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  • 1251. Yu, Feifan
    et al.
    Gudmundsdotter, Lindvi
    Akal, Anastassja
    Gunneriusson, Elin
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Nygren, Per-Ake
    An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo2014In: MABS, ISSN 1942-0862, Vol. 6, no 6, p. 1598-1607Article in journal (Refereed)
    Abstract [en]

    In inflammatory disease conditions, the regulation of the cytokine system is impaired, leading to tissue damages. Here, we used protein engineering to develop biologicals suitable for blocking a combination of inflammation driving cytokines by a single construct. From a set of interleukin (IL)-6-binding affibody molecules selected by phage display, five variants with a capability of blocking the interaction between complexes of soluble IL-6 receptor a (sIL-6R alpha) and IL6 and the co-receptor gp130 were identified. In cell assays designed to analyze any blocking capacity of the classical or the alternative (trans) signaling IL-6 pathways, one variant, Z(IL-6_13) with an affinity (K-D) for IL-6 of similar to 500 pM, showed the best performance. To construct fusion proteins ("AffiMabs") with dual cytokine specificities, Z(IL-6_13) was fused to either the N-or C-terminus of both the heavy and light chains of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (Humira (R)). One AffiMab construct with Z(IL-6_13) positioned at the N-terminus of the heavy chain, denoted Z(IL-6_13)-HCAda, was determined to be the most optimal, and it was subsequently evaluated in an acute Serum Amyloid A (SAA) model in mice. Administration of the AffiMab or adalimumab prior to challenge with a mix of IL-6 and TNF reduced the levels of serum SAA in a dose-dependent manner. Interestingly, the highest dose (70 mg/kg body weight) of adalimumab only resulted in a 50% reduction of SAA-levels, whereas the corresponding dose of the Z(IL-6_13)-HCAda AffiMab with combined IL-6/TNF specificity, resulted in SAA levels below the detection limit.

  • 1252. Zduniak, K.
    et al.
    Ziolkowski, P.
    Ahlin, C.
    Agrawal, A.
    Agrawal, S.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Weber, G. F.
    Nuclear osteopontin-c is a prognostic breast cancer marker2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 4, p. 729-738Article in journal (Refereed)
    Abstract [en]

    Background: Although Osteopontin has been known as a marker for cancer progression, the elevated production of this cytokine is not specific for cancer. We have identified the splice variant Osteopontin-c as being absent from healthy tissue but associated with about 75% of breast cancer cases. However, in previous studies of Osteopontin-c, follow-up information was not available. Methods: Here we have analysed 671 patients, comprising a cohort of 291 paraffin blocks plus a population-based case-control study of 380 arrayed breast tumor tissues. Results: We find that high staining intensity of nuclear Osteopontin-c is strongly associated with mortality in patients with early breast cancer. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome. By contrast, total Osteopontin does not correlate with prognosis. These diverse assessments of Osteopontin also do not correlate with each other, suggesting distinct expression patterns for the variant forms. Consistent with its role in tumor progression, not tumor initiation, Osteopontin-c is not correlated with proliferation markers (Ki-67, cyclin A, cyclin B, cyclin E and cyclin D), neither is it correlated with ER, PR or HER2. Conclusions: The addition of Osteopontin-c immunohistochemistry to standard pathology work-ups may have prognostic benefit in early breast cancer diagnosis.

  • 1253. Zhang, Xiaonan
    et al.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hernlund, Emma
    Fayad, Walid
    De Milito, Angelo
    Olofsson, Maria Hagg
    Gogvadze, Vladimir
    Dang, Long
    Pahlman, Sven
    Schughart, Leoni A. Kunz
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Darcy, Padraig
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Linder, Stig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 3295-Article in journal (Refereed)
    Abstract [en]

    Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

  • 1254.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirström, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sollie, Thomas
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sørlie, Therese
    Blomqvist, Carl
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, p. 512-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Different molecular subtypes of breast cancer have been identified based on gene expression profiling. Treatment suggestions based on an approximation of these subtypes by immunohistochemical criteria have been published by the St Gallen international expert consensus panel. Ductal carcinoma in situ (DCIS) can be classified into the same molecular subtypes. Our aim was to study the relation between these newly defined subtypes and prognosis in DCIS.

