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  • 151. Emdin, Stefan O.
    et al.
    Granstrand, Bengt
    Ringberg, Anita
    Sandelin, Kerstin
    Arnesson, Lars-Gunnar
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Anderson, Harald
    Garmo, Hans
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wallgren, Arne
    SweDCIS: Radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening2006In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 45, no 5, p. 536-543Article in journal (Refereed)
    Abstract [en]

    We studied the effect of postoperative radiotherapy (RT) after breast sector resection for ductal carcinoma in situ (DCIS). The study protocol stipulated radical surgery but microscopically clear margins were not mandatory. We randomised 1,046 operated women to postoperative RT or control between 1987 and 1999. The primary endpoint was ipsilateral local recurrence. Secondary endpoints were contralateral breast cancer, distant metastasis and death. After a median follow-up of 5.2 years (range 0.1-13.8) there were 44 recurrences in the RT group corresponding to a cumulative incidence of 0.07 (95% confidence interval (CI) 0.05-0.10). In the control group there were 117 recurrences giving a cumulative incidence of 0.22 (95% CI 0.18-0.26) giving an overall hazard ratio of 0.33 (95% CI 0.24-0.47, p < 0.0001). Twenty two percent of the patients had microscopically unknown or involved margins. We found no evidence for different effects of RT on the relative risk of invasive or in situ recurrence. Secondary endpoints did not differ. Women undergoing sector resection for DCIS under conditions of population based screening mammography benefit from postoperative RT to the breast. Seven patients needed RT-treatment to prevent one recurrence.

  • 152. Enberg, U.
    et al.
    Hennings, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Volpe, C.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Höög, A.
    Hamberger, B.
    Thorén, M.
    Increased ratio of mRNA expression of the genes CYP17 and CYP11B1 indicates autonomous cortisol production in adrenocortical tumors2009In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 32, no 10, p. 810-815Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Due to increased use of imaging techniques, adrenal incidentalomas are frequently detected. The majority are non-hyperfunctioning adrenocortical tumors. We have previously shown that expression of the gene CYP17, coding for the enzyme in the cortisol pathway, correlates with cortisol release from adrenocortical tumors in vitro. The aim of this study was to compare clinical data with mRNA expression of CYP17 and CYP11B1 in adrenocortical tumors from patients with and without Cushing's syndrome and to identify adrenal tumors that may cause subclinical Cushing's syndrome. DESIGN: A retrospective study of 34 patients undergoing adrenalectomy due to an adrenal tumor. METHODS: Clinical data were collected. In the adrenal gland the mRNA expression of the genes CYP17 and CYP11B1 was studied with in situ hybridisation technique. RESULTS: The median ratio of CYP17/CYP11B1 expression in tumors from patients with Cushing's syndrome was significantly higher than the median ratio in the non-hyperfunctioning tumors. Tumors from 2 patients with subclinical Cushing's syndrome had ratios within the upper range for non-hyperfunctioning tumors. CONCLUSIONS: The ratio between the expression of the genes CYP17 and CYP11B1 in tumors from patients with Cushing's syndrome is significantly higher than in the non-hyperfunctioning tumors. This indicates that 17alpha-hydroxylase is a major determinant of cortisol overproduction. The patients with subclinical Cushing's syndrome in this study are too few to draw any firm conclusions although the results suggest that subclinical Cushing's syndrome may be identified post-operatively with this method.

  • 153.
    Enell, Jacob
    et al.
    Umea Univ, Dept Surg & Perioperat Sci, S-90185 Umea, Sweden.
    Bayadsi, Haytham
    Umea Univ, Dept Surg & Perioperat Sci, S-90185 Umea, Sweden.
    Lundgren, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hennings, Joakim
    Umea Univ, Dept Surg & Perioperat Sci, S-90185 Umea, Sweden.
    Primary Hyperparathyroidism is Underdiagnosed and Suboptimally Treated in the Clinical Setting2018In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 42, no 9, p. 2825-2834Article in journal (Refereed)
    Abstract [en]

    To evaluate whether patients presenting with laboratory results consistent with primary hyperparathyroidism (pHPT) are managed in accordance with guidelines. The laboratory database at a hospital in Sweden, serving 127,000 inhabitants, was searched for patients with biochemically determined pHPT. During 2014, a total of 365 patients with biochemical laboratory tests consistent with pHPT were identified. Patients with possible differential diagnoses or other reasons for not being investigated according to international guidelines were excluded after scrutinizing records, after new blood tests, and clinical assessments by endocrine surgeons. Altogether, 92 patients had been referred to specialists and 82 had not. The latter group had lower serum calcium (median 2.54 mmol/L) and PTH (5.7 pmol/L). Out of these 82 cases, 9 patients were diagnosed with pHPT or had some sort of long-term follow-up planned as outpatients. Primary hyperparathyroidism is overlooked and underdiagnosed in a number of patients in the clinical setting. It is important to provide local guidelines for the management of patients presenting with mild pHPT to ensure that these patients receive proper evaluation and follow-up according to current research.

  • 154. Engholm, Gerda
    et al.
    Kejs, Anne Mette T.
    Brewster, David H.
    Gaard, Maria
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hartley, Roger
    Iddenden, Robert
    Möller, Henrik
    Sankila, Risto
    Thomson, Catherine S.
    Storm, Hans H.
    Colorectal cancer survival in the Nordic countries and the United Kingdom: Excess mortality risk analysis of 5 year relative period survival in the period 1999 to 20002007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 5, p. 1115-1122Article in journal (Refereed)
    Abstract [en]

    A deficit in colorectal cancer survival in Denmark and in the UK compared to Sweden, Norway and Finland was found in the EUROCARE studies. We set out to explore if these differences still exist. Patients diagnosed with colorectal cancer as their first invasive cancer at age 15-89 in the period 1994-2000 were identified using data from 11 cancer registries in the UK and from four Nordic countries. Five-year relative period survival using deaths in 1999-2000 following cancers diagnosed in 1994-2000 was analysed with excess mortality risk modelling. Follow-up time since diagnosis with age as an effect-modifier in the first half year was the most important factor with the highest excess risk of death immediately after diagnosis and with higher age and decreasing with length of follow-up. Variations between countries were bigger in the first half year following diagnosis than in the interval 0.5-5 years with about 30% higher risk in UK and Denmark. The differences between countries are still substantial and the order has not changed, even if the five year relative survival has improved since the EUROCARE studies. Patient management, diagnostics, and comorbidity likely explain the excess deaths in UK and Denmark during the first 6 months. The effect of stage and quality of management and treatment should be examined in population based studies with detailed patient information. Use of more detailed age-intervals than conventionally applied in survival studies proved to be important in statistical modelling and is recommended for future studies.

