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  • 1.
    Aho, Sonja
    et al.
    Tampere Univ Hosp, Tays Canc Ctr, Dept Oncol, Elamanaukio 2, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, Arvo Ylpon Katu 23, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, TUNI Palliat Care Res Grp, Arvo Ylpon Katu 23, Tampere 33520, Finland.;Tampere Univ Hosp, Palliat Care Ctr, Elamanaukio 2, Tampere 33520, Finland..
    Österlund, Emerik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Helsinki Univ Hosp, Dept Transplantat & Liver Surg, Haartmaninkatu 4, Helsinki 00290, Finland..
    Ristimäki, Ari
    Helsinki Univ Hosp, Dept Pathol, HUS Diagnost Ctr, HUSLAB, Haartmaninkatu 3, Helsinki 00290, Finland.;Univ Helsinki, Fac Med, Res Programs Unit, Appl Tumor Genom Res Program, Haartmaninkatu 8, Helsinki 00290, Finland..
    Nieminen, Lasse
    Tampere Univ Hosp, Dept Obstet & Gynecol, Elamanaukio 2, Tampere 33520, Finland.;Univ Tampere, Dept Pathol, Arvo Ylpon Katu 23, Tampere 33520, Finland..
    Sundström, Jari
    Turku Univ Hosp, Dept Pathol, Kiinanmyllynkatu 4-8, Turku 20520, Finland.;Univ Turku, Inst Biomed, Kiinanmyllynkatu 10, Turku 20520, Finland..
    Mäkinen, Markus J.
    Oulu Univ Hosp, Dept Pathol, Kajaanintie 50, Oulu 90220, Finland.;Univ Oulu, Dept Pathol, Translat Med Res Unit, Pentti Kaiteran Katu 1, Oulu 90570, Finland.;Med Res Ctr Oulu, Pentti Kaiteran Katu 1, Oulu 90570, Finland..
    Kuopio, Teijo
    Hosp Nova, Dept Pathol, Hoitajantie 3, Jyvaskyla 40620, Finland.;Univ Jyvaskyla, Dept Biol & Environm Sci, Seminaarinkatu 15, Jyvaskyla 40014, Finland..
    Kytölä, Soili
    Helsinki Univ Hosp, HUS Diagnost Ctr, Dept Genet, HUSLAB, Haartmaninkatu 3, Helsinki 00290, Finland.;Univ Helsinki, Dept Genet, Haartmaninkatu 8, Helsinki 00290, Finland..
    Ålgars, Annika
    Turku Univ Hosp, Dept Oncol, Hameentie 11, Turku 20520, Finland..
    Ristamäki, Raija
    Turku Univ Hosp, Dept Oncol, Hameentie 11, Turku 20520, Finland..
    Heervä, Eetu
    Turku Univ Hosp, Dept Oncol, Hameentie 11, Turku 20520, Finland..
    Kallio, Raija
    Oulu Univ Hosp, Dept Oncol, Kajaanintie 50, Oulu 90220, Finland.;Univ Oulu, Dept Oncol, Pentti Kaiteran Katu 1, Oulu 90570, Finland..
    Halonen, Päivi
    Helsinki Univ Hosp, Dept Oncol, Haartmaninkatu 4, Helsinki 00290, Finland.;Univ Helsinki, Dept Oncol, Haartmaninkatu 8, Helsinki 00290, Finland..
    Soