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  • 1.
    Aarnivala, Henri
    et al.
    Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland.;Univ Oulu, PEDEGO Res Unit, Oulu, Finland..
    Harila-Saari, Arja H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Niinimaki, Riitta
    Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland.;Univ Oulu, PEDEGO Res Unit, Oulu, Finland..
    Reply to Ian J. Cohen2022In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 30, no 3, p. 1901-1902Article in journal (Other academic)
  • 2.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Granath, Fredrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetry2019In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 128, p. 54-60Article in journal (Refereed)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for improved cancer risk estimation of genotoxic compounds. According to this model, cancer risk is proportional to the background tumor incidence and to the internal dose of the genotoxic compound. Furthermore, the relative risk coefficient per internal dose is considered to be approximately the same across tumor sites, sex, and species. In the present study, we demonstrate that the relative risk model is valid for cancer risk estimation of glycidol, a common food contaminant. Published tumor data from glycidol carcinogenicity studies in mice and rats were evaluated in combination with internal dose estimates from hemoglobin adduct measurements in blood from mice and rats treated with glycidol in short-term studies. A good agreement between predicted and observed tumor incidence in responding sites was demonstrated in the animals, supporting a relative risk coefficient that is independent of tumor site, sex, and species. There was no significant difference between the risk coefficients for mice (5.1% per mMh) and rats (5.4% per mMh) when considering internal doses of glycidol. Altogether, this mechanism-based risk model gives a reliable risk coefficient, which then was extrapolated to humans considering internal dose, and background cancer incidence.

  • 3.
    Aasebö, Kristine Ö.
    et al.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    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.
    Eide, Geir Egil
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Lifestyle Epidemiol Grp, Bergen, Norway;Haukeland Hosp, Ctr Clin Res, Bergen, Norway.
    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, Clinical and experimental pathology.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sorbye, Halfdan
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients2019In: Cancer Medicine, E-ISSN 2045-7634, Vol. 8, no 7, p. 3623-3635Article in journal (Refereed)
    Abstract [en]

    Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

    Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

    Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

    Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

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    FULLTEXT01
  • 4. Aasebø, Kristine
    et al.
    Bruun, Jarle
    Bergsland, Christian H
    Nunes, Luís
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eide, Geir Egil
    Pfeiffer, Per
    Dahl, Olav
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lothe, Ragnhild A
    Sorbye, Halfdan
    Prognostic role of tumour-infiltrating lymphocytes and macrophages in relation to MSI, CDX2 and BRAF status: a population-based study of metastatic colorectal cancer patients2022In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 126, no 1, p. 48-56Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages are associated with favourable prognosis in localised colorectal cancer, but the effect in metastatic colorectal cancer (mCRC) is not established.

    METHODS: A Scandinavian population-based cohort of non-resectable mCRC patients was studied. Tissue microarrays (n = 460) were stained with CD3, CD8 and CD68 using fluorescence-based multiplex immunohistochemistry. Associations with clinicopathological variables, overall survival (OS) and progression-free survival were estimated.

    RESULTS: Two-thirds of microsatellite instable (MSI) and one-fourth of microsatellite stable (MSS) tumours displayed the highest quartile density of CD8. For CD3 high vs low cases, median OS was 20 vs 16 months (HR: 0.76, 95% CI: 0.59, 0.76, p = 0.025) with 3-year OS of 27 vs 13%. For CD68 high vs low cases, median OS was 23 vs 15 months (HR: 0.69, 95% CI: 0.54, 0.88, p = 0.003) with 3-year OS of 28 vs 12%. MSI, BRAF mutation and CDX2 loss were negative prognostic markers independent of tumour immune infiltration.

    CONCLUSIONS: In mCRC, high lymphocyte infiltration was found in proportions of MSI and MSS tumours-potential subgroups of immunotherapy response. Tumour-infiltrating CD3 lymphocytes and CD68 macrophages were associated with median and long-term survival. MSI was a significant negative prognostic marker despite high immunogenicity.

  • 5.
    Abalo, Kossi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Karolinska Inst, Dept Med Solna, Clin Epidemiol Div, Stockholm, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Div, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Ekberg, Sara
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Div, Stockholm, Sweden..
    Eloranta, Sandra
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Div, Stockholm, Sweden..
    Pahnke, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Albertsson-Lindblad, Alexandra
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Div Oncol, Lund, Sweden..
    Jerkeman, Mats
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Div Oncol, Lund, Sweden..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Karolinska Inst, Dept Med Solna, Clin Epidemiol Div, Stockholm, Sweden..
    Secondary malignancies among mantle cell lymphoma patients2023In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 195, article id 113403Article in journal (Refereed)
    Abstract [en]

    Purpose:

    With modern treatments, mantle cell lymphoma (MCL) patients more frequently experience long-lasting remission resulting in a growing population of long-term survivors. Follow-up care includes identification and management of treatment-related late-effects, such as secondary malignancies (SM). We conducted a populationbased study to describe the burden of SM in MCL patients.

    Methods:

    All patients with a primary diagnosis of MCL, aged >= 18 years and diagnosed between 2000 and 2017 in Sweden were included along with up to 10 individually matched population comparators. Follow-up was from twelve months after diagnosis/matching until death, emigration, or December 2019, whichever occurred first. Rates of SM among patients and comparators were estimated using the Anderson-Gill method (accounting for repeated events) and presented as hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age at diagnosis, calendar year, sex, and the number of previous events.

    Results:

    Overall, 1 452 patients and 13 992 comparators were followed for 6.6 years on average. Among patients, 230 (16%) developed at least one SM, and 264 SM were observed. Relative to comparators, patients had a higher rate of SM, HRadj= 1.6 (95%CI:1.4-1.8), and higher rates were observed across all primary treatment groups: the Nordic-MCL2 protocol, R-CHOP, R-bendamustine, ibrutinib, lenalidomide, and R-CHOP/Cytarabine. Compared to Nordic-MCL2, treatment with R-bendamustine was independently associated with an increased risk of SM, HRadj= 2.0 (95%CI:1.3-3.2). Risk groups among patients were those with a higher age at diagnosis (p < 0.001), males (p = 0.006), and having a family history of lymphoma (p = 0.009). Patients had preferably higher risk of melanoma, other neoplasms of the skin and other hematopoietic and lymphoid malignancies.

    Conclusions:

    MCL survivors have an increased risk of SM, particularly if treated with R-bendamustine. The intensive treatments needed for long-term remissions are a concern, and transition to treatment protocols with sustained efficacy but with a lower risk of SM is needed.

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  • 6.
    Abbas, Hassan
    et al.
    Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine.
    Huzeirovic, Melisa
    Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine.
    En jämförelse mellan två sjukdomsgrupper med PET/CT som undersökningsmetod: Beräkning av den totala effektiva dosen från PET- och CT-undersökning2019Independent thesis Basic level (degree of Bachelor), 180 HE creditsStudent thesis
    Abstract [en]

    Background: Lung cancer and malignant melanoma are diseases investigated by the dual-modality positron emission tomography/computed tomography (PET/CT). There are radiation risks with the examination that can appear as stochastic effects such as cancer. The aim of this study was to compare the radiation doses between the lung cancer group (suspected or verified) and the malignant melanoma group by calculating the total effective radiation dose and to declare the risk with the PET/CT examination. Material and method: The material contained parameters regarding the examination and the sample contained 20 patients from the two groups. The method was retrospective with a quantitative approach. Results: There was a significant difference (p <0,001) between these two groups, were the lung cancer group received 11,95 milliSievert (mSv) and the malignant melanoma group 6,03 mSv and the percentage risk for lethal cancer increased by 0,06% and 0,03%, respectively. Conclusions: The lung cancer group received twice as much effective dose than the malignant melanoma group. However, the effective dose is so low that the risk increase of the lethal cancer is marginal, and the benefit of the examination outweighs the risks.

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    FULLTEXT01
  • 7. Abbas, Sascha
    et al.
    Linseisen, Jakob
    Rohrmann, Sabine
    Chang-Claude, Jenny
    Peeters, Petra H
    Engel, Pierre
    Brustad, Magritt
    Lund, Eiliv
    Skeie, Guri
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Kaaks, Rudolf
    Boeing, Heiner
    Buijsse, Brian
    Adarakis, George
    Ouranos, Vassilis
    Trichopoulou, Antonia
    Masala, Giovanna
    Krogh, Vittorio
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Buckland, Genevieve
    Suárez, Marcial Vicente Argüelles
    Sánchez, Maria-José
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Amiano, Pilar
    Manjer, Jonas
    Wirfält, Elisabet
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bueno-de-Mesquita, H B
    van Duijnhoven, Fränzel J B
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J
    Fedirko, Veronika
    Romieu, Isabelle
    Gallo, Valentina
    Norat, Teresa
    Wark, Petra A
    Riboli, Elio
    Dietary intake of vitamin D and calcium and breast cancer risk in the European prospective investigation into cancer and nutrition2013In: Nutrition and Cancer, ISSN 0163-5581, E-ISSN 1532-7914, Vol. 65, no 2, p. 178-187Article in journal (Refereed)
    Abstract [en]

    Studies assessing the effects of vitamin D or calcium intake on breast cancer risk have been inconclusive. Furthermore, few studies have evaluated them jointly. This study is the largest so far examining the association of dietary vitamin D and calcium intake with breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. During a mean follow-up of 8.8 yr, 7760 incident invasive breast cancer cases were identified among 319,985 women. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pre- and postmenopausal breast cancer risk. Comparing the highest with the lowest quintile of vitamin D intake, HR and 95% CI were 1.07 (0.87-1.32) and 1.02 (0.90-1.16) for pre- and postmenopausal women, respectively. The corresponding HR and 95% CIs for calcium intake were 0.98 (0.80-1.19) and 0.90 (0.79-1.02), respectively. For calcium intake in postmenopausal women, the test for trend was borderline statistically significant (P(trend) = 0.05). There was no significant interaction between vitamin D and calcium intake and cancer risk (P(interaction) = 0.57 and 0.22 in pre- and postmenopausal women, respectively). In this large prospective cohort, we found no evidence for an association between dietary vitamin D or calcium intake and breast cancer risk.