  • 155.
    Eriksson, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prognostic Factors for Death in Small Intestinal Neuroendocrine Tumours2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tumours in the small intestine are rare compared to those in other gastrointestinal organs. Small intestinal neuroendocrine tumours (SI-NETs) are the most common small bowel tumours with an annual incidence of 0.3-1.7 per 100 000 persons. They are characterised by their usually indolent nature and, even though many patients present with metastatic disease, survival is favourable compared to most other gastrointestinal malignancies. The principal aim of this thesis was to establish prognostic factors over the entire life span of patients with SI-NETs. Paper I confirmed the known prognostic factors of metastatic and symptomatic disease as preoperative prognostic factors. In this paper, we also showed that patients with symptomatic Stage IV disease are the most likely patients to die from their SI-NET. Patients who undergo surgery in an emergency setting fared better than patients who had elective surgery and this can possibly be explained by patients having less advanced disease in emergency procedures.  Paper II focused on the perioperative period, during which liver metastases and peritoneal carcinomatosis stood out as the most important prognostic factors. A macroscopically radical surgery had a positive prognostic impact, as did radical locoregional surgery (LRS). In univariable analysis, LRS was a positive prognostic factor regardless of TNM stage. In Paper III, the specific findings that had prognostic impacts in the postoperative period were the negative impacts of carcinoid heart disease and non-radical secondary surgery.  The occurrence of a second malignancy seemed to have positive prognostic value but was most likely a result of study design. Paper IV studied expression patterns seen on immunohistochemistry of primary and metastatic tissue sections from the primary operation in 40 patients.  In this study, low TFF3 expression in primary tumours was correlated to decreased survival. We also proposed a dual mechanism for TFF3 in the dedifferentiation of SI-NETs based on the finding of high TFF3 expressions in metastatic tissue. The expression of mindin and ACTG2 was higher in G2 tumours and we suggested that mindin played a role as an indirect promoter of proliferation and cell migration. Finally, in Paper V, we calculated the mean annual incidence of clinical and subclinical SI-NETs from autopsy material comprised of the very high number of autopsies from the Malmö region between the years 1970 and 1982. The total mean annual incidence of SI-NETs was 5.7 per 100 000 and males were more likely to harbour a SI-NET than females. In this material, 40% of those with a SI-NET had at least one other malignancy, which constitutes a more than three-fold increased rate of synchronous malignancies in SI-NET cases.

    List of papers
    1. The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors
    Open this publication in new window or tab >>The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors
    2017 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 24, no 5, p. 1214-1220Article in journal (Refereed) Published
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are uncommon tumors with an annual incidence of about 1 per 100,000. Usually, SI-NETs have a slow progression, and patients often present with generalized disease. Many patients do well, and the disease has a relatively favorable 5-year survival rate. Some SI-NETs, however, have a more negative prognosis. This study aimed to establish prognostic factors for death identifiable at primary surgery. A nested case-control study investigated 1150 patients from the cohort of all patients with a diagnosis of SI-NETs in Sweden between 1961 and 2001. The study cases consisted of all patients who died of SI-NETs during the study period. Each case was assigned a control subject matched by age at diagnosis and calendar period. Possible prognostic factors [gender, degree of symptoms, indication for surgery, World Health Organization (WHO) stage] were evaluated in uni- and multivariable analyses. The patients with symptomatic disease had an increased risk of dying. The indication for primary surgery influenced survival, showing a more negative prognosis for elective surgery. The WHO stage influenced survival, and stage 4 patients had an almost threefold risk of dying compared with stages 1 to 3b patients. This study showed that preoperative symptoms are important in prognostication for SI-NETs. Hormonal symptoms generally signify a patient with a more advanced disease stage and a worse prognosis. Including symptomatic disease together with the WHO stage and grade could possibly increase the accuracy of prognostication.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-322084 (URN)10.1245/s10434-016-5703-4 (DOI)000399013200012 ()27904972 (PubMedID)
    Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2018-03-28Bibliographically approved
    2. Symptomatic disease at the time of surgery have prognostic impact in small intestinal neuroendocrine tumours
    Open this publication in new window or tab >>Symptomatic disease at the time of surgery have prognostic impact in small intestinal neuroendocrine tumours
    (English)In: British Journal of Surgery OpenArticle in journal (Refereed) Accepted
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-347231 (URN)
    Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-04-08
    3. Prognostic factors for death after surgery for small intestinal neuroendocrine tumours
    Open this publication in new window or tab >>Prognostic factors for death after surgery for small intestinal neuroendocrine tumours
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Surgery
    Research subject
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-347232 (URN)
    Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-04-08
    4. TFF3 in primary tumours has a negative impact on survival in small intestinal neuroendocrine tumours
    Open this publication in new window or tab >>TFF3 in primary tumours has a negative impact on survival in small intestinal neuroendocrine tumours
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Surgery
    Research subject
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-347233 (URN)
    Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-03-28
    5. Primary small intestinal tumours are highly prevalent and often multiple before metastatic disease develops
    Open this publication in new window or tab >>Primary small intestinal tumours are highly prevalent and often multiple before metastatic disease develops
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Surgery
    Research subject
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-347234 (URN)
    Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-03-28
  • 156.
    Eriksson, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Kings Coll London, Res Oncol, Canc Epidemiol Grp, Div Canc Studies, London, England..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ihre-Lundgren, Catharina
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors2017In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 24, no 5, p. 1214-1220Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are uncommon tumors with an annual incidence of about 1 per 100,000. Usually, SI-NETs have a slow progression, and patients often present with generalized disease. Many patients do well, and the disease has a relatively favorable 5-year survival rate. Some SI-NETs, however, have a more negative prognosis. This study aimed to establish prognostic factors for death identifiable at primary surgery. A nested case-control study investigated 1150 patients from the cohort of all patients with a diagnosis of SI-NETs in Sweden between 1961 and 2001. The study cases consisted of all patients who died of SI-NETs during the study period. Each case was assigned a control subject matched by age at diagnosis and calendar period. Possible prognostic factors [gender, degree of symptoms, indication for surgery, World Health Organization (WHO) stage] were evaluated in uni- and multivariable analyses. The patients with symptomatic disease had an increased risk of dying. The indication for primary surgery influenced survival, showing a more negative prognosis for elective surgery. The WHO stage influenced survival, and stage 4 patients had an almost threefold risk of dying compared with stages 1 to 3b patients. This study showed that preoperative symptoms are important in prognostication for SI-NETs. Hormonal symptoms generally signify a patient with a more advanced disease stage and a worse prognosis. Including symptomatic disease together with the WHO stage and grade could possibly increase the accuracy of prognostication.