    METHODS: TMA including 458 women from a population-based cohort with DCIS diagnosed 1986-2004 was used. Stainings for ER, PR, HER2 and Ki67 were used to classify the surrogate molecular subtypes according to the St Gallen criteria from 2011. The associations with prognosis were examined using Kaplan-Meier analyses and Cox proportional hazards regression models.

    RESULTS: Surrogate molecular subtyping could be done in 381 cases. Mean follow up was 164 months. Of the classified DCIS 186 were Luminal A (48.8%), 33 Luminal B/HER2- (8.7%), 74 Luminal B/HER2+ (17.4%), 61 HER2+/ER- (16.0%) and 27 Triple Negative (7.1%). One hundred and two women had a local recurrence of which 58 were invasive. Twenty-two women had generalised disease, 8 without a prior local recurrence. We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8).

    CONCLUSIONS: The results from this large population-based cohort, with long-term follow up failed to demonstrate a prognostic value for the surrogate molecular subtyping of DCIS using the St Gallen criteria up to ten years after diagnosis. More than ten years after diagnosis Triple Negative DCIS had an elevated risk of recurrence.

  • 1255.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jirström, Karin
    Department of Clinical Sciences, Pathology, Lund University.
    Ringberg, Anita
    Department of Plastic and Reconstructive Surgery, Malmö Hospital.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542XArticle in journal (Other academic)
    Abstract [en]

    Introduction:

    About half of all recurrences after a primary ductal carcinoma in situ (DCIS) are invasive. The determinants for type of recurrence, in situ or invasive, are not known. We studied markers in primary DCIS in relation to type of recurrence.

    Methods:

    Two hundred and sixty six primary DCIS with a known recurrence were included. One hundred were from a population based cohort with 458 women diagnosed 1986-2004 in Uppland/Västmanland region, Sweden, and all 166 women with a recurrence from the randomized nationwide SweDCIS Trial (1987-1999). The 358 women without a recurrence were used as a reference group. TMA-blocks were constructed and estrogen receptor- (ER), progesterone receptor- (PR), HER2, EGFR, cytokeratin 5/6, Ki67, FOXA1, FOXC1, GATA-3 and CD10 status were evaluated in the primary tumors. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses (adjusted for age, free margin, surgical method and molecular subtype).

    Results:

    One hundred and thirty of the recurrences were in situ and 136 invasive. In multivariate analyses, a recurrence was more often invasive if the primary was ER positive (OR 2.5, CI 95 1.2 – 5.1). Primaries being HER2 positive (OR 0.5, CI 95 0.3-0.9), EGFR positive (OR 0.4, CI 95 0.2-0.9) and ER-/HER2+ (OR 0.2, CI 95 0.1-0.6) had a lower risk of the recurrence being invasive. Primaries of the molecular subtype ER+/HER2+ had higher risk of any recurrence (OR 1.9, CI 95 1.1-3.4) as did primaries expressing FOXA1 (OR 3.1, CI 95 1.5-6.2) and FOXC1 (OR 2.9, CI 95 1.7-5.0).

    Conclusions:

    Surprisingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

  • 1256.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jirström, Karin
    Ringberg, Anita
    Blomqvist, Carl
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ2013In: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, Vol. 2013, p. 582134-Article in journal (Refereed)
    Abstract [en]

    Introduction

    About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ).

    Methods

    Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses.

    Results

    One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2-5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3-0.9), EGFR+ (OR 0.4, 95% CI 0.2-0.9), and ER95-/HER2+ (OR 0.2, 95% CI 0.1-0.6) had a lower risk of a recurrence being invasive.

    Conclusions

    In this study, comparing type of recurrence after a DCIS showed that the ER-/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2-, and EGFR- were related to a recurrence being invasive cancer.

  • 1257.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sollie, Thomas
    Univ Örebro, Dept Pathol, Örebro, Sweden..
    Tot, Tibor
    Falun Cent Hosp, Dept Pathol, Falun, Sweden..
    Blomqvist, Carl
    Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland..
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Liljegren, Göran
    Univ Örebro, Dept Surg, Örebro, Sweden..
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ductal Breast Carcinoma In Situ: Mammographic Features and Its Relation to Prognosis and Tumour Biology in a Population Based Cohort2017In: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, article id 4351319Article in journal (Refereed)
    Abstract [en]

    Casting-type calcifications and a histopathological picture with cancer-filled duct-like structures have been presented as breast cancer with neoductgenesis. We correlated mammographic features and histopathological neoductgenesis with prognosis in a DCIS cohort with long follow-up. Mammographic features were classified into seven groups according to Tabar. Histopathological neoductgenesis was defined by concentration of ducts, lymphocyte infiltration, and periductal fibrosis. Endpoints were ipsilateral (IBE) in situ and invasive events. Casting-type calcifications and neoductgenesis were both related to high nuclear grade, ER-and PR-negativity, and HER2 overexpression but not to each other. Casting-type calcifications and neoductgenesis were both related to a nonsignificant lower risk of invasive IBE, HR 0.38 (0.13-1.08) and 0.82 (0.29-2.27), respectively, and the HR of an in situ IBE was 0.90 (0.41-1.95) and 1.60 (0.75-3.39), respectively. Casting-type calcifications could not be related to a worse prognosis in DCIS. We cannot explain why a more aggressive phenotype of DCIS did not correspond to a worse prognosis. Further studies on how the progression from in situ to invasive carcinoma is driven are needed.

  • 1258.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sollie, Thomas
    Tot, Tibor
    Pinder, Sarah E
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Blomqvist, Carl
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Christensson, Gunilla
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Breast cancer with neoductgenesis: histopathological criteria and its correlation with mammographic and tumour features2014In: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, Vol. 2014, article id 581706Article in journal (Refereed)
    Abstract [en]

    Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers.

    Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied.

    Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41-0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers).

    Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.

  • 1259.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tot, Tibor
    Department of Pathology, Falun Central Hospital.
    Tabár, László
    Department of Mammography, Falun Central Hospital.
    Pinder, Sarah
    Department of Pathology, King´s College, London.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Gunilla, Christensson
    Department of Surgery, Falun Central Hospital.
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Sollie, Thomas
    Department of Pathology, Örebro University.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Breast carcinoma with neoductgenesis: a new subgroup of breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: A new subgroup of breast cancer has been proposed: breast carcinoma with neoductgenesis. Cases presenting with casting type calcifications on the mammogram, histologically high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction and lymphocyte infiltration has been suggested to represent a more aggressive form of breast cancer. Treatment decision based on traditional histopathology showing DCIS might be challenged if neoductgenesis is diagnosed. We evaluated a histological classification system proposed for neoductgenesis and studied tumor biology in cases with and without neoductgenesis.

     

    Material and Method: Seventy-four tumors with DCIS grade 2-3, with or without an invasive component, were blocked in TMAs. A classification system based on a pathological evaluation and Tenascin-C (Tn-C) expression was used to categorize tumors as showing neoductgenesis or not. Immunohistochemical staining for known tumor markers and correlation with mammographic features was performed. Logistic regression model was use to evaluate the correlation between breast carcinoma with neoductgenesis and molecular- and mammographic features.

     

    Results: Four pathologists could categorize cases as “possible neoductgenesis” with an overall correlation of 72% and a kappa value of 0.44. Adding Tn-C staining resulted in a group with neoductgenesis (n=37) and one without (n=31). Neoductgenesis correlated significantly with mammographic casting- and crushed stone microcalcifications and estrogen receptor status (p-values 0.04 and 0.03, respectively). High nuclear grade, HER2 positivity, progesterone receptor negativity and high proliferation were also more often seen in the group with neoductgenesis, but this was not statistically significant (0.10, 0.07, 0.20 and 0.29).

     

    Discussion: We developed reproducible histologic criteria for a new entity: breast carcinoma with neoductgenesis. The system seemed to be useful in receiving reproducibility between pathologists making the diagnosis. Neoductgenesis was related to more aggressive tumor biology and to the mammographic features. Our findings have to be repeated and the relation to prognosis further studied. However, we can already predict a potential benefit for women earlier considered having a pure DCIS but now diagnosed as breast carcinoma with neoductgenesis and a need to develop appropriate treatment regiments.

  • 1260.
    Åberg, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    (AlF)-F-18-labelling of NOTA-P2-RM26 and its evaluation as a PET ligand for GRPR/BB22013In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, no S1, p. S404-S404Article in journal (Other academic)
  • 1261.
    Ågren, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Björkstrand, Johannes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Disruption of reconsolidation erases a fear memory trace in the human amygdala2012In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 337, no 6101, p. 1550-1552Article in journal (Refereed)
    Abstract [en]

    Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism.

  • 1262.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Medial temporal lobe resection attenuates superior temporal sulcus response to faces2014In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 61, p. 291-298Article in journal (Refereed)
    Abstract [en]

    Face perception depends on activation of a core face processing network including the fusiform face area, the occipital face area and the superior temporal sulcus (STS). The medial temporal lobe (MTL) is also involved in decoding facial expression and damage to the anterior MTL, including the amygdala, generally interferes with emotion recognition. The impairment in emotion recognition following anterior MTL injury can be a direct result from injured MTL circuitry, as well as an indirect result from decreased MTL modulation of areas in the core face network. To test whether the MTL modulates activity in the core face network, we used functional magnetic resonance imaging to investigate activation in the core face processing network in patients with right or left anterior temporal lobe resections (ATR) due to intractable epilepsy. We found reductions of face-related activation in the right STS after both right and left ATR together with impaired recognition of facial expressions. Reduced activity in the fusiform and the occipital face areas was also observed in patients after right ATR suggesting widespread effects on activity in the core face network in this group. The reduction in face-related STS activity after both right and left ATR suggests that MTL modulation of the STS may facilitate recognition of facial expression.

  • 1263.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Michelgård, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake phobia2009In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 172, no 2, p. 103-108Article in journal (Refereed)
    Abstract [en]

    The objective was to study effects of fear on brain activity, functional connectivity and brain-behavior relationships during symptom provocation in subjects with specific phobia. Positron emission tomography (PET) and (15)O water was used to measure regional cerebral blood flow (rCBF) in 16 women phobic of either snakes or spiders but not both. Subjects watched pictures of snakes and spiders serving either as phobic or fear-relevant, but non-phobic, control stimuli depending on phobia type. Presentation of phobic as compared with non-phobic cues was associated with increased activation of the right amygdala and cerebellum as well as the left visual cortex and circumscribed frontal areas. Activity decreased in the prefrontal, orbitofrontal and ventromedial cortices as well as in the primary somatosensory cortex and auditory cortices. Furthermore, amygdala activation correlated positively with the subjective experience of distress. Connectivity analyses of activity in the phobic state revealed increased functional couplings between voxels in the right amygdala and the periamygdaloid area, fusiform gyrus and motor cortex. During non-phobic stimulation, prefrontal activity correlated negatively with amygdala rCBF, suggesting a phobia-related functional decoupling. These results suggest that visually elicited phobic reactions activate object recognition areas and deactivate prefrontal areas involved in cognitive control over emotion-triggering areas like the amygdala, resulting in motor readiness to support fight or flight.

  • 1264.
    Åström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Brenning, G C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    MR imaging of primary, secondary, and mixed forms of lymphedema2001In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 42, no 4, p. 409-416Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To describe the pathological features and assess the diagnostic information of different MR sequences in patients with primary, secondary, and mixed (phlebo-, lipophlebo-, or lipolymphedema) forms of lymphedema of the lower leg.

    MATERIAL AND METHODS:

    In 26 patients with clinical diagnoses of primary (n=10), pure secondary (n=4), mixed (n=9) and combined secondary and mixed forms of lymphedema (n=3), MR imaging was performed with coronal and axial T1 SE, T2 TSE, fat-suppressed (SPIR) T2 sequences and axial T1 SE after i.v. injection of Gd-DTPA.

    RESULTS:

    In 24 patients there was a honeycomb pattern in the subcutis with a signal intensity corresponding to fluid (n=11), fibrosis (n=3), or both (n=10). Five patients with primary lymphedema showed subfascial fluid accumulation. Dermal edema was noted in 23 patients. Fat or edema components in the muscles were mostly seen in patients with phlebolymphedema. The honeycomb pattern was best seen on coronal T1 images, and fluid accumulations on axial SPIR-T2 images. Fibrosis was only assessible from the T2 TSE sequence. Gd-DTPA did not improve the diagnostic information.

    CONCLUSION:

    For evaluation of lymphedema and its mixed forms, an axial T2-weighted SPIR sequence in conjunction with a coronal T1 SE sequence are sufficient.

  • 1265.
    Åström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    CT-guided transsternal core biopsy of anterior mediastinal masses1996In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 199, no 2, p. 564-567Article in journal (Refereed)
    Abstract [en]

    Computed tomography-guided transsternal biopsy was successful in 10 anterior mediastinal masses in 10 patients, with use of a coaxial length-matched bone biopsy system comprising an outer cannula and an inner eccentric drill bit. No complications occurred in nine of 10 biopsies (eight performed with an automatic cutting needle, two with a fine needle), with less discomfort than was caused by injection of anesthetic.

  • 1266.
    Åström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundström, J C
    Lindgren, P G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Automatic biopsy instruments used through a coaxial bone biopsy system with an eccentric drill tip1995In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 36, no 3, p. 237-242Article in journal (Refereed)
    Abstract [en]

    Twenty-eight consecutive CT (n = 23) or ultrasonographically (n = 5) guided biopsy procedures were performed on musculoskeletal lytic lesions covered (n = 13) or not covered (n = 15) with intact bone. Specimens were obtained by means of Biopty techniques (n = 27), i.e. Biopty and Monopty instruments, through different cannulas with normal or shortened needle-throws. Four out of 5 bone penetrations were successful with an Ostycut needle, and all 8 bone penetrations by a coaxial bone biopsy system with an eccentric drill. The eccentric drill makes a hole in the cortical bone larger than the diameter of the outer cannula of this system, making it easy to anchor the cannula and then coaxially insert a Biopty-Gun needle for example. The overall histopathological diagnostic accuracy of the Biopty techniques was 25/27 (92.6%).

  • 1267.
    Örlefors, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    PET-Guided Surgery: High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours2012In: Cancers, ISSN 2072-6694, Vol. 4, no 1, p. 100-112Article in journal (Other academic)
    Abstract [en]

    Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

  • 1268.
    Örlefors, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Garske, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Endokrin tumörbiologi.
    Långstrom, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Whole-Body 11C-5-Hydroxytryptophan Positron Emission Tomography as a Universal Imaging Technique for Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and Computed Tomography2005In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 90, no 6, p. 3392-3400Article in journal (Refereed)
  • 1269.
    Örlefors, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Sundín, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergström, M
    Lilja, A
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, B
    Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors1998In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 16, no 7, p. 2534-2541Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Carcinoid tumors, especially those of midgut origin, produce serotonin via the precursors tryptophan and 5-hydroxytryptophan (5-HTP). We have evaluated the usefulness of positron emission tomography (PET) with carbon-11-labeled 5-HTP in the diagnosis and treatment follow-up evaluation of patients with neuroendocrine tumors.

    PATIENTS AND METHODS:

    PET using 11C-labeled 5-HTP was compared with computed tomography (CT) in 18 patients (14 midgut, one foregut, one hindgut carcinoid, and two endocrine pancreatic tumors [EPT]). In addition, 10 of 18 patients were monitored with PET examinations during treatment.

    RESULTS:

    All 18 patients, including two with normal urinary 5-hydroxyindole acetic acid (U-5-HIAA), had increased uptake of 11C-labeled 5-HTP in tumorous tissue as compared with normal tissue. Liver metastases, as well as lymph node, pleural, and skeletal metastases, showed enhanced 5-HTP uptake and PET could detect more lesions than CT in 10 patients and equal numbers in the others. Tumor visibility was better for PET than for CT due to the high and selective uptake of 5-HTP with a high tumor-to-background ratio. Binding studies indicated an irreversible trapping of 5-HTP in the tumors. Linear regression analyses showed a clear correlation (r = .907) between changes in U-5-HIAA and changes in the transport rate constant for 5-HTP during treatment.

    CONCLUSION:

    PET with 11C-labeled 5-HTP demonstrated high uptake in neuroendocrine gastrointestinal tumors and thereby allowed improved visualization compared with CT. The in vivo data on regional tumor metabolism, as expressed in 11C-5-HTP uptake and transport rate, provided additional information over conventional radiologic techniques. The close correlation between the changes in 11C-5-HTP transport rate and U-HIAA during medical treatment indicates the potential of 11C-5-HTP-PET as a means to monitor therapy.

23242526 1251 - 1269 of 1269
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