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  • Cui, Tao, 1982- (författare)
  • Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Small intestine neuroendocrine tumors (SI-NETs) and lung carcinoids (LCs) are relatively indolent tumors, which originate from neuroendocrine (NE) cells of the diffuse NE system. Metastases can spread before diagnosis. Thus, potential cures become unavailable, which entitles new biomarker development. Indeed, we aimed at developing Ma2 autoantibodies and olfactory receptor 51E1 (OR51E1) as potential novel biomarkers and exploring other candidate protein markers in patients’ serum.</p><p>First, we established a sensitive, specific and reliable anti-Ma2 indirect ELISA to distinguish SI-NET patients from healthy controls. We detected longer progression-free and recurrence-free survivals in patients expressing low anti-Ma2 titers. Moreover, a high anti-Ma2 titer was more sensitive than chromogranin A for the risk of recurrence after radical operation of SI-NET patients.</p><p>We then investigated OR51E1 expression in SI-NETs and LCs. OR51E1 mRNA expression, analyzed by quantitative real-time PCR, was high in microdissected SI-NET cells, in LC cell lines and in frozen LC specimens. Immunohistochemistry (IHC) showed abundant OR51E1 protein expression in SI-NETs. OR51E1 co-expressed with vesicular-monoamine-transporter-1 in the majority of normal and neoplastic enterochromaffin cells.</p><p>Furthermore, the study on LCs revealed that OR51E1, somatostatin receptor (SSTR) 2, SSTR3, and SSTR5 are expressed in 85%, 71%, 25% and 39% of typical carcinoids (TCs), whereas in 86%, 79%, 43% and 36% of atypical carcinoids (ACs). Based on the proposed IHC scoring system, in the LC cases, where all SSTR subtypes were absent, membrane OR51E1 expression was detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 scores were detected in 5 out of 6 OctreoScan-negative LC lesions.</p><p>In addition, the last presented study used a novel suspension bead array, which targeted 124 unique proteins, by using Human Protein Atlas antibodies, to profile biotinylated serum samples from SI-NET patients and healthy controls. We showed 9 proteins, IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP as significant contributors to tumor classification.</p><p>In conclusion, we proposed Ma2 autoantibodies as a sensitive circulating marker for SI-NET recurrence; OR51E1 as a candidate therapeutic target for SI-NETs; whereas as a novel diagnostic marker for LCs and 9 serum proteins as novel potential SI-NET markers.</p>
  • Darmanis, Spyros, et al. (författare)
  • Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
  • 2013
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 8:11, s. e81712
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Background</strong></p><p>Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.</p><p><strong>Materials and methods</strong></p><p>Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.</p><p><strong>Results </strong></p><p>A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.</p><p><strong>Conclusions</strong></p><p>We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.</p>
  • Slind Olsen, Renate (författare)
  • Circulating and genetic factors in colorectal cancer Potential factors for establishing prognosis?