  • 157.
    Eriksson, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ihre-Lundgren, Catharina
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prognostic factors for death after surgery for small intestinal neuroendocrine tumoursIn: Article in journal (Refereed)
  • 158.
    Eriksson, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ihre-Lundgren, Catharina
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Symptomatic disease at the time of surgery have prognostic impact in small intestinal neuroendocrine tumoursIn: British Journal of Surgery OpenArticle in journal (Refereed)
  • 159.
    Eriksson, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, J E H
    Ihre-Lundgren, C
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prognostic factors for death after surgery for small intestinal neuroendocrine tumours.2018In: BJS open, ISSN 2474-9842, Vol. 2, no 5, p. 345-352Article in journal (Refereed)
    Abstract [en]

    Background: Neuroendocrine tumours of the small intestine (SI-NETs) are rare gastrointestinal neoplasms with an annual incidence of about one per 100 000. Patients with apparently similar tumours have variable outcomes. The aim of this study was to identify postoperative prognostic factors identifiable after initial surgery.

    Methods: This was a nested case-control study of patients with SI-NETs who were treated between 1961 and 2001. Data were retrieved from the Swedish Cancer Registry. Patients who died from the SI-NET and corresponding controls (who outlived cases by at least 1 month), matched by age at diagnosis and calendar period, were included. Sex, postoperative symptoms, postoperative 5-hydroxyindoleacetic acid (5-HIAA) values, European Neuroendocrine Tumor Society (ENETS) stage, insufficiency of the tricuspid valve, radical secondary surgery and secondary malignancy were studied as potential prognostic factors.

    Results: In total, 1122 patients were included (561 cases, 561 controls). Postoperative factors of prognostic importance included hormone-related symptoms, stage IV disease, raised levels of 5-HIAA, insufficiency of the tricuspid valve, secondary surgery not being macroscopically radical and a second malignancy.

    Conclusion: Stage and symptomatic disease are important prognostic factors in SI-NET.

  • 160.
    Eriksson, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Juhlin, Christofer
    Backman, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Edfeldt, Katarina
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ihre-Lundgren, Catharina
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    TFF3 in primary tumours has a negative impact on survival in small intestinal neuroendocrine tumoursIn: Article in journal (Refereed)
  • 161.
    Eriksson, John
    et al.
    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.
    Ögren, Mats
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ihre-Lundgren, Catharina
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Primary small intestinal tumours are highly prevalent and often multiple before metastatic disease developsIn: Article in journal (Refereed)
  • 162.
    Eriksson, John
    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.
    Nilsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Krause, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Lundberg, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors2008In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 32, no 5, p. 930-938Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Many neuroendocrine tumors (NETs) have a tendency to metastasize to the liver. In case of limited number of metastases, liver surgery or radiofrequency ablation (RFA) may result in apparently total clearance of metastases. However, it is not clear whether such therapy will provide symptom reduction or increased survival.

    METHODS:

    Seventy-three patients with foregut (n=6) or midgut carcinoids (n=37) or endocrine pancreatic tumors (n=28), and two patients with NETs without discernable origin were studied. Symptoms were evaluated using a Symptom Severity Score. Liver surgery was performed in 42 operations and RFA on 205 lesions.

    RESULTS:

    Apparently total clearance of liver metastases was attained in 1 of 6 patients with foregut carcinoids, 15 of 37 with midgut carcinoids, and 13 of 28 with EPT. Symptom improvement was noted in 12 of 17 (70.6%) patients with carcinoid syndrome, and 75% also reduced their 5-HIAA and P-CgA by at least 50%. Patients with nonfunctioning EPT generally had no improvement of symptoms after surgical/RFA liver treatment, but eight patients had functioning EPT, and four of these reduced their biochemical markers by at least 50%. NETs with higher Ki67 index tended to recur more often. Complications occurred in 9 of 45 open surgery procedures, and in 8 of 203 RFA procedures.

    CONCLUSIONS:

    Treatment of liver metastases is successful in midgut carcinoid patients with limited liver metastases. Patients with foregut carcinoid and EPTs recur more often, possibly related to higher Ki67 index, and treatment of liver lesions less often reduces symptoms. Liver resections and RFA may be safely performed, and RFA is associated with few complications.

  • 163.
    Eriksson, Louise
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, S-17176 Stockholm, Sweden;Karolinska Inst, Radiumhemmet, Dept Oncol, Dept Oncol Pathol,Canc Ctr Karolinska, S-17176 Stockholm, Sweden.
    Bergh, Jonas
    Karolinska Univ Hosp, S-17176 Stockholm, Sweden;Karolinska Inst, Radiumhemmet, Dept Oncol, Dept Oncol Pathol,Canc Ctr Karolinska, S-17176 Stockholm, Sweden.
    Humphreys, Keith
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Törnberg, Sven
    Stockholm Gotland Reg Canc Ctr, Dept Canc Screening, Stockholm, Sweden.
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
    Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis: A population-based cohort study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 5, p. 1093-1104Article in journal (Refereed)
    Abstract [en]

