is, however, little information on the effect in the post-treatment period. Using data from the Swedish Breast Cancer Group adjuvant trial of 5 vs 2 years of tamoxifen treatment, we now report both short-term and long-term effects on morbidity as well as mortality because of cerebrovascular disease. METHODS: Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry was used to define events of disease. Hazard ratios (HRs) were estimated using Cox regression. RESULTS: Comparing patients randomised to 5 years of tamoxifen with patients randomised to 2 years of tamoxifen, the incidence of cerebrovascular diseases was increased (HR 1.70, 95% CI 1.05-2.75) during the active treatment phase and reduced after the active treatment period (HR 0.78, 95% CI 0.63-0.96), and the difference in HR between the two time-periods was significant (P 0.0033). The mortality from cerebrovascular diseases was increased during the treatment period (HR 3.18, 95% CI 1.03-9.87) and decreased during the post-treatment period (HR 0.60, 95% CI 0.40-0.90) with a significant difference in HR between the two periods of follow-up (P=0.0066). Similar results were seen for subgroups of cerebrovascular diseases, such as stroke and ischaemic stroke. CONCLUSION: In an adjuvant setting, tamoxifen was associated with an increased risk of cerebrovascular disease during treatment, but a decreased risk in the post-treatment period.

  • 323. Rosell, Johan
    et al.
    Nordenskjold, Bo
    Bengtsson, Nils-Olof
    Fornander, Tommy
    Hatschek, Thomas
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Malmstrom, Per-Olof
    Wallgren, Arne
    Stal, Olle
    Carstensen, John
    Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, no 2, p. 467-473Article in journal (Refereed)
    Abstract [en]

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

  • 324. Rosik, Daniel
    et al.
    Thibblin, Alf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with (18)F-4-Fluorobenzaldehyde2014In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 25, no 1, p. 82-92Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are a class of affinity agents for molecular imaging based on a non-immunoglobulin protein scaffold. Previous studies have demonstrated high contrast for in vivo imaging of cancer-associated molecular abnormalities using Affibody molecules. Using the radionuclide (18)F for labeling and PET as the imaging modality, the sensitivity of molecular imaging using Affibody molecules can be further increased. The use of oxime formation between an aminooxy-functionalized peptide and (18)F-fluorobenzaldehyde ((18)F-FBA) is a promising way of radiolabeling of targeting peptides. However, previous studies demonstrated that application of this method to Affibody molecules is associated with high liver uptake. We hypothesized that incorporation of a triglutamyl spacer between the aminooxy moiety and the N-terminus of a synthetic Affibody molecule would decrease the hepatic uptake of the (18)F-N-(4-fluorobenzylidine)oxime) ((18)F-FBO)-labeled tracer. To verify this, we have produced two variants of the HER2-targeting ZHER2:342 Affibody molecule by peptide synthesis: OA-PEP4313, where aminooxyacetic acid was conjugated directly to the N-terminal alanine, and OA-E3-PEP4313, where a triglutamyl spacer was introduced between the aminooxy moiety and the N-terminus. We have found that the use of the spacer is associated with a minor decrease of affinity, from KD = 49 pM to KD = 180 pM. Radiolabeled (18)F-FBO-E3-PEP4313 demonstrated specific binding to HER2-expressing ovarian carcinoma SKOV-3 cells and slow internalization. Biodistribution studies in mice demonstrated that the use of a triglutamyl linker decreased uptake of radioactivity in liver 2.7-fold at 2 h after injection. Interestingly, radioactivity uptake in kidneys was also reduced (2.4-fold). Experiments in BALB/C nu/nu mice bearing SKOV-3 xenografts demonstrated HER2-specific uptake of (18)F-FBO-E3-PEP4313 in tumors. At 2 h pi, the tumor uptake (20 ± 2% ID/g) exceeded uptake in liver 5-fold and uptake in kidneys 3.6-fold. The tumor-to-blood ratio was 21 ± 3. The microPET/CT imaging experiment confirmed the biodistribution data. In conclusion, the use of a triglutamyl spacer is a convenient way to improve the biodistribution profile of Affibody molecules labeled at the N-terminus using (18)F-FBA. It provides a tracer capable of producing high-contrast images of HER2-expressing tumors.

  • 325.
    Sadeghi, Arian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tötterman, Thomas H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rapid expansion of T cells: Effects of culture and cryopreservation and importance of short-term cell recovery2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, p. 978-986Article in journal (Refereed)
    Abstract [en]

    Background

    Successful cell therapy relies on the identification and mass expansion of functional cells for infusion. Cryopreservation of cells is an inevitable step in most cell therapies which also entails consequences for the frozen cells.

