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  • 301.
    Popova, Svetlana N
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edqvist, Per-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Sooman, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Subtyping of gliomas of various WHO grades by the application of immunohistochemistry2014Inngår i: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 64, nr 3, s. 365-379Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 trial2011Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 22, nr 1, s. 39-48Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Role of radiotherapy2008Inngår i: International Handbook of Colorectal Cancer / [ed] Jim Cassidy, Euromed Commincations Ltd , 2008, s. 57-70Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 304.
    Quartino, Angelica L.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Characterization of Endogenous G-CSF and the Inverse Correlation to Chemotherapy-Induced Neutropenia in Patients with Breast Cancer Using Population Modeling2014Inngår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, nr 12, s. 3390-3403Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 evolution2013Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, nr 5, s. 1155-1164Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Simonsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Johansson, Karl-Axel
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Radiophys, Gothenburg, Sweden..
    Turesson, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Double strand break induction and kinetics indicate preserved hypersensitivity in keratinocytes to subtherapeutic doses for 7 weeks of radiotherapy2017Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 122, nr 1, s. 163-169Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Simonsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Tran, Thuy A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Effects of affinity on binding of HER2-targeting Affibody molecules: Model experiments in breast cancer spheroids2011Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 39, nr 2, s. 353-359Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 decades2012Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, nr S9, s. 188-188Artikkel i tidsskrift (Annet vitenskapelig)
  • 309. Racadot, S.
    et al.
    Hammel, P.
    Chibaudel, B.
    Goldstein, D.
    Spry, N.
    Van Laethem, J.
    Van Houtte, P.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Gubanski, M.
    Huguet, F.
    Dummy Run in the Phase III LAP07 Pancreatic Cancer Trial: First Evaluation of Quality of Radiation Therapy Planning2012Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 84, nr 3, s. S322-S322Artikkel i tidsskrift (Annet vitenskapelig)
  • 310.
    Radu, Calin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Optimising Radiotherapy in Rectal Cancer Patients2012Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. Short-course preoperative radiotherapy with delayed surgery in rectal cancer: a retrospective study
    Åpne denne publikasjonen i ny fane eller vindu >>Short-course preoperative radiotherapy with delayed surgery in rectal cancer: a retrospective study
    2008 (engelsk)Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 87, nr 3, s. 343-9Artikkel i tidsskrift (Fagfellevurdert) 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.

