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  • 1.
    Abdsaleh, Shahin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wärnberg, F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Azavedo, E
    Lindgren, PG
    Amini, RM
    Comparison of Core Needle Biopsy and Surgical Specimens in Malignant Breast Lesions Regarding Histologic Features and Hormone Receptor Expression.Manuscript (Other academic)
  • 2.
    Abdsaleh, Shahin
    et al.
    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.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Azavedo, E
    Lindgren, P G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Comparison of core needle biopsy and surgical specimens in malignant breast lesions regarding histological features and hormone receptor expression2008In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 52, no 6, p. 773-775Article in journal (Refereed)
  • 3. Adami, Hans-Olov
    et al.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Jan-Erik
    Radikal prostatektomi utvärderad: 18 års uppföljning i svensk randomiserad multicenterstudie2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 11, no 15, p. 682-683Article in journal (Other academic)
  • 4. Adolfsson, Jan
    et al.
    Garmo, Hans
    Varenhorst, Eberhard
    Ahlgren, Göran
    Ahlstrand, Christer
    Andrén, Ove
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bratt, Ola
    Damber, Jan-Erik
    Hellström, Karin
    Hellström, Magnus
    Holmberg, Erik
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hugosson, Jonas
    Johansson, Jan-Erik
    Petterson, Bill
    Törnblom, Magnus
    Widmark, Anders
    Stattin, Pär
    Clinical characteristics and primary treatment of prostate cancer in Sweden between 1996 and 20052007In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, no 6, p. 456-477Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The incidence of prostate cancer is rising rapidly in Sweden and there is a need to better understand the pattern of diagnosis, tumor characteristics and treatment. MATERIAL AND METHODS: Between 1996 and 2005, all new cases of adenocarcinoma of the prostate gland were intended to be registered in the National Prostate Cancer Register (NPCR). This register contains information on diagnosing unit, date of diagnosis, cause of diagnosis, tumor grade, tumor stage according to the TNM classification in force, serum prostate-specific antigen (PSA) levels at diagnosis and primary treatment given within the first 6 months after diagnosis. RESULTS: In total, 72,028 patients were registered, comprising >97% of all pertinent incident cases of prostate cancer in the Swedish Cancer Register (SCR). During the study period there was a considerable decrease in median age at the time of diagnosis, a stage migration towards smaller tumors, a decrease in median serum PSA values at diagnosis, a decrease in the age-standardized incidence rate of men diagnosed with distant metastases or with a PSA level of > 100 ng/ml at diagnosis and an increase in the proportion of tumors with Gleason score <6. Relatively large geographical differences in the median age at diagnosis and the age-standardized incidence of cases with category T1c tumors were observed. Treatment with curative intent increased dramatically and treatment patterns varied according to geographical region. In men with localized tumors and a PSA level of <20 ng/ml at diagnosis, expectant treatment was more commonly used in those aged > or =75 years than in those aged <75 years. Also, the pattern of endocrine treatment varied in different parts of Sweden. CONCLUSIONS: All changes in the register seen over time are consistent with increased diagnostic activity, especially PSA testing, resulting in an increased number of cases with early disease, predominantly tumors in category T1c. The patterns of diagnosis and treatment of prostate cancer vary considerably in different parts of Sweden. The NPCR continues to be an important source for research, epidemiological surveillance of the incidence, diagnosis and treatment of prostate cancer.

  • 5. Ahlbom, Anders
    et al.
    Feychting, Maria
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Lars Age
    Mathiesen, Tiit
    Pettersson, David
    Schüz, Joachim
    Talbäck, Mats
    Comments on Hardell and Carlberg Increasing Rates of Brain Tumors in the Swedish National Inpatient Register and the Causes of Death Register. Int. J. Environ. Res. Public Health 2015, 12, 3793-3813.2015In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 12, no 9Article in journal (Refereed)
  • 6.
    Ahlin, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Holmqvist, Marit
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    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.
    Jirström, Karin
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cyclin A is a proliferative marker with good prognostic value in node-negative breast cancer2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 9, p. 2501-2506Article in journal (Refereed)
    Abstract [en]

    Background: Proliferative markers are not recommended as prognostic   factors for clinical use in breast cancer due to lack of   standardization in methodology. However, proliferation is driving   several gene expression signatures emphasizing the need for a reliable   proliferative marker IF or clinical use. Studies suggest that cyclin A   is a prognostic marker with satisfying reproducibility. We investigated   cyclin A as a prognostic marker in node-negative breast cancer using   previously defined cutoff values.   Patients and Methods: In a case-control study, we defined 190 women who   died from breast cancer as cases and 190 women alive at the time for   the corresponding case's death as controls. Inclusion criteria were   tumor size <= 50 mm, no lymph node metastases and no adjuvant   chemotherapy. Tumor tissues were immunostained for cyclin A using   commercially available antibodies.   Results: We found a statistically significant association between   expression of cyclin A and breast cancer death in a univariate model:   odds ratio for cyclin A(ave) 2.7 [95% confidence interval (CI),   1.7-4.3] and cyclin A(max) 3.4 (CI, 2.1-5.5). Corresponding odds ratio   for Ki67 were Ki67(ave) 1.9 (CI, 1.2-3.1) and Ki67(max) 1.7 (CI,   1.1-2.7) and for grade 3.1 (CI, 1.8-5.1). Cyclin A was strongly   correlated to Ki67 and grade why a model including all was not   appropriate.   Conclusions: Cyclin A is a prognostic factor for breast cancer death in   node-negative patients using standardized methodology regarding scoring   and cutoff values. Adding cyclin A as a proliferative marker to established clinicopathologic factors will improve the separation of  low and high risk breast cancer.

  • 7. Ahlman, Håkan
    et al.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Endokrina sjukdomar2001Chapter in book (Other academic)
  • 8.
    Ahlström, Tommy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rudberg, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women2009In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 71, no 5, p. 673-678Article in journal (Refereed)
    Abstract [en]

    CONTEXT: In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear.

    OBJECTIVE: To describe correlations between plasma calcium and PTH and the various abnormalities present in the MetS in a healthy population.

    DESIGN: We studied 1016 healthy individuals from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) population of 70 years old, by means of plasma analyses of calcium, PTH, creatinine, lipids, insulin and glucose, as well as by standardized blood pressure measurements. Further, body mass index (BMI) and waist circumference were determined.

    RESULTS: The more National Cholesterol Education Program (NCEP) criteria for the MetS that were met, the higher the s-PTH and albumin-corrected s-calcium. Further, positive correlations between plasma calcium and BMI (P = 0.0003), waist circumference (P = 0.0009) and insulin resistance (P = 0.079) were found. PTH and BMI (P < 0.0001), waist circumference (P < 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated.

    CONCLUSIONS: We conclude that PTH correlates with several of the metabolic factors included in the MetS within a normocalcaemic population. In addition, individuals with mild pHPT present significantly more NCEP criteria for MetS. We postulate that increased levels of PTH in pHPT may be associated with the increased cardiovascular morbidity and mortality seen in pHPT.