    Theoretically, time from breast cancer diagnosis to therapeutic surgery should affect survival. However, it is unclear whether this holds true in a modern healthcare setting in which breast cancer surgery is carried out within weeks to months of diagnosis. This is a population- and register-based study of all women diagnosed with invasive breast cancer in the Stockholm-Gotland healthcare region in Sweden, 2001-2008, and who were initially operated. Follow-up of vital status ended 2014. 7,017 women were included in analysis. Our main outcome was overall survival. Main analyses were carried out using Cox proportional hazards models. We adjusted for likely confounders and stratified on mode of detection, tumor size and lymph node metastasis. We found that a longer interval between date of morphological diagnosis and therapeutic surgery was associated with a poorer prognosis. Assuming a linear association, the hazard rate of death from all causes increased by 1.011 (95% CI 1.006-1.017) per day. Comparing, for example, surgery 6 weeks after diagnosis to surgery 3 weeks after diagnosis, thereby confers a 1.26-fold increased hazard rate. The increase in hazard rate associated with surgical delay was strongest in women with largest tumors. Whilst there was a clear association between delays and survival in women without lymph node metastasis, the association may be attenuated in subgroups with increasing number of lymph node metastases. We found no evidence of an interaction between time to surgery and mode of detection. In conclusion, unwarranted delays to primary treatment of breast cancer should be avoided. What's new? Theoretically, an increase in the interval between breast-cancer diagnosis and therapeutic surgery should affect survival, but it is uncertain whether that holds true in a modern healthcare setting. In this prospective study, the authors found that even fairly short delays (on the order of days or weeks) from diagnosis to surgery are associated with decreased survival. These results suggest that the time between diagnosis and therapeutic surgery should be kept as short as possible without hampering diagnostic work-up and preoperative patient optimization.

  • 164.
    Essen, Anneli
    et al.
    Kings Coll London, Sch Canc & Pharmaceut Sci, Guys Hosp, Res Oncol Translat Oncol & Urol Res TOUR, 3rd Floor,Bermondsey Wing, London SE1 9RT, England.
    Santaolalla, Aida
    Kings Coll London, Sch Canc & Pharmaceut Sci, Guys Hosp, Res Oncol Translat Oncol & Urol Res TOUR, 3rd Floor,Bermondsey Wing, London SE1 9RT, England.
    Garmo, Hans
    Kings Coll London, Sch Canc & Pharmaceut Sci, Guys Hosp, Res Oncol Translat Oncol & Urol Res TOUR, 3rd Floor,Bermondsey Wing, London SE1 9RT, England;Reg Canc Ctr, Uppsala, Sweden.
    Hammar, Niklas
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden;AstraZeneca, Global Med Affairs, Med Evidence & Observat Res, Molndal, Sweden.
    Walldius, Göran
    Karolinska Inst, Inst Environm Med, Dept Cardiovasc Epidemiol, Stockholm, Sweden.
    Jungner, Ingmar
    Karolinska Inst, Dept Clin Epidemiol, Stockholm, Sweden;CALAB Res, Stockholm, Sweden.
    Malmström, Håkan
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden;Swedish Orphan Biovitrum AB, Biostat Res & Dev, Stockholm, Sweden.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Sch Canc & Pharmaceut Sci, Guys Hosp, Res Oncol Translat Oncol & Urol Res TOUR, 3rd Floor,Bermondsey Wing, London SE1 9RT, England.
    Van Hemelrijck, Mieke
    Kings Coll London, Sch Canc & Pharmaceut Sci, Guys Hosp, Res Oncol Translat Oncol & Urol Res TOUR, 3rd Floor,Bermondsey Wing, London SE1 9RT, England;Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden.
    Baseline serum folate, vitamin B12 and the risk of prostate and breast cancer using data from the Swedish AMORIS cohort2019In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 30, no 6, p. 603-615Article in journal (Refereed)
    Abstract [en]

    Purpose: The roles of folate and vitamin B12 in prostate cancer (PCa) or breast cancer (BC) development are unclear. We investigated their roles using the prospective Swedish Apolipoprotein MOrtality RISk (AMORIS) study.

    Methods: 8,783 men and 19,775 women with vitamin B12 and folate serum measurements were included. Their associations with PCa and BC risk categories were evaluated using Cox proportional hazards regression.

    Results: During mean follow-up of 13years, 703 men developed PCa. There was an inverse association between folate>32nmol/L and high-risk PCa [hazard ratio (HR) 0.12, 95% confidence interval (CI) 0.02-0.90], and a positive association between folate<5nmol/L and metastatic PCa (HR 5.25, 95% CI 1.29-21.41), compared with folate 5-32nmol/L. No associations with vitamin B12 were found. 795 women developed BC during mean follow-up of 14years. When restricting to the fasting population, there was a positive association between folate>32nmol/L and BC (HR 1.47, 95% CI 1.06-2.04).

    Conclusion: High folate levels may protect against PCa and low folate levels may increase risk of metastatic PCa. High fasting folate levels may be associated with an increased BC risk. Vitamin B12 was not found to be linked with risk of PCa or BC. Longitudinal studies with serum and dietary information could help define new prevention targets and add information on the role of folate fortification.

  • 165. Fall, Katja
    et al.
    Garmo, Hans
    Regional Oncological Center, Uppsala University.
    Andrén, Ove
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Adolfsson, Jan
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prostate-specific antigen levels as a predictor of lethal prostate cancer2007In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 99, no 7, p. 526-532Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Rates of long-term survival among patients with untreated localized prostate cancer are high. To avoid unnecessary treatment, tools are needed to identify the small proportion of patients who are destined to develop lethal prostate cancer. METHODS: To evaluate the accuracy of early changes in prostate-specific antigen (PSA) levels as predictors of prostate cancer outcome, we assessed serial measurements of PSA level among 267 men with localized prostate cancer in a Scandinavian cohort of men who were diagnosed between 1989 and 1999 and who were managed by watchful waiting. We then 1) fitted individual regression lines to the PSA values assessed for each patient during the first 2 years of follow-up by using three different models, 2) evaluated early PSA curve characteristics as determinants of the cumulative incidence of lethal prostate cancer and calculated hazard ratios for baseline PSA value and rate of change in PSA level to prostate cancer outcome, and 3) plotted time-dependent receiver operating characteristic (ROC) curves. All P values are two-sided. RESULTS: During complete follow-up for a mean of 8.5 years, 34 patients (13%) died from prostate cancer, and 18 (7%) developed metastases but were still alive at end of follow-up. In a log-linear model, both PSA value at baseline (P = .05) and the rate of PSA change (P<.001) were associated with the development of lethal prostate cancer. In the ROC analysis, however, the accuracy of classifying the disease as either indolent or destined to progress was low, regardless of the cut point chosen for initial PSA level or rate of change in PSA level. CONCLUSIONS: Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer, they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are managed by watchful waiting.