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Kolorektal cancer är en tumör i kolon eller rektum. I Sverige diagnosticerades år 2014 ca6300 individer med denna cancertyp och ca 2550 personer dör årligen till följd av kolorektalcancer. Operation är det huvudsakliga behandlingsalternativet för kolorektal cancer och vidfjärrmetastaser är överlevnaden &lt; 10 %. Det är därför viktigt att hitta markörer somtillsammans med TNM-stadium kan ge tidig information om sjukdomens prognos och lämpliguppföljning av patienter.</p><p>Utveckling av kolorektal cancer sker genom ackumulering av genetiska mutationer ochepigenetisk nedreglering av tumörsuppressorgener. Därutöver spelar interaktionen mellantumören och dess närmaste omgivning, innehållande tillväxt- och inflammatoriska faktorer,en viktig roll i tumörens utveckling och metastasering.</p><p>Syftet med avhandlingen var att studera associationen mellan CD93, PLA2G4C, PDGF-D samtinflammatoriska cytokiner och kolorektal cancer progression.</p><p>En prospektiv studie visade att CD93 och PLA2G4C SNP var potentiellt viktiga förbedömningav kolorektal cancer prognos. T/T genotypen av SNP rs2749817 i CD93 var associerad medhögre uttryck av CD93 i kolorektal cancer vävnad, främst bland patienter i stadium IV.Därutöver observerades fler återfall efter operation hos patienter med T/T genotypen. Aallelen hos PLA2G4C SNP rs1549637 är en möjligtvis bättre markör för cancerspecifiköverlevnad vid stadium II än faktorer som idag används för att selektera patienter tilladjuvant behandling. Sammantaget antyder detta att T/T genotypen av CD93 och A allelenav PLA2G4C kan vara genetiska markörer relaterade till allvarlig tumörsjukdom ochspridning. Därutöver kan de eventuellt selektera patienter som kräver tätare uppföljning ochadjuvant behandling.</p><p>För att studera den förmodade inblandningen av PDGF-D i kolorektal cancer undersöktesdess effekt på PDGF-D signalering in vitro. PDGF-D signaleringen förändradegenexpressionen av gener involverade i tumörutveckling och spridning, vilken kundeblockeras av tyrosinkinashämmaren imatinib. Det antyder att PDGF-D signalering kan vara enviktig faktor vid kolorektal cancer progression och ett potentiellt mål för behandling. Analysen av ett flertal inflammatoriska cytokiner visade en korrelation mellan högacytokinnivåer och ökad cancerspecifik och total dödlighet två år efter operation. Höga CCL1och CCL24 nivåer var de enda faktorerna som förblev signifikant associerade medcancerspecifik mortalitet vid fördjupad statistisk analys och bör studeras vidare.</p><p>Sammanfattningsvis presenterar denna avhandling cirkulerande och genetiska faktorersåsom CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 som eventuellt är viktiga vid bedömning avkolorektal cancer progression tillsammans med TNM stadium.</p>
  • Gustafson, Lars, et al. (författare)
  • A factor analytic approach to symptom patterns in dementia.
  • 2010
  • Ingår i: International Journal of Alzheimer's Disease. - Hindawi Limited. - 2090-0252.
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales.
  • Kaboteh, Reza, et al. (författare)
  • Evaluation of changes in Bone Scan Index at different acquisition time-points in bone scintigraphy
  • 2018
  • Ingår i: Clinical Physiology and Functional Imaging. - Wiley Online Library. - 1475-0961. ; 38:6, s. 1015-1020
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone Scan Index (BSI) is a validated imaging biomarker to objectively assess tumour burden in bone in patients with prostate cancer, and can be used to monitor treatment response. It is not known if BSI is significantly altered when images are acquired at a time difference of 1 h. The aim of this study was to investigate if automatic calculation of BSI is affected when images are acquired 1 hour apart, after approximately 3 and 4 h. We prospectively studied patients with prostate cancer who were referred for bone scintigraphy according to clinical routine. The patients performed a whole-body bone scan at approximately 3 h after injection of radiolabelled bisphosphonate and a second 1 h after the first. BSI values for each bone scintigraphy were obtained using EXINI boneBSI software. A total of 25 patients were included. Median BSI for the first acquisition was 0·05 (range 0-11·93) and for the second acquisition 0·21 (range 0-13·06). There was a statistically significant increase in BSI at the second image acquisition compared to the first (P<0·001). In seven of 25 patients (28%) and in seven of 13 patients with BSI > 0 (54%), a clinically significant increase (>0·3) was observed. The time between injection and scanning should be fixed when changes in BSI are important, for example when monitoring therapeutic efficacy.