  • 9. Andersson, Jenny
    et al.
    Larsson, L.
    Klaar, S.
    Holmberg, Lars
    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 Surgical Sciences, Endocrine Surgery.
    Nilsson, J.
    Inganäs, M.
    Carlsson, G.
    Ohd, J.
    Rudenstam, C-M.
    Gustavsson, B.
    Bergh, J.
    Worse survival for TP53 (p53)-mutated breast cancer patients receiving adjuvant CMF2005In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 16, no 5, p. 743-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: TP53 has been described as a prognostic factor in many malignancies, including breast cancer. Whether it also might be a predictive factor with reference to chemo- and endocrine therapy is more controversial. PATIENTS AND METHODS: We investigated relapse-free (RFS), breast cancer-corrected (BCCS) and overall survival (OS) related to TP53 status in node-positive breast cancer patients that had received polychemotherapy [cyclophosphamide, methotrexate, 5-fluorouracil (CMF)] and/or endocrine therapy (tamoxifen). Sequence analyses of the whole TP53 coding region was performed in 376 patients operated on for primary breast cancer with axillary lymph node metastases between 1984 and 1989 (median follow-up time 84 months). RESULTS: TP53 mutations were found in 105 patients (28%). We found 90 (82%) of the 110 mutations in the more frequently analysed exons 5-8, while the other 20 (18%) were located in exons 3-4 and 9-10, respectively. Univariate analyses showed TP53 to be a significant prognostic factor with regard to RFS, BCCS and OS in patients who received adjuvant CMF. CONCLUSIONS: TP53 mutations might induce resistance to certain modalities of breast cancer therapy. Sequence-determined TP53 mutation was of negative prognostic value in the total patient population and in the CMF treated patients.

  • 10.
    Annerbo, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Centrum för klinisk forskning dalarna.
    Calcium Homeostasis in Patients with Graves' Disease2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with Graves´ Disease (GD) have a higher risk of developing more severe and prolonged hypocalcaemia after total thyroidectomy (TT) than patients who undergo surgery for benign atoxic goitre. Since TT is the most effective treatment for GD, it is crucial to identify mechanisms for postoperative hypocalcaemia. The aim of this thesis was to study the mechanisms of calcium metabolism in patients with GD.

    It is safe to operate on GD patients with TT. Results in Paper I showed fewer recurrences and equal complication rates compared to patients who underwent subtotal thyroidectomy (ST). The transient lowering of PTH seen in the hypocalcaemic patients was fully restored one month after surgery (Papers II and V).

    The calcium-sensing receptor (CaSR) is crucial for maintaining plasma calcium, and single nucleotide polymorphisms (SNPs) in the gene may alter the sensing function. Thus, we analysed SNPs in CaSR in GD patients (Paper II) and showed that they had a more left-shifted calcium-PTH set-point compared to controls, implicating higher sensitivity. This is also supported by the results in the group of postoperatively hypocalcaemic patients. They already had lower plasma calcium preoperatively (Papers II, IV and V) and lacked the T/G G/A G/C, a haplotype shown in Paper III to have a close relationship to higher p-calcium levels. Moreover, a lack of the T allele in rs1801725 was seen in the group of patients needing permanent treatment with calcium and vitamin D, i.e. > 12 months, (paper V).

    Patients who became hypocalcaemic (p-calcium < 2.00 mmol/L) on day one postoperatively, had lower preoperative levels of thyroid stimulating hormone (TSH) and higher levels of  T3, this was also applied to the patient groups requiring temporary or permanent postoperative treatment (Papers II and V). In addition, hypocalcaemic patients treated for less than six months with anti-thyroid drugs had higher levels of bone metabolism markers CTX and P1NP than normocalcaemic patients (Paper V).

    In conclusion, the postoperative period of hypocalcaemia seen in patients with GD is a complex medical condition, caused by a combination of surgical trauma, different SNPs in CaSR, and high bone metabolism related to preoperative thyroid metabolism.

    List of papers
    1. Management of Grave's Disease Is Improved by Total Thyroidectomy
    Open this publication in new window or tab >>Management of Grave's Disease Is Improved by Total Thyroidectomy
    2012 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 8, p. 1943-1946Article in journal (Refereed) Published
    Abstract [en]

    A retrospective analysis was performed on 267 consecutive patients with Graves' disease (GD). The principal aim of this study was to evaluate the risk for recurrence and complications when changing the surgical method from subtotal (ST) to total thyroidectomy (TT). Information from 267 consecutive patients operated on for GD between 2000 and 2006 was collected at Uppsala University Hospital (143) and Falun County Hospital (128). There were 229 women and 38 men. Four patients were operated on twice. A total of 40 STs and 229 TTs were performed. Results were compared to those of a previous cohort from the same hospital, with a majority of STs (157/176) performed from 1980 to 1992. The risk for relapse of GD was reduced from 20 to 3.3 % after the shift from ST to TT. In terms of surgical complications, 2.2 % demonstrated permanent vocal cord paralysis and 4.5 % had persistent hypocalcemia, not significant when compared to the previous cohort. In spite of TT, there were four recurrences, all due to remnant thyroid tissue high up at the hyoid bone. Changing the surgical method did not affect postoperative progression of dysthyroid ophthalmopathy (DO, 7.0 vs. 7.5 %). There were no differences in outcome with respect to which hospital the patients had their operation. Change from ST to TT dramatically reduced the risk for recurrence of GD without increasing the rate of complications. TT is not more effective than ST in hampering progression of DO as has been advocated by some. Careful surgical dissection up to the hyoid bone is necessary to avoid recurrence.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-178078 (URN)10.1007/s00268-012-1617-x (DOI)000305988400029 ()
    Available from: 2012-07-30 Created: 2012-07-27 Last updated: 2017-12-07Bibliographically approved
    2. Left-shifted relation between calcium and parathyroid hormone in Graves' Disease
    Open this publication in new window or tab >>Left-shifted relation between calcium and parathyroid hormone in Graves' Disease
    2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 2, p. 545-551Article in journal (Refereed) Published
    Abstract [en]

    Background:

    Patients with Graves' disease (GD) have disturbances in calcium regulation with manifestations such as postoperative hypocalcemia. We have investigated the thyroid as well as the parathyroid function in detail.

    Material and Method:

    A series of patients undergoing total thyroidectomy for GD (n=56) or Multi Nodular Goitre (MNG, n=50) were scrutinized for postoperative hypocalcemia, need for calcium and/or vitamin D substitution. CiCa-clamp was used in 14 patients and 21 controls to quantify the secretion of PTH in relation to the ionized plasma calcium level. The setpoint, equal to the plasma ionized calcium concentration at which 50% of the maximal secretion of PTH is inhibited, as well as other CiCa-related parameters were calculated.

    Results:

    Hypocalcemia was present in 48% of GD and 41.2% of patients with MNG postoperatively. Patients with GD had lower calcium levels, 18% had S-Ca< 2.00 mmol/L compared to 4.0% in the MNG group, p=0.02. A higher degree of GD patients were given parenteral calcium-substitution during the hospital stay (3.6% vs 0 %) and oral calcium substitution at discharge (48% vs 10%), although they had normal vitamin D3 levels. The GD group showed a significantly left-shifted setpoint compared to the normal group on CiCa clamp, 1.16 mmol/l vs. 1.20 mmol/L (p<0.001), as well as an increased PTH release to hypocalcemic stimulus. GD patients also show an association between degree of subclinical toxicosis at time of surgery and risk for developing postoperative hypocalcemia.