    Material and methods

    This study assessed the impact of cryopreservation and the widely used protocol for rapid expansion of T lymphocytes. The effects on cell viability, immunocompetence and the impact on apoptotic and immunosuppressive marker expression were analyzed using validated assays.

    Results and conclusion

    Cryopreservation of lymphocytes during the rapid expansion protocol did not affect cell viability. Lymphocytes that underwent mass expansion or culture in high dose IL-2 were unable to respond to PHA stimulation by intracellular ATP production immediately after thawing (ATP = 16 ± 11 ng/ml). However, their reactivity to PHA was regained within 48 hours of recovery (ATP = 356 ± 61 ng/ml). Analysis of mRNA levels revealed downregulation of TGF-β and IL-10 at all time points. Culture in high dose IL-2 led to upregulation of p73 and BCL-2 mRNA levels while FoxP3 expression was elevated after culture in IL-2 and artificial TCR stimuli. FoxP3 levels decreased after short-term recovery without IL-2 or stimulation. Antigen specificity, as determined by IFNγ secretion, was unaffected by cryopreservation but was completely lost after addition of high dose IL-2 and artificial TCR stimuli. In conclusion, allowing short-time recovery of mass expanded and cryopreserved cells before reinfusion could enhance the outcome of adoptive cell therapy as the cells regain immune competence and specificity.

  • 326.
    Sahlberg, Sara Haggblad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gustafsson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Radiation response in colorectal cancer cells2012In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, no S1, p. S7-S7Article in journal (Other academic)
  • 327. Salazar, Ramon
    et al.
    Capdevila, Jaume
    Rosenberg, Robert
    de Waard, Jan Willem
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bibeau, Frederic
    Klaase, Joost
    Van der Hoeven, Jacobus J. M.
    Midgley, Rachel A.
    Chang, George J.
    Bachleitner-Hofmann, Thomas
    Asano, Michio
    Ziebermayr, Reinhard
    Levine, Edward Allen
    Deck, Kenneth B.
    Sington, Jamie
    Law, Wai Lun
    Shbeeb, Imad
    Stork, Lisette
    Marshall, John
    Comparison of ColoPrint risk classification with clinical risk in the prospective PARSC trial2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 3Article in journal (Other academic)
  • 328.
    Sandberg, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Feldwisch, J.
    Wennborg, A.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Carlsson, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sandström, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Molecular imaging using the Affibody molecule [111In]ABY-025 can identify the HER2 status in breast cancer patients2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no S2, p. S296-S296Article in journal (Other academic)
  • 329.
    Sandström, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Haylock, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kareem, Heewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio.Manuscript (preprint) (Other academic)
  • 330.
    Sandström, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Haylock, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio2012In: International Journal of Oncology, ISSN 1019-6439, Vol. 40, no 5, p. 1525-1532Article in journal (Refereed)
    Abstract [en]

    The chimeric monoclonal antibody U36 (cMAb U36) recognizes the CD44v6 antigen. Its potential as a radioimmunotargeting agent, as well as its safety, has been shown in previous studies in head and neck cancer patients. However, intact MAbs have long circulation time in the blood and tumor targeting may also be hampered due to the slow and incomplete diffusion into solid tumors. In comparison, smaller monovalent Fab' and divalent F(ab')2 fragments are expected to exhibit shorter circulating half-lives, better tumor penetration and are thus more likely to yield better imaging results. In this study, novel F(ab')2 and Fab' fragments from cMAb U36 were radiolabeled with 125I and the characteristics of the conjugates in vitro were examined. The biodistribution of the conjugates were then evaluated in nude mice bearing CD44v6-expressing xenograft tumors. Furthermore, the penetration depth and distribution in tumor tissue was assessed by autoradiography in selected tumor samples. The in vitro experiments showed that the conjugates were stable and had intact affinity to CD44v6. The biodistribution study demonstrated superior tumor-to-blood ratio for the novel cMAb U36 fragment 125I-F(ab')2 compared with both the intact MAb and the monovalent fragment form. Autoradiography also revealed better tumor penetration for 125I-F(ab')2. This study demonstrates that the use of antibody fragments may improve radioimmunotargeting and possibly improve the management of head and neck malignancies.

  • 331.
    Sandström, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lidbrink, Elisabet
    Bergh, Jonas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Model describing the relations between pharmacokinetics and hematological toxicity of the epirubicin-docetaxel regimen in breast cancer2005In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 23, no 3, p. 413-421Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients.