  • 8.
    Abdalla Omer, Hemn
    et al.
    University of Sulaimani.
    Amin, Kawa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    TGFβ1, SMAD2, CTNNβ1, and Wnt3a gene mutational status and serum concentrations in individuals with non-small cell lung cancer2023In: Cellular and Molecular Biology, ISSN 0145-5680, E-ISSN 1165-158X, Vol. 69, no 11, p. 81-91Article in journal (Refereed)
    Abstract [en]

    The objective of the current investigation was to investigate the diagnostic utility of the serum concentrations and mutational status of TGFβ1, SMAD2, CTNNβ1, and Wnt3a. and the expression levels of human-rela-ted genes in patients with non-small cell lung cancer (NSCLC). The serum concentrations were determined using the ELISA technique, and PCR for genotype variations of TGFβ1, SMAD2, CTNNβ1, and Wnt3a were examined using Sanger sequencing in tissue samples obtained from 93 patients with NSCLC and 84 healthy individuals for blood, and 20 Formalin Fixed Paraffin Embedded (FFPE) from normal samples dissected adja-cent to the tumour. The findings of the current investigation indicate that individuals diagnosed with NSCLC exhibited significant elevation in the serum levels of CEA and CYFRA21-1, as well as TGFβ1, SMAD2, CTNNβ1, and Wnt3a. In total, 325 mutations in four trialled genes (243 mutations in TGFβ1, 24 mutations in SMAD2,47 mutation Wnt3a and 11 mutations in CTNNβ1) were identified in patients with NSCLC. Fur-thermore, all mutations were recorded in adenocarcinoma, not squamous and normal adjacent tumour cells. CYFRA21-1 and CEA are more significant between NSCLC and HC, gender, and NSCLC types (p<0.001). In detail, TGFβ1 exhibited the highest rate of mutations among other genes and three types of genomic mutations. Elevated levels and genetic polymorphisms of TGFβ1, SMAD2, CTNNβ1, and Wnt3a may play crucial func-tions in the pathogenesis and angiogenesis of non-small cell lung cancer (NSCLC). These biomarkers might play a role in future immunologic response and pharmacologically targeted NSCLC therapy.

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  • 9.
    Abdalla Omer, Hemn
    et al.
    Department of Microbiology/Immunology, College of Medicine, University of Suleimani, Sulaymaniyah, Iraq.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Amin, Kawa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Department of Microbiology/Immunology, College of Medicine, University of Suleimani, Sulaymaniyah, Iraq.
    The role of inflammatory and remodelling biomarkers in patients with non-small cell lung cancer2023In: Central European Journal of Immunology, ISSN 1426-3912, E-ISSN 1644-4124, Vol. 48, no 4, p. 330-337Article in journal (Refereed)
    Abstract [en]

    Introduction:

    Biomarkers play a crucial role in evaluating the prognosis, diagnosis, and monitoringof non-small cell lung cancer (NSCLC). The aim of this study was to compare the levels of inflammatoryand remodelling biomarkers among patients with NSCLC and healthy controls (HCs) and to investigatethe correlation between these biomarkers.

    Material and methods:

    Blood samples were taken from 93 NSCLC and 84 HCs. Each sample wasanalysed for the inflammatory biomarkers transforming growth factor β1 (TGF-β1), mothers againstdecapentaplegic homolog 2 (SMAD2) and the remodelling biomarkers Wingless-related integration site(Wnt3a) and β-catenin (CTNN-β1).

    Results:

    The patients with NSCLC had significantly higher levels of all the measured biomarkers.In the NSCLC patients, TGF-β1 correlated significantly with SMAD2 (r = 0.34, p = 0.0008), Wnt3a(r = 0.328, p = 0.0013), and CTNN-β1 levels (r = 0.30, p = 0.004). SMAD2 correlated significantlywith CTNN-β1 (r = 0.546, p = 0.0001) and Wnt3a (r = 0.598, p = 0.0001). CTNN-β1 level also correlated with the level of Wnt3a (r = 0.61, p = 0.0001). No correlation was found between biomarkersand symptom scores.

    Discussion:

    In this study, patients with NSCLC had higher inflammatory and remodelling biomarker levels than HCs. In the NSCLC, there were significant associations between inflammatory andremodelling biomarkers. This indicates that measuring biomarkers could be valuable in the workupof NSCLC patients.

    Conclusions:

    Our investigation showed that inflammatory and remodelling biomarkers might playa role in future immunologic response and pharmacologically targeted NSCLC therapy.

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    Lung Cancer
  • 10.
    Abdelaal, Abdelrahman
    et al.
    Department of General Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    El Ansari, Walid
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Department of Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar / College of Medicine, Qatar University, Doha, Qatar.
    Abusabeib, Abdelrahman
    Department of General Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    Farghaly, Hanan
    Department of Lab Medicine & Pathology, Hamad General Hospital, Doha, Qatar.
    Tabeb, Abdelhakem A. M.
    Department of General Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    Simultaneous occurrence of follicular and papillary thyroid carcinomas in same thyroid lobe: A case series of six patients from Qatar2020In: International Journal of Surgery Case Reports, E-ISSN 2210-2612, Vol. 73, p. 65-70Article in journal (Refereed)
    Abstract [en]

    Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are the first and second most common thyroid cancers comprising about 85% and 10% of all thyroid cancers. Simultaneous occurrence of medullary and papillary thyroid cancer has been reported with various presentations, but simultaneous occurrence of FTC in addition to PTC as differentiated cancers, is an unusual event that is rarely reported. Presentation of cases: We report our experience of six rare cases of synchronous coexistence of FTC and PTC with unique features. Case 1 is 31 old Egyptian female. Case 2 is a 61 year old Sudanese male. Case 3 is a 59 year old Sudanese male. Case 4 is a 56 years old Indian female. Case 5 is a 35 years old Filipina female. Case 6 is a 52 years old Qatari female. The six cases are special in their co-occurrence of two thyroid carcinoma, consisting of histologic features of follicular thyroid carcinomas, and classical papillary thyroid carcinoma, possibly the first case series of simultaneous occurrence of these two types of thyroid cancer in the Middle East and North Africa Region. Conclusions: We present rare cases of concurrent FTC and PTC. These six cases add more data highlighting the coincidental simultaneous coexistence of FTC and PTC. Endocrinologists and pathologists should be aware of and vigilant to this variety. © 2020 The Author(s)

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  • 11.
    Abdellah, Tebani
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. Normandie Univ, Dept Metab Biochem, UNIROUEN, INSERM,U1245,CHU Rouen, F-76000 Rouen, France..
    Jotanovic, Jelena
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.;Uppsala Univ Hosp, Dept Clin Pathol, Uppsala, Sweden..
    Hekmati, Neda
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Sivertsson, Åsa
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Gudjonsson, Olafur
    Uppsala Univ, Dept Neurosci, Uppsala, Sweden..
    Engstrom, Britt Eden
    Uppsala Univ, Dept Med Sci Endocrinol & Mineral Metab, Uppsala, Sweden..
    Wikstrom, Johan
    Uppsala Univ, Dept Surg Sci, Neuroradiol, Uppsala, Sweden..
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Casar-Borota, Olivera
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.;Uppsala Univ Hosp, Dept Clin Pathol, Uppsala, Sweden..
    Ponten, Fredrik
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Annotation of pituitary neuroendocrine tumors with genome-wide expression analysis2021In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, no 1, article id 181Article in journal (Refereed)
    Abstract [en]

    Pituitary neuroendocrine tumors (PitNETs) are common, generally benign tumors with complex clinical characteristics related to hormone hypersecretion and/or growing sellar tumor mass. PitNETs can be classified based on the expression pattern of anterior pituitary hormones and three main transcriptions factors (TF), SF1, PIT1 and TPIT that regulate differentiation of adenohypophysial cells. Here, we have extended this classification based on the global transcriptomics landscape using tumor tissue from a well-defined cohort comprising 51 PitNETs of different clinical and histological types. The molecular profiles were compared with current classification schemes based on immunohistochemistry. Our results identified three main clusters of PitNETs that were aligned with the main pituitary TFs expression patterns. Our analyses enabled further identification of specific genes and expression patterns, including both known and unknown genes, that could distinguish the three different classes of PitNETs. We conclude that the current classification of PitNETs based on the expression of SF1, PIT1 and TPIT reflects three distinct subtypes of PitNETs with different underlying biology and partly independent from the expression of corresponding hormones. The transcriptomic analysis reveals several potentially targetable tumor-driving genes with previously unknown role in pituitary tumorigenesis.

  • 12.
    AbdelMageed, Manar
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
    Ali, Haytham
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
    Ohlsson, Lina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lindmark, Gudrun
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sitohy, Basel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The Chemokine CXCL16 Is a New Biomarker for Lymph Node Analysis of Colon Cancer Outcome2019In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 20, no 22, article id 5793Article in journal (Refereed)
    Abstract [en]

    hemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient’s survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(−) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis.