    Conclusion:

    Patients with GD demonstrate dysregulation of the calcium homeostasis by several parameters. GD patients have lower postoperative S-calcium compared to patients with MNG, lower calcium/PTH setpoint and a significantly increased release of PTH to hypocalcemic stimulus compared to controls. The CiCa clamp response in GD patients with normal 25-OH-vitamin D3 levels mimics that of obese patients in which vitamin D insufficiency has been proposed as an underlying cause.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-212144 (URN)10.1210/jc.2013-2500 (DOI)000333460300053 ()24248181 (PubMedID)
    Available from: 2013-12-06 Created: 2013-12-06 Last updated: 2017-12-06Bibliographically approved
    3. Association between Calcium Sensing Receptor Polymorphisms and Plasma Calcium and Parathyroid hormone in a Swedish well characterized Cohort
    Open this publication in new window or tab >>Association between Calcium Sensing Receptor Polymorphisms and Plasma Calcium and Parathyroid hormone in a Swedish well characterized Cohort
    Show others...
    (English)Article, review/survey (Other academic) Submitted
    Keywords
    Calcium sensing receptor, PIVUS, Calcium, Parathyroid hormone
    National Category
    Clinical Medicine
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-282594 (URN)
    Available from: 2016-04-10 Created: 2016-04-05 Last updated: 2017-03-23Bibliographically approved
    4. Calcium Sensing Receptor Polymorphisms and their realtionships to postoperative hypocalcaemia in Graves´disease
    Open this publication in new window or tab >>Calcium Sensing Receptor Polymorphisms and their realtionships to postoperative hypocalcaemia in Graves´disease
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Graves' Disease, Calcium sensing receptor, Hypocalcemi, Total thyroidectomy
    National Category
    Medical and Health Sciences
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-282596 (URN)
    Available from: 2016-04-10 Created: 2016-04-05 Last updated: 2016-06-01
    5. Biochemical Markers in Bone Metabolism in Patients with Graves' Disease
    Open this publication in new window or tab >>Biochemical Markers in Bone Metabolism in Patients with Graves' Disease
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Graves' Disease, Bone metabolism, Calcium sensing receptor, Hypocalcaemia, Total thyroidectomy
    National Category
    Clinical Medicine
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-282595 (URN)
    Available from: 2016-04-10 Created: 2016-04-05 Last updated: 2016-06-01
  • 11.
    Annerbo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Azadi, Afsoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Calcium Sensing Receptor Polymorphisms and their realtionships to postoperative hypocalcaemia in Graves´diseaseManuscript (preprint) (Other academic)
  • 12.
    Annerbo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Carlsson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Biochemical Markers in Bone Metabolism in Patients with Graves' DiseaseManuscript (preprint) (Other academic)
  • 13.
    Annerbo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hultin, Hella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Left-shifted relation between calcium and parathyroid hormone in Graves' Disease2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 2, p. 545-551Article in journal (Refereed)
    Abstract [en]

    Background:

    Patients with Graves' disease (GD) have disturbances in calcium regulation with manifestations such as postoperative hypocalcemia. We have investigated the thyroid as well as the parathyroid function in detail.

    Material and Method:

    A series of patients undergoing total thyroidectomy for GD (n=56) or Multi Nodular Goitre (MNG, n=50) were scrutinized for postoperative hypocalcemia, need for calcium and/or vitamin D substitution. CiCa-clamp was used in 14 patients and 21 controls to quantify the secretion of PTH in relation to the ionized plasma calcium level. The setpoint, equal to the plasma ionized calcium concentration at which 50% of the maximal secretion of PTH is inhibited, as well as other CiCa-related parameters were calculated.

    Results:

    Hypocalcemia was present in 48% of GD and 41.2% of patients with MNG postoperatively. Patients with GD had lower calcium levels, 18% had S-Ca< 2.00 mmol/L compared to 4.0% in the MNG group, p=0.02. A higher degree of GD patients were given parenteral calcium-substitution during the hospital stay (3.6% vs 0 %) and oral calcium substitution at discharge (48% vs 10%), although they had normal vitamin D3 levels. The GD group showed a significantly left-shifted setpoint compared to the normal group on CiCa clamp, 1.16 mmol/l vs. 1.20 mmol/L (p<0.001), as well as an increased PTH release to hypocalcemic stimulus. GD patients also show an association between degree of subclinical toxicosis at time of surgery and risk for developing postoperative hypocalcemia.

    Conclusion:

    Patients with GD demonstrate dysregulation of the calcium homeostasis by several parameters. GD patients have lower postoperative S-calcium compared to patients with MNG, lower calcium/PTH setpoint and a significantly increased release of PTH to hypocalcemic stimulus compared to controls. The CiCa clamp response in GD patients with normal 25-OH-vitamin D3 levels mimics that of obese patients in which vitamin D insufficiency has been proposed as an underlying cause.

  • 14.
    Annerbo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Association between Calcium Sensing Receptor Polymorphisms and Plasma Calcium and Parathyroid hormone in a Swedish well characterized CohortArticle, review/survey (Other academic)
  • 15.
    Annerbo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Management of Grave's Disease Is Improved by Total Thyroidectomy2012In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 8, p. 1943-1946Article in journal (Refereed)
    Abstract [en]

    A retrospective analysis was performed on 267 consecutive patients with Graves' disease (GD). The principal aim of this study was to evaluate the risk for recurrence and complications when changing the surgical method from subtotal (ST) to total thyroidectomy (TT). Information from 267 consecutive patients operated on for GD between 2000 and 2006 was collected at Uppsala University Hospital (143) and Falun County Hospital (128). There were 229 women and 38 men. Four patients were operated on twice. A total of 40 STs and 229 TTs were performed. Results were compared to those of a previous cohort from the same hospital, with a majority of STs (157/176) performed from 1980 to 1992. The risk for relapse of GD was reduced from 20 to 3.3 % after the shift from ST to TT. In terms of surgical complications, 2.2 % demonstrated permanent vocal cord paralysis and 4.5 % had persistent hypocalcemia, not significant when compared to the previous cohort. In spite of TT, there were four recurrences, all due to remnant thyroid tissue high up at the hyoid bone. Changing the surgical method did not affect postoperative progression of dysthyroid ophthalmopathy (DO, 7.0 vs. 7.5 %). There were no differences in outcome with respect to which hospital the patients had their operation. Change from ST to TT dramatically reduced the risk for recurrence of GD without increasing the rate of complications. TT is not more effective than ST in hampering progression of DO as has been advocated by some. Careful surgical dissection up to the hyoid bone is necessary to avoid recurrence.

  • 16.
    Athlin, Åsa Muntlin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Univ Adelaide, Sch Nursing, Adelaide, SA, Australia..
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Jangland, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Education in Nursing.
    Lack of existing guidelines for a large group of patients in Sweden: a national survey across the acute surgical care delivery chain2017In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 23, no 1, p. 89-95Article in journal (Refereed)
    Abstract [en]

    Rationale, aims and objectivesEvidence-informed healthcare is the fundament for prac-tice, whereby guidelines based on the best available evidence should assist health profes-sionals in managing patients. Patients seeking care for acute abdominal pain form acommon group in acute care settings worldwide, for whom decision-making and timelytreatment are of paramount importance. There is ambiguity about the existence, use andcontent of guidelines for patients with acute abdomen. The objective was to describe andcompare guidelines and management of patients with acute abdomen in different settingsacross the acute care delivery chain in Sweden.MethodA national cross-sectional design was used. Twenty-nine ambulance stations, 17emergency departments and 33 surgical wards covering all six Swedish health regions wereincluded, and 23 guidelines were quality appraised using the validated Appraisal of Guide-lines for Research & Evaluation II tool.ResultsThere is a lack of guidelines in use for the management of this large group of pa-tients between and within different healthcare areas across the acute care delivery chain.The quality appraisal identified that several guidelines were of poor quality, especiallythe in-hospital ones. Further, range orders for analgesics are common in the ambulance ser-vices and the surgical wards, but are seldom present in the emergency departments. Also,education in pain management is more common in the ambulance services. Thesefindingsare noteworthy as, hypothetically, the same patient could be treated in three different waysduring the same care episode.ConclusionsThere is an urgent need to develop high-quality evidence-based clinicalguidelines for this patient group, with the entire care process in focus