  • 166. Fall, Katja
    et al.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bra prognosstudier kan ge bättre kliniska beslut2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 6, p. 279-283Article in journal (Refereed)
    Abstract [sv]

    Syftet med prognosstudier är primärt att skatta risken för ett utfall bland patienter på grupp- eller individnivå. För att kunna göra individuella riskbedömningar krävs prognosmodeller som baseras på risk- eller pro­gnosfaktorer.

    Modellens användbarhet är beroende av dess validitet och förmåga att korrekt skilja ut personer som i framtiden kommer att få ett ogynnsamt utfall från personer som inte kommer att få det.

    En kliniskt relevant risk- eller prognosfaktor (eller riskekvation som kombinerar flera sådana faktorer) kan kännas igen på att den när den används förändrar predicerad risk i hög grad och åt rätt håll, hos personer med en relevant absolut risk, vilket gör att den påverkar kliniskt beslutsfattande.

  • 167. Flanagan, John N.
    et al.
    Linder, Kristina
    Mejhert, Niklas
    Dungner, Elisabeth
    Wahlen, Kerstin
    Decaunes, Pauline
    Rydén, Mikael
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Arver, Stefan
    Bhasin, Shalender
    Bouloumie, Anne
    Arner, Peter
    Dahlman, Ingrid
    Role of follistatin in promoting adipogenesis in women2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 8, p. 3003-9Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Follistatin is a glycoprotein that binds and neutralizes biological activities of TGFbeta superfamily members including activin and myostatin. We previously identified by expression profiling that follistatin levels in white adipose tissue (WAT) were regulated by obesity. OBJECTIVE: The objective of the study was to elucidate the role of follistatin in human WAT and obesity. DESIGN: We measured secreted follistatin protein from WAT biopsies and fat cells in vitro. We also quantified follistatin mRNA expression in sc and visceral WAT and in WAT-fractionated cells and related it to obesity status, body region, and cellular origin. We investigated the effects of follistatin on adipocyte differentiation of progenitor cells in vitro. PARTICIPANTS: Women (n = 66) with a wide variation in body mass index were recruited by advertisement and from a clinic for weight-reduction therapy. RESULTS: WAT secreted follistatin in vitro. Follistatin mRNA levels in sc but not visceral WAT were decreased in obesity and restored to nonobese levels after weight reduction. Follistatin mRNA levels were high in the stroma-vascular fraction of WAT and low in adipocytes. Recombinant follistatin treatment promoted adipogenic differentiation of progenitor cells and neutralized the inhibitory action of myostatin on differentiation in vitro. Moreover, activin and myostatin signaling receptors were detected in WAT and adipocytes. CONCLUSION: Follistatin is a new adipokine important for adipogenesis. Down-regulated WAT expression of follistatin in obesity may counteract adiposity but could, by inhibiting adipogenesis, contribute to hypertrophic obesity (large fat cells) and insulin resistance.

  • 168. Fleischer, Thomas
    et al.
    Frigessi, Arnoldo
    Johnson, Kevin C.
    Edvardsen, Hege
    Touleimat, Nizar
    Klajic, Jovana
    Riis, Margit L. H.
    Haakensen, Vilde D.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Naume, Bjorn
    Helland, Aslaug
    Borresen-Dale, Anne-Lise
    Tost, Jorg
    Christensen, Brock C.
    Kristensen, Vessela N.
    Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 8, p. 435-Article in journal (Refereed)
    Abstract [en]

    Background: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. Results: We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. Conclusions: This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.

  • 169. Fonseca, Annabelle L.
    et al.
    Kugelberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Starker, Lee F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Scholl, Ute
    Choi, Murim
    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.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lifton, Richard P.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Carling, Tobias
    Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors2012In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 51, no 10, p. 949-960Article in journal (Refereed)
    Abstract [en]

    The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development. (c) 2012 Wiley Periodicals, Inc.

  • 170.
    Fraser, Sheila
    et al.
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Bender, Kyle
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Davidson, Joanne
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Bajenov, Sonya
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Fahey, David
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Li, Shawn
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Sidhu, Stan
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Sywak, Mark
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Randomized trial of low versus high carbon dioxide insufflation pressures in posterior retroperitoneoscopic adrenalectomy2018In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 163, no 5, p. 1128-1133Article in journal (Refereed)
    Abstract [en]

    Background: Posterior retroperitoneoscopic adrenalectomy has gained widespread acceptance for the removal of benign adrenal tumors. Higher insufflation pressures using carbon dioxide (CO2) are required, although the ideal starting pressure is unclear. This prospective, randomized, single-blinded, study aims to compare physiologic differences with 2 different CO2 insufflation pressures during posterior retroperitoneoscopic adrenalectomy.

    Methods: Participants were randomly assigned to a starting insufflation pressure of 20 mm Hg (low pressure) or 25 mm Hg (high pressure). The primary outcome measure was partial pressure of arterial CO2 at 60 minutes. Secondary outcomes included end-tidal CO2, arterial pH, blood pressure, and peak airway pressure. Breaches of protocol to change insufflation pressure were permitted if required and were recorded.

    Results: A prospective randomized trial including 31 patients (low pressure: n = 16; high pressure: n = 15) was undertaken. At 60 minutes, the high pressure group had greater mean partial pressure of arterial CO2 (64 vs 50 mm Hg, P = .003) and end-tidal CO2 (54 vs 45 mm Hg, P = .008) and a lesser pH (7.21 vs 7.29, P = .0005). There were no significant differences in base excess, peak airway pressure, operative time, or duration of hospital stay. Clinically indicated protocol breaches were more common in the low pressure than the high pressure group (8 vs 3, P = .03).

    Conclusion: In posterior retroperitoneoscopic adrenalectomy, greater insufflation pressures are associated with greater partial pressure of arterial CO2 and end-tidal CO2 and lesser pH at 60 minutes, be significant. Commencing with lesser CO2 insufflation pressures decreases intraoperative acidosis.