  • Ahlgren, Johan, 1960- (författare)
  • Studies on Prediction of Axillary Lymph Node Status in Invasive Breast Cancer
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Breast cancer is the most common malignancy among females in Sweden. Axillary lymph-node dissection is a standard procedure in the management of breast cancer, aiming at obtaining prognostic information for adjuvant therapy decisions. Axillary dissection entails considerable morbidity. The aims of this study were to establish more selective surgical approaches and to investigate angiogenesis, a potential predictor for lymph-node metastases and prognosis.</p><p>Clinical nodal status, tumour size and S-phase were associated with nodal metastases in cohort of 1145 women. The proportion of nodal metastases was 13% in the subgroup with the lowest risk.</p><p>In a study from two registries, 675 and 1035 breast cancers ≤10 mm diagnosed by screening mammography had nodal metastases in 6,5% and 7%, respectively. Clinically detected cancers had a risk of 16% and 14%, respectively.</p><p>In a study on 415 women, a 5-node biopsy of the axilla had a sensitivity of 97,3% and a false negative rate of 2,7% in comparison with axillary dissection.</p><p>Six sections from 21 breast cancers were analysed for microvessel density (MVD). The inter-section variation contributed more to the total variance than inter-tumour variation, 45,0% and 37,3%, respectively.</p><p>In a cohort of 315 women, breast cancers with high MVD more frequently had p53 mutations (27,1%) compared with cases with low MVD (18,4%). This difference was not statistically significant (p=0,075). p53 mutations were associated with a worse outcome, whereas MVD was not.</p><p>In conclusion, women with screening detected ≤10 mm breast cancers have a low risk of lymph node metastases and some may not need axillary dissection in the future. The 5-node biopsy could be an alternative to axillary dissection. MVD is associated with methodological weaknesses and routine use is not recommended.</p>
  • Berglund, Åke, 1961- (författare)
  • Optimisation of Chemotherapy Treatment in Advanced Colorectal Cancer
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Colorectal cancer is one of the most common malignant diseases in Sweden – more than 5000 new cases are diagnosed each year. The overall five-year survival is about 60% and in cases of recurrence the prognosis is poor.</p><p>In a phase III study in advanced colorectal cancer the response rate was doubled when 5-FU was given as a bolus injection versus as a short infusion. The toxicity was similar and time to progression was longer in the injection group. However, overall survival was not significantly different. Dose-effect relationships of 5-FU were studied in another phase III study recruiting 312 patients. A decrease from 500 mg/m<sup>2</sup> to 400 mg/m<sup>2</sup> worsened the treatment results. A low incidence of severe toxicity was seen in both groups. An increase to 600 mg/m<sup>2</sup> worsened the toxicity without any improvement of the results.</p><p>A cytotoxic drug sensitivity test in different tumour types, mainly gastrointestinal cancer, poorly predicted treatment outcome in a phase II study.</p><p>The conventional Nordic Flv regimen was split in a phase I/II trial. An escalation of dose was possible and the response rate was 20%.</p><p>Thymidylate synthase (TS) and the gene expression of p53 were investigated by immunohistochemical technique in the primary tumours of 132 patients. None of the markers predicted the later palliative chemotherapy result. However, TS significantly predicted time to recurrence.</p><p>Serum markers were analysed before and during FLv treatment to early predict outcomes among 87 patients. TPS is promising, both as a predictive marker before start of treatment and after a short period of treatment. In the same setting, CEA had lower predictive value. S-VEGF and S-bFGF did not yield any prognostic information of later outcome. In all studies B-haemoglobin values, performance status and subjective response were strong markers, both for prediction of objective response and for survival.</p>
  • Bergqvist, Michael, 1971- (författare)
  • Radiosensitivity in lung cancer with focus on p53
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>In Sweden approximately 2800 new lung cancer patients are diagnosed every year. Radiotherapy is used with curative intention in certain groups of patients. The aim of this thesis is to study the basis of differences in radioresistance and the possibility to predict response to radiotherapy.</p><p>In the first study we investigated, using the comet assay, four lung cancer cell lines with different sensitivity towards radiation. A clear dose-response relationship for radiation-induced DNA single strand and double strand breaks were found. All cell lines showed a remarkably efficient repair of both the DNA single strand and double strand breaks one hour after irradiation. However, further studies in one radioresistant and one radiosensitive cell line demonstrated that repair during the first 15 min had the best accordance with radiosensitivity measured as surviving fraction.