  • 17.
    Ax, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Garmo, Hans
    Regional Cancer Center , Uppsala University Hospital , Uppsala , Sweden.
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Becker, Wulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Dietary Patterns and Prostate Cancer Risk: Report from the Population Based ULSAM Cohort Study of Swedish Men2014In: Nutrition and Cancer, ISSN 0163-5581, E-ISSN 1532-7914, Vol. 66, no 1, p. 77-87Article in journal (Refereed)
    Abstract [en]

    Dietary pattern analyses have increased the possibilities to detect associations between diet and disease. However, studies on dietary pattern and prostate cancer are scarce. Food intake data in the Uppsala Longitudinal Study of Adult Men cohort was determined by 7-day food records. Adherence to a modified Mediterranean Diet Score (mMDS) and a low carbohydrate-high protein (LCHP) score were grouped as low, medium, or high in the whole study population (n = 1,044) and in those identified as adequate reporters of energy intake (n = 566), respectively. Prostate cancer risk was analyzed with Cox proportional hazard regression (median follow-up 13years) and competing risk of death was considered. There were no associations between dietary patterns and prostate cancer (n = 133) in the whole study population. Among adequate reporters the mMDS was not associated with prostate cancer (n = 72). The LCHP score was inversely related to prostate cancer in adequate reporters, adjusted hazard ratios; 0.55 (0.32-0.96) for medium and 0.47 (0.21-1.04) for high compared to low adherent participants (P-for-trend 0.04). Risk relations were not attributable to competing risk of death. In this study, a LCHP diet was associated with lower prostate cancer incidence. Relations emerged in adequate reporters, underscoring the importance of high-quality dietary data.

  • 18.
    Ax, Erika Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Grundmark, Birgitta
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Wulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Holmberg, Lars
    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.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Dietary Patterns and prostate cancer risk: a population based cohort study in elderly Swedish men2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no S1, p. 847.8-Article in journal (Other academic)
  • 19.
    Backlin, Carin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wiberg, K
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Monoclonal antibodies recognizing normal and neoplastic human adrenal cortex1995In: Endocr Pathol, Vol. 6, p. 21-Article in journal (Refereed)
  • 20.
    Backlin, Carin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    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, Endocrine Tumor Biology.
    Hellman, Per
    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, Endocrine Tumor Biology.
    Åkerström, Göran
    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, Endocrine Surgery.
    Immunohistochemical expression of insulin-like growth factor 1 and its receptor in normal and neoplastic human adrenal cortex1995In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 15, no 6B, p. 2453-2459Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Insulin-like growth factor 1 (IGF-1) may influence cellular growth, differentiation and secretion.

    MATERIAL AND METHODS:

    Cryosectioned normal human adrenal glands (n = 6), cortical adenoma (n = 21), and carcinoma (n = 17) were stained immunohistochemically for IGF-1 and its receptor, and human adrenocortical cancer cells expressing the receptor were analysed for influences on proliferation.

    RESULTS:

    Normal cortical parenchyma generally displayed faint IGF-1 reactivity and intracellular receptor staining. Similar labelling encompassed the adenomas, but only 6 of them were receptor reactive. IGF-1 expression was conspicuous in 11 carcinomas, and 6 of them displayed cell surface receptor reactivity. All aldosterone producing lesions were receptor antibody unreactive. Recombinant IGF-1 dose-dependently stimulated the cell proliferation, and this effect was reversed by the receptor antibody.

    CONCLUSION:

    IGF-1 may interact with function and proliferation of the human adrenal cortex with particular reference to cortical carcinomas lacking discernible aldosterone excess.

  • 21.
    Backman, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Cupisti, Kenko
    Marien Hosp, Dept Surg, Euskirchen, Germany..
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 44943Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.

  • 22.
    Backman, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 2, p. 705-712Article in journal (Refereed)
    Abstract [en]

    Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.

    PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.

    RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.

    CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

  • 23.
    Barazeghi, Elham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs).

    In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells.

    Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene.

    In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs.

    In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.  

    List of papers
    1. 5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
    Open this publication in new window or tab >>5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
    Show others...
    2016 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, article id 31Article in journal (Refereed) Published
    Abstract [en]

    Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.

    Keywords
    5-hydroxymethylcytosine, 5hmC, Parathyroid cancer, Primary hyperparathyroidism, TET1
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-282795 (URN)10.1186/s13148-016-0197-2 (DOI)000371782000002 ()26973719 (PubMedID)
    Funder
    Swedish Cancer Society
    Available from: 2016-04-14 Created: 2016-04-07 Last updated: 2017-11-30Bibliographically approved
    2. A role for TET2 in parathyroid carcinoma
    Open this publication in new window or tab >>A role for TET2 in parathyroid carcinoma
    Show others...
    2017 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 7, p. 329-338Article in journal (Refereed) Published
    Abstract [en]

    Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.

    Keywords
    5-hydroxymethylcytosine, TET2, primary hyperparathyroidism, parathyroid carcinoma, promoter hypermethylation, tumor suppressor
    National Category
    Endocrinology and Diabetes Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-330022 (URN)10.1530/ERC-17-0009 (DOI)000404978400007 ()
    Funder
    Swedish Cancer Society
    Available from: 2017-10-09 Created: 2017-10-09 Last updated: 2018-04-03Bibliographically approved
    3. Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors
    Open this publication in new window or tab >>Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-330575 (URN)
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-04
    4. Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
    Open this publication in new window or tab >>Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-330794 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
  • 24.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gill, Anthony J.
    Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW 2065, Australia.;Univ Sydney, Sydney, NSW 2006, Australia..
    Sidhu, Stan
    Univ Sydney, Sydney, NSW 2006, Australia.;Royal N Shore Hosp, Dept Surg, St Leonards, NSW 2065, Australia..
    Norlen, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Sydney, Sydney, NSW 2006, Australia.;Royal N Shore Hosp, Dept Surg, St Leonards, NSW 2065, Australia..
    Dina, Roberto
    Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Histopathol, London, England..
    Palazzo, F. Fausto
    Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Endocrine Surg, London, England..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    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.
    5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma2016In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, article id 31Article in journal (Refereed)
    Abstract [en]

    Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.

  • 25.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gill, Anthony J.
    Kolling Inst Med Res, Canc Diag & Pathol Res Grp, St Leonards, NSW, Australia..
    Sidhu, Stan
    Royal North Shore Hosp, Dept Surg, St Leonards, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Norlen, Olov
    Uppsala Univ, Rudbeck Lab, Endocrine Unit, Dept Surg Sci, Uppsala, Sweden.;Royal North Shore Hosp, Dept Surg, St Leonards, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Dina, Roberto
    Imperial Coll, Hammersmith Hosp, Dept Histopathol, London, England..
    Palazzo, F. Fausto
    Imperial Coll, Hammersmith Hosp, Dept Endocrine Surg, London, England..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    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.
    A role for TET2 in parathyroid carcinoma2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 7, p. 329-338Article in journal (Refereed)
    Abstract [en]

    Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.