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  • 13.
    AbdelMageed, Manar
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
    Ismail, Hager
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
    Ohlsson, Lina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lindmark, Gudrun
    Institution of Clinical Sciences, Lund University, Helsingborg, Sweden.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sitohy, Basel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Clinical significance of stem cell biomarkers epcam, lgr5 and lgr4 mrna levels in lymph nodes of colon cancer patients2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 1, article id 403Article in journal (Refereed)
    Abstract [en]

    The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan‐Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA cop-ies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12‐year follow‐up (p = 0.022, p = 0.005 and p = 0.011, respec-tively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence.

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  • 14.
    Abdollahi, Maryam
    et al.
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran.;Semnan Univ Med Sci, Student Res Comm, Semnan, Iran..
    Mohammadlou, Maryam
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran.;Semnan Univ Med Sci, Student Res Comm, Semnan, Iran..
    Hemati, Maral
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran..
    Baharlou, Rasoul
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran..
    Doulabi, Ehsan Manouchehri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghahremanfard, Farahnaz
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran..
    Sarabi, Mohammad Amir
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran..
    Kokhaei, Parviz
    Arak Univ Med Sci, Sch Med, Dept Immunol, Arak, Iran.;Karolinska Univ Hosp Solna, Dept Oncol Pathol, BioClinicum, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Anti-tumor effect of berberine on chronic lymphocytic leukemia cells2022In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 39, no 12, article id 217Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a blood malignancy that is characterized by remarkable expression of CD69 and Ki67 in CLL cells. Elevated levels of Cleaved-Poly (ADP-ribose) polymerase-1 (PARP1) and microRNA-155 (MiR-155) are related to poor prognosis of disease. Berberine as a natural isoquinoline alkaloid, has shown an anti-tumor potential in tumor cells. The objective of present study was to explore some aspects of molecular mechanisms of berberine effect in CLL cells. To analyze the expression of CD69 and Ki67 using flow cytometry, 16 peripheral blood samples and seven bone marrow aspirates were collected from CLL patients. Isolated peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) were treated with 25 mu M of berberine for 24 h. The level of miR-155 expression was subsequently evaluated by real-time PCR. Furthermore, western blot was used for assessment of cleaved PARP1. Our results demonstrated a significant reduction in CD69 and Ki67 expression on CD19(+) cells when the cells were treated by berberine. Interestingly, the expression level of miR-155 was reduced after berberine treatment in compare to the control group. Furthermore, western blotting revealed an increased level of cleaved PARP1 in dose-dependently manner in CLL cells. The results confirmed the anti-tumor impact of berberine on CLL cells through reducing CD69, Ki67, and miR-155 expression and increasing cleaved PARP1 may be considered as an option for future clinical studies.

  • 15.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Alexsson, Andrei
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ladenvall, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mansouri, Larry
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS2021In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 60, no 4, p. 531-538Article in journal (Refereed)
    Abstract [en]

    Background

    Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL).

    Material and methods

    Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) in situ hybridization were analyzed.

    Results

    High proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of IDO1 was high in patients with high proportion of PD-L1 positive leukocytes (p = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of IDO1 was high in EBER-positive cases (p = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases.

    Conclusion

    Our study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.

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  • 16.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Hosp, Uppsala, Sweden..
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Hosp, Uppsala, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Hosp, Uppsala, Sweden..
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Hosp, Uppsala, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Saft, Leonie
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Hosp, Uppsala, Sweden..
    Outcome in PCNSL patients and its association with PD-L1+leukocytes in the tumor microenvironment2022In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, no 7, p. 824-829Article in journal (Refereed)
  • 17.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Biosci & Nutr, Novum, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 9-10, p. 1126-1131Article in journal (Refereed)
    Abstract [en]

    Aim: To determine the prognostic significance of co-expression of MYC, BCL-2 and BCL-6 proteins in combination with other biomarkers and clinical characteristics within a population-based cohort of diffuse large B-cell lymphoma (DLBCL) patients uniformly treated with R-CHOP.

    Patients and methods: The immunohistochemical (IHC) expression of CD10, BCL-2, BCL-6, MUM1, MYC, CD5, CD30, Ki-67 and p53 was evaluated in a retrospective, population-based study comprising 188 DLBCL patients treated with R-CHOP and diagnosed in Sweden between 2002 and 2012.

    Results: Patients had a median age at diagnosis of 64 years (26-85 years) with a male:female ratio of 1.4:1. Approximately half (52%) of the patients presented with an International Prognostic Index (IPI) age adjusted (IPIaa)2. Median follow-up time was 51 months (range 0.4-158) and the five-year lymphoma-specific survival (LSS) was 76%, five-year overall survival (OS) was 65% and five-year progression-free survival (PFS) was 61%. A high Ki-67 value was found in 59% of patients, while p53 overexpression was detected in 12% of patients and MYC, BCL-2 and BCL-6 expression were detected in 42%, 55% and 74% of patients, respectively. IPIaa2 (p=0.002), Ki-6770% (p=0.04) and p53 overexpression50% (p=0.02) were associated with inferior LSS and OS. Co-expression of both MYC (>40%) and BCL-2 (>70%) proteins was detected in 27% of patients and correlated with a significantly inferior LSS (p=0.0002), OS (p=0.009) and PFS (p=0.03). In addition, triple expression of MYC, BCL-2 and BCL-6, also correlated with a significantly inferior LSS (p=0.02).

    Conclusion: Concurrent expression of MYC and BCL-2 proteins, as detected by IHC, was strongly associated with an inferior survival in DLBCL patients treated with R-CHOP. Other markers affecting survival were triple expression of MYC, BCL-2 and BCL-6, IPIaa, high Ki-67 and p53 overexpression.

  • 18.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, p. 106-109Article in journal (Refereed)
  • 19.
    Abdullah Nasir, Ahmad
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ligand-specific regulation of transforming growth factor beta superfamily factors by leucine-rich repeats and immunoglobulin-like domains proteins2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 8, article id e0289726Article in journal (Refereed)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains (LRIG) are transmembrane proteins shown to promote bone morphogenetic protein (BMP) signaling in Caenorhabditis elegans, Drosophila melanogaster, and mammals. BMPs comprise a subfamily of the transforming growth factor beta (TGFβ) superfamily, or TGFβ family, of ligands. In mammals, LRIG1 and LRIG3 promote BMP4 signaling. BMP6 signaling, but not BMP9 signaling, is also regulated by LRIG proteins, although the specific contributions of LRIG1, LRIG2, and LRIG3 have not been investigated, nor is it known whether other mammalian TGFβ family members are regulated by LRIG proteins. To address these questions, we took advantage of Lrig-null mouse embryonic fibroblasts (MEFs) with doxycycline-inducible LRIG1, LRIG2, and LRIG3 alleles, which were stimulated with ligands representing all the major TGFβ family subgroups. By analyzing the signal mediators pSmad1/5 and pSmad3, as well as the induction of Id1 expression, we showed that LRIG1 promoted BMP2, BMP4, and BMP6 signaling and suppressed GDF7 signaling; LRIG2 promoted BMP2 and BMP4 signaling; and LRIG3 promoted BMP2, BMP4, BMP6, and GDF7 signaling. BMP9 and BMP10 signaling was not regulated by individual LRIG proteins, however, it was enhanced in Lrig-null cells. LRIG proteins did not regulate TGFβ1-induced pSmad1/5 signaling, or GDF11- or TGFβ1-induced pSmad3 signaling. Taken together, our results show that some, but not all, TGFβ family ligands are regulated by LRIG proteins and that the three LRIG proteins display differential regulatory effects. LRIG proteins thereby provide regulatory means for the cell to further diversify the signaling outcomes generated by a limited number of TGFβ family ligands and receptors.

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  • 20.
    Abdullah Nasir, Ahmad
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Oncology Research Laboratory, NUS M31, Umeå, Sweden.
    Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 8585Article in journal (Refereed)
    Abstract [en]

    Netrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

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  • 21.
    Abildgaard, Niels
    et al.
    Hematology Research Unit, Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Anttila, Pekka
    Comprehensive Cancer Center, Department of Hematology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
    Waage, Anders
    Department of Hematology, St Olav's University Hospital, Trondheim, Norway.
    Rubin, Katrine Hass
    Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Ørstavik, Sigurd
    Takeda Pharmaceuticals International AG, Oslo, Norway.
    Bent-Ennakhil, Nawal
    Takeda Pharmaceuticals International AG, Zurich, Switzerland.
    Gavini, François
    Takeda Pharmaceuticals International AG, Zurich, Switzerland.
    Ma, Yuanjun
    Parexel International, Stockholm, Sweden.
    Freilich, Jonatan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Parexel International, Stockholm, Sweden.
    Hansson, Markus
    Sahlgrenska Academy and Sahlgrenska University Hospital, Göteborg, Sweden.
    Real-world treatment patterns and outcomes for patients with multiple myeloma in Denmark, Finland and Sweden: An analysis using linked Nordic registries2024In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 201, article id 113921Article in journal (Refereed)
    Abstract [en]

    Aim: The Health outcomes and Understanding of MyelomA multi-National Study (HUMANS) was a large-scale, retrospective study conducted across Denmark, Finland and Sweden using linked data from national registries. We describe the characteristics, treatment patterns and clinical outcomes for patients with newly diagnosed multiple myeloma (NDMM) over 2010–2018.