  • 171.
    Fraser, Sheila
    et al.
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, St Leonards, NSW, Australia..
    Zaidi, Nisar
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, St Leonards, NSW, Australia..
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Glover, Anthony
    Univ Sydney, Kolling Inst Med Res, St Leonards, NSW, Australia..
    Kruijff, Schelto
    Univ Med Ctr Groningen, Dept Surg Oncol, Groningen, Netherlands..
    Sywak, Mark
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, St Leonards, NSW, Australia..
    Delbridge, Leigh
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, St Leonards, NSW, Australia..
    Sidhu, Stan B.
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, St Leonards, NSW, Australia.;Univ Sydney, Kolling Inst Med Res, St Leonards, NSW, Australia..
    Incidence and Risk Factors for Occult Level 3 Lymph Node Metastases in Papillary Thyroid Cancer2016In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 23, no 11, p. 3587-3592Article in journal (Refereed)
    Abstract [en]

    Papillary thyroid cancer (PTC) frequently disseminates into cervical lymph nodes. Lateral node involvement is described in up to 50 % patients undergoing prophylactic lateral neck dissection. This study aimed to assess this finding and identify which factors predict for occult lateral node disease. Patients with fine needle aspiration-confirmed PTC (Bethesda V or VI), without evidence of cervical lymph node metastases, underwent a total thyroidectomy with prophylactic ipsilateral central and level 3 dissection. Level 3 nodes were removed by compartmental dissection or by sampling the sentinel nodes overlying the jugular vein, according to surgeon preference. Data were collected prospectively from January 2011 to August 2014. Statistical analysis was performed by SPSS software. A total of 137 patients underwent total thyroidectomy with prophylactic ipsilateral central and level 3 dissection for PTC. The incidence of occult level 3 disease was 30 % (41/137 patients). A total of 48 % of patients (66/137) harbored occult central neck disease. A total of 80.5 % of patients with pN1b disease had macrometastases (aeyen2 mm), and 15 % exhibited skip metastases with central compartment sparing. In patients with pN1b disease, a median of 6 level 3 nodes were retrieved, with an average involved nodal ratio of 0.29. Multivariate regression demonstrated risk factors for occult lateral neck metastasis include tumor size (odds ratio 1.1), upper pole tumors (odds ratio 6.6), and vascular invasion (odds ratio 3.2) (p < 0.05). PTC is associated with a significant incidence of occult central and lateral nodal metastases. In patients undergoing prophylactic central neck dissection, inclusion of level 3 dissection should be considered in patients with large upper lobe cancers.

  • 172. Fredholm, H.
    et al.
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindstrom, L. S.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eaker, Sonja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bergh, J.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Frisell, J.
    Fredriksson, I.
    Breast cancer in young women - age a risk factor only in those not given chemotherapy2014In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 23, no S1, p. S12-S12, article id HM31Article in journal (Other academic)
  • 173. Fredholm, Hanna
    et al.
    Eaker, Sonja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Frisell, Jan
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Fredriksson, Irma
    Lindman, Henrik
    Breast cancer in young women: poor survival despite intensive treatment2009In: PLoS one, ISSN 1932-6203, Vol. 4, no 11, p. e7695-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Breast cancer is uncommon in young women and correlates with a less favourable prognosis; still it is the most frequent cancer in women under 40, accounting for 30-40% of all incident female cancer. The aim of this study was to study prognosis in young women, quantifying how much stage at diagnosis and management on the one hand, and tumour biology on the other; each contribute to the worse prognosis seen in this age group. METHODOLOGY/PRINCIPAL FINDINGS: In a registry based cohort of women aged 20-69 (n = 22 017) with a primary diagnosis of invasive breast cancer (1992-2005), women aged 20-34 (n = 471), 35-39 (n = 858) and 40-49 (n = 4789) were compared with women aged 50-69 years (n = 15 899). The cumulative 5-year relative survival ratio and the relative excess mortality (RER) were calculated. The cumulative 5-year relative survival ratio was lowest in women aged 20-34. The RER was 2.84 for women aged 20-34 and decreased with increasing age (RER 1.76 and 1.17 for women aged 35-39 and 40-49, respectively). The excess risk was, however, present only in disease stages I and II. For women aged 20-34 with stage I disease RER was 4.63, and 6.70 in the subgroup with tumour size 1-10 mm. The absolute difference in stage I between the youngest and the reference groups amounted to nearly 8%, with a 90% 5-year survival in women aged 20-34. In stages IIa and IIb, the relative excess risk was not as dramatic, but the absolute differences approached 15%. The youngest women with small tumours generally received more aggressive treatment than women in older age groups. CONCLUSIONS: After correction for stage, tumour characteristics and treatment, age remained an independent risk factor for breast cancer death in women <35 years of age. The excess risk for young women was only seen in early stages of disease and was most pronounced in women with small tumours. Young women affected by breast cancer have a high risk of dying compared to their middle-aged counterparts even if diagnosed early and receiving an intense treatment.

  • 174.
    Fredholm, Hanna
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, P9 03, SE-17176 Stockholm, Sweden..
    Magnusson, Kristina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindstrom, Linda S.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Tobin, Nicholas P.
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, Stockholm, Sweden..
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bergh, Jonas
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, Stockholm, Sweden.;Karolinska Oncol, Radiumhemmet, Karolinska Univ Hosp, Stockholm, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Regional Cancer Center, Uppsala University Hospital, Uppsala, Sweden.
    Ponten, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Frisell, Jan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, P9 03, SE-17176 Stockholm, Sweden..
    Fredriksson, Irma
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, P9 03, SE-17176 Stockholm, Sweden..
    Breast cancer in young women and prognosis: How important are proliferation markers?2017In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 84, p. 278-289Article in journal (Refereed)
    Abstract [en]

    Aim:

    Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis.

    Methods:

    Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged >= 40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins.

    Results:

    Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR- tumours (hazard ratio [HR] 0.47 [0.24-0.92]). Age < 40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22-4.50]). Young women with luminal B PR- tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A ( HR 6.21 [2.17-17.6]).

    Conclusions:

    The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours.