  • 26.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prabhawa, Surendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Uppsala Univ Hosp, Rudbeck Lab, Uppsala, Sweden..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    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.
    A Role of TETs and 5-Hydroxymethylcytosine in SI-NETs2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 18-18Article in journal (Other academic)
  • 27. Barlow, Lotti
    et al.
    Westergren, Kerstin
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Talbäck, Mats
    The completeness of the Swedish Cancer Register: a sample survey for year 19982009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The Swedish Cancer Register (SCR) is used extensively for monitoring cancer incidence and survival and for research purposes. Completeness and reliability of cancer registration are thus of great importance for all types of use of the cancer register. The aim of the study was to estimate the overall coverage of malignant cancer cases in 1998 and to reveal possible reasons behind non-reporting. METHODS: We selected all malignant cancer cases in the Hospital Discharge Register (HDR) from 1998 and compared these records to those reported to the SCR. There were 43,761 discharges for 42,010 individuals of whom 3,429 individuals were not recorded in the SCR. From these 3 429 records we randomly selected 202 patients for review of their medical records to determine whether they should have been registered on the SCR as incident cases in 1998. RESULTS: About half of the 202 cases (93 malignant and 8 benign) should have been reported, which translates into an additional 1 579 malignant cases (95% CI 1 349-1 808), or 3.7% of the cases reported in 1998. The crude incidence rate for males and females combined would increase from 493 per 100,000 to 511 (95% CI 508-514) if these cases were taken into account. CONCLUSION: The overall completeness of the SCR is high and comparable to other high quality registers in Northern Europe. For most uses in epidemiological or public health surveillance, the underreporting will be without major impact. However, for specific research questions our findings have implications, as the degree of underreporting is site specific, increases with age, and does not seem to be random, as diagnoses without histology or cytology verification are overrepresented. An annual comparison of the SCR against the HDR could point to hospitals, geographic areas or specific diagnoses where organizational and administrative changes should be introduced to improve reporting.

  • 28. Barnes, N. L. P.
    et al.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Farnie, G.
    White, D.
    Jiang, W
    Anderson, E.
    Bundred, N. J.
    Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 4, p. 575-582Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is associated with poor-prognosis breast cancer. We used a nude mouse xenograft model to determine the effects of COX-2 inhibition in breast cancer. Oestrogen receptor (ER)-positive MCF7/HER2-18 and ER-negative MDAMB231 breast cancer cell lines were injected into nude mice and allowed to form tumours. Mice then received either chow containing Celecoxib (a COX-2 inhibitor) or control and tumour growth measured. Tumour proliferation, apoptosis, COX-2, lymphangiogenesis and angiogenesis were assessed by immunohistochemistry (IHC), Western blotting or Q-PCR. Celecoxib inhibited median tumour growth in MCF7/HER2-18 (58.7%, P=0.029) and MDAMB231 (46.3%, P=0.0002) cell lines compared to control. Cyclooxygenase-2 expression decreased following Celecoxib treatment (MCF7/HER2-18 median control 65.3% vs treated 22.5%, P=0.0001). Celecoxib increased apoptosis in MCF7/HER2-18 tumours (TUNEL 0.52% control vs 0.73% treated, P=0.0004) via inactivation of AKT (median pAKT(ser473) 57.3% control vs 35.5% treated, P=0.0001--confirmed at Western blotting). Q-PCR demonstrated decreased podoplanin RNA (lymphangiogenesis marker) in the MCF7/HER2-18 - median 2.9 copies treated vs 66.6 control (P=0.05) and MDAMB231-treated groups--median 160.7 copies vs 0.05 control copies (P=0.015), confirmed at IHC. Cyclooxygenase-2 is associated with high levels of activated AKT(ser473) and lymphangiogenesis in breast cancer. Cyclooxygenase-2 inhibition decreases tumour growth, and may potentially decrease recurrence, by inactivating AKT and decreasing lymphangiogenesis.

  • 29. Beral, Valerie
    et al.
    Alexander, Maggie
    Duffy, Stephen
    Ellis, Ian O
    Given-Wilson, Rosalind
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Moss, Sue M
    Ramirez, Amanda
    Reed, Malcolm W R
    Rubin, Caroline
    Whelehan, Patsy
    Wilson, Robin
    Young, Kenneth C
    The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer2011In: Journal of medical screening, ISSN 1475-5793, Vol. 18, no 4, p. 210-212Article in journal (Refereed)
    Abstract [en]

    The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50-70 years regularly screened over a ten-year period.

  • 30. Bergenfelz, Anders O.
    et al.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Harrison, Barney
    Sitges-Serra, Antonio
    Dralle, Henning
    Positional statement of the European Society of Endocrine Surgeons (ESES) on modern techniques in pHPT surgery2009In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 394, no 5, p. 761-764Article in journal (Refereed)
  • 31. Bergholtz, H.
    et al.
    Lesurf, R.
    Myhre, S.
    Haakensen, V. D.
    Borresen-Dale, A. L.
    Bathen, T.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Kristensen, V. N.
    Helland, A.
    Sorlie, T.
    A molecular study of breast cancer progression stages from normal breast tissue to invasive cancer2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, p. S112-S112Article in journal (Other academic)
  • 32.
    Berglund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Robinson, David
    Tishelman, Carol
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bratt, Ola
    Adolfsson, Jan
    Stattin, Pär
    Lambe, Mats
    Differences according to socioeconomic status in the management and mortality in men with high risk prostate cancer2012In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no 1, p. 75-84Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Outcomes for many cancer forms are associated with socioeconomic status (SES).We investigated if SES was associated with management and mortality in men with high risk prostate cancer.

    MATERIAL AND METHODS:

    A nation-wide population-based cohort in Prostate Cancer Data Base Sweden (PCBaSe), a merged database including data on incident prostate cancer identified in the National Prostate Cancer Register (NPCR) between 1997 and 2006. High risk PCa was defined as T3 tumour, and/or Gleason score 8-10 and/or PSA 20-50ng/mL. Use of bone scan, curative treatment, and mortality in relation to SES was assessed by logistic, Cox, and competing risk regression with hazard ratios (HR), sub-distributed HR and 95% confidence intervals (CI) adjusted for co-morbidity, age, calendar period and clinical subgroups.

    RESULTS:

    Amongst 17,522 high risk prostate cancer patients, a bone scan was more often performed in higher white-collar than in blue-collar workers (OR 1.30; 95% CI 1.21-1.40). Amongst men without metastases, the likelihood of intention to treat was higher in higher white-collar workers (OR 1.43; 95% CI 1.28-1.57). In men who received curative treatment, the likelihood was higher to undergo radical prostatectomy for higher white-collar patients (OR 1.29; 95% CI 1.10-1.47). In men without metastases, not only overall mortality was lower amongst higher white-collar workers (HR, 0.76; 95% CI 0.60-0.97), but also prostate cancer-specific mortality (sHR 0.70; 95% CI, 0.49-0.99).

    CONCLUSIONS:

    We conclude that socioeconomic disparities in the management and mortality in men with high risk prostate cancer exist also within the setting of a National Health Care System aiming to provide care on equal terms to all residents.

  • 33. Berglund, Anders
    et al.
    Garmo, Hans
    Tishelman, Carol
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stattin, Pär
    Lambe, Mats
    Comorbidity, treatment and mortality: a population based cohort study of prostate cancer in PCBaSe Sweden2011In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 185, no 3, p. 833-840Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    We examined associations among comorbidity, treatment decisions and mortality in patients with prostate cancer.

    MATERIALS AND METHODS:

    A total of 77,536 men diagnosed with prostate cancer between 1997 and 2006 were identified in PCBaSe Sweden from the National Prostate Cancer Register of Sweden. Logistic, Cox and competing risk regression were used to assess associations among Charlson comorbidity index, treatment and mortality. The Charlson comorbidity index was categorized into no (0), mild (1) and severe comorbidity (2+).

    RESULTS:

    In men with low risk prostate cancer 5,975 of the 13,245 (45.1%) patients without comorbidity underwent radical prostatectomy compared to 256 of the 1,399 (18.9%) men with severe comorbidity. Following adjustment for age and period of diagnosis, radical prostatectomy was less likely to be offered to men with severe comorbidity (OR 0.48, 95% CI 0.41-0.55). In men with high risk prostate cancer, radiotherapy was more common (range 7.7% to 21.3%) than radical prostatectomy (range 3.0% to 11.2%) regardless of comorbidity burden. All cause and competing cause but not prostate cancer specific mortality were increased in men with severe comorbidity (all cause HR 1.99, 95% CI 1.93-2.05; competing cause sHR 2.66, 95% CI 2.56-2.78; prostate cancer specific sHR 0.98, 95% CI 0.93-1.03). The cumulative probability of prostate cancer death given no death from competing causes was significantly higher in men with severe comorbidity in all risk groups (p<0.01).