    Emneord
    Rectal cancer, Radiotheraphy, Non-resectable, 5 ×5 Gy, Delay surgery
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98972 (URN)10.1016/j.radonc.2007.11.025 (DOI)000257631700007 ()18093674 (PubMedID)
    Tilgjengelig fra: 2009-03-05 Laget: 2009-03-05 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    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
    Åpne denne publikasjonen i ny fane eller vindu >>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
    Vise andre…
    2011 (engelsk)Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 81, nr 4, s. e439-e445Artikkel i tidsskrift (Fagfellevurdert) 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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-169858 (URN)10.1016/j.ijrobp.2011.03.031 (DOI)000309412300031 ()21641122 (PubMedID)
    Tilgjengelig fra: 2012-03-06 Laget: 2012-03-06 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    3. Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients
    Åpne denne publikasjonen i ny fane eller vindu >>Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172407 (URN)
    Tilgjengelig fra: 2012-04-10 Laget: 2012-04-10 Sist oppdatert: 2012-08-01
    4. Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172410 (URN)
    Tilgjengelig fra: 2012-04-10 Laget: 2012-04-10 Sist oppdatert: 2012-08-01
    5. Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172410 (URN)
    Tilgjengelig fra: 2012-04-10 Laget: 2012-04-10 Sist oppdatert: 2012-08-01
  • 311.
    Radu, Calin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Johansson, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancerManuskript (preprint) (Annet vitenskapelig)
  • 312.
    Radu, Calin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Norrlid, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patientsManuskript (preprint) (Annet vitenskapelig)
  • 313.
    Radu, Calin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Norrlid, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients2013Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 3, s. 528-537Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Kultima, Hanna Göransson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Birgisson, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity2011Inngår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, nr 10, s. R108-Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Linder, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lödén, Britta
    Holmqvist, Marit
    Regional Cancer Centre, Uppsala, Sweden.
    Hellström, Karin
    von Beckerath, Mattias
    Blomquist, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergström, Stefan N
    Time trends in T3 to T4 laryngeal cancer: a population-based long-term analysis2014Inngår i: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 36, nr 12, s. 1727-1731Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Agnarsdóttir, Margrét
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergman, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Uhlen, Mathias
    Gallagher, William M.
    Lundberg, Emma
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A Texture Based Pattern Recognition Approach to Distinguish Melanoma from Non-Melanoma Cells in Histopathological Tissue Microarray Sections2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e62070-Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Rehn, S M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Nyman, Rickard S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Sundström, J C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Glimelius, Bengt L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    CT in malignancy grading and prognostic prediction of non-Hodgkin's lymphoma1999Inngår i: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 40, nr 2, s. 191-197Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Sundín, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Rehn, Suzanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    [18F] FDG PET in gastric non-Hodgkin's lymphoma1997Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 36, nr 6, s. 577-584Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Rehn, Suzanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Predicting malignancy grade with PET in non-Hodgkin's lymphoma1995Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 36, nr 10, s. 1790-1796Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lorinc, Esther
    Blomqvist, Lennart
    Potentials of high resolution magnetic resonance imaging versus computed tomography for preoperative local staging of colon cancer2013Inngår i: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 54, nr 7, s. 722-730Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Beck, Olof
    Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography-tandem mass spectrometry2011Inngår i: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 879, nr 5-6, s. 326-334Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Malmström, P-O
    Wallgren, A.
    Stål, O.
    Carstensen, J.
    Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial2011Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, nr 6, s. 899-902Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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-up2013Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, nr 2, s. 467-473Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Strand, Joanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with (18)F-4-Fluorobenzaldehyde2014Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 25, nr 1, s. 82-92Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ullenhag, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Wagenius, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Tötterman, Thomas H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Eriksson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Rapid expansion of T cells: Effects of culture and cryopreservation and importance of short-term cell recovery2013Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 5, s. 978-986Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Gustafsson, Ann-Sofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Radiation response in colorectal cancer cells2012Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, nr S1, s. S7-S7Artikkel i tidsskrift (Annet vitenskapelig)
  • 327. Salazar, Ramon
    et al.
    Capdevila, Jaume
    Rosenberg, Robert
    de Waard, Jan Willem
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 trial2014Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, nr 3Artikkel i tidsskrift (Annet vitenskapelig)
  • 328.
    Sandberg, Dan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Feldwisch, J.
    Wennborg, A.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Carlsson, J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Sandström, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Molecular imaging using the Affibody molecule [111In]ABY-025 can identify the HER2 status in breast cancer patients2012Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, nr S2, s. S296-S296Artikkel i tidsskrift (Annet vitenskapelig)
  • 329.
    Sandström, Karl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Haylock, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Qvarnström, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Kareem, Heewa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio.Manuskript (preprint) (Annet vitenskapelig)
  • 330.
    Sandström, Karl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Haylock, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Spiegelberg, Diana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Qvarnström, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio2012Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 40, nr 5, s. 1525-1532Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Sjukgymnastik.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lidbrink, Elisabet
    Bergh, Jonas
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Model describing the relations between pharmacokinetics and hematological toxicity of the epirubicin-docetaxel regimen in breast cancer2005Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 23, nr 3, s. 413-421Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Garske, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Widström, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Absorbed doses to kidney and bone marrow in 200 patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotateManuskript (preprint) (Annet vitenskapelig)
  • 333.
    Sandström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Garske-Román, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Widström, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment2013Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, nr 1, s. 33-41Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 study2014Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 25, nr 3, s. 700-706Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 Health2014Inngår i: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 68, nr 10, s. 1088-1094Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 making2012Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, nr 10, s. 2479-2516Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Cervantes, A.
    Peckitt, C.
    Tait, D.
    Brown, G.
    De Castro, D. Gonzalez
    Chau, I.
    Updated survival analysis of EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab in MRI-defined high risk rectal cancer patients2013Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, nr Suppl. 2, s. S487-S487Artikkel i tidsskrift (Annet vitenskapelig)
  • 338. Sclafani, F.
    et al.
    Gonzalez, D.
    Cunningham, D.
    Wilson, S. Hulkki
    Peckitt, C.
    Giralt, J.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Rosello Keraenen, S.
    Wotherspoon, A.
    Brown, G.
    Tait, D.
    Oates, J.
    Chau, I.
    RAS mutations and cetuximab in locally advanced rectal cancer: Results of the EXPERT-C trial2014Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, nr 8, s. 1430-1436Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial. Methods: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed. Results: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n = 40; CAPOX-C, n = 38). In this population, after a median follow-up of 63.8 months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p = 0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p = 0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p = 0.20). Conclusions: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted. (C) 2014 Elsevier Ltd. All rights reserved.