  • 175.
    Fredholm, Hanna
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, S-17176 Stockholm, Sweden..
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindström, Linda S.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Fält, Sonja Eaker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Bergh, Jonas
    Karolinska Inst, Karolinska Univ Hosp, Dept Pathol & Oncol, Canc Ctr Karolinska & Karolinska Oncol,Radiumhemm, Stockholm, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frisell, Jan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, S-17176 Stockholm, Sweden..
    Fredriksson, Irma
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, S-17176 Stockholm, Sweden..
    Long-term outcome in young women with breast cancer: a population-based study2016In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 160, no 1, p. 131-143Article in journal (Refereed)
    Abstract [en]

    Whether young age at diagnosis of breast cancer is an independent risk factor for death remains controversial, and the question whether young age should be considered in treatment decisions is still to be answered. From a population-based cohort of 22,017 women with breast cancer, all women < 35 years (n = 471) were compared to a random sample of 700 women aged 35-69 years from the same cohort. Information on patient and tumor characteristics, treatment, and follow-up was collected from the medical records. Tissue microarrays were produced for analysis of classical biomarkers. Breast cancer-specific survival (BCSS), distant disease-free survival (DDFS), and locoregional recurrence-free survival (LRFS) by age were compared using women 50-69 years as reference. At 10 years follow-up, women < 35 years and 35-39 years had a worse BCSS [age < 35 years 69 % (HR 2.75, 95 % CI 1.93-3.94), age 35-39 years 76 % (HR 2.33, 95 % CI 1.54-3.52), age 40-49 years 84 % (HR 1.53, 95 % CI 0.97-2.39), and age 50-69 years 89 % (reference)]. The worse BCSS was statistically significant in stages I-IIa and Luminal B tumors. At multivariate analysis age < 35 years and 35-39 years confined a risk in LRFS (HR 2.13, 95 % CI 1.21-3.76 and HR 1.97, 95 % CI 1.06-3.68) but not in DDFS and BCSS. In the subgroup of women < 40 years with luminal tumors stage I-IIa, low age remained an independent risk factor also in DDFS (HR 1.87, 95 % CI 1.03-3.44). Young women have a high risk of systemic disease even when diagnosed in an early stage. The excess risk of relapse is most pronounced in Luminal B tumors, where low age is an independent prognostic factor of DDFS and LRFS.

  • 176. Frilling, A.
    et al.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Falconi, M.
    Pavel, M.
    Ramos, J.
    Kidd, M.
    Modlin, I. M.
    Neuroendocrine tumor disease: An evolving landscape2012In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 19, no 5, p. R163-R185Article, review/survey (Refereed)
    Abstract [en]

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of amultidimensional prognostic nomogrammay be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic diseasemay benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.

  • 177.
    Fyrsten, Ellen
    et al.
    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.
    Hessman, Ola
    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.
    Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism?2016In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 40, no 3, p. 615-621Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) is surgically treated with either a subtotal parathyroidectomy removing 3 or 3,5 glands (SPX), less than 3 glands (LSPX), or a total parathyroidectomy with autotransplantation (TPX). Previous studies with shorter follow-up have shown that LSPX and SPX are associated with recurrent HPT, and TPX with hypocalcemia and substitution therapy. We examined the situation after long-term follow-up (median 20,6 years).

    METHODS: Sixty-nine patients with MEN1 HPT underwent 110 operations, the first operation being 31 LSPX, 30 SPX, and 8 TPX. Thirty patients underwent reoperative surgery in median 120 months later, as completion to TPX (n = 12), completion of LSPX to SPX (n = 9), extirpation of single glands (n = 3) still resulting in LSPX, and resection of forearm grafts (n = 3). Nine patients underwent a second, and 2 a third reoperation. In 24 patients genetic testing confirmed MEN1, and in the remaining heredity and phenotype led to the diagnosis.

    RESULTS: TPX had higher risk for hypoparathyroidism necessitating substitution therapy, at latest follow-up 50 %, compared to SPX (16 % after 3-6 months; none at latest follow-up). Recurrent HPT was common after LSPX, leading to 24 reoperations in 17 patients. No need for substitution therapy after SPX indicated forthcoming recurrent disease. Not having hypocalcemia in the postoperative period and less radical surgery than TPX were significantly associated to risk for recurrence. Further, mutation in exon 3 in the MEN1 gene may eventually be linked to risk of recurrence.

    CONCLUSION: LSPX is highly associated with recurrence and TPX with continuous hypoparathyroidism, also after long-term follow-up. SPX should be the chosen method in the majority of patients with MEN1 HPT.

  • 178.
    Galichanin, Konstantin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Svedlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Söderberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Kinetics of GADD45a, TP53 and CASP3 gene expression in the rat lens in vivo in response to exposure to double threshold dose of UV-B radiation2012In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 97, no 1, p. 19-23Article in journal (Refereed)
    Abstract [en]

    The purpose of the present study was to investigate the evolution of expression of mRNA message for the genes for the genome stress sensor GADD45α, the apoptosis initiator TP53 and the apoptosis executor CASP3 in the rat lens in vivo in response to exposure to UVR around 300 nm. Forty six week old female albino Sprague-Dawley rats were unilaterally exposed to double threshold dose for cataract induction, 8 kJ/m2 (8.9 W/m2 for 15 min), of UVR (λmax = 300 nm). The animals were sacrificed at 1, 5, 24 and 120 h following exposure to UVR-B. For each of the GADD45α, TP53 and CASP3 genes, respectively, mRNA expression in the lenses was measured by quantitative RT-PCR. It was found that expression of mRNA for GADD45α transiently increases between 5 and 24 h after exposure. TP53 is slightly downregulated in exposed lenses at 1 and 5 h after exposure and thereafter the mRNA expression increases with a constant rate of 9.4∗10−3 rel. units/h to a 1.8 fold increase at 120 h after exposure. Expression of mRNA for CASP3 is downregulated at 1, 5 and 24 h after in vivo exposure and then increases with a constant rate of 4.7∗10−3 rel. units/h, upto a 1.3 fold upregulation at 120 h. Double threshold dose of UVR, for short delay onset of cataract, in vivo causes a transient upregulation of the stress sensor GADD45α, a concurrent downregulation of TP53 and CASP3, followed by a constant upregulation of TP53 that precedes a constant upregulation of CASP3.

  • 179.
    Garske, Ulrike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fröss-Baron, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lundin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Khan, Tanweera Shaheena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no 6, p. 970-988Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

    METHODS: Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%).

    RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

    CONCLUSIONS: Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

  • 180.
    Ghuan, Sundeep
    et al.
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Van Hemelrijck, Mieke
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England..
    Garmo, Hans
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England.;Reg Canc Ctr, Uppsala, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England.;Reg Canc Ctr, Uppsala, Sweden..
    Malmström, Håkan
    Karolinska Inst, Inst Environm Med, Dept Epidemiol, Stockholm, Sweden..
    Lambe, Mats
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hammar, Niklas
    AstraZeneca R&D, Molndal, Sweden.;Karolinska Inst, Inst Environm Med, Dept Cardiovasc Epidemiol, Stockholm, Sweden..
    Walldius, Göran
    Karolinska Inst, Inst Environm Med, Dept Cardiovasc Epidemiol, Stockholm, Sweden..
    Jungner, Ingmar
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;CALAB Res, Stockholm, Sweden..
    Wulaningsih, Wahyu
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London, England.;UCL, MRC, Unit Lifelong Hlth & Ageing, London, England..
    Serum inflammatory markers and colorectal cancer risk and survival2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 116, no 10, p. 1358-1365Article in journal (Refereed)
    Abstract [en]

    Background: Inflammation has been linked with development of some cancers. We investigated systemic inflammation in relation to colorectal cancer incidence and subsequent survival using common serum inflammatory markers

    Design: A cohort of men and women aged 20 years and older in greater Stockholm area with serum C-reactive protein (CRP) and albumin measured between 1986 and 1999 were included (n-325 599). A subset of these had baseline measurements of haptoglobin and leukocytes. Multivariable Cox regression was performed to assess risk of colorectal cancer by levels of inflammatory markers, adjusting for potential confounders. Analyses were stratified by circulating glucose, total cholesterol and triglycerides. Overall and CRC-specific death following diagnosis were assessed as secondary outcomes.

    Results: A total of 4764 individuals were diagnosed with colorectal cancer. A positive association between haptoglobin and colorectal cancer incidence was found (hazard ratio (HR): 1.17; 95% CI: 1.06-1.28). A positive association was also observed with leukocytes (HR: 1.21; 95% CI: 1.03-1.42). No evidence of association was noted between CRP and colorectal cancer risk. Higher risks of all-cause death were seen with haptoglobin and leukocytes levels. Higher haptoglobin levels were linked with an increased risk of colorectal cancer death (HR: 1.19; 95% CI: 1.01-1.41).

    Conclusions: Prediagnostic systemic inflammation may impact colorectal cancer incidence and survival; therefore, prompting investigations linking inflammatory pathways preceding colorectal cancer with disease severity and progression.

  • 181.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 182. Glover, Anthony R
    et al.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gundara, Justin S
    Morris, Michael
    Sidhu, Stan B
    Use of the Nerve Integrity Monitor during Thyroid Surgery Aids Identification of the External Branch of the Superior Laryngeal Nerve.2015In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 22, no 6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The external branch of the superior laryngeal nerve (EBSLN) is at risk during thyroid surgery. Despite meticulous dissection and visualization, the EBSLN can be mistaken for other structures. The nerve integrity monitor (NIM) allows EBSLN confirmation with cricothyroid twitch on stimulation.

    AIMS: The aim of this study was to assess any difference in identification of EBSLN and its anatomical sub-types by dissection alone compared to NIM-aided dissection.

    METHODS: Routine intra-operative nerve monitoring (IONM) was used, when available, for 228 consecutive thyroid operations (129 total thyroidectomies, 99 hemi-thyroidectomies) over a 10-month period. EBSLN identification by dissection alone (with NIM confirmation of cricothyroid twitch) and by NIM-assisted dissection was recorded prospectively. Anatomical sub-types were defined by the Cernea classification.

    RESULTS: Of 357 nerves at risk, 97.2 % EBSLNs (95 % confidence interval [CI], 95.5-98.9) were identified by visualization and NIM-aided dissection compared to 85.7 % (95 % CI, 82.1-89.3) identified by dissection alone (<0.001). EBSLN frequency was 34 % for type 1, 55 % for type 2a, and 11 % for type 2b. All identified EBSLNs were stimulated to confirm a cricothyroid twitch after superior thyroid vessel ligation.

    CONCLUSION: Using the NIM and meticulous dissection of the upper thyroid pole improves EBSLN identification. As the EBSLN is at risk during thyroidectomy and can lead to voice morbidity, the NIM can aid identification of the EBSLN and provide a functional assessment of the EBSLN after thyroid resection.

  • 183.
    Gobl, Anders E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berg, Mikael
    Lopez-Egido, Juan R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism1999In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1447, no 1, p. 51-56Article in journal (Refereed)
    Abstract [en]

    Recently the multiple endocrine neoplasia type 1 (MEN-1) tumor suppressor gene was cloned. MEN-1 encodes a nuclear protein, called menin, of hitherto unknown function. In order to investigate the biological function of menin we employed the yeast two-hybrid system to identify menin-interacting proteins. Here we report that menin functions as a transcriptional repressor through interaction with the transcription factor JunD. The interaction is mediated via the N-terminal transcription activation domain of JunD, and the C-terminal part of menin. In transient co-transfection experiments, expression of menin leads to specific repression of JunD transcriptional activity, which is dependent on the integrity of the menin C-terminal region. C-Terminal truncations of the protein not only abolish repression, but increase JunD transcriptional activity, implying the existence of a functional domain separate from the JunD-binding region. Menin-mediated repression is relieved by the histone deacetylase inhibitor trichostatin A, indicating that deacetylation of histones is an essential component of this repression mechanism, as has recently been demonstrated for the retinoblastoma protein. Missense, in-frame deletions, frameshift and nonsense mutations lead to inactivation of menin or possibly to truncated proteins. This would result in loss of repression of menin/JunD target genes, as well as non-target genes through indirect mechanisms, deregulation of cellular growth control and endocrine tumorigenesis.

  • 184. Goh, Gerald
    et al.
    Scholl, Ute
    Healy, James
    Choi, Murim
    Prasad, Manju L
    Nelson-Williams, Carol
    Kuntsman, John W
    Korah, Reju
    Suttorp, Anna-Carinna
    Dietrich, Dimo
    Haase, Mathias
    Willenberg, Holger S
    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.
    Åkerström, Göran
    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.
    Carling, Tobias
    Lifton, Richard P
    Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 6, p. 613-617Article in journal (Refereed)