    CONCLUSIONS:

    Comorbidity affects treatment choices, and is associated with all cause, competing cause and conditional prostate cancer specific mortality. An increased conditional prostate cancer specific mortality in men with severe comorbidity may reflect less aggressive treatment, impaired tumor defense, lifestyle factors and poor general health behavior.

  • 34. Berglund, Anders
    et al.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tishelman, Carol
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Eaker, Sonja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Social inequalities in non-small cell lung cancer management and survival: a population-based study in central Sweden2010In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 65, no 4, p. 327-333Article in journal (Refereed)
    Abstract [en]

    Objectives To examine possible associations between socioeconomic status, management and survival of patients with non-small cell lung cancer (NSCLC). Methods In a population-based cohort study, information was retrieved from the Regional Lung Cancer Register in central Sweden, the Cause of Death Register and a social database. ORs and HRs were compared to assess associations between educational level and management and survival. Results 3370 eligible patients with an NSCLC diagnosis between 1996 and 2004 were identified. There were no differences in stage at diagnosis between educational groups. A higher diagnostic intensity was observed in patients with high compared with low education. There were also social gradients in time between referral and diagnosis in early stage disease ( median time: low, 32 days; high, 17 days). Social differences in treatment remained following adjustment for prognostic factors ( surgery in early stage disease, high vs low OR 2.84; CI 1.40 to 5.79). Following adjustment for prognostic factors and treatment, the risk of death in early stage disease was lower in women with a high education ( high vs low HR 0.33; CI 0.14 to 0.77). Conclusion The results of this study indicate that socioeconomically disadvantaged groups with NSCLC receive less intensive care. Low education remained an independent predictor of poor survival only in women with early stage disease. The exact underlying mechanisms of these social inequalities are unknown, but differences in access to care, co-morbidity and lifestyle factors may all contribute.

  • 35.
    Berglund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lüchtenborg, Margreet
    Linklater, Karen
    Peake, Michael D
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Møller, Henrik
    Social differences in lung cancer management and survival in South East England: a cohort study2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 3, p. e001048-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To examine possible social variations in lung cancer survival and assess if any such gradients can be attributed to social differences in comorbidity, stage at diagnosis or treatment.

    DESIGN:

    Population-based cohort identified in the Thames Cancer Registry.

    SETTING:

    South East England.

    PARTICIPANTS:

    15 582 lung cancer patients diagnosed between 2006 and 2008.

    MAIN OUTCOME MEASURES:

    Stage at diagnosis, surgery, radiotherapy, chemotherapy and survival.

    RESULTS:

    The likelihood of being diagnosed as having early-stage disease did not vary by socioeconomic quintiles (p=0.58). In early-stage non-small-cell lung cancer, the likelihood of undergoing surgery was lowest in the most deprived group. There were no socioeconomic differences in the likelihood of receiving radiotherapy in stage III disease, while in advanced disease and in small-cell lung cancer, receipt of chemotherapy differed over socioeconomic quintiles (p<0.01). In early-stage disease and following adjustment for confounders, the HR between the most deprived and the most affluent group was 1.24 (95% CI 0.98 to 1.56). Corresponding estimates in stage III and advanced disease or small-cell lung cancer were 1.16 (95% CI 1.01 to 1.34) and 1.12 (95% CI 1.05 to 1.20), respectively. In early-stage disease, the crude HR between the most deprived and the most affluent group was approximately 1.4 and constant through follow-up, while in patients with advanced disease or small-cell lung cancer, no difference was detectable after 3 months.

    CONCLUSION:

    We observed socioeconomic variations in management and survival in patients diagnosed as having lung cancer in South East England between 2006 and 2008, differences which could not fully be explained by social differences in stage at diagnosis, co-morbidity and treatment. The survival observed in the most affluent group should set the target for what is achievable for all lung cancer patients, managed in the same healthcare system.

  • 36.
    Berglund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wigertz, Annette
    Adolfsson, Jan
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Fornander, Tommy
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Impact of comorbidity on management and mortality in women diagnosed with breast cancer2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 135, no 1, p. 281-289Article in journal (Refereed)
    Abstract [en]

    To investigate associations between comorbidity burden, management, and mortality in women with breast cancer. A total of 42,646 women diagnosed with breast cancer between 1992 and 2008 were identified in two Clinical Quality Registers in Central Sweden. Breast cancer-specific, conditional breast cancer, competing-cause and all-cause mortality were estimated in relation to comorbidity burden assessed by the Charlson comorbidity index. All analyses were stratified by stage at diagnosis using competing risk analyses, and all-cause mortality was estimated as a function of follow-up time. Following adjustment for age and calendar period, breast conserving surgery was significantly less likely to be offered to women with severe comorbidity (OR 0.63; 95 % CI 0.58-0.69). Similarly, the proportion treated with radiotherapy, tamoxifen, or chemotherapy was lower in women with severe compared to those with no comorbidity. In women with early stage disease, breast cancer-specific mortality was higher among patients with severe comorbidity (sHR 1.47; 95 % CI 1.11-1.94). In all stages of breast cancer, conditional breast cancer and competing-cause mortality were elevated in women with severe comorbidity. For all stages, the relative risk of all-cause mortality between women with severe versus no comorbidity varied by time since diagnosis, and was most pronounced at early follow-up. Comorbidity affects treatment decisions and mortality. In women with early stage breast cancer, severe comorbidity was associated not only with conditional breast cancer, competing-cause and all-cause mortality, but also breast cancer-specific mortality. The observed differences in breast cancer-specific mortality may be due to less extensive treatment, impaired tumor defense and differences in general health status and lifestyle factors.

  • 37. Bergström, Mats
    et al.
    Juhlin, Claes
    Bonasera, Tomas A
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Rastad, Jonas
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Långström, Bengt
    PET imaging of adrenal cortical tumors with the 11beta-hydroxylase tracer 11C-metomidate2000In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 41, no 2, p. 275-282Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to evaluate PET with the tracer 11C-metomidate as a method to identify adrenal cortical lesions.

    METHODS:

    PET with 11C-metomidate was performed in 15 patients with unilateral adrenal mass confirmed by CT. All patients subsequently underwent surgery, except 2 who underwent biopsy only. The lesions were histopathologically examined and diagnosed as adrenal cortical adenoma (n = 6; 3 nonfunctioning), adrenocortical carcinoma (n = 2), and nodular hyperplasia (n = 1). The remaining were noncortical lesions, including 1 pheochromocytoma, 1 myelolipoma, 2 adrenal cysts, and 2 metastases.

    RESULTS:

    All cortical lesions were easily identified because of exceedingly high uptake of 11C-metomidate, whereas the noncortical lesions showed very low uptake. High uptake was also seen in normal adrenal glands and in the stomach. The uptake was intermediate in the liver and low in other abdominal organs. Images obtained immediately after tracer injection displayed high uptake in the renal cortex and spleen. The tracer uptake in the cortical lesions increased throughout the examination. For quantitative evaluation of tracer binding in individual lesions, a model with the splenic radioactivity concentration assigned to represent nonspecific uptake was applied. Values derived with this method, however, did show the same specificity as the simpler standardized uptake value concept, with similar difference observed for cortical versus noncortical lesions.

    CONCLUSION:

    PET with 11C-metomidate has the potential to be an attractive method for the characterization of adrenal masses with the ability to discriminate lesions of adrenal cortical origin from noncortical lesions.

