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  • 301.
    Karakatsanis, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, H. M.
    Eriksson, S.
    Andersson, Y.
    Bergkvist, Leif A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Mohammed, I.
    Sundqvist, M.
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bagge, R. Olofsson
    Sund, M.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    SentiNot: A way to avoid sentinel node biopsy (SNB) in patients with a preoperative diagnosis of ductal cancer in situ (DCIS)2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77Article in journal (Refereed)
  • 302.
    Karakatsanis, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Abdsaleh, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Simplifying Logistics and Avoiding the Unnecessary in Patients with Breast Cancer Undergoing Sentinel Node Biopsy. A Prospective Feasibility Trial of the Preoperative Injection of Super Paramagnetic Iron Oxide Nanoparticles2018In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 107, no 2, p. 130-137Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Sentinel node is routinely localized with the intraoperative use of a radioactive tracer, involving challenging logistics. Super paramagnetic iron oxide nanoparticle is a non-radioactive tracer with comparable performance that could allow for preoperative localization, would simplify the procedure, and possibly be of value in axillary mapping before neoadjuvant treatment. The current trial aimed to determine the a priori hypothesis that the injection of super paramagnetic iron oxide nanoparticles in the preoperative period for the localization of the sentinel node is feasible.

    METHODS: This is a prospective feasibility trial, conducted from 9 September 2014 to 22 October 2014 at Uppsala University Hospital. In all, 12 consecutive patients with primary breast cancer planned for resection of the primary and sentinel node biopsy were recruited. Super paramagnetic iron oxide nanoparticles were injected in the preoperative visit in the outpatient clinic. The radioactive tracer (99mTc) and the blue dye were injected perioperatively in standard fashion. A volunteer was injected with super paramagnetic iron oxide nanoparticles to follow the decline in the magnetic signal in the sentinel node over time. The primary outcome was successful sentinel node detection.

    RESULTS: Super paramagnetic iron oxide nanoparticles' detection after preoperative injection (3-15 days) was successful in all cases (100%). In the volunteer, axillary signal was presented for 4 weeks. No adverse effects were noted. Conclusion and relevance: Preoperative super paramagnetic iron oxide nanoparticles' injection is feasible and leads to successful detection of the sentinel node. That may lead to simplified logistics as well as the identification, sampling, and marking of the sentinel node in patients planned for neoadjuvant treatment.

  • 303.
    Karakatsanis, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Royal Marsden Hosp, Breast Surg Unit, London, England.
    Tasoulis, M. K.
    Royal Marsden Hosp, Breast Surg Unit, London, England.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nilsson, Greger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala Univ Hosp, Sect Expt & Clin Oncol, Dept Immunol Genet & Pathol, Uppsala, Sweden;Gavle Cent Hosp, Dept Oncol, Gavle, Sweden;Visby Hosp, Sect Oncol, Visby, Sweden.
    MacNeill, F.
    Royal Marsden Hosp, Breast Surg Unit, London, England.
    Meta-analysis of neoadjuvant therapy and its impact in facilitating breast conservation in operable breast cancer2018In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 105, no 5, p. 469-481Article in journal (Refereed)
    Abstract [en]

    Background

    Neoadjuvant therapy (NAT) for operable breast cancer may facilitate more breast-conserving surgery (BCS). It seems, however, that this benefit is not being realized fully.

    Methods

    A systematic review of the literature was performed. RCTs were included. The criteria for inclusion were: documentation of surgical assessment before and after NAT, surgery performed (BCS or mastectomy), and clinical and pathological responses.

    Results

    A total of 1452 patients from seven RCTs met the inclusion criteria. After NAT, the feasibilityof BCS increased from 43⋅3to60⋅4 per cent (P < 0⋅001), but BCS was performed in only 51⋅8percent(P = 0⋅04). Only 31 per cent of patients who became eligible for BCS (assessed on clinical response)underwent BCS (pooled rate ratio 0⋅31, 95 per cent c.i. 0⋅22 to 0⋅44; P < 0⋅001). Of the mastectomycandidates who achieved a pathological complete response after NAT, only 41 per cent underwent BCS(pooled rate ratio 0⋅41, 0⋅23 to 0⋅74; P = 0⋅003). The main factors that influenced the decision not to shiftto BCS, even though it was feasible, were clinical assessment before NAT, multicentricity and tumoursize at presentation.

    Conclusion

    Breast surgery performed after NAT does not reflect tumour response, resulting in potentially unnecessary radical surgery, especially mastectomy. The barriers to maximizing the surgical benefits of NAT need to be better understood and explored. Still unnecessary mastectomies

  • 304.
    Karlsson, Britt-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Andersson Forsman, Catarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindgren, Per-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Jacobson, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Efficiency of percutaneous core biopsy in pancreatic tumor diagnosis1996In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 120, no 1, p. 75-79Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Radiologic diagnosis of pancreatic tumors exhibits limited precision. The aim of this study was to investigate the outcome and complications of pancreatic core biopsy in patients with suspected pancreatic neoplasms.

    METHODS:

    One hundred patients underwent ultrasonography-guided core biopsy of 1.2 mm external diameter. Medical charts were examined for biochemical and clinical signs of complications. Final diagnosis was settled by operation, autopsy, and clinical signs of the disease including survival with at least 2.3 years of follow-up.

    RESULTS:

    Histopathologic biopsy evaluation showed correct discrimination between exocrine and endocrine tumors and nonneoplastic conditions in 89 patients. No false-positive cancer diagnosis was found, and guidance on nature of primary tumors was obtained for eight of eight metastases. The sensitivity was 91% for exocrine and 87% for endocrine pancreatic tumors, and negative predictive values of these diagnoses were 83% and 97%, respectively. No clinically significant complications were noted.

    CONCLUSIONS:

    Core biopsy is an attractive alternative to diagnostic laparotomy in unresectable pancreatic cancer and efficiently provides diagnosis of endocrine tumors and pancreatic metastases in conjunction with rare complications. Benign biopsy findings cannot be used to exclude presence of primary or metastatic pancreatic neoplasms.

  • 305. Kehr, Elizabeth
    et al.
    Batista, Julie
    Zadra, Giorgia
    Arthur, Rhonda
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Van Hemelrijck, Mieke
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Loda, Massimo
    Immunohistochemical Analysis of the AMPK Pathway in Prostate Cancer in the Context of the Metabolic Syndrome2015In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 95, no S1, p. 233A-234A, article id 930Article in journal (Other academic)
  • 306. Kehr, Elizabeth
    et al.
    Batista, Julie
    Zadra, Giorgia
    Arthur, Rhonda
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Van Hemelrijck, Mieke
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Loda, Massimo
    Immunohistochemical Analysis of the AMPK Pathway in Prostate Cancer in the Context of the Metabolic Syndrome2015In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 28, p. 233A-234AArticle in journal (Other academic)
  • 307.
    Khan, Tanweera Shaheena
    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 Surgical Sciences, Radiology.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    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, Endocrin Oncology.
    11C-metomidate PET imaging of adrenocortical cancer2003In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070 (Paper) 1619-7089 (Online), Vol. 30, no 3, p. 403-410Article in journal (Refereed)
  • 308.
    Killander, F.
    et al.
    Lund Univ, Dept Clin Sci, Oncol, Lund, Sweden.;Skane Univ Hosp, Skane Dept Oncol, Lund, Sweden..
    Karlsson, P.
    Sahlgrens Univ Hosp, Sahlgrenska Acad, Inst Clin Sci, Dept Oncol, Gothenburg, Sweden..
    Anderson, H.
    Dept Clin Sci, Canc Epidemiol, Lund, Sweden..
    Mattsson, J.
    Sahlgrens Univ Hosp, Dept Surg, Gothenburg, Sweden..
    Holmberg, E.
    Sahlgrens Univ Hosp, Reg Oncol Ctr, Gothenburg, Sweden..
    Lundstedt, D.
    Sahlgrens Univ Hosp, Sahlgrenska Acad, Inst Clin Sci, Dept Oncol, Gothenburg, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Uppsala Hosp, Reg Oncol Ctr, Uppsala, Sweden.;Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Malmström, P.
    Lund Univ, Dept Clin Sci, Oncol, Lund, Sweden.;Skane Univ Hosp, Skane Dept Oncol, Lund, Sweden..
    No breast cancer subgroup can be spared postoperative radiotherapy after breast-conserving surgery. Fifteen-year results from the Swedish Breast Cancer Group randomised trial, SweBCG 91 RT2016In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 67, p. 57-65Article in journal (Refereed)
    Abstract [en]