  • 339. Sclafani, F.
    et al.
    Roy, A.
    Cunningham, D.
    Wotherspoon, A.
    Peckitt, C.
    Gonzalez de Castro, D.
    Tabernero, J.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Cervantes, A.
    Eltahir, Z.
    Oates, J.
    Chau, I.
    HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab2013Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, nr 12, s. 3123-3128Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT +/- cetuximab in the EXPERT-C trial. Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio >= 2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated +/- cetuximab. Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. Trial registration: ISRCTN Register: 99828560.

  • 340. Sclafani, Francesco
    et al.
    de Castro, David Gonzalez
    Cunningham, David
    Wilson, Sanna Hulkki
    Peckitt, Clare
    Capdevila, Jaume
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Keraenen, Susana Rosello
    Wotherspoon, Andrew
    Brown, Gina
    Tait, Diana
    Begum, Ruwaida
    Thomas, Janet
    Oates, Jacqueline
    Chau, Ian
    Fc gamma RIIa and Fc gamma RIIIa Polymorphisms and Cetuximab Benefit in the Microscopic Disease2014Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, nr 17, s. 4511-4519Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Fc gamma R polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX +/- cetuximab in high-risk, locally advanced rectal cancer. Experimental Design: Fc gamma RIIa-H131R and Fc gamma RIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation fromthe Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. Fc gamma RIIa-131R (HR, 0.38; P = 0.058) and Fc gamma RIIIa-158F alleles (HR, 0.21; P = 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P = 0.017) and remained significant after adjusting for prognostic variables (P = 0.003). Conclusion: This is the first study investigating Fc gamma RIIa and Fc gamma RIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

  • 341. Sclafani, Francesco
    et al.
    Gonzalez, David
    Cunningham, David
    Wilson, Sanna Hulkki
    Peckitt, Clare
    Tabernero, Josep
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Cervantes, Andres
    Dewdney, Alice
    Wotherspoon, Andrew
    Brown, Gina
    Tait, Diana
    Oates, Jacqueline
    Chau, Ian
    TP53 Mutational Status and Cetuximab Benefit in Rectal Cancer: 5-Year Results of the EXPERT-C Trial2014Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, nr 7, s. dju121-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P < .05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.