    Methods: Patients with NDMM who received MM-specific, first-line treatments, were categorised by treatment (autologous stem cell transplantation [ASCT] or a combination chemotherapy regimen based on bortezomib, lenalidomide or melphalan-prednisolone-thalidomide).

    Results: 11,023 patients received treatment over 2010–2018. Time between diagnosis and treatment was shortest in Denmark (0.9 months), then Sweden (2.9 months) and Finland (4.6 months). Around one third of patients underwent ASCT. Lenalidomide-based regimens were prescribed to 23–28% of patients in Denmark and Finland, versus 12% in Sweden. Patients receiving lenalidomide had the longest wait for treatment, from 3.2 months (Denmark) to 12.1 months (Sweden). Treatment persistence was highest among patients receiving melphalan-prednisolone-thalidomide (7–8 months) in Finland and Sweden and lowest among those receiving bortezomib (3.5 months) in Finland. Overall survival (OS) was longest among patients with ASCT (7–10 years). Among patients receiving chemotherapy, OS (from diagnosis/treatment initiation), varied between cohorts. In a sensitivity analysis excluding patients with smouldering MM, OS decreased for all; for patients receiving bortezomib or lenalidomide, OS from diagnosis was 40–49 and 27–54 months, respectively.

    Conclusions: This population-based study of patients with NDMM receiving first-line MM-specific treatment, provides real-world data on treatment patterns and outcomes to complement data from randomised clinical trials.

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  • 22.
    Abildgaard, Niels
    et al.
    Hematology Research Unit, Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Freilich, Jonatan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Department of Access Consulting, PAREXEL International, Stockholm, Sweden.
    Anttila, Pekka
    Comprehensive Cancer Center, Department of Hematology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
    Bent-Ennakhil, Nawal
    Takeda Pharmaceuticals International AG, Zurich, Switzerland.
    Ma, Yuanjun
    Department of Access Consulting, PAREXEL International, Stockholm, Sweden.
    Lassenius, Mariann
    Medaffcon, Espoo, Finland.
    Ørstavik, Sigurd
    Takeda Pharmaceuticals International AG, Oslo, Norway.
    Toppila, Iiro
    Medaffcon, Espoo, Finland.
    Waage, Anders
    Department of Hematology, St Olav’s University Hospital, Trondheim, Norway.
    Turesson, Ingemar
    Lund University Cancer Centre, University of Lund, Skåne University Hospital, Lund, Sweden.
    Hansson, Markus
    Sahlgrenska Academy and Sahlgrenska University Hospital, Göteborg, Sweden.
    Use of linked nordic registries for population studies in hematologic cancers: the case of multiple myeloma2023In: Clinical Epidemiology, E-ISSN 1179-1349, Vol. 15, p. 987-999Article in journal (Refereed)
    Abstract [en]

    Purpose: Linked health-care registries and high coverage in Nordic countries lend themselves well to epidemiologic research. Given its relatively high incidence in Western Europe, complexity in diagnosis, and challenges in registration, multiple myeloma (MM) was selected to compare registries in Denmark, Finland, and Sweden.

    Patients and Methods: Data were obtained from four archetypal registries in each country (spanning January 2005–October 2018): National Patient Registry (NPR), Prescribed Drug Registry (PDR), Cancer Registry (CR), and Cause of Death Registry. Patients newly diagnosed with MM who received MM-specific treatment were included. PDR/NPR treatment records were used to assess incident NPR cases. The registration quality of MM-specific drugs in the PDR of each country was also evaluated.

    Results: In Denmark, only 6% of patients in the NPR were not registered in the CR; in Sweden, it was 16.9%. No systematic differences were identified that could explain this discrepancy. In Denmark, lenalidomide and bortezomib were registered in the NPR with high coverage, but less expensive drugs typically given in combination with bortezomib were not covered in any of the registries. In Finland and Sweden, bortezomib records were not identified in the PDR, but some were in the NPR; other drugs had good coverage in the PDR.

    Conclusions: The registries evaluated in this study can be used to identify the MM population; however, given the gaps in MM registration in the Finnish and Swedish CRs, Danish registries provide the most comprehensive datasets for research on treatment patterns for MM.

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  • 23.
    Abosedera, Dalia A.
    et al.
    Univ Sadat City, Environm Studies & Res Inst, Dept Nat Resources, Sadat City, Egypt..
    Emara, S. A.
    Univ Sadat City, Fac Vet Med, Dept Cytol & Histol, Sadat City, Egypt..
    Tamam, Omar A. S.
    Univ Sadat City, Environm Studies & Res Inst, Dept Nat Resources, Sadat City, Egypt..
    Badr, Osama M.
    Univ Sadat City, Anim Biotechnol Dept, Genet Engn & Biotechnol Inst GEBRI, Sadat City, Egypt..
    Khalifa, Shaden A. M.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden..
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. BJiangsu Univ, Int Res Ctr Food Nutr & Safety, Zhenjiang 212013, Jiangsu, Peoples R China.;Jiangsu Univ, Jiangsu Educ Dept, Int Joint Res Lab Intelligent Agr & Agriprod Proc, Zhenjiang, Jiangsu, Peoples R China.;Menoufia Univ, Fac Sci, Dept Chem, Menoufia 32511, Egypt..
    Refaey, Mohamed S.
    Univ Sadat City, Fac Pharm, Dept Pharmacognosy, Menoufia 32897, Egypt..
    Metabolomic profile and in vitro evaluation of the cytotoxic activity of Asphodelus microcarpus against human malignant melanoma cells A3752022In: Arabian Journal of Chemistry, ISSN 1878-5352, E-ISSN 1878-5379 , Vol. 15, no 10, article id 104174Article in journal (Refereed)
    Abstract [en]

    Melanoma is a huge worldwide health problem that must be handled more effectively with better therapeutic options. As a result, new treatment drugs are required to treat this condition. The goal of this study was to investigate the cytotoxic activity of the anthraquinone-rich fractions obtained from Asphodelus microcarpus against human melanoma cell A375. On these melanoma cell lines; the cytotoxicity of these fractions had never been studied before. Liquid chromatography linked to mass spectrometry (LC-MS-MS) and Nuclear Magnetic Resonance was used to determine the chemical profiles of these fractions. The cytotoxicity of the fractions studied was determined by measuring cell viability and calculating IC50 values. Both ethyl acetate (EtOAC) and the precipitate fractions (PPT) exhibited selective cytotoxicity on human melanoma A 375 cell line with IC50 values of 83 and 65 mu g/mL, respectively. The antiproliferative properties of EtOAc fraction and PPT were supported by a noticeable decrease in cell numbers during the G2/M cell cycle arrest. Our findings suggest that the anthraquinone content of A. microcarpus tubers is responsible for its anti-proliferative and apoptotic properties and that further in vivo investigations should be conducted to establish the viability of using them to treat human melanomas.

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  • 24.
    Abouzayed, Ayman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Theranostic Targeting of GRPR and PSMA in Prostate Cancer2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on five original articles that investigated the theranostics of prostate cancer by gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) targeting. GRPR and PSMA are two extensively evaluated prostate cancer cell markers due to their overexpression in the majority of prostate cancer samples. Theranostic targeting of GRPR and PSMA is an attractive strategy to improve the management of prostate cancer patients.

    Papers I and II focused on the dual targeting of GRPR and PSMA. The effect of linker modification on the affinity for GRPR and PSMA and the pharmacokinetic profile was evaluated. In Paper III, the effect of the GRPR antagonist RM26 conjugation to an albumin-binding domain on the pharmacokinetic profile and its potential use in therapy was investigated. Paper IV focused on developing a GRPR antagonist that was suitable for single-photon emission computed tomography (SPECT) using technetium-99m. In Paper V, the GRPR antagonist developed in Paper IV was translated into a phase I clinical trial to assess safety and dosimetry.

    Modifying the linkers in GRPR and PSMA heterodimers can largely impact the affinity for both targets. This modification influenced the in vivo targeting specificity and biodistribution, with [125I]I-BO530 in Paper I and [111In]In-BQ7812 in Paper II outperforming other analogues. Our findings in Paper III indicated that the conjugation of an albumin-binding domain to RM26 increased the blood concentration of the radiotracer. This increase led to elevated and stable tumour uptake of [111In]In-DOTA-ABD-RM26 after several days of injection. However, [111In]In-DOTA-ABD-RM26 was also increasingly taken up by various healthy organs. The GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26, studied in Paper IV, showed high specificity and affinity for GRPR. This resulted in elevated GRPR-mediated uptake. Additionally, maSSS-PEG2-RM26 could be radiolabelled via a straightforward radiolabelling protocol. Clinical evaluation of [99mTc]Tc-maSSS-PEG2-RM26 in prostate and breast cancer patients (Paper V) demonstrated the safety and tolerability of the radiotracer, with favourable dosimetry and no side effects.

    In conclusion, this thesis evaluated different tools for the theranostic targeting of GRPR and PSMA. The findings warrant further investigation to optimise the reported radiotracers.