    Background: Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an established treatment for women with T1-2N0 breast cancers. Since subgroups of patients have low ipsilateral breast tumour recurrence (IBTR) rates, it is important to study whether RT is necessary for all patients. Patients and methods: A total of 1187 women with primary T1-2N0M0 breast cancer were randomised, after standardised sector resection, to postoperative whole breast RT or no local treatment. Adjuvant systemic therapy was offered to patients with stage II cancers. Patients were followed with clinical examinations and annual mammography for 10 years and thereafter referred to the Swedish mammography screening program. Results: After 15 years of follow-up, a higher cumulative incidence of IBTR was observed in control patients, 23.9%, versus irradiated patients, 11.5%, P < 0.001. Recurrence-free survival was inferior, 51.7% versus 60.4%, P = 0.0013. The main effect of RT was seen during the first 5 years. However, overall survival was not significantly lower 68.4% versus 71.1%, P = 0.68, nor was breast cancer specific mortality significantly higher. Conclusions: RT after BCS significantly reduced the incidence of IBTR at 15 years of followup. We were unable to identify subgroups which could be spared RT. Breast cancer mortality was not significantly reduced after RT. Good predictive markers for radiation sensitivity and improved adjuvant systeinic therapy are needed to omit RT after BCS.

  • 309. Klajic, Jovana
    et al.
    Fleischer, Thomas
    Dejeux, Emelyne
    Edvardsen, Hege
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bukholm, Ida
    Lonning, Per Eystein
    Solvang, Hiroko
    Borresen-Dale, Anne-Lise
    Tost, Jorg
    Kristensen, Vessela N.
    Quantitative DNA methylation analyses reveal stage dependent DNA methylation and association to clinico-pathological factors in breast tumors2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, p. 456-Article in journal (Refereed)
    Abstract [en]

    Background: Aberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression. Methods: Quantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV. Results: Significant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival. Conclusions: In the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above.

  • 310. Klint, Åsa
    et al.
    Talbäck, Mats
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rapportering till Cancerregistret kan förbättras2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 11, p. 752-3Article in journal (Refereed)
    Abstract [sv]

    En studie som nyligen publicerades i Acta Oncologica pekar på brister i rapporteringen till Cancerregistret.

    Studien visar att fall av exempelvis hjärntumörer, lymfom och leukemier inte rapporteras till Cancerregistret i samma utsträckning som bröstcancer och urologiska cancerformer. Underrapporteringen varierar med bland annat typ av vårdinrättning och patientens kön och ålder.

    Artikeln identifierar problemområden som behöver åtgärdas för att förbättra täckningsgraden i Cancerregistret. Detaljer om uppgiftsskyldigheten till Cancerregistret finns i Socialstyrelsens föreskrift SOSFS 2006:15 (M).

  • 311. Koinberg, Ingalill
    et al.
    Engholm, G-B.
    Genell, A.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    A health economic evaluation of follow-up after breast cancer surgery: results of an rct study2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 1, p. 99-104Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Breast cancer follow-up programmes consume large resources and despite the indications that several alternative approaches could be used effectively, there is no coherent discussion about costs and/or cost-effectiveness of follow-up programmes. PATIENT AND METHODS: In a prospective trial there were 264 breast cancer patients, stage I and II, randomised to two different follow-up programmes- PG (physician group) and NG (nurse group). The trial period was 5 years. The women in the two intervention groups did not differ in anxiety and depression, their satisfaction with care, their experienced accessibility to the medical centre or their medical outcome as measured by recurrence or death. The analyses were done from different lists representing costs at three hospitals in Sweden according to the principles of a cost minimization study. RESULTS: The cost per person year of follow-up differed between the groups, with 630 euro per person year in PG compared to 495 euro per person year in NG. Thus, specialist nurse intervention with check-ups on demand was 20% less expensive than routine follow-up visits to the physician. The main difference in cost between the groups was explained by the numbers of visits to the physician in the respective study arms. There were 21% more primary contacts in PG than NG. DISCUSSION: The difference in cost per year and patient by study arm is modest, but transforms to nearly 900 euro per patient and 5-year period, offering a substantial opportunity for reallocating resources since breast cancer is the most prevalent tumour worldwide.

  • 312. Koinberg, Inga-Lill
    et al.
    Langius-Eklöf, Ann
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Fridlund, Bengt
    The usefulness of a multidisciplinary educational programme after breast cancer surgery: A prospective and comparative study2006In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 10, no 4, p. 273-282Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to compare and evaluate a multidisciplinary educational programme with traditional follow-up visits to a physician after breast cancer surgery in terms of well-being, aspects of self-care and coping ability 1 year after diagnosis. A reduction in the intensity of follow-up after breast cancer surgery is recommended. New follow-up models are being debated and could be of interest. The study design was non-randomised and comparative. Ninety-six consecutively selected women with newly diagnosed breast cancer, classified as stage I or stage II, participated in either a multidisciplinary educational programme (n=50), or traditional follow-up by a physician (n=46). Three questionnaires were used: Functional Assessment of Cancer Therapy-General (FACT-G), a study specific questionnaire regarding self-care aspects (SCA) and Sense of Coherence (SOC). With the exception of physical well-being at baseline there was no significant difference between the groups. The women in the multidisciplinary educational programme increased their physical and functional well-being (P<0.01). The women in traditional follow-up by a physician increased their functional well-being while social/family well-being (P<0.01) decreased over time. There was a statistically significant difference in SOC (P<0.001) in the traditional follow-up by a physician between baseline (mean=74.4, SD=12.4) and the 1-year follow up (mean=67.7, SD=11.4). Thus, women in the traditional follow-up by a physician scored lower in the area of SOC 1 year after diagnosis. A multidisciplinary educational programme may be an alternative to traditional follow-up by a physician after breast cancer surgery, but more research is needed about the financial benefits and effectiveness of such a programme.

  • 313.
    Koliadi, Anthoula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nilsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Holmqvist, Marit
    Uppsala-Örebro Regional Oncologic Centre, Uppsala, Sweden.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer2010In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, no 6, p. 816-820Article in journal (Refereed)
    Abstract [en]

    Patients with low-risk node negative breast cancer have an excellent prognosis with 5% breast cancer mortality at 10 years. However, prognostic factors are needed to identify poor prognostic patients who might benefit from adjuvant systemic therapy. Proliferation has been identified as the most important component of gene expression profiles. Cyclin B is a proliferative marker easily assessed by immunohistochemistry. We wanted to examine cyclin B as a prognostic factor in low-risk breast cancer patients. Patients and methods. Using an experimental study design, we compared women dying early from their breast cancer (n=17) with women free from relapse more than eight years after initial diagnosis (n=24). All women had stage I, node negative and hormone receptor positive disease. None had received adjuvant chemotherapy. Tumor samples were immunostained for cyclin B using commercial antibodies. Results. The mean percentage of cyclin B (12%) was significantly higher (p=0.001) in women dying from their breast cancer compared with women free from relapse ( 5%). High cyclin B (>= 9%) identified 11/17 patients dying from breast cancer and low cyclin B identified 22/24 patients free from relapse. The sensitivity and specificity of cyclin B was 65% and 92%, respectively. Discussion. We found that low-risk node negative patients with high expression of cylin B had a significantly worse outcome than patients with low expression of cyclin B. Cyclin B could separate patients with poor survival from those with good survival with 80% accuracy. We suggest that cyclin B might be a potent prognostic factor in this low-risk patient group.

  • 314.
    Kontos, M
    et al.
    Breast Unit, Guy’s Hospital, London, UK.
    Lewis, R S
    Breast Unit, Guy’s Hospital, London, UK.
    Lüchtenborg, M
    Division of Cancer Studies, King’s College, London, UK.
    Holmberg, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hamed, H
    Breast Unit, Guy’s Hospital, London, UK.
    Does immediate breast reconstruction using free flaps lead to delay in the administration of adjuvant chemotherapy for breast cancer?2010In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 36, no 8, p. 745-749Article in journal (Refereed)
    Abstract [en]

    There is a significant delay in the commencement of adjuvant treatment after mastectomy and free flap IBR in comparison to mastectomy alone patients due to reconstruction related surgical complications. The effects of this delay on survival have not been fully investigated yet and may be significant for at least some of the patients.

  • 315. Kontos, Michalis
    et al.
    Allen, D.
    Trafalis, D. T.
    Jones, G.
    Garmo, H.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hamed, H.
    Follow-up may not be beneficial after treatment of grade 1 breast cancer2009In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 96, no 9, p. 999-1004Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Identification of women treated for breast cancer who have a low risk of locoregional recurrence or contralateral breast cancer, and who can be discharged safely from follow-up, would lower costs without compromising prognosis. This study investigated the risk of locoregional recurrence and contralateral breast cancer in women treated for grade 1 breast cancer. METHODS: Some 1143 women who had surgery for breast cancer were followed, and the rate of locoregional recurrence or contralateral breast cancer was determined. The risk was compared to the tumour grade. RESULTS: At a mean follow-up of 9.1 years, 10-year estimates of the cumulative risk of locoregional recurrence or contralateral breast cancer for grade 1, 2 and 3 breast cancer were 0.03 (95 per cent confidence interval (c.i.) 0.01 to 0.08), 0.12 (0.09 to 0.15) and 0.16 (0.13 to 0.20) respectively. Grade 1 tumours had a risk of locoregional recurrence or contralateral breast cancer of 285 (95 per cent c.i. 93 to 670) per 100,000 person-years. CONCLUSION: Women treated for grade 1 breast cancer could be discharged from follow-up after completion of the primary treatment, without compromising their quality of care.

  • 316.
    Krajisnik, Tijana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Olauson, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Mirza, Majd A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson*, Tobias, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Björklund*, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Parathyroid Klotho Expression Declines with Renal Function in Hyperparathyroid CKD PatientsManuscript (preprint) (Other academic)
    Abstract [en]

    Current data suggest that type I membrane-bound α-Klotho plays a dual role in the regulation of PTH secretion. While stimulating PTH release during hypocalcemia, Klotho inhibits PTH production by mediating the suppressive effect of fibroblast growth factor-23 (FGF23). In chronic kidney disease (CKD), secondary hyperparathyroidism (sHPT) often develops in the presence of high serum FGF23, indicating parathyroid resistance to FGF23 action. This could in part be due to reduced Klotho expression, as reported in kidneys of CKD patients. Herein, we analyzed parathyroid Klotho expression level in 31 patients with sHPT as well as regulation of Klotho in isolated bovine parathyroid cells using real-time PCR analysis and IHC staining. Klotho expression was variable in secondary hyperplastic glands, yet the mRNA levels correlated positively with glomerular filtration rate and significantly decreased over CKD stages. In vitro treatment with either FGF23 or calcium dose-dependently reduced the Klotho level, whereas vitamin D treatment increased its expression. This stimulatory effect was blunted in the presence of either high FGF23 or calcium. No effect on Klotho level was observed after treatment with phosphate or PTH. In summary, parathyroid Klotho expression was variable in sHPT but decreased with declining renal function. This may be due to a complex co-regulation by calcium, FGF23 and vitamin D, and explain the lack of suppressive effects of FGF23 on PTH secretion in late CKD.

  • 317.
    Krauss, Tobias
    et al.
    Univ Freiburg, Med Ctr, Fac Med, Dept Radiol, Freiburg, Germany.
    Ferrara, Alfonso Massimiliano
    IRCCS, Veneto Inst Oncol IOV, Familial Canc Clin & Oncoendocrinol, Padua, Italy.
    Links, Thera P.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands.
    Wellner, Ulrich
    Univ Lubeck, Dept Surg, Lubeck, Germany.
    Bancoss, Irina
    Mayo Clin, Div Endocrinol Diabet Metab &Nutr, Rochester, MN USA.
    Kvachenyuk, Andrey
    NAMS Ukraine, Inst Endocrinol & Metab, Kiev, Ukraine.
    Gomez de las Heras, Karim Villar
    Serv Salud Castilla La Mancha SESCAM, Cent Serv, Toledo, Spain.
    Yukina, Marina Y.
    Endocrinol Res Ctr, Dept Surg, Moscow, Russia.
    Petrov, Roman
    Bakhrushin Bros Moscow City Hosp, Dept Surg, Moscow, Russia.
    Bullivant, Garrett
    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada.
    von Duecker, Laura
    Albert Ludwigs Univ, Fac Med, Dept Med 4, Freiburg, Germany.
    Jadhav, Swati
    King Edward Mem Hosp, Dept Endocrinol, Bombay, Maharashtra, India.
    Ploeckinger, Ursula
    Charite Univ Med Berlin, Interdisciplinary Ctr Metab Endocrinol Diabet & M, Campus Virchow Klinikum, Berlin, Germany.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Schalin-Jantti, Camilla
    Univ Helsinki, Abdominal Ctr, Endocrinol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Gimm, Oliver
    Univ Linkoping, Dept Clin & Expt Med, Dept Surg, Linkoping, Sweden.
    Pfeifer, Marija
    Univ Med Ctr, Dept Endocrinol, Ljubljana, Slovenia.
    Ngeow, Joanne
    Nanyang Technol Univ, Natl Canc Ctr Singapore, Canc Genet Serv, Div Med Oncol, Singapore, Singapore;Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore.
    Hasse-Lazar, Kornelia
    MSC Mem Inst, Ctr Oncol, Dept Endocrine Oncol & Nucl Med, Gliwice, Poland.
    Sanso, Gabriela
    Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol Dr Cesar Bergada CEDIE, Buenos Aires, DF, Argentina.
    Qi, Xiaoping
    Wenzhou Med Univ, PLA Hosp 117, Dept Oncol & Urol Surg, Hangzhou, Zhejiang, Peoples R China.
    Ugurlu, M. Umit
    Marmara Univ, Dept Gen Surg, Breast & Endocrine Surg Unit, Sch Med, Istanbul, Turkey.
    Diaz, Rene E.
    Hosp Salvador, Endocrine Sect, Santiago, Chile.
    Wohllk, Nelson
    Univ Chile, Hosp Salvador, Dept Med, Endocrine Sect, Santiago, Chile.
    Peczkowska, Mariola
    Inst Cardiol, Dept Hypertens, Warsaw, Poland.
    Aberle, Jens
    Univ Med Ctr Hamburg Eppendorf, Dept Med 3, Hamburg, Germany.
    Lourenco Jr, Delmar M.
    Univ Sao Paulo, Serv Endocrinol, Hosp Clin HCFMUSP, Sao Paulo, Brazil;Univ Sao Paulo, ICESP, Fac Med, Sao Paulo, Brazil.
    Pereira, Maria A. A.
    Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Serv Endocrinol, Sao Paulo, Brazil.
    Fragoso, Maria C. B., V
    Univ Sao Paulo, Serv Endocrinol, Hosp Clin HCFMUSP, Sao Paulo, Brazil;Univ Sao Paulo, ICESP, Fac Med, Sao Paulo, Brazil.
    Hoff, Ana O.
    Univ Sao Paulo, Serv Endocrinol, Hosp Clin HCFMUSP, Sao Paulo, Brazil;Univ Sao Paulo, ICESP, Fac Med, Sao Paulo, Brazil.
    Almeida, Madson Q.
    Univ Sao Paulo, Serv Endocrinol, Hosp Clin HCFMUSP, Sao Paulo, Brazil;Univ Sao Paulo, ICESP, Fac Med, Sao Paulo, Brazil.
    Violante, Alice H. D.
    Univ Fed Rio de Janeiro, Dept Internal Med Endocrinol, Fac Med, Hosp Univ Clementino Fraga Filho, Rio De Janeiro, Brazil.
    Ouidute, Ana R. P.
    Fed Univ Ceara UFC, Fac Med, Dept Physiol & Pharmacol, Drug Res & Dev Ctr NPDM, Fortaleza, Ceara, Brazil.
    Zhang, Zhewei
    Zhejiang Univ, Sch Med, Dept Urol, Hosp 2, Hangzhou, Zhejiang, Peoples R China.
    Recasens, Monica
    Hosp Univ Girona, Inst Catala Salut, Gerencia Terr Girona, Girona, Spain.
    Robles Diaz, Luis
    Hosp Univ 12 Octubre, Serv Oncol Med, Unidad Tumores Digest, Madrid, Spain.
    Kunavisarut, Tada
    Mahidol Univ, Siriraj Hosp, Div Endocrinol & Metab, Bangkok, Thailand.
    Wannachalee, Taweesak
    Mahidol Univ, Siriraj Hosp, Div Endocrinol & Metab, Bangkok, Thailand.
    Sirinvaravong, Sirinart
    Mahidol Univ, Siriraj Hosp, Div Endocrinol & Metab, Bangkok, Thailand.
    Jonasch, Eric
    Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Div Canc Med, Houston, TX 77030 USA.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Dept Med, Endocrinol & Metab Serv, Neuroendocrine Tumor Div,Med Ctr, Jerusalem, Israel.
    Fraenkel, Merav
    Hadassah Hebrew Univ, Dept Med, Endocrinol & Metab Serv, Neuroendocrine Tumor Div,Med Ctr, Jerusalem, Israel.
    Beltsevich, Dmitry
    Endocrinol Res Ctr, Dept Surg, Moscow, Russia.
    Egorov, Viacheslav, I
    Bakhrushin Bros Moscow City Hosp, Dept Surg, Moscow, Russia.
    Bausch, Dirk
    Univ Lubeck, Dept Surg, Lubeck, Germany.
    Schott, Matthias
    Heinrich Heine Univ, Dept Endocrinol, Dusseldorf, Germany.
    Tiling, Nikolaus
    Charite Univ Med Berlin, Interdisciplinary Ctr Metab Endocrinol Diabet & M, Campus Virchow Klinikum, Berlin, Germany.
    Pennelli, Gianmaria
    Univ Padua, Dept Med DIMED, Surg Pathol Unit, Padua, Italy.
    Zschiedrich, Stefan
    Albert Ludwigs Univ, Fac Med, Dept Med 4, Freiburg, Germany.
    Daerr, Roland
    Albert Ludwigs Univ, Fac Med, Dept Med 4, Freiburg, Germany;Univ Freiburg, Heart Ctr Freiburg Univ, Fac Med, Dept Cardiol & Angiol 1, Freiburg, Germany.
    Ruf, Juri
    Albert Ludwigs Univ, Fac Med, Dept Nucl Med, Freiburg, Germany.
    Denecke, Timm
    Charite Univ Med Berlin, Dept Radiol, Campus Virchow Klinikum, Berlin, Germany.
    Link, Karl-Heinrich
    Asklepios Paulinen Klin, Dept Surg, Wiesbaden, Germany.
    Zovato, Stefania
    IRCCS, Veneto Inst Oncol IOV, Familial Canc Clin & Oncoendocrinol, Padua, Italy.
    von Dobschuetz, Ernst
    Acad Teaching Hosp Univ Hamburg, Reinbek Hosp, Sect Endocrine Surg, Reinbek, Germany.
    Yaremchuk, Svetlana
    NAMS Ukraine, Inst Endocrinol & Metab, Kiev, Ukraine.
    Amthauer, Holger
    Charite Univ Med Berlin, Dept Clin Nucl Med, Berlin, Germany.
    Makay, Ozer
    Dept Gen Surg, Div Endocrine Surg, Izmir, Turkey.
    Patocs, Attila
    Semmelweis Univ, Hungarian Acad Sci, Dept Med 2, Budapest, Hungary;Semmelweis Univ, Hungarian Acad Sci, Mol Med Res Grp, Budapest, Hungary.
    Walz, Martin K.
    Huyssens Fdn Clin, Dept Surg, Essen, Germany.
    Huber, Tobias B.
    Univ Med Ctr Hamburg Eppendorf, Dept Med 3, Hamburg, Germany.
    Seufert, Jochen
    Univ Freiburg, Med Ctr, Fac Med, Dept Med 2, Freiburg, Germany.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Ekaterina, Raymond H.
    Univ Toronto, Univ Hlth Network, Dept Med, Toronto, ON, Canada;Mt Sinai Hosp, Fred Litwin Family Ctr Genet Med, Toronto, ON, Canada.
    Kuchinskaya, Ekaterina
    Linkoping Univ, Dept Clin Genet, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Schiavi, Francesca
    IRCCS, Veneto Inst Oncol IOV, Familial Canc Clin & Oncoendocrinol, Padua, Italy.
    Malinoc, Angelica
    Albert Ludwigs Univ, Fac Med, Dept Med 4, Freiburg, Germany.
    Reisch, Nicole
    Ludwigs Maximilians Univ Munich, Dept Endocrinol, Munich, Germany.
    Jarzab, Barbara
    MSC Mem Inst, Ctr Oncol, Dept Endocrine Oncol & Nucl Med, Gliwice, Poland.
    Barontini, Marta
    Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol Dr Cesar Bergada CEDIE, Buenos Aires, DF, Argentina.
    Januszewicz, Andrzej
    Inst Cardiol, Dept Hypertens, Warsaw, Poland.
    Shah, Nalini
    King Edward Mem Hosp, Dept Endocrinol, Bombay, Maharashtra, India.
    Young, William F., Jr.
    Mayo Clin, Div Endocrinol Diabet Metab &Nutr, Rochester, MN USA.
    Opocher, Giuseppe
    Veneto Inst Oncol IOV IRCCS, Sci Direct, Padua, Italy.
    Eng, Charis
    Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs Univ, Fac Med, Sect Prevent Med, Freiburg, Germany.
    Bausch, Birke
    Univ Freiburg, Med Ctr, Fac Med, Dept Med 2, Freiburg, Germany.
    Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors2018In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 9, p. 783-793Article in journal (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were >= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off >= 2.8 cm, 44% and 91% for TVDT cut-off of <= 24 months). In 117 of 273 patients, PanNETs > 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs < 2.8 cm vs >= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

  • 318. Kristensen, Vessela N
    et al.
    Vaske, Charles J
    Ursini-Siegel, Josie
    van Loo, Peter
    Nordgard, Silje H
    Sachidanandam, Ravi
    Sørlie, Therese
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Haakensen, Vilde D
    Helland, Aslaug
    Naume, Bjørn
    Perou, Charles M
    Haussler, David
    Troyanskaya, Olga G
    Børresen-Dale, Anne-Lise
    Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 8, p. 2802-2807Article in journal (Refereed)
    Abstract [en]

    We use an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We demonstrate that combining mRNA expression and DNA copy number classified the patients in groups that provide the best predictive value with respect to prognosis and identified key molecular and stromal signatures. A chronic inflammatory signature, which promotes the development and/or progression of various epithelial tumors, is uniformly present in all breast cancers. We further demonstrate that within the adaptive immune lineage, the strongest predictor of good outcome is the acquisition of a gene signature that favors a high T-helper 1 (Th1)/cytotoxic T-lymphocyte response at the expense of Th2-driven humoral immunity. Patients who have breast cancer with a basal HER2-negative molecular profile (PDGM2) are characterized by high expression of protumorigenic Th2/humoral-related genes (24-38%) and a low Th1/Th2 ratio. The luminal molecular subtypes are again differentiated by low or high FOXM1 and ERBB4 signaling. We show that the interleukin signaling profiles observed in invasive cancers are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. The most prominent difference between low and high mammographic density in healthy breast tissue by PARADIGM was that of STAT4 signaling. In conclusion, by means of a pathway-based modeling methodology (PARADIGM) integrating different layers of molecular data from whole-tumor samples, we demonstrate that we can stratify immune signatures that predict patient survival.

  • 319.
    Källestedt, Marie-Louise S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Berglund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Herlitz, Johan
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Enlund, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    The impact of CPR and AED training on healthcare professionals' self-perceived attitudes to performing resuscitation2012In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 20, p. 26-Article in journal (Refereed)
    Abstract [en]

    Background: Healthcare professionals have shown concern about performing mouth-to-mouth ventilation due to the risks to themselves with the procedure. However, little is known about healthcare professionals' fears and attitudes to start CPR and the impact of training. Objective: To examine whether there were any changes in the attitudes among healthcare professionals to performing CPR from before to after training. Methods: Healthcare professionals from two Swedish hospitals were asked to answer a questionnaire before and after training. The questions were relating to physical and mental discomfort and attitudes to CPR. Statistical analysis used was generalized McNemar's test. Results: Overall, there was significant improvement in 10 of 11 items, reflecting various aspects of attitudes to CPR. All groups of health care professionals (physicians, nurses, assistant nurses, and "others" = physiotherapists, occupational therapists, social welfare officers, psychologists, biomedical analysts) felt more secure in CPR knowledge after education. In other aspects, such as anxiety prior to a possible cardiac arrest, only nurses and assistant nurses improved. The concern about being infected, when performing mouth to mouth ventilation, was reduced with the most marked reduction in physicians (75%; P < 0.001). Conclusion: In this hospital-based setting, we found a positive outcome of education and training in CPR concerning healthcare professionals' attitudes to perform CPR. They felt more secure in their knowledge of cardiopulmonary resuscitation. In some aspects of attitudes to resuscitation nurses and assistant nurses appeared to be the groups that were most markedly influenced. The concern of being infected by a disease was low.

  • 320.
    Ladjevardi, Sam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Juhlin, C
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    [A case report. FDG-PET in occult breast cancer]2002In: Lakartidningen, Vol. 99, p. 524-Article in journal (Other academic)
  • 321.
    Ladjevardi, Sam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    FDG-PET vic ockult bröstcancer2002In: Läkartidningen, Vol. 99, p. 524-Article in journal (Other academic)
  • 322.
    Lamarca, Angela
    et al.
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom .
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Ronot, Maxime
    Department of Radiology, Beaujon University Hospital, Clichy, France .
    Opalinska, Marta
    Nuclear Medicine Unit, Department of Endocrinology, University Hospital, Krakow, Poland .
    Lopez Lopez, Carlos
    Department of Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander, Spain .
    Pezzutti, Daniela
    Department of Radiology, Israelita Albert Einstein Hospital, Sao Paulo, Brazil .
    Najran, Pavan
    Department of Radiology, The Christie NHS Foundation Trust, Manchester, United Kingdom .
    Carvhalo, Luciana
    Department of Medical Oncology, Sirio‐Libanes Hospital, Sao Paulo, Brazil .
    Franca Bezerra, Regis Otaviano
    Department of Radiology, Sirio‐Libanes Hospital, Sao Paulo, Brazil ; São Paulo Cancer Institute Octavio Frias de Oliveira, Sao Paulo, Brazil .
    Borg, Philip
    Department of Radiology, The Christie NHS Foundation Trust, Manchester, United Kingdom .
    Vietti Violi, Naik
    Department of Radiology, CHUV University Hospital, Lausanne, Switzerland .
    Vidal Trueba, Hector
    Department of Radiology, Hospital Universitario Marques de Valdecilla, Santander, Spain .
    de Mestier, Louis
    Department of Gastroenterology, Beaujon University Hospital, Clichy, France.
    Schaefer, Niklaus
    Department of Medical Oncology, CHUV University Hospital, Lausanne, Switzerland .
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Costa, Frederico
    Department of Medical Oncology, Sirio‐Libanes Hospital, Sao Paulo, Brazil.
    Pavel, Marianne
    Department of Medicine 1, Division of Endocrinology, Friedrich‐Alexander University Erlangen‐Nürnberg, Erlangen, Germany.
    Dromain, Clarisse
    Department of Radiology, CHUV University Hospital, Lausanne, Switzerland .
    Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET): The GREPONET Study2019In: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 24, no 11, p. E1082-E1090Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications.

    MATERIALS AND METHODS: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m).

    RESULTS: Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS.

    CONCLUSION: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up.

    IMPLICATIONS FOR PRACTICE: Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

  • 323. Lambert, Paul C
    et al.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sandin, Fredrik
    Bray, Freddie
    Linklater, Karen M
    Purushotham, Arnie
    Robinson, David
    Møller, Henrik
    Quantifying differences in breast cancer survival between England and Norway2011In: Cancer Epidemiology, ISSN 1877-7821, E-ISSN 1877-783X, Vol. 35, no 6, p. 526-533Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Survival from breast cancer is lower in the UK than in some other European countries. We compared survival in England and Norway by age and time from diagnosis.

    METHODS:

    We included 303,648 English and 24,919 Norwegian cases of breast cancer diagnosed 1996-2004 using flexible parametric relative survival models, enabling improved quantification of differences in survival. Crude probabilities were estimated to partition the probability of death due to all causes into that due to cancer and other causes and to estimate the number of "avoidable" deaths.

    RESULTS:

    England had lower relative survival for all ages with the difference increasing with age. Much of the difference was due to higher excess mortality in England in the first few months after diagnosis. Older patients had a higher proportion of deaths due to other causes. At 5 years post diagnosis, a woman aged 85 in England had probabilities of 0.35 of dying of cancer and 0.32 of dying of other causes, whilst in Norway they were 0.26 and 0.35. By eight years the number of "avoidable" all-cause deaths in England was 1020 with the number of "avoidable" breast cancer related deaths 1488.

    CONCLUSION:

    Lower breast cancer survival in England is mainly due to higher mortality in the first year after diagnosis. Crude probabilities aid our understanding of the impact of disease on individual patients and help assess different treatment options.

  • 324. Langusch, Catherine C
    et al.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Titmuss, Angela
    Donoghue, Kim
    Holland, Andrew J A
    Shun, Albert
    Delbridge, Leigh
    Focused image-guided parathyroidectomy in the current management of primary hyperparathyroidism.2015In: Archives of Disease in Childhood, ISSN 0003-9888, E-ISSN 1468-2044, Vol. 100, no 10Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Primary hyperparathyroidism (PHPT) in childhood and adolescence has been considered a different disease to that seen in adults, with predominantly familial aetiology mandating open exploration to exclude parathyroid hyperplasia in contrast to the adoption of focused image-guided parathyroidectomy (FP) in adults.

    STUDY DESIGN: A retrospective cohort study in a tertiary referral hospital setting of all children and adolescents (<18 years) undergoing parathyroid surgery for PHPT. Data were obtained from a dedicated endocrine surgery database and hospital medical records.

    RESULTS: Over the 35-year study period (1980-2014), there were 31 patients who underwent parathyroidectomy for PHPT. 3 patients were from known multiple endocrine neoplasia type 1 syndrome (MEN1) families, 3 had an isolated family history of PHPT and 25 were sporadic. In the sporadic group, 24 (96%) presented with symptomatic hypercalcaemia, affecting the gastrointestinal, musculoskeletal, genitourinary or neuropsychiatric systems. In the 25 patients with sporadic PHPT, nine (36%) had FP with a single adenoma removed with a 100% initial cure rate. Sixteen patients (64%) in the sporadic group had an open exploration: 14 had single gland disease while 2 patients required a second procedure to achieve a final cure rate of 100%. Of the three patients with MEN1, one was cured, one has persistent hyperparathyroidism after FP and the third has permanent hypoparathyroidism after open exploration.

    CONCLUSIONS: The majority of children and adolescents with PHPT have symptomatic disease due to a single adenoma. They can therefore be managed in a similar fashion to their adult counterparts with preoperative localisation studies aiming to permit FP in a day case setting.

  • 325. Larsson, Susanna C.
    et al.
    Rafter, Joseph
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Wolk, Alicja
    Red meat consumption and risk of cancers of the proximal colon, distal colon and rectum: the Swedish Mammography Cohort2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 113, no 5, p. 829-34Article in journal (Refereed)
    Abstract [en]

    Although there is considerable evidence that high consumption of red meat may increase the risk of colorectal cancer, data by subsite within the colon are sparse. The objective of our study was to prospectively examine whether the association of red meat consumption with cancer risk varies by subsite within the large bowel. We analyzed data from the Swedish Mammography Cohort of 61,433 women aged 40-75 years and free from diagnosed cancer at baseline in 1987-1990. Diet was assessed at baseline using a self-administered food-frequency questionnaire. Over a mean follow-up of 13.9 years, we identified 234 proximal colon cancers, 155 distal colon cancers and 230 rectal cancers. We observed a significant positive association between red meat consumption and risk of distal colon cancer (p for trend = 0.001) but not of cancers of the proximal colon (p for trend = 0.95) or rectum (p for trend = 0.32). The multivariate rate ratio for women who consumed 94 or more g/day of red meat compared to those who consumed less than 50 g/day was 2.22 (95% confidence interval [CI] 1.34-3.68) for distal colon, 1.03 (95% CI 0.67-1.60) for proximal colon and 1.28 (95% CI 0.83-1.98) for rectum. Although there was no association between consumption of fish and risk of cancer at any subsite, poultry consumption was weakly inversely related to risk of total colorectal cancer (p for trend = 0.04). These findings suggest that high consumption of red meat may substantially increase the risk of distal colon cancer. Future investigations on red meat and colorectal cancer risk should consider cancer subsites separately.

  • 326.
    Lawler, Katherine
    et al.
    Kings Coll London, Sch Canc Studies, CRUK Kings Hlth Partners Ctr, Guys Campus, London SE1 1UL, England.;Kings Coll London, Ins Math & Mol Biomed, Hodgkin Bldg,Guys Campus, London SE1 1UL, England..
    Papouli, Efterpi
    Guys & St Thomas NHS Fdn Trust, NIHR Comprehens Biomed Res Ctr, London WC2R 2LS, England.;Kings Coll London, London WC2R 2LS, England..
    Naceur-Lombardelli, Cristina
    Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England..
    Mera, Anca
    Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England.;Kings Coll London, Guys Hosp, Canc Epidemiol Unit, London SE1 9RT, England..
    Ougham, Kayleigh
    Kings Coll London, Guys Hosp, Canc Bioinformat, Innovat Ctr,Canc Ctr, London SE1 9RT, England..
    Tutt, Andrew
    Kimbung, Siker
    Kings Coll London, Breast Canc Now Res Unit, Kings Hlth Partners AHSC, Canc Ctr,Guys Hosp,Innovat Ctr,Fac Life Sci & Med, London SE1 9RT, England.;Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.;Lund Univ, CREATE Hlth Strateg Ctr Translat Canc Res, Lund, Sweden..
    Hedenfalk, Ingrid
    Kings Coll London, Breast Canc Now Res Unit, Kings Hlth Partners AHSC, Canc Ctr,Guys Hosp,Innovat Ctr,Fac Life Sci & Med, London SE1 9RT, England.;Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.;Lund Univ, CREATE Hlth Strateg Ctr Translat Canc Res, Lund, Sweden..
    Zhan, Jun
    Minist Educ Beijing, Key Lab Carcinogenesis & Translat Res, Beijing, Peoples R China.;Peking Univ, Dept Anat Histol & Embryol, Lab Mol Cell Biol & Tumor Biol, Hlth Sci Ctr, Beijing, Peoples R China..
    Zhang, Hongquan
    Minist Educ Beijing, Key Lab Carcinogenesis & Translat Res, Beijing, Peoples R China.;Peking Univ, Dept Anat Histol & Embryol, Lab Mol Cell Biol & Tumor Biol, Hlth Sci Ctr, Beijing, Peoples R China..
    Buus, Richard
    Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England..
    Dowsett, Mitch
    Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England..
    Ng, Tony
    Kings Coll London, Sch Canc Studies, CRUK Kings Hlth Partners Ctr, Guys Campus, London SE1 1UL, England.;Kings Coll London, Richard Dimbleby Dept Canc Res, Randall Div Cell & Mol Biophys, Guys Campus, London SE1 1UL, England.;UCL, UCL Canc Inst, Paul OGorman Bldg, London WC1E 6DD, England..
    Pinder, Sarah E.
    Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England..
    Parker, Peter
    Kings Coll London, Sch Canc Studies, CRUK Kings Hlth Partners Ctr, Guys Campus, London SE1 1UL, England.;London Res Inst, Lincolns Inn Fields, London WC2A 3LY, England..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Guys Hosp, Canc Epidemiol Unit, London SE1 9RT, England.
    Gillett, Cheryl E.
    Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England..
    Grigoriadis, Anita
    Kings Coll London, Sch Canc Studies, CRUK Kings Hlth Partners Ctr, Guys Campus, London SE1 1UL, England.;Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England.;Kings Coll London, Guys Hosp, Canc Bioinformat, Innovat Ctr,Canc Ctr, London SE1 9RT, England..
    Purushotham, Arnie
    Kings Coll London, Sch Canc Studies, CRUK Kings Hlth Partners Ctr, Guys Campus, London SE1 1UL, England.;Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England..
    Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study2017In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 19, article id 113Article in journal (Refereed)
    Abstract [en]

    Background: Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.

    Methods: A case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated.

    Results: Metasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1-4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2-5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56-1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort.

    Conclusion: This case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.

  • 327.
    Leja, Justyna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8916-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We have previously developed an oncolytic serotype 5 adenovirus (Ad5) with chromogranin-A (CgA) promoter-controlled E1A expression, Ad[CgA-E1A], with the intention to treat neuroendocrine tumors, including carcinoids. Since carcinoids tend to metastasize to the liver it is important to fully repress viral replication in hepatocytes to avoid adenovirus-related liver toxicity. Herein, we explore miRNA-based regulation of E1A expression as a complementary mechanism to promoter-based transcriptional control.

    METHODOLOGY/PRINCIPAL FINDINGS:

    Ad[CgA-E1A-miR122], where E1A expression is further controlled by six tandem repeats of the target sequence for the liver-specific miR122, was constructed and compared to Ad[CgA-E1A]. We observed E1A suppression and replication arrest of the miR122-detargeted adenovirus in normal hepatocytes, while the two viruses killed carcinoid cells to the same degree. Repeated intravenous injections of Ad[CgA-E1A] induced liver toxicity in mice while Ad[CgA-E1A-miR122] injections did not. Furthermore, a miR122-detargeted adenovirus with the wild-type E1A promoter showed reduced replication in hepatic cells compared to wild-type Ad5 but not to the same extent as the miR122-detargeted adenovirus with the neuroendocrine-selective CgA promoter.

    CONCLUSIONS/SIGNIFICANCE:

    A combination of transcriptional (promoter) and post-transcriptional (miRNA target) regulation to control virus replication may allow for the use of higher doses of adenovirus for efficient tumors treatment without liver toxicity.

  • 328.
    Leja, Justyna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hakkarainen, Tanja
    University of Helsinki, Finnish Institute for Molecular Medicine.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells2011In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 18, no 11, p. 1052-1062Article in journal (Refereed)
    Abstract [en]

    We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5 while it transduces normal hepatocytes at about 50% of Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systematic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.

  • 329.
    Lejonklou, Margareta H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stålberg, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor2012In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 6, p. 2588-2598Article in journal (Refereed)
    Abstract [en]

    Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. Wild-type littermates were used for comparison. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. 1.74%; P = 0.024). The microarray results demonstrated that several genes were differentially expressed. Some selected genes were studied on the protein level, e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate (Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting (P < 0.001 and P < 0.01, respectively). Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. chromatin maintenance and apoptosis. Lower mRNA was observed for genes involved in growth factor binding. In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor.

  • 330.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Edfeldt, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Térèse A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells2009In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 38, no 3, p. 259-266Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.

    METHODS:

    The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.

    RESULTS:

    Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.

    CONCLUSIONS:

    Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.

  • 331.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Bisphenol A increases cortisol production by enhancing phosphorylation of CREB in normal human adrenocortical cells2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S243-S243Article in journal (Other academic)
  • 332.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Induction of LINE-1 promoter hypomethylation, a hallmark of tumorigenesis, in normal human adrenocortical cells by Bisphenol A2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S149-S149Article in journal (Other academic)
  • 333.
    Lesurf, Robert
    et al.
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, McGill Ctr Bioinformat, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada..
    Aure, Miriam Ragle
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway..
    Mörk, Hanne Haberg
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway..
    Vitelli, Valeria
    Univ Oslo, Oslo Ctr Biostat & Epidemiol, N-0317 Oslo, Norway.;Univ Oslo, Dept Biostat, N-0317 Oslo, Norway. St Olavs Univ Hosp, Dept Oncol, N-7006 Trondheim, Norway..
    Lundgren, Steinar
    Department of Oncology, St. Olav’s University Hospital, 7006 Trondheim, Norway.; Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
    Börresen-Dale, Anne-Lise
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway..
    Kristensen, Vessela
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway.;Akershus Univ Hosp, Dept Clin Mol Biol & Lab Sci EpiGen, Div Med, N-1478 Lorenskog, Norway..
    Wämberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hallett, Michael
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, McGill Ctr Bioinformat, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Sch Comp Sci, Montreal, PQ H3A 0E9, Canada..
    Sörlie, Therese
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway..
    Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 4, p. 1166-1179Article in journal (Refereed)
    Abstract [en]

    Breast cancer consists of at least five main molecular "intrinsic'' subtypes that are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA, and DNA copy-number profiles from a total of 59 in situ lesions and 85 invasive tumors in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression.

  • 334.
    Li, Weiqiang
    et al.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Middha, Mridu
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Bicak, Mesude
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Sjoberg, Daniel D.
    Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA.
    Vertosick, Emily
    Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA.
    Dahlin, Anders
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Häggström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umeå Univ, Dept Biobank Res, Umeå, Sweden.
    Hallmans, Goran
    Umea Univ, Dept Publ Hlth & Clin Med, Nutr Res, Umea, Sweden.
    Ronn, Ann-Charlotte
    Karolinska Univ Hosp, Clin Res Ctr, Huddinge, Sweden.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Ulmert, David
    Sloan Kettering Inst, Mol Pharmacol Program, New York, NY USA.
    Lilja, Hans
    Mem Sloan Kettering Canc Ctr, Dept Lab Med, New York, NY 10065 USA;Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA;Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA;Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Lund Univ, Dept Translat Med, Malmo, Sweden.
    Klein, Robert J.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 710-719Article in journal (Refereed)
    Abstract [en]

    Background: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging. Objective: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer. Design, setting, and participants: Blood samples from 11 506 men in Sweden were collected during 1991-1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped. Outcome measurements and statistical analysis: A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1 x 10(-6) was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis. Results and limitations: We found 12 SNPs at seven independent loci associated with prostate-cancerspecific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p < 5 x 10(-8)) and replicated in an independent cohort: rs73055188 (p = 5.27 x 10(-9), per-allele hazard ratio [HR] = 2.27, 95% confidence interval [CI] 1.72-2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p <1 x 10(-6)) and replicated in an independent cohort: rs2702185 (p = 7.1 x 10(-7), per-allele HR = 2.55, 95% CI = 1.76-3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups. Conclusions: The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer. Patient summary: We identify two genetic markers that are associated with prostate-cancer-specific survival time.

  • 335.
    Liedberg, Fredrik
    et al.
    Skane Univ Hosp, Dept Urol, Jan Waldenstroms Gata 7, SE-20502 Malmo, Sweden;Lund Univ, Inst Translat Med, Jan Waldenstroms Gata 7, SE-20502 Malmo, Sweden.
    Hagberg, Oskar
    Reg Canc Ctr South, Lund, Sweden.
    Aljabery, Firas
    Linkoping Univ, Dept Clin & Expt Med, Div Urol, Linkoping, Sweden.
    Gardmark, Truls
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Hosseini, Abolfazl
    Karolinska Univ Hosp, Dept Urol, Stockholm, Sweden.
    Jahnson, Staffan
    Linkoping Univ, Dept Clin & Expt Med, Div Urol, Linkoping, Sweden.
    Jancke, Georg
    Skane Univ Hosp, Dept Urol, Jan Waldenstroms Gata 7, SE-20502 Malmo, Sweden;Lund Univ, Inst Translat Med, Jan Waldenstroms Gata 7, SE-20502 Malmo, Sweden.
    Jerlstrom, Tomas
    Orebro Univ, Sch Hlth & Med Sci, Dept Urol, Orebro, Sweden.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Sherif, Amir
    Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden.
    Strock, Viveka
    Sahlgrens Univ Hosp, Dept Urol, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Gothenburg, Sweden.
    Häggström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umea Univ, Dept Biobank Res, Umea, Sweden.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Sch Med, London, England.
    Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study2019In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 124, no 3, p. 449-456Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate the association between hospital volume and overall survival (OS), cancer‐specific survival (CSS), and quality of care of patients with bladder cancer who undergo radical cystectomy (RC), defined as the use of extended lymphadenectomy (eLND), continent reconstruction, neoadjuvant chemotherapy (NAC), and treatment delay of <3 months.

    Patients and Methods

    We used the Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent RC for primary invasive bladder cancer stage T1–T3 in Sweden between 1997 and 2014. The period‐specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level, and NAC. PSMAV was either categorised in tertiles, dichotomised (at ≥25 RCs annually), or used as a continuous variable for every increase of 10 RCs annually.

    Results

    PSMAV in the highest tertile (≥25 RCs annually) was associated with improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.75–1.0), whereas the corresponding HR for CSS was 0.87 (95% CI 0.73–1.04). With PSMAV as a continuous variable, OS was improved for every increase of 10 RCs annually (HR 0.95, 95% CI 0.90–0.99). Moreover, higher PSMAV was associated with increased use of eLND, continent reconstruction and NAC, but also more frequently with a treatment delay of >3 months after diagnosis.

    Conclusions

    The current study supports centralisation of RC for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

  • 336.
    Linder, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Holmberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Thorbjörnsen, Knut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Wisinger, Jan
    Polleryd, Per
    Eklöf, Hampus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Mani, Kevin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    A prospective stepped wedge cohort evaluation of the new national trauma team activation criteria in Sweden - the TRAUMALERT study.2019In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 27, no 1, article id 52Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Trauma triage based on prehospital information facilitates correct allocation of in-hospital resources. The Swedish national two-tier trauma team activation (TTA) criteria were revised in 2016. The current study aimed to evaluate the safety and efficacy of the new criteria.

    METHODS: Five centres covering trauma care for 1.2 million inhabitants registered all trauma patients prospectively in the Swedish trauma registry (SweTrau) prior to and after stepwise introduction of new TTA criteria within the cohort (a prospective stepped-wedge cohort study design; period August 2016-November 2017). Evaluation of full- and limited-TTA frequency, under- and overtriage were performed at equal duration before and after this change.

    RESULTS: The centres registered 1948 patients, 1882 (96.6%) of which were included in the study. With new criteria, frequency of full-TTA was unchanged, while limited-TTA decreased with 46.3% (from 988 to 531). 30-day trauma mortality was unchanged. The overtriage was 107/150 (71.3%) with former criteria, and 104/144 (72.2%) with new criteria, p = 0.866. Undertriage was 50/1037 (4.8%) versus 39/551 (7.1%), p = 0.063. Undertriage was consistently > 20% in patients with fall injury. Among patients with Injury Severity Score (ISS) > 15, 50/93 (53.8%) did not initiate full-TTA with former, vs 39/79 (49.4%) with new criteria, p = 0.565. Age > 60-years was a risk factor for undertriage (OR 2.89, p < 0.001), while low fall injuries indicated a trend (OR 2.70, p = 0.051).

    CONCLUSIONS: The newly implemented Swedish TTA criteria result in a reduction in limited TTA frequency, indicating an increased efficiency in use of resources. The over- and undertriage is unchanged compared to former criteria, thus upholding patient safety.

  • 337. Linke, Steven P.
    et al.
    Bremer, Troy M.
    Whitworth, Pat
    Lui, Aflred
    Savala, Jess
    Noskina, Yelina
    Barry, Todd
    Lyle, Stephen
    Walters, Stephanie C.
    Taglienti, Cherie
    Simin, Karl
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Warnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    FOXA1 and PR predict ipsilateral event risk and identify a group with strong radiation response in ductal carcinoma in situ (DCIS)2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P4-11-18Article in journal (Other academic)
  • 338. Linke, Steven P.
    et al.
    Bremer, Troy M.
    Whitworth, Pat
    Lui, Alfred
    Savala, Jess
    Noskina, Yelina
    Barry, Todd
    Lyle, Stephen
    Walters, Stephanie C.
    Taglienti, Cherie
    Simin, Karl
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Validation of a multi-marker test that predicts recurrence in patients diagnosed with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS)2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P4-11-17Article in journal (Other academic)
  • 339. Liu, Yanhong
    et al.
    Zhou, Renke
    Baumbusch, Lars O
    Tsavachidis, Spyros
    Brewster, Abenaa M
    Do, Kim-Anh
    Sahin, Aysegul
    Hortobagyi, Gabriel N
    Taube, Joseph H
    Mani, Sendurai A
    Aarøe, Jørgen
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Børresen-Dale, Anne-Lise
    Mills, Gordon B
    Thompson, Patricia A
    Bondy, Melissa L
    Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer2014In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 143, no 1, p. 189-201Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3-22.2, 3q27.1, 10q23.1, and 14q13.2-3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios. For bone metastasis, the hazard (95 % confidence interval) for the low-risk group was 0.32 (0.11-0.92) compared to the intermediate-risk group and 2.99 (1.74-5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17-0.66) and 2.33 (1.59-3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk.

  • 340. Loch-Wilkinson, Thorbjorn J.
    et al.
    Stålberg, Peter L. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sidhu, Stan B.
    Sywak, Mark S.
    Wilkinson, James F.
    Delbridge, Leigh W.
    Nerve stimulation in thyroid surgery: is it really useful?2007In: ANZ journal of surgery, ISSN 1445-1433, E-ISSN 1445-2197, Vol. 77, no 5, p. 377-380Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Monitoring of the recurrent laryngeal nerve (RLN) has been claimed in some studies to reduce rates of nerve injury during thyroid surgery compared with anatomical dissection and visual identification of the RLN alone, whereas other studies have found no benefit. Continuous monitoring with endotracheal electrodes is expensive whereas discontinuous monitoring by laryngeal palpation with nerve stimulation is a simple and inexpensive technique. This study aimed to assess the value of nerve stimulation with laryngeal palpation as a means of identifying and assessing the function of the RLN and external branch of the superior laryngeal nerve (EBSLN) during thyroid surgery. METHODS: This was a prospective case series comprising 50 consecutive patients undergoing total thyroidectomy providing 100 RLN and 100 EBSLN for examination. All patients underwent preoperative and postoperative vocal cord and voice assessment by an independent ear, nose and throat surgeon, laryngeal examination at extubation and all were asked to complete a postoperative dysphagia score sheet. Dysphagia scores in the study group were compared with a control group (n = 20) undergoing total thyroidectomy without nerve stimulation. RESULTS: One hundred of 100 (100%) RLN were located without the use of the nerve stimulator. A negative twitch response occurred in seven (7%) RLN stimulated (two bilateral, three unilateral). Postoperative testing, however, only showed one true unilateral RLN palsy postoperatively (1%), which recovered in 7 weeks giving six false-positive and one true-positive results. Eighty-six of 100 (86%) EBSLN were located without the nerve stimulator. Thirteen of 100 (13%) EBSLN could not be identified and 1 of 100 (1%) was located with the use of the nerve stimulator. Fourteen per cent of EBSLN showed no cricothyroid twitch on EBSLN sti