  • 342. Sclafani, Francesco
    et al.
    Gonzalez, David
    Cunningham, David
    Wilson, Sanna Hullki
    Peckitt, Clare
    Tabernero, Josep
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Cervantes, Andres
    Wotherspoon, Andrew
    Brown, Gina
    Tait, Diana M.
    Oates, Jacqueline Rose
    Chau, Ian
    RAS mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).2014Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, nr 3Artikkel i tidsskrift (Annet vitenskapelig)
  • 343. Sclafani, Francesco
    et al.
    Gonzalez, David
    Cunningham, David
    Wilson, Sanna Hullki
    Peckitt, Clare
    Tabernero, Josep
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Cervantes, Andres
    Wotherspoon, Andrew
    Dewdney, Alice
    Brown, Gina
    Tait, Diana M.
    Oates, Jacqueline Rose
    Chau, Ian
    Relationship of RAS and TP53 predictive value for cetuximab (C) benefit: Results of the EXPERT-C trial2014Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, nr 3Artikkel i tidsskrift (Annet vitenskapelig)
  • 344. Sharma, R.
    et al.
    Kallur, K. G.
    Ryu, J. S.
    Parameswaran, R. V.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Avril, N.
    Gleeson, F. V.
    Lee, J. D.
    Lee, K. H.
    O'Doherty, M. J.
    Groves, A. M.
    Miller, M. P.
    Paterson, C. L.
    Coombes, C.
    Aboagye, E. O.
    Test-retest reproducibility of [F-18]fluciclatide PET imaging in subjects with solid tumors2012Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, nr S2, s. S226-S226Artikkel i tidsskrift (Annet vitenskapelig)
  • 345. Sherwood, Victoria
    et al.
    Chaurasiya, Shivendra Kumar
    Ekström, Elin J
    Guilmain, William
    Liu, Qing
    Koeck, Tomas
    Brown, Kate
    Hansson, Karin
    Agnarsdóttir, Margrét
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Jirström, Karin
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    James, Peter
    Andersson, Tommy
    WNT5A-mediated β-catenin-independent signalling is a novel regulator of cancer cell metabolism2014Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, nr 4, s. 784-794Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    WNT5A has been identified as an important ligand in the malignant progression of a number of tumours. Although WNT5A signalling is often altered in cancer, the ligands role as either a tumour suppressor or oncogene varies between tumour types and is a contemporary issue for investigators of -catenin-independent WNT signalling in oncology. Here, we report that one of the initial effects of active WNT5A signalling in malignant melanoma cells is an alteration in cellular energy metabolism and specifically an increase in aerobic glycolysis. This was found to be at least in part due to an increase in active Akt signalling and lactate dehydrogenase (LDH) activity. The clinical relevance of these findings was strengthened by a strong correlation (P < 0.001) between the expression of WNT5A and LDH isoform V in a cohort of melanocytic neoplasms. We also found effects of WNT5A on energy metabolism in breast cancer cells, but rather than promoting aerobic glycolysis as it does in melanoma, WNT5A signalling increased oxidative phosphorylation rates in breast cancer cells. These findings support a new role for WNT5A in the metabolic reprogramming of cancer cells that is a context- dependent event.

  • 346. Simard, J. F.
    et al.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Kinch, Amelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Brattström, C.
    Ingvar, Å.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Adami, J.
    Fernberg, P.
    Wilczek, H.
    Ekbom, A.
    Smedby, K. E.
    Pediatric Organ Transplantation and Risk of Premalignant and Malignant Tumors in Sweden2011Inngår i: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, nr 1, s. 146-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged < 18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.

  • 347. Simard, Julia F
    et al.
    Baecklund, Fredrik
    Chang, Ellen T
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hjalgrim, Henrik
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Smedby, Karin E
    Lifestyle factors, autoimmune disease and family history in prognosis of non-hodgkin lymphoma overall and subtypes2013Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, nr 11, s. 2659-2666Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lifestyle factors and medical history are known to influence risk of non-Hodgkin lymphoma (NHL). Whether these factors affect the prognosis of NHL, especially its subtypes, is unclear. To investigate this, the association between these factors and all-cause and lymphoma-related mortality was assessed in a population-based cohort of 1,523 Swedish NHL patients included in the Scandinavian Lymphoma Etiology study in 1999-2002. Participants contributed time from NHL diagnosis until death or October 1, 2010, with virtually complete follow-up through linkage to the Swedish Cause of Death Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using stratified and multivariable-adjusted Cox regression models. During a median follow-up of 8.8 years, 670 patients (44%) died, with the majority of deaths attributed to lymphoma (86%). Current versus never smoking at diagnosis was associated with increased rate of all-cause death for all NHL (HR = 1.5, 1.2-1.8) and diffuse large B-cell lymphoma (HR = 1.8, 1.2-2.7). Low educational level (HR = 1.3, 1.1-1.7, <9 vs. >12 years) and NHL risk-associated autoimmune disease (HR = 1.4, 1.0-1.8) were associated with death for all NHL combined. However, evidence of an association with lymphoma-related death was limited. Body mass index, recent sunbathing and family history of hematopoietic malignancy were not consistently associated with death after NHL or its specific subtypes. These results add to the evidence that cigarette smoking, socioeconomic status and certain autoimmune diseases affect survival after NHL. Further investigations are needed to determine how these factors should be incorporated into clinical prognostic assessment.