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  • 25.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Borin, Jesper
    KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden..
    Lundmark, Fanny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Rybina, Anastasiya
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden..
    Zelchan, Roman
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The GRPR Antagonist [99mTc]Tc-maSSS-PEG2-RM26 towards Phase I Clinical Trial: Kit Preparation, Characterization and Toxicity2023In: Diagnostics, ISSN 2075-4418, Vol. 13, no 9, article id 1611Article in journal (Refereed)
    Abstract [en]

    Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26 (based on [D-Phe6, Sta13, Leu14-NH2]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models. In this study, we aimed to prepare and test kits for prospective use in an early-phase clinical study. The kits were prepared to allow for a one-pot single-step radiolabeling with technetium-99m pertechnetate. The kit vials were tested for sterility and labeling efficacy. The radiolabeled by using the kit GRPR antagonist was evaluated in vitro for binding specificity to GRPR on PC-3 cells (GRPR-positive). In vivo, the toxicity of the kit constituents was evaluated in rats. The labeling efficacy of the kits stored at 4 °C was monitored for 18 months. The biological properties of [99mTc]Tc-maSSS-PEG2-RM26, which were obtained after this period, were examined both in vitro and in vivo. The one-pot (gluconic acid, ethylenediaminetetraacetic acid, stannous chloride, and maSSS-PEG2-RM26) single-step radiolabeling with technetium-99m was successful with high radiochemical yields (>97%) and high molar activities (16–24 MBq/nmol). The radiolabeled peptide maintained its binding properties to GRPR. The kit constituents were sterile and non-toxic when tested in living subjects. In conclusion, the prepared kit is considered safe in animal models and can be further evaluated for use in clinics.

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  • 26.
    Abouzayed, Ayman
    et al.
    Uppsala Univ, Dept Med Chem, S-75183 Uppsala, Sweden..
    Borin, Jesper
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Lundmark, Fanny
    Uppsala Univ, Dept Med Chem, S-75183 Uppsala, Sweden..
    Rybina, Anastasiya
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Hober, Sophia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Zelchan, Roman
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75237 Uppsala, Sweden..
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75183 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, S-75237 Uppsala, Sweden..
    The GRPR Antagonist [Tc-99m]Tc-maSSS-PEG(2)-RM26 towards Phase I Clinical Trial: Kit Preparation, Characterization and Toxicity2023In: Diagnostics, ISSN 2075-4418, Vol. 13, no 9, p. 1611-, article id 1611Article in journal (Refereed)
    Abstract [en]

    Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [Tc-99m]Tc-maSSS-PEG2-RM26 (based on [D-Phe(6), Sta(13), Leu(14)-NH2]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models. In this study, we aimed to prepare and test kits for prospective use in an early-phase clinical study. The kits were prepared to allow for a one-pot single-step radiolabeling with technetium-99m pertechnetate. The kit vials were tested for sterility and labeling efficacy. The radiolabeled by using the kit GRPR antagonist was evaluated in vitro for binding specificity to GRPR on PC-3 cells (GRPR-positive). In vivo, the toxicity of the kit constituents was evaluated in rats. The labeling efficacy of the kits stored at 4 degrees C was monitored for 18 months. The biological properties of [Tc-99m]Tc-maSSS-PEG2-RM26, which were obtained after this period, were examined both in vitro and in vivo. The one-pot (gluconic acid, ethylenediaminetetraacetic acid, stannous chloride, and maSSS-PEG(2)-RM26) single-step radiolabeling with technetium-99m was successful with high radiochemical yields (>97%) and high molar activities (16-24 MBq/nmol). The radiolabeled peptide maintained its binding properties to GRPR. The kit constituents were sterile and non-toxic when tested in living subjects. In conclusion, the prepared kit is considered safe in animal models and can be further evaluated for use in clinics.

  • 27.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Kanellopoulos, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15310, Greece..
    Gorislav, Alisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Maina, Theodosia
    NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15310, Greece..
    Nock, Berthold A.
    NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15310, Greece..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Preclinical Characterization of a Stabilized Gastrin-Releasing Peptide Receptor Antagonist for Targeted Cancer Theranostics2023In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 7, article id 1134Article in journal (Refereed)
    Abstract [en]

    Radiolabeled gastrin-releasing peptide receptor (GRPR) antagonists have shown great promise for the theranostics of prostate cancer; however, their suboptimal metabolic stability leaves room for improvements. It was recently shown that the replacement of Gly(11) with Sar(11) in the peptidic [D-Phe(6),Leu(13)-NHEt,des-Met(14)]BBN(6-14) chain stabilized the [Tc-99m]Tc-DB15 radiotracer against neprilysin (NEP). We herein present DOTAGA-PEG(2)-(Sar(11))RM26 (AU-RM26-M1), after Gly(11) to Sar(11)-replacement. The impact of this replacement on the metabolic stability and overall biological performance of [In-111]In-AU-RM26-M1 was studied using a head-to-head comparison with the unmodified reference [In-111]In-DOTAGA-PEG(2)-RM26. In vitro, the cell uptake of [In-111]In-AU-RM26-M1 could be significantly reduced in the presence of a high-excess GRPR-blocker that demonstrated its specificity. The cell uptake of both radiolabeled GRPR antagonists increased with time and was superior for [In-111]In-AU-RM26-M1. The dissociation constant reflected strong affinities for GRPR (500 pM for [In-111]In-AU-RM26-M1). [In-111]In-AU-RM26-M1 showed significantly higher stability in peripheral mice blood at 5 min pi (88 & PLUSMN; 8% intact) than unmodified [In-111]In-DOTAGA-PEG(2)-RM26 (69 & PLUSMN; 2% intact; p < 0.0001). The administration of a NEP inhibitor had no significant impact on the Sar(11)-compound (91 & PLUSMN; 2% intact; p > 0.05). In vivo, [In-111]In-AU-RM26-M1 showed high and GRPR-mediated uptake in the PC-3 tumors (7.0 & PLUSMN; 0.7%IA/g vs. 0.9 & PLUSMN; 0.6%IA/g in blocked mice) and pancreas (2.2 & PLUSMN; 0.6%IA/g vs. 0.3 & PLUSMN; 0.2%IA/g in blocked mice) at 1 h pi, with rapid clearance from healthy tissues. The tumor uptake of [In-111]In-AU-RM26-M1 was higher than for [In-111]In-DOTAGA-PEG(2)-RM26 (at 4 h pi, 5.7 & PLUSMN; 1.8%IA/g vs. 3 & PLUSMN; 1%IA/g), concordant with its higher stability. The implanted PC-3 tumors were visualized with high contrast in mice using [In-111]In-AU-RM26-M1 SPECT/CT. The Gly(11) to Sar(11)-substitution stabilized [In-111]In-DOTAGA-PEG(2)-(Sar(11))RM26 against NEP without negatively affecting other important biological features. These results support the further evaluation of AU-RM26-M1 for prostate cancer theranostics after labeling with clinically relevant radionuclides.

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  • 28.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Sabahnoo, Hamideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Dept Nucl Med, Tomsk Natl Res Med Ctr, Tomsk 634009, Russia; Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634009, Russia.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634009, Russia.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab. Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634009, Russia.
    Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer2021In: Pharmaceutics, E-ISSN 1999-4923, Vol. 13, no 2, article id 182Article in journal (Refereed)
    Abstract [en]

    Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced 99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers.

    Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG2-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG2-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) were radiolabeled with 99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [99mTc]Tc-maSSS-PEG2-RM26.

    Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [99mTc]Tc-maSSS-PEG2-RM26 outperformed [99mTc]Tc-maSES-PEG2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [99mTc]Tc-maSSS-PEG2-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [99mTc]Tc-maSSS-PEG2-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [99mTc]Tc-maSSS-PEG2-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10−3 mGy/MBq), and the effective dose is 3.49 × 10−3 mSv/MBq.

    Conclusion: The GRPR antagonist maSSS-PEG2-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced 99mTc and used for imaging of GRPR-expressing prostate cancer.

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  • 29.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Seitova, Kamila
    Siberian State Med Univ, Sci & Res Lab Chem & Pharmaceut Res, Tomsk, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk, Russia..
    Lundmark, Fanny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Bodenko, Vitalina
    Siberian State Med Univ, Sci & Res Lab Chem & Pharmaceut Res, Tomsk, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk, Russia..
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Affibody AB, Solna, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk, Russia..
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry2023In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 13, article id 1221103Article in journal (Refereed)
    Abstract [en]

    <bold>Introduction:</bold> Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that Lu-177-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.<bold>Methods:</bold> BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [Lu-177]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [Lu-177]Lu-PSMA-617 was simultaneously evaluated for comparison.<bold>Results:</bold> BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [Lu-177]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K-D1 = 3.8 nM and K-D2 = 25 nM. The half-maximal inhibitory concentration for Lu-nat-BQ7876 was 59 nM that is equal to 61 nM for Lu-nat-PSMA-617. Cellular processing of [Lu-177]Lu-BQ7876 was accompanied by slow internalization. [Lu-177]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 +/- 3%ID/g) did not differ significantly from tumor uptake (9 +/- 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.<bold>Discussion:</bold> Biodistribution studies in mice demonstrated that targeting properties of [Lu-177]Lu-BQ7876 are not inferior to properties of [Lu-177]Lu-PSMA-617, but do not offer any decisive advantages.

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  • 30.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Yim, Cheng-Bin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer2019In: Pharmaceutics, E-ISSN 1999-4923, Vol. 11, no 7, article id 358Article in journal (Refereed)
    Abstract [en]

    Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)(8) (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [I-125]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [I-125]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [I-125]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%-35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [I-125]I-BO530 is a promising agent for theranostics application in prostate cancer.

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  • 31.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Zedan, Wahed
    Lund Univ, Dept Oncol, Lund, Sweden..
    Altai, Mohamed
    Lund Univ, Dept Oncol, Lund, Sweden..
    Strand, Joanna
    Lund Univ, Dept Oncol, Lund, Sweden..
    Orbom, Anders
    Lund Univ, Dept Oncol, Lund, Sweden..
    Co-injection of anti-HER2 antibody Trastuzumab does not increase efficacy of [Lu-177]Lu-PSMA-617 therapy in an animal model of prostate cancer2023In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 13, no 3, p. 107-+Article in journal (Refereed)
    Abstract [en]

    One novel option for treating metastatic castration resistant prostate cancer is radionuclide therapy targeting prostate-specific membrane antigen (PSMA), e.g. [Lu-177]Lu-PSMA-617. Overexpression of HER2 has been found in 80% of metastatic cases of prostate cancer. Previous research showed that HER2 is elevated post irradiation in PC-3 prostate cancer cells. Co-treating with anti-HER2 antibody Trastuzumab gave less proliferation of irradiated tumor cells in vitro, and when using radionuclide therapy, also in vivo. The aim of this study is to determine whether the same holds true in PSMA-expressing PC-3 PIP cells using [Lu-177]Lu-PSMA-617 radionuclide therapy. PC-3 PIP and 22Rv1 prostate cancer cells were tested in vitro, treated with 6 Gy of x-rays with or without Trastuzumab incubation. We measured uptake of HER2-targeting affibody [Ga-68]Ga-ABY-025 and cell survival, e.g. using the WST-1 assay. Three groups (n=10 each) of male nude Balb/c mice were inoculated with PC-3 PIP xenograft tumors and treated with just [Lu-177]Lu-PSMA-617 (20 MBq), [Lu-177]Lu-PSMA-617 (20 MBq) and Trastuzumab (4 x 5 mg/kg), or left untreated. Tumor sizes and animal survival was observed. In vitro, x-ray irradiation did reduce survival in 22Rv1 but not PC-3 PIP cells, and there was no significant effect of Trastuzumab treatment. Cells expressed HER2 but not significantly elevated post irradiation. In vivo, mice co-treated with Trastuzumab had significantly longer survival than untreated mice, but not than only [Lu-177]Lu-PSMA-617. Staining of tumor sections showed similar HER2 and PSMA expression across groups. In conclusion, these results give no support for any benefit from co-treatment with anti-HER2 antibody for PSMA-targeted radioligand therapy.

  • 32. Abrahams, Harriët J. G.
    et al.
    Knoop, Hans
    Schreurs, Maartje
    Aaronson, Neil K.
    Jacobsen, Paul B.
    Newton, Robert U.
    Courneya, Kerry S.
    Aitken, Joanne F.
    Arving, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Brandberg, Yvonne
    Chambers, Suzanne K.
    Gielissen, Marieke F. M.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Goedendorp, Martine M.
    Graves, Kristi D.
    Heiney, Sue P.
    Horne, Rob
    Hunter, Myra S.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Northouse, Laurel L.
    Oldenburg, Hester S. A.
    Prins, Judith B.
    Savard, Josée
    van Beurden, Marc
    van den Berg, Sanne W.
    Verdonck-de Leeuw, Irma M.
    Buffart, Laurien M.
    Moderators of the effect of psychosocial interventions on fatigue in women with breast cancer and men with prostate cancer: Individual patient data meta-analyses2020In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 29, no 11, p. 1772-1785Article, review/survey (Refereed)
    Abstract [en]

    Objective

    Psychosocial interventions can reduce cancer‐related fatigue effectively. However, it is still unclear if intervention effects differ across subgroups of patients. These meta‐analyses aimed at evaluating moderator effects of (a) sociodemographic characteristics, (b) clinical characteristics, (c) baseline levels of fatigue and other symptoms, and (d) intervention‐related characteristics on the effect of psychosocial interventions on cancer‐related fatigue in patients with non‐metastatic breast and prostate cancer.

    Methods

    Data were retrieved from the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium. Potential moderators were studied with meta‐analyses of pooled individual patient data from 14 randomized controlled trials through linear mixed‐effects models with interaction tests. The analyses were conducted separately in patients with breast (n = 1091) and prostate cancer (n = 1008).

    Results

    Statistically significant, small overall effects of psychosocial interventions on fatigue were found (breast cancer: β = −0.19 [95% confidence interval (95%CI) = −0.30; −0.08]; prostate cancer: β = −0.11 [95%CI = −0.21; −0.00]). In both patient groups, intervention effects did not differ significantly by sociodemographic or clinical characteristics, nor by baseline levels of fatigue or pain. For intervention‐related moderators (only tested among women with breast cancer), statistically significant larger effects were found for cognitive behavioral therapy as intervention strategy (β = −0.27 [95%CI = −0.40; −0.15]), fatigue‐specific interventions (β = −0.48 [95%CI = −0.79; −0.18]), and interventions that only targeted patients with clinically relevant fatigue (β = −0.85 [95%CI = −1.40; −0.30]).

    Conclusions

    Our findings did not provide evidence that any selected demographic or clinical characteristic, or baseline levels of fatigue or pain, moderated effects of psychosocial interventions on fatigue. A specific focus on decreasing fatigue seems beneficial for patients with breast cancer with clinically relevant fatigue.

  • 33.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Capodanno, Alessandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women2017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 54, p. 92134-92142Article in journal (Refereed)
    Abstract [en]

    Women with dense breast tissue on mammography are at higher risk of developing breast cancer but the underlying mechanisms are not well understood. De-regulation of microRNAs (miRNAs) has been associated with the onset of breast cancer. miRNAs in the extracellular space participate in the regulation of the local tissue microenvironment. Here, we recruited 39 healthy postmenopausal women attending their mammography-screen that were assessed having extreme dense or entirely fatty breasts (nondense). Microdialysis was performed in breast tissue and a reference catheter was inserted in abdominal subcutaneous fat for local sampling of extracellular compounds. Three miRNAs, associated with tumor suppression, miR-193b, miR-365a, and miR-452 were significantly down-regulated in dense breast tissue compared with nondense breast tissue. In addition, miR-452 exhibited significant negative correlations with several pro-inflammatory cytokines in vivo, which was confirmed in vitro by overexpression of miR-452 in breast cancer cells. No differences were found of miR-21, -29a, -30c, 146a, -148a, -203, or -451 in breast tissue and no miRs were different in plasma. Extracellular miRNAs may be among factors that should be included in studies of novel prevention strategies for breast cancer.

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  • 34.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Increased nutrient availability in dense breast tissue of postmenopausal women in vivo2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 42733Article in journal (Refereed)
    Abstract [en]

    Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.

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  • 35.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Borga, Magnus
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lundberg, Peter
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo2016In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 10, article id e1229723Article in journal (Refereed)
    Abstract [en]

    Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1 was decreased in dense breasts. No differences were found in levels of IL-1, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.

  • 36.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Vazquez Rodriguez, Gabriela
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dabrosin, Charlotta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen2020In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 20, p. 4487-4499Article in journal (Refereed)
    Abstract [en]

    Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response. Significance: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ERthorn breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.

  • 37.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hariri, Mehran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-75185, Sweden.
    Nilsson, Sten
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines2022In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 26, article id 101543Article in journal (Refereed)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended sur-vival and palliative effects in treatment of bone metastases in prostate cancer. The alpha-particle emitter Ra-223, targets regions undergoing active bone remodeling and strongly binds to bone hydroxyapatite (HAp). However, the toxicity mechanism and properties of Ra-223 binding to hydroxyapatite are not fully understood. By exposing 2D and 3D (spheroid) prostate cancer cell models to free and HAp-bound Ra-223 we here studied cell toxicity, apoptosis and formation and repair of DNA double-strand breaks (DSBs). The rapid binding with a high affinity of Ra-223 to bone-like HAp structures was evident (KD= 19.2 x 10-18 M) and almost no dissociation was detected within 24 h. Importantly, there was no significant uptake of Ra-223 in cells. The Ra-223 alpha-particle decay produced track-like distributions of the DNA damage response proteins 53BP1 and gamma H2AX induced high amounts of clustered DSBs in prostate cancer cells and activated DSB repair through non-homologous end-joining (NHEJ). Ra-223 inhibited growth of prostate cancer cells, independent of cell type, and induced high levels of apoptosis. In summary, we suggest the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by alpha-particles.

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  • 38.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209594Article in journal (Refereed)
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

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  • 39.
    Abramian, David
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Blystad, Ida
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Eklund, Anders
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning.
    Evaluation of inverse treatment planning for gamma knife radiosurgery using fMRI brain activation maps as organs at risk2023In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 50, no 9, p. 5297-5311Article in journal (Refereed)
    Abstract [en]

    Background: Stereotactic radiosurgery (SRS) can be an effective primary or adjuvant treatment option for intracranial tumors. However, it carries risks of various radiation toxicities, which can lead to functional deficits for the patients. Current inverse planning algorithms for SRS provide an efficient way for sparing organs at risk (OARs) by setting maximum radiation dose constraints in the treatment planning process.Purpose: We propose using activation maps from functional MRI (fMRI) to map the eloquent regions of the brain and define functional OARs (fOARs) for Gamma Knife SRS treatment planning.Methods: We implemented a pipeline for analyzing patient fMRI data, generating fOARs from the resulting activation maps, and loading them onto the GammaPlan treatment planning software. We used the Lightning inverse planner to generate multiple treatment plans from open MRI data of five subjects, and evaluated the effects of incorporating the proposed fOARs.Results: The Lightning optimizer designs treatment plans with high conformity to the specified parameters. Setting maximum dose constraints on fOARs successfully limits the radiation dose incident on them, but can have a negative impact on treatment plan quality metrics. By masking out fOAR voxels surrounding the tumor target it is possible to achieve high quality treatment plans while controlling the radiation dose on fOARs.Conclusions: The proposed method can effectively reduce the radiation dose incident on the eloquent brain areas during Gamma Knife SRS of brain tumors.

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  • 40.
    Abreu, Miguel Henriques
    et al.
    Department of Medical Oncology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; Porto Comprehensive Cancer Center Raquel Seruca (PCCC), Porto, Portugal.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bartosch, Carla
    Porto Comprehensive Cancer Center Raquel Seruca (PCCC), Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; Cancer Biology & Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (CI-IPO-Porto)/Health Research Network (RISE@CI-IPO-Porto), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
    Ricardo, Sara
    Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, Porto, Portugal; 1H-TOXRUN - One Health Toxicology Research Unit, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal; Department of Pathology, Faculty of Medicine from University of Porto (FMUP), Porto, Portugal.
    Editorial: New molecular approaches to improve gynecological cancer management2023In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 13, article id 1235035Article in journal (Other academic)
  • 41.
    Abril, Jazmine
    et al.
    Univ Utah, Sch Med, Salt Lake City, UT USA..
    Trabert, Britton
    Huntsman Canc Inst Univ Utah, Huntsman Canc Inst, Dept Obstet & Gynecol, 2000 Circle Hope Dr Res South 4719, Salt Lake City, UT 84112 USA..
    Troisi, Rebecca
    NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD USA..
    Grotmol, Tom
    Canc Registry Norway, Oslo, Norway..
    Ekbom, Anders
    Karolinska Inst, Dept Med, Clin Epidemiol Div, Stockholm, Sweden..
    Engeland, Anders
    Norwegian Inst Publ Hlth, Dept Chron Dis, Oslo, Norway.;Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway..
    Gissler, Mika
    THL Finnish Inst Hlth & Welf, Dept Knowledge Brokers, Helsinki, Finland.;Acad Primary Hlth Care Ctr Reg Stockholm, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Karolinska Inst, Dept Med, Clin Epidemiol Div, Stockholm, Sweden..
    Madanat-Harjuoja, Laura
    Finnish Canc Registry, Helsinki, Finland.;Univ Helsinki, Dept Pediat, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Ording, Anne Gulbech
    Helsinki Univ Hosp, Helsinki, Finland..
    Sorensen, Henrik Toft
    Aarhus Univ, Dept Clin Epidemiol, Aarhus, Denmark..
    Tretli, Steinar
    Canc Registry Norway, Oslo, Norway..
    Bjorge, Tone
    Canc Registry Norway, Oslo, Norway.;Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway..
    Associations between pregnancy-related factors and birth characteristics with risk of rare uterine cancer subtypes: a Nordic population-based case-control study2024In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 35, no 5, p. 741-747Article in journal (Refereed)
    Abstract [en]

    Purpose:  Uterine sarcomas are a rare group of uterine malignancies. Due to the low incidence and changes in uterine sarcoma classification, risk factors are not well characterized. Our objective was to evaluate risk factors for uterine sarcoma and compare risk factors between uterine sarcoma, malignant mixed Mullerian tumors (MMMTs), and type I endometrial carcinomas.

    Methods: This nested case-control study utilized linked data from population-based medical birth and cancer registries in Denmark, Finland, Norway, and Sweden. Up to 10 controls were matched on country and birth year for each uterine cancer case. Using multivariable adjusted multinomial logistic regression, estimates of the associations between pregnancy-related factors and risk of uterine sarcoma, MMMTs, and type I endometrial carcinomas were determined.

    Results: Having a very-low-birth-weight infant (< 1500 vs. 2500-3999 g: OR [95% CI] 2.83 [1.61-4.96]) was associated with an increased risk of uterine sarcoma. Whereas, having a more recent pregnancy was associated with reduced risks of MMMT (< 10 vs. >= 30 years: 0.66 [0.20-2.23]) and type 1 endometrial carcinomas (0.35 [0.30-0.41]) but not uterine sarcomas (1.33 [0.90-1.98], p-heterogeneity < 0.01).

    Conclusion: Our study provides evidence that risk factors for uterine sarcoma and MMMT, previously grouped with uterine sarcomas, vary substantially. Additionally, MMMT and type I endometrial carcinomas are more similar than uterine sarcoma in that pregnancy complications like gestational hypertension and preeclampsia were associated with reduced risks of both but not uterine sarcoma, suggesting different etiologies.

  • 42.
    Abtahi, Jahan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Ajan, Aida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Malignant Transformation of Ossifying Fibroma into Parosteal Osteosarcoma with High-grade Component: Presentation of an Unusual Case and Review of the Literature2018In: The Open Dentistry Journal, E-ISSN 1874-2106, Vol. 12, p. 1059-1068Article in journal (Refereed)
    Abstract [en]

    Background: Parosteal Osteosarcoma of the Jaw (POSJ) is a rare entity that is associated with a high survival rate. Several case reports and case series of POSJ have been published in the literature, but few authors have described development of this tumor by possible transformation from a fibro-osseous neoplasm. Objective: We present a rare occurrence of parosteal osteosarcoma with involvement of the posterior maxilla, orbit floor, and infra-temporal fossa in a 20-year-old man. Furthermore, we performed a literature review regarding clinical, radiological, and histological features; treatment strategies; and etiology/pathophysiology. Methods: A PubMed search yielded a total of 74 articles and the articles were sorted according to their corresponding key area of focus. Results: This was a case of POSJ with high-grade component in the maxillofacial region of a 20-year old male. Co-expression of MDM2 and CDK4 was confirmed. At 2.5-year follow-up, the patient had died. The literature review revealed 18 articles including 20 cases of POSJ. Four cases represent the possible development of this tumor by transformation from a fibro-osseous neoplasm: Two cases of fibrous dysplasia, one case of cemento-ossifying fibroma, and the case of Ossifying Fibroma (OF) in the present study. Conclusion: In conclusion, we found an unusual case of POSJ of the midface in a patient with a previous diagnosis of OF in the same region. To our knowledge, there have been no previous reports of development of POSJ in OF. Furthermore, this is the first described case of high-grade surface osteosarcoma in the craniofacial region.

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  • 43.
    Abu Sabaa, Amal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Clinical and Molecular Studies of Diffuse Large B-cell Lymphoma2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The general aim of this thesis was to study the prognostic clinical and biological markers of Diffuse Large B-cell Lymphoma (DLBCL).

    Paper I: Utilizing population-based data for patients with DLBCL in Sweden, the study aimed to establish whether event free survival at 24 months (EFS24) was a reproducible milestone. The disease-free survival for lymphoma patients was compared with that of age and sex matched Swedish general population. We demonstrated that overall survival was similar to age and sex matched general population only for younger patients (<60 years of age) achieving ES24. Patients older than that had worse prognosis. Death was mainly linked to cardiovascular disease and secondary malignancies.

    Paper II: Plasma samples collected via the bio bank U-CAN were analyzed using multiplex extension assay (PEA) utilizing preselected protein panels to examine the possibility of distinguishing lymphomas, leukemias and controls. The study confirmed that  PEA technology could be used not only to effectively screen for large number of plasma protein biomarkers in low plasma sample volumes (1 µL), but even to discriminate between controls and different haematological malignancies. 

    Paper III: Plasma protein pattern evolution in DLBCL patients was highlighted by PEA analysis of plasma proteins at different time points under treatment with Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Significant distinctions in protein patterns at diagnosis compared to controls and striking differences in protein levels before and after treatment in patient who responded to treatment were evident. The three top proteins were TCL1A, CXCL13 and IL2RA. 

    Paper IV: An interesting protein that emerged from the above studies was TCL1A. This plasma protein was analyzed in plasma samples by PEA. Validation by plasma enzyme immunosorbent assay (ELISA) was attempted. The cytoplasm and nucleus bound form of TCL1A were analyzed with the help of immunohistochemistry in tissue microarray samples. The study included 178 patients of which 125 received R-CHOP. Clinical risk factor analysis showed no significant correlation with tissue IHC. Significantly higher levels of plasma TCL1A were seen in male patients (measured by ELISA and PEA) and in patients with Ann Arbor stages II-IV (measured by PEA). Survival analysis showed no statistical significance. 

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  • 44.
    Abu Sabaa, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Mörth, Charlott
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research Sörmland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Hashemi, Jamileh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kamali-Moghaddam, Masood
    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 Tools and Functional Genomics.
    Robelius, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    T-cell Leukaemia/Lymphoma Protein 1A (TCL1A) In Diffuse Large B-cell lymphoma (DLBCL)Manuscript (preprint) (Other academic)
  • 45.
    Abu Sabaa, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Mörth, Charlott
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research Sörmland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kamali-Moghaddam, Masood
    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 Tools and Functional Genomics.
    Robelius, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Plasma Protein Profiling using Multiplex Extension Assay in Diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP: A descriptive studyManuscript (preprint) (Other academic)
  • 46.
    Abu-Ghanem, Yasmin
    et al.
    UCL Division of Surgical and Interventional Science, Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, United Kingdom.
    Powles, Thomas
    Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Capitanio, Umberto
    Division of Experimental Oncology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy.
    Beisland, Christian
    Department of Urology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
    Järvinen, Petrus
    Urology, Abdominal Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Stewart, Grant D.
    Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
    Gudmundsson, Eirikur
    Department of Urology, Landspitali University Hospital, Reykjavik, Iceland.
    Lam, Thomas B.L.
    Academic Urology Unit, University of Aberdeen, Aberdeen, United Kingdom.
    Marconi, Lorenzo
    Department of Urology, Coimbra University Hospital, Coimbra, Portugal.
    Fernandéz-Pello, Sergio
    Department of Urology, Cabueñes University Hospital, Gijón, Spain.
    Nisen, Harry
    Urology, Abdominal Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Meijer, Richard P.
    Department of Oncological Urology, University Medical Centre Utrecht, Utrecht, Netherlands.
    Volpe, Alessandro
    Department of Urology, Maggiore della Carità Hospital, University of Eastern Piedmont, Novara, Italy.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Klatte, Tobias
    Department of Surgery, University of Cambridge, Cambridge, United Kingdom; Department of Urology, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, United Kingdom.
    Bensalah, Karim
    Department of Urology, University Hospital of Rennes, Rennes, France.
    Dabestani, Saeed
    Division of Urological Cancers, Department of Translational Medicine, Central Hospital Kristianstad, Lund University, Lund, Sweden.
    Bex, Axel
    UCL Division of Surgical and Interventional Science, Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, United Kingdom; Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands.
    Should patients with low-risk renal cell carcinoma be followed differently after nephron-sparing surgery vs radical nephrectomy?2021In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 128, no 3, p. 386-394Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR).