  • 38.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Christensson, Anna
    Carlsson, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Experiences of randomization: Interviews with patients and clinicians in the SPCG-IV trial2008In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 42, no 4, p. 358-363Article in journal (Refereed)
    Abstract [en]

    Objective. Recruitment of both patients and clinicians to randomized trials is difficult. Low participation carries the risk of terminating studies early and making them invalid owing to insufficient statistical power. This study investigated patients' and clinicians' experiences of randomization with the aim of facilitating trial participation in the future. Material and methods. This was a qualitative study using content analysis. Patients offered to participate in a randomized trial and randomizing clinicians were interviewed. Five participants, four non-participants and five randomizing clinicians were interviewed, 2-8 years from randomization. Results. Clinicians used strategies in interaction with the patients to facilitate decision making. Patients' attitudes differed and experiences of relatives or friends were often stated as reasons for treatment preferences. Patients described that letting chance decide treatment was a difficult barrier to overcome for randomization. The clinicians used a number of different strategies perceived to make randomization more acceptable to their patients. The clinicians' own motivation for randomizing patients for trials depended on the medical relevance of the study question and the clinicians' major obstacle was to maintain equipoise over time. Regular meetings with the study group helped to maintain equipoise and motivation. Conclusions. To establish a good platform for randomization the clinician needs to know about the patient's treatment preferences and the patient's attitude concerning the role of the clinician to facilitate decision making. The strategies used by the clinicians were perceived as helpful and could be tested in an intervention study.

  • 39.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Filén, Frej
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ruutu, Mirja
    Garmo, Hans
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Bratell, Stefan
    Spångberg, Anders
    Palmgren, Juni
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Lindeborg, T.
    Einarsson, G.
    Ekman, P.
    Wijkström, H.
    Karlberg, L.
    Hagberg, G.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindgren, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mavadati, E.
    Gobén, B.
    Pettersson, I.
    Damber, J.E.
    Lindgren, A.
    Varenhorst, E.
    Norlén, B.J.
    Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 16, p. 1144-54Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up. METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided. RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001). CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.

  • 40.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Norberg, Mona
    No increased prostate cancer incidence after negative transrectal ultrasound guided multiple biopsies in men with increased prostate specific antigen and/or abnormal digital rectal examination.2003In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 170, no 4 Pt 1, p. 1180-3Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We investigated the incidence of prostate cancer after negative transrectal ultrasound (TRUS) guided multiple biopsies. Our secondary aim was to calculate the sensitivity of the extended protocol used.

    MATERIALS AND METHODS: A cohort of 547 men with elevated prostate specific antigen and/or abnormal digital rectal examination but with results negative for prostate cancer on a mean of 9 TRUS guided biopsies was followed through record linkage to the national cancer Registry. The observed number of prostate cancers was compared with the expected number during the same calendar period in an age matched male population to determine the standardized incidence ratio. The sensitivity of TRUS with multiple biopsies after 5 years of followup was calculated. Relative survival was estimated if there was an excess death rate due to undiagnosed prostate cancer.

    RESULTS: We found 11 men diagnosed with prostate cancer. The expected number in the age standardized male population was 15, resulting in a standardized incidence ratio of 0.8 (95% CI 0.4 to 1.2). Five-year sensitivity of the extended protocol of TRUS guided biopsies was 95.2% (95% CI 93.5 to 96.4) and relative survival was more than 100%, indicating a selection of men deemed candidates for curative treatment.

    CONCLUSIONS: Men with clinical suspicion of prostate cancer who are examined by an extended protocol of TRUS guided biopsies negative for cancer do not have an increased incidence of prostate cancer within 6 years compared with an age matched male population. Five-year sensitivity of this protocol was high.

  • 41.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Garmo, Hans
    Stark, Jennifer R.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Bratell, Stefan
    Spångberg, Anders
    Linköpings universitet.
    Palmgren, Juni
    Karolinska Inst. Institutionen för Medicinsk Epidemiologi och Biostatistik.
    Steineck, Gunnar
    Karolinska Inst. institutionen för onkologi-patologi..
    Adami, Hans-Olov
    Harvard, Department of Epidemiology.
    Johansson, Jan-Erik
    Örebro Universitet.
    Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 18, p. 1708-1717Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.

    METHODS

    From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.

    RESULTS

    During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).

    CONCLUSIONS

    Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment.

  • 42.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Sven-Olof
    Bratell, Stefan
    Spångberg, Anders
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordling, Stig
    Garmo, Hans
    Palmgren, J
    Adami, HO
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, JE
    Radical prostatectomy versus watchful waiting in early prostate cancer2005In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 352, no 19, p. 1977-1944Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.

    METHODS:

    From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.

    RESULTS:

    During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).

    CONCLUSIONS:

    Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

  • 43.
    Bindra, Amarinder
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Kisekka, Robinah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Nordgren, Hans
    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.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Search for DNA of exogenous mouse mammary tumor virus-related virus in human breast cancer samples2007In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 88, p. 1806-1809Article in journal (Refereed)
    Abstract [en]

    Earlier reports of a human exogenous retrovirus (HMTV) related closely to mouse mammary tumor virus (MMTV) led us to search for these viral sequences in breast cancer tissues and normal tissues. A real-time PCR was developed based on MMTV and published HMTV envelope sequences. The real-time PCR method can detect one to ten copies of MMTV target DNA. Tissue samples were collected prospectively from 18 breast cancer patients and 11 non-malignant control cases, as well as peripheral blood leukocytes from the same women. Despite the high sensitivity of the real-time PCR method used, none of the samples were positive for HMTV DNA or RNA. The absence of HMTV DNA in both breast cancer samples and controls indicates either that the concentration of putative HMTV DNA in the breast cancers was too low for detection or that it did not exist there.

  • 44.
    Birgisson, Helgi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Wallin, Ulrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Survival endpoints in colorectal cancer and the effect of second primary other cancer on disease free survival2011In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, p. 438-Article in journal (Refereed)
    Abstract [en]

    Background: In cancer research the selection and definitions of survival endpoints are important and yet they are not used consistently. The aim of this study was to compare different survival endpoints in patients with primary colorectal cancer (CRC) and to understand the effect of second primary other cancer on disease-free survival (DFS) calculations.

    Methods: A population-based cohort of 415 patients with CRC, 332 of whom were treated with curative intention between the years 2000-2003, was analysed. Events such as locoregional recurrence, distant metastases, second primary cancers, death, cause of death and loss to follow-up were recorded. Different survival endpoints, including DFS, overall survival, cancer-specific survival, relapse-free survival, time to treatment failure and time to recurrence were compared and DFS was calculated with and without inclusion of second primary other cancers.

    Results: The events that occurred most often in patients treated with curative intention were non-cancer-related death (n = 74), distant metastases (n = 66) and death from CRC (n = 59). DFS was the survival endpoint with most events (n = 170) followed by overall survival (n = 144) and relapse-free survival (n = 139). Fewer events were seen for time to treatment failure (n = 80), time to recurrence (n = 68) and cancer-specific survival (n = 59). Second primary other cancer occurred in 26 patients and its inclusion as an event in DFS calculations had a detrimental effect on the survival. The DFS for patients with stage I-III disease was 62% after 5 years if second primary other cancer was not included as an event, compared with 58% if it was. However, the difference was larger for stage II (68 vs 60%) than for stage III (49 vs 47%).

    Conclusions: The inclusion of second primary other cancer as an endpoint in DFS analyses significantly alters the DFS for patients with CRC. Researchers and journals must clearly define survival endpoints in all trial protocols and published manuscripts.