  • 348.
    Sjöberg, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för medicinsk strålfysik.
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för medicinsk strålfysik.
    How much will linked deformable registrations decrease the quality of multi-atlas segmentation fusions?2014Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 9, artikkel-id 251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose: Multi-atlas segmentation can yield better results than single atlas segmentation, but practical applications are limited by long calculation times for deformable registration. To shorten the calculation time pre-calculated registrations of atlases could be linked via a single atlas registered in runtime to the current patient. The primary purpose of this work is to investigate and quantify segmentation quality changes introduced by such linked registrations. We also determine the optimal parameters for fusing linked multi-atlas labels using probabilistic weighted fusion. Material and methods: Computed tomography images of 10 head and neck cancer patients were used as atlases, with parotid glands, submandibular glands, the mandible and lymph node levels II-IV segmented by an experienced radiation oncologist following published consensus guidelines. The change in segmentation quality scored by Dice similarity coefficient (DSC) for linking free-form deformable registrations, modeled by B-splines, was investigated for both single-and multi-atlas label fusion by using a leave-one-out approach. Results: The median decrease of the DSC was in the range 2.8% to 8.4% compared to direct registrations for all structures while reducing the computer calculation time to that of a single deformable registration. Linking several registrations showed a DSC decrease almost linear to the number of links, suggesting that extrapolation to zero links provides an observer independent measure of the inherent precision with which the segmentation guidelines can be applied. Conclusions: Linking pre-made registrations of multiple atlases via a runtime registration of a single atlas provides a feasible method for reducing computation time in multi-atlas registration.

  • 349.
    Sjöberg, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Lundmark, Martin
    Granberg, Christoffer
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Montelius, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Clinical evaluation of multi-atlas based segmentation of lymph node regions in head and neck and prostate cancer patients2013Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 8, s. 229-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Semi-automated segmentation using deformable registration of selected atlas cases consisting of expert segmented patient images has been proposed to facilitate the delineation of lymph node regions for three-dimensional conformal and intensity-modulated radiotherapy planning of head and neck and prostate tumours. Our aim is to investigate if fusion of multiple atlases will lead to clinical workload reductions and more accurate segmentation proposals compared to the use of a single atlas segmentation, due to a more complete representation of the anatomical variations. Methods: Atlases for lymph node regions were constructed using 11 head and neck patients and 15 prostate patients based on published recommendations for segmentations. A commercial registration software (Velocity AI) was used to create individual segmentations through deformable registration. Ten head and neck patients, and ten prostate patients, all different from the atlas patients, were randomly chosen for the study from retrospective data. Each patient was first delineated three times, (a) manually by a radiation oncologist, (b) automatically using a single atlas segmentation proposal from a chosen atlas and (c) automatically by fusing the atlas proposals from all cases in the database using the probabilistic weighting fusion algorithm. In a subsequent step a radiation oncologist corrected the segmentation proposals achieved from step (b) and (c) without using the result from method (a) as reference. The time spent for editing the segmentations was recorded separately for each method and for each individual structure. Finally, the Dice Similarity Coefficient and the volume of the structures were used to evaluate the similarity between the structures delineated with the different methods. Results: For the single atlas method, the time reduction compared to manual segmentation was 29% and 23% for head and neck and pelvis lymph nodes, respectively, while editing the fused atlas proposal resulted in time reductions of 49% and 34%. The average volume of the fused atlas proposals was only 74% of the manual segmentation for the head and neck cases and 82% for the prostate cases due to a blurring effect from the fusion process. After editing of the proposals the resulting volume differences were no longer statistically significant, although a slight influence by the proposals could be noticed since the average edited volume was still slightly smaller than the manual segmentation, 9% and 5%, respectively. Conclusions: Segmentation based on fusion of multiple atlases reduces the time needed for delineation of lymph node regions compared to the use of a single atlas segmentation. Even though the time saving is large, the quality of the segmentation is maintained compared to manual segmentation.