    Subjects: A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear-cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence-free survival (RFS) and cancer-specific mortality (CSM).

    Results: From the database 1995 patients were identified as low-risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14–1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73–3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03–2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3–4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3–8.5; P < 0.001). Kaplan–Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above-mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study.

    Conclusion: Our results showed that follow-up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow-up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow-up strategy is proposed.

  • 47.
    Abuhasanein, Suleiman
    et al.
    Univ Gothenburg, Sweden; NU Hosp Grp, Sweden.
    Jahnson, Staffan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Abdul-Sattar Aljabery, Firas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Gårdmark, Truls
    Karolinska Inst, Sweden.
    Jerlström, Tomas
    Örebro Univ, Sweden.
    Liedberg, Fredrik
    Skåne Univ Hosp, Sweden; Lund Univ, Sweden.
    Sherif, Amir
    Umeå Univ, Sweden.
    Ströck, Viveka
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Kjölhede, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Do not throw out the baby with the bath water2022In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 56, no 3, p. 235-236Article in journal (Other academic)
  • 48.
    Abuhasanein, Suleiman
    et al.
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Surgery, Urology Section, NU Hospital Group, Trollhättan, Sweden.
    Jahnson, Staffan
    Department of Clinical and Experimental Medicine, Division of Urology, Linköping University, Linköping, Sweden.
    Aljabery, Firas
    Department of Clinical and Experimental Medicine, Division of Urology, Linköping University, Linköping, Sweden.
    Gårdmark, Truls
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.
    Jerlström, Tomas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Liedberg, Fredrik
    Department of Urology, Skåne University Hospital, Malmö, Sweden; Institution of Translational Medicine, Lund University, Malmö, Sweden.
    Sherif, Amir
    Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
    Ströck, Viveka
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Urology, Sahlgrenska University Hospital, Region Västra Götaland, Göteborg, Sweden.
    Kjölhede, Henrik
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Urology, Sahlgrenska University Hospital, Region Västra Götaland, Göteborg, Sweden.
    Standardized care pathways for patients with suspected urinary bladder cancer: the Swedish experience2022In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 56, no 3, p. 227-232Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To compare time intervals to diagnosis and treatment, tumor characteristics, and management in patients with primary urinary bladder cancer, diagnosed before and after the implementation of a standardized care pathway (SCP) in Sweden.

    MATERIALS AND METHODS: Data from the Swedish National Register of Urinary Bladder Cancer was studied before (2011-2015) and after (2016-2019) SCP. Data about time from referral to transurethral resection of bladder tumor (TURBT), patients and tumor characteristics, and management were analyzed. Subgroup analyses were performed for cT1 and cT2-4 tumors.

    RESULTS: Out of 26,795 patients, median time to TURBT decreased from 37 to 27 days after the implementation of SCP. While the proportion of cT2-T4 tumors decreased slightly (22-21%, p < 0.001), this change was not stable over time and the proportions cN + and cM1 remained unchanged. In the subgroups with cT1 and cT2-4 tumors, the median time to TURBT decreased and the proportions of patients discussed at a multidisciplinary team conference (MDTC) increased after SCP. In neither of these subgroups was a change in the proportions of cN + and cM1 observed, while treatment according to guidelines increased after SCP in the cT1 group.

    CONCLUSION: After the implementation of SCP, time from referral to TURBT decreased and the proportion of patients discussed at MDTC increased, although not at the levels recommended by guidelines. Thus, our findings point to the need for measures to increase adherence to SCP recommendations and to guidelines.

  • 49.
    Abuhasanein, Suleiman
    et al.
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Surgery, Urology Section, NU Hospital Group, Trollhättan, Sweden.
    Jahnson, Staffan
    Department of Clinical and Experimental Medicine, Division of Urology, Linköping University, Linköping, Sweden.
    Aljabery, Firas
    Department of Clinical and Experimental Medicine, Division of Urology, Linköping University, Linköping, Sweden.
    Gårdmark, Truls
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.
    Jerlström, Tomas
    Department of Urology, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Liedberg, Fredrik
    Department of Urology, Skåne University Hospital, Malmö, Sweden; Institution of Translational Medicine, Lund University, Malmö, Sweden.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Urology, Sahlgrenska University Hospital, Region Västra Götaland, Göteborg, Sweden.
    Kjölhede, Henrik
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Urology, Sahlgrenska University Hospital, Region Västra Götaland, Göteborg, Sweden.
    Standardized care pathways for patients with suspected urinary bladder cancer: the Swedish experience2022In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 56, no 3, p. 227-232Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To compare time intervals to diagnosis and treatment, tumor characteristics, and management in patients with primary urinary bladder cancer, diagnosed before and after the implementation of a standardized care pathway (SCP) in Sweden.

    MATERIALS AND METHODS: Data from the Swedish National Register of Urinary Bladder Cancer was studied before (2011-2015) and after (2016-2019) SCP. Data about time from referral to transurethral resection of bladder tumor (TURBT), patients and tumor characteristics, and management were analyzed. Subgroup analyses were performed for cT1 and cT2-4 tumors.

    RESULTS: Out of 26,795 patients, median time to TURBT decreased from 37 to 27 days after the implementation of SCP. While the proportion of cT2-T4 tumors decreased slightly (22-21%, p < 0.001), this change was not stable over time and the proportions cN + and cM1 remained unchanged. In the subgroups with cT1 and cT2-4 tumors, the median time to TURBT decreased and the proportions of patients discussed at a multidisciplinary team conference (MDTC) increased after SCP. In neither of these subgroups was a change in the proportions of cN + and cM1 observed, while treatment according to guidelines increased after SCP in the cT1 group.

    CONCLUSION: After the implementation of SCP, time from referral to TURBT decreased and the proportion of patients discussed at MDTC increased, although not at the levels recommended by guidelines. Thus, our findings point to the need for measures to increase adherence to SCP recommendations and to guidelines.

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  • 50.
    Abusabeib, Abdelrahman
    et al.
    Department of General Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    El Ansari, Walid
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Department of Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar ; College of Medicine, Qatar University, Doha, Qatar.
    Al Hassan, Mohamed S.
    Department of General Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    Petkar, Mahir
    Department of Laboratory Medicine & Pathology, Hamad Medical Corporation, Doha, Qatar.
    Mohamed, Sugad
    Department of Laboratory Medicine & Pathology, Hamad Medical Corporation, Doha, Qatar.
    First case of huge classic papillary thyroid cancer rupturing spontaneously leading to ischemic necrosis, perforation and inflammation of overlying skin: Case report and review of the literature2021In: International Journal of Surgery Case Reports, E-ISSN 2210-2612, Vol. 85, article id 106136Article in journal (Refereed)
    Abstract [en]

    Introduction: Papillary thyroid cancer (PTC) is the commonest form of well-differentiated endocrine carcinoma. It is categorized into indolent and aggressive, where the indolent subtypes (classic, follicular) rarely demonstrate aggressive behavior. We present a classic PTC presenting with a rapidly growing huge anterior neck mass that subsequently spontaneously ruptured subcutaneously resulting in ischemia, necrosis, and perforation of overlying skin leading to inflammation. Presentation of case: A 37-year-old female with no comorbidities presented to our emergency department with a neck swelling of 2 years duration that rapidly enlarged one week prior to presentation. Though the mass initially appeared of inflammatory nature, the tumor was a PTC, and she underwent total thyroidectomy with selective right side neck dissection and debridement of necrotic skin. The gross specimen revealed a fragmented non-intact right thyroid lobe mass causing pressure ischemia, necrosis and perforation of the skin. Histopathology showed a 9 × 9 × 5 cm classic PTC staged as pT3b N1b. Postoperative course was uneventful, she was discharged by the eighth postoperative day, and then she received a high dose of radioactive iodine ablation (RAI). Discussion: Classic PTC is usually of a smaller size and a relatively benign course compared to other PTC subtypes and thyroid cancers. It is indolent with favorable prognosis. Although it is associated with increased risk of lymph node metastases at the time of diagnosis, it is slow growing with high survival rates approaching 95%. Conclusion: Despite that classic PTC progresses slowly, it should still be suspected in neck swellings presenting with rapid and aggressive behavior. Prompt and systematic assessment is required with surgical intervention and radioactive iodine ablation therapy. 

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