</p><p>In the second and third study, sequencing studies of the p53 gene were performed on cell lines as well as on tumour material. Cell lines that were expressing a mutation in exon 7 were associated with increased radiosensitivity compared with tumor cell lines with mutations in other exons. In the clinical study, 10 patients were found to be mutated in the p53 gene whereas the other 10 patients were not. No correlation to clinical parameters could be drawn.</p><p>In the fourth study, serum from 67 patients with a confirmed diagnosis of non-small cell lung cancer was investigated for the presence of p53 antibodies. P53 antibodies in sera, taken prior to radiation treatment, were associated with increased survival.</p><p>The summary of this thesis indicates that the p53 gene has an impact on the effect of radiotherapy in lung cancer. The presence of p53 antibodies might be of clinical interest for predicting survival after radiotherapy. Further studies on the importance of the p53 gene on early repair are of interest. </p>
  • Carlsson, Maria (författare)
  • Informational support for patients with gynaecological cancer and their families
  • 1997
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The main purpose of the present thesis was to gain a deeper knowledge and understanding of the informational need by women with gynaecological cancer and their families. The studies evaluate the experience of different kind of information giving; a telephone-help line; a 3 years educational group support programme; and information givings in ordinary care.</p><p>There was a significant correlation to interest in an educational supportive group in the prestudy depending on age, legal status, educational level. Younger individuals, couples and people with a higher formal education were generally more interesting in participating (p&lt;0.05). Patients who actively chose to participate m a an educational support group differed from the unselected control group even prior the intervention, they with a higher formal education were generally more interesting in participating, they felt more confused and angry than the control group. After intervention, the patients in the interventional group reported a significant improved level of knowledge about cancer.</p><p>Both patients and next-of-kin request information about medical- and psychological aspects of the disease and its treatment. The evaluation of the questions in the educational supportive group show that patients and their relatives asked questions of a general nature, related to basic knowledge of cancer and treatment principles, and not directly related to their own illness. There was no general difference in knowledge level between cancer patients and the controls of healthy women. The length of formal education was the most important determinator of correct answers (p&lt;0.01).</p><p>Two main themes were revealed at the interviews about the patients informations preferences. These were to actively address questions and the right to receive honest information;</p><p>It is concluded that differential information giving techniques are required to satisfy the patients' different preferences. The patients express an active role in the information giving process. They preferred information with numerous opportunities to address questions, that the staff have time for questions and that the questions are honestly answered.</p>
  • Jansson, Tomas (författare)
  • Methods for selection and optimisation of radiotherapy and early therapy evaluation in breast cancer
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Adjuvant systemic therapy for breast cancer, the most common malignancy in females, increases survival and this has recently also been demonstrated for postoperative radiotherapy. The aims of this study were to develop an optimised radiotherapeutic technique for postoperative treatment, to analyse the association between p53 status in node-negative patients and radiotherapy, to investigate the incidence of in-breast relapses after conservative surgery and radiotherapy and to determine if positron emissiontomography could be useful for early evaluation of polychemotherapy.</p><p>A technique with mixed photon and electron beams from an accelerator equipped with a multileaf collimator was developed for irradiation of the breast parenchyma and regional lymph nodes after breast-conserving surgery.</p><p>Lymph node negative patients with p53 mutated cancers treated with radiotherapy to either the ipsilateral breast parenchyma after sector resection, or the parasternal and supraclavicular fossa after modified radical mastectomy due to medial or central tumours had a statistically significant longer relapse-free, breast cancer-corrected, and overall survival (<i>p</i>=0.0007, <i>p</i>=0.001, <i>p</i>=0.02, respectively) compared with non-irradiated patients.</p><p>In 672 patients with pT1N0M0 cancers treated with radiotherapy (54 Gy) after breast-conserving surgery 2.5% in-breast relapses appeared after a mean follow-up of 6.8 years.</p><p>Positron emission tomography with <sup>18</sup>FDG and <sup>11</sup>C-methionine revealed a decrease in tumour metabolism one to two weeks after the first course of polychemotherapy in 11 of 12 clinically responding patients.</p>
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