  • 350. Skibola, Christine F.
    et al.
    Berndt, Sonja I.
    Vijai, Joseph
    Conde, Lucia
    Wang, Zhaoming
    Yeager, Meredith
    de Bakker, Paul I. W.
    Birmann, Brenda M.
    Vajdic, Claire M.
    Foo, Jia-Nee
    Bracci, Paige M.
    Vermeulen, Roel C. H.
    Slager, Susan L.
    de Sanjose, Silvia
    Wang, Sophia S.
    Linet, Martha S.
    Salles, Gilles
    Lan, Qing
    Severi, Gianluca
    Hjalgrim, Henrik
    Lightfoot, Tracy
    Melbye, Mads
    Gu, Jian
    Ghesquieres, Herve
    Link, Brian K.
    Morton, Lindsay M.
    Holly, Elizabeth A.
    Smith, Alex
    Tinker, Lesley F.
    Teras, Lauren R.
    Kricker, Anne
    Becker, Nikolaus
    Purdue, Mark P.
    Spinelli, John J.
    Zhang, Yawei
    Giles, Graham G.
    Vineis, Paolo
    Monnereau, Alain
    Bertrand, Kimberly A.
    Albanes, Demetrius
    Zeleniuch-Jacquotte, Anne
    Gabbas, Attilio
    Chung, Charles C.
    Burdett, Laurie
    Hutchinson, Amy
    Lawrence, Charles
    Montalvan, Rebecca
    Liang, Liming
    Huang, Jinyan
    Ma, Baoshan
    Liu, Jianjun
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ye, Yuanqing
    Nowakowski, Grzegorz S.
    Dogan, Ahmet
    Thompson, Carrie A.
    Habermann, Thomas M.
    Novak, Anne J.
    Liebow, Mark
    Witzig, Thomas E.
    Weiner, George J.
    Schenk, Maryjean
    Hartge, Patricia
    De Roos, Anneclaire J.
    Cozen, Wendy
    Zhi, Degui
    Akers, Nicholas K.
    Riby, Jacques
    Smith, Martyn T.
    Lacher, Mortimer
    Villano, Danylo J.
    Maria, Ann
    Roman, Eve
    Kane, Eleanor
    Jackson, Rebecca D.
    North, Kari E.
    Diver, W. Ryan
    Turner, Jenny
    Armstrong, Bruce K.
    Benavente, Yolanda
    Boffetta, Paolo
    Brennan, Paul
    Foretova, Lenka
    Maynadie, Marc
    Staines, Anthony
    McKay, James
    Brooks-Wilson, Angela R.
    Zheng, Tongzhang
    Holford, Theodore R.
    Chamosa, Saioa
    Kaaks, Rudolph
    Kelly, Rachel S.
    Ohlsson, Bodil
    Travis, Ruth C.
    Weiderpass, Elisabete
    Clave, Jacqueline
    Giovannucci, Edward
    Kraft, Peter
    Virtamo, Jarmo
    Mazza, Patrizio
    Cocco, Pierluigi
    Ennas, Maria Grazia
    Chiu, Brian C. H.
    Fraumeni, Joseph R., Jr.
    Nieters, Alexandra
    Offit, Kenneth
    Wu, Xifeng
    Cerhan, James R.
    Smedby, Karin E.
    Chanock, Stephen J.
    Rothman, Nathaniel
    Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region2014Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 95, nr 4, s. 462-471Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 x 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 x 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 x 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 x 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 x 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DR beta 1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (P-omnibus = 4.20 x 10(-67) to 2.67 x 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 x 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 x 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

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