    PATIENTS AND METHODS:

    Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m(2). Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m(2)) or reduced (minimum, 40/50 mg/m(2)). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment.

    RESULTS:

    In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data.

    CONCLUSION:

    The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.

  • 332.
    Sandström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Garske, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Absorbed doses to kidney and bone marrow in 200 patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotateManuscript (preprint) (Other academic)
  • 333.
    Sandström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Garske-Román, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment2013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 1, p. 33-41Article in journal (Refereed)
    Abstract [en]

    The organs at risk in radionuclide therapy with 177Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys. Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of 177Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT. Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of 177Lu-octreotate could be administered before the upper dose limit for the individual patient was reached. Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of 177Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.

  • 334. Schadendorf, D.
    et al.
    Amonkar, M. M.
    Milhem, M.
    Grotzinger, K.
    Demidov, L. V.
    Rutkowski, P.
    Garbe, C.
    Dummer, R.
    Hassel, J. C.
    Wolter, P.
    Mohr, P.
    Trefzer, U.
    Lefeuvre-Plesse, C.
    Rutten, A.
    Steven, N.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sherman, L.
    Wu, F. S.
    Patel, K.
    Casey, M.
    Robert, C.
    Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study2014In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 25, no 3, p. 700-706Article in journal (Refereed)
    Abstract [en]

    We report the first quality-of-life assessment of a MEK inhibitor in metastatic melanoma from a phase III study. Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Less functional impairment, smaller declines in health status, and less exacerbation of symptoms were observed with trametinib.In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.

  • 335. Schmidt, J. A.
    et al.
    Gorst-Rasmussen, A.
    Nyström, Petra Mariann Witt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Christensen, J. H.
    Schmidt, E. B.
    Dethlefsen, C.
    Tjonneland, A.
    Overvad, K.
    Dahm, C. C.
    Baseline patterns of adipose tissue fatty acids and long-term risk of breast cancer: a case-cohort study in the Danish cohort Diet, Cancer and Health2014In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 68, no 10, p. 1088-1094Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVES: The evidence regarding fatty acids and breast cancer risk is inconclusive. Adipose tissue fatty acids can be used as biomarkers of fatty acid intake and of endogenous fatty acid exposure. Fatty acids in adipose tissue are correlated. owing to common dietary sources and shared metabolic pathways, which group fatty acids into naturally occurring patterns. We aimed to prospectively investigate associations between adipose tissue fatty acid patterns and long-term risk of total breast cancer and breast cancer subtypes characterised by oestrogen and progesterone receptor status (ER and PR). SUBJECTS/METHODS: This case-cohort study was based on data from the Danish cohort Diet, Cancer and Health. At baseline, a fat biopsy and information on lifestyle and reproductive factors were collected. From the 31 original fatty acids measured, patterns of fatty acids were identified using the treelet transform. During a median follow-up of 5.3 years, 474 breast cancer cases were identified. Hazard ratios and 95% confidence intervals of risk of total breast cancer and of subtypes according to quintiles of factor score were determined by weighted Cox proportional hazards regression. RESULTS: After adjustment for potential confounders, factor scores for the seven patterns identified by the treelet transform were not associated with risk of total breast cancer, nor with risk of ER+, ER, PR+ or PR tumours. CONCLUSIONS: No clear associations between the patterns of fatty acids at baseline and long-term risk of total breast cancer or ER+, ER, PR+ or PR tumours were observed.

  • 336. Schmoll, H. J.
    et al.
    Van Cutsem, E.
    Stein, A.
    Valentini, V.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Haustermans, K.
    Nordlinger, B.
    van de Velde, C. J.
    Balmana, J.
    Regula, J.
    Nagtegaal, I. D.
    Beets-Tan, R. G.
    Arnold, D.
    Ciardiello, F.
    Hoff, P.
    Kerr, D.
    Koehne, C. H.
    Labianca, R.
    Price, T.
    Scheithauer, W.
    Sobrero, A.
    Tabernero, J.
    Aderka, D.
    Barroso, S.
    Bodoky, G.
    Douillard, J. Y.
    El Ghazaly, H.
    Gallardo, J.
    Garin, A.
    Glynne-Jones, R.
    Jordan, K.
    Meshcheryakov, A.
    Papamichail, D.
    Pfeiffer, P.
    Souglakos, I.
    Turhal, S.
    Cervantes, A.
    ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making2012In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, no 10, p. 2479-2516Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

  • 337. Sclafani, F.
    et al.
    Cunningham, D.
    Tabernero, J.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Cervantes, A.
    Peckitt, C.
    Tait, D.
    Brown, G.
    De Castro, D. Gonzalez
    Chau, I.