  • 45.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Culture of Parathyroid Cells2012In: Human Cell Culture Protocols: Third edition / [ed] Ragai R. Mitry and Robin D. Hughes, Springer, 2012, p. 43-53Chapter in book (Refereed)
    Abstract [en]

    The parathyroid cells are highly differentiated with more or less their only function to secrete parathyroid hormone in response to the extracellular calcium level. Tumours from the parathyroid glands are >99% benign, and have a slow proliferation rate. Culture of parathyroid cells is known to be very difficult most likely due to the high differentiation level. This chapter reveals some details in order how to get parathyroid cells to survive in culture after dispersion of normal bovine parathyroid glands or pathological human parathyroid tumours. Detailed protocols describing cell dispersion with collagenase, short-term cultures, and establishment of long-term cultures are presented.

  • 46.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Krajisnik, Tijana
    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.
    Type I membrane Klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 10, p. 4152-4157Article in journal (Refereed)
    Abstract [en]

    Context: The type I membrane protein Klotho was recently shownto mediate PTH secretion in parathyroid cells in response tolow extracellular calcium. In contrast, Klotho inhibits PTHsecretion indirectly through the action of fibroblast growthfactor-23. Abnormal Klotho expression in parathyroid disordersremains to be elucidated.

    Objective: The aim of the study was to determine: 1) Klothoexpression in parathyroid adenomas from patients with primaryhyperparathyroidism (pHPT) compared to normal tissue; and 2)its relation to the serum calcium and PTH levels.

    Design: Surgically removed parathyroid glands (n = 40) and fournormal parathyroid tissue specimens were analyzed for KlothomRNA and protein levels by quantitative real-time PCR and immunohistochemistry.In vitro effects of calcium on Klotho mRNA expression were studiedin bovine parathyroid cells.

    Results: Klotho mRNA levels were significantly decreased (n= 23) or undetectable (n = 17) in parathyroid adenomas comparedto normal tissues (P < 0.001). Reduced Klotho protein expressionwas confirmed by immunohistochemistry. Klotho mRNA levels wereinversely correlated to serum calcium (r = –0.97; P <0.0001), and calcium dose-dependently decreased Klotho mRNAexpression in normal parathyroid cells in vitro (P < 0.01).Serum calcium was the only significant marker of Klotho expressionin multivariate analysis with calcium, phosphate, PTH, and adenomaweight as independent variables.

    Conclusions: Parathyroid Klotho expression is decreased or undetectablein pHPT. We provide evidence that 1) serum calcium is stronglyassociated with parathyroid Klotho expression in pHPT; and 2)abnormal PTH secretion in hypercalcemic pHPT subjects is mediatedby Klotho-independent mechanisms.

  • 47.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Pacak, K.
    NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol Program Reprod & Adult E, Bethesda, MD USA..
    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 Surgical Sciences, Experimental Surgery.
    Precision medicine in pheochromocytoma and paraganglioma: current and future concepts2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 559-573Article in journal (Refereed)
    Abstract [en]

    Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.

  • 48.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Starker, Lee F
    Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
    Fonseca, A
    Carling, T
    Molecular Basis of Primary Hyperparathyroidism2010In: World Journal of Endocrine Surgery, ISSN 0975-5039, Vol. 2, no 2, p. 63-70Article in journal (Other academic)
    Abstract [en]

    During the past decade and a half, studies of genetic predisposition, parathyroid tumorigenesis, and molecular genetics of familialhyperparathyroid disorders have started to unveil the molecular basis of pHPT. Primary HPT is found in several distinct disorders withautosomal dominant inheritance such as in multiple endocrine neoplasia type 1 (MEN1), MEN2A, the HPT-jaw tumor syndrome (HPT-JT),familial isolated hyperparathyroidism (FIHPT), autosomal dominant mild hyperparathyroidism (ADMH), and neonatal severe HPT (NSHPT).

  • 49.
    Blom, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Yin, Li
    Liden, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dolk, Anders
    Jeppsson, Bengt
    Pahlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nyren, Olof
    Toward understanding non participation in sigmoidoscopy screening for colorectal cancer2008In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 122, no 7, p. 1618-1623Article in journal (Refereed)
    Abstract [en]

    Understanding the reasons for nonparticipation in cancer screening may give clues about how to improve compliance. However, limited cooperation has hampered research on nonparticipant profiles. We took advantage of Sweden's comprehensive demographic and health care registers to investigate characteristics of all participants and nonparticipants in a pilot program for colorectal cancer screening with sigmoidoscopy. A population-based sample of 1986 Swedish residents 59-61 years old was invited. Registers provided information on each individual's gender, country of birth, marital status, education, income, hospital contacts, place of residence, distance to screening center and cancer within the family. Odds ratios (ORs) with 95% confidence intervals (CIs), modeled with multivariable logistic regression, estimated the independent associations between each background factor and the propensity for nonparticipation after control for the effects of other factors. All statistical tests were 2-sided. Being male (OR = 1.27, 95% CI = 1.03-1.57, relative to female), unmarried or divorced (OR = 1.69, 95% CI = 1.23-2.30 and OR = 1.49, 95% CI = 1.14-1.95, respectively, relative to married) and having an income in the lowest tertile (OR = 1.68, 95% CI = 1.27-2.23, relative to highest tertile) was associated with increased nonparticipation. Living in the countryside or in small communities and having a documented family history of colorectal cancer was associated with better participation. Distance to the screening center did not significantly affect participation, nor did recent hospital care consumption or immigrant status. To increase compliance, invitations must appeal to men, unmarried or divorced people and people with low socioeconomic status.

  • 50.
    Blom, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Yin, Li
    Lidén, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dolk, Anders
    Jeppsson, Bengt
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nyrén, Olof
    A 9-year follow-up study of participants and nonparticipants in sigmoidoscopy screening: importance of self-selection2008In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, no 5, p. 1163-1168Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Self-selection may compromise cost-effectiveness of screening programs. We hypothesized that nonparticipants have generally higher morbidity and mortality than participants. METHODS: A Swedish population-based random sample of 1,986 subjects ages 59 to 61 years was invited to sigmoidoscopy screening and followed up for 9 years by means of multiple record linkages to health and population registers. Gender-adjusted cancer incidence rate ratio (IRR) and overall and disease group-specific and mortality rate ratio (MRR) with 95% confidence intervals (95% CI) were estimated for nonparticipants relative to participants. Cancer and mortality rates were also estimated relative to the age-matched, gender-matched, and calendar period-matched Swedish population using standardized incidence ratios and standardized mortality ratios. RESULTS: Thirty-nine percent participated. The incidence of colorectal cancer (IRR, 2.2; 95% CI, 0.8-5.9), other gastrointestinal cancer (IRR, 2.7; 95% CI, 0.6-12.8), lung cancer (IRR, 2.2; 95% CI, 0.8-5.9), and smoking-related cancer overall (IRR, 1.4; 95% CI, 0.7-2.5) tended to be increased among nonparticipants relative to participants. Standardized incidence ratios for most of the studied cancers tended to be >1.0 among nonparticipants and <1.0 among participants. Mortality from all causes (MRR, 2.4; 95% CI, 1.7-3.4), neoplastic diseases (MRR, 1.9; 95% CI, 1.1-3.5), gastrointestinal cancer (MRR, 4.7; 95% CI, 1.1-20.7), and circulatory diseases (MRR, 2.3; 95% CI, 1.2-4.2) was significantly higher among nonparticipants than among participants. Standardized mortality ratio for the studied outcomes tended to be increased among nonparticipants and was generally decreased among participants. CONCLUSION: Individuals who might benefit most from screening are overrepresented among nonparticipants. This self-selection may attenuate the cost-effectiveness of screening programs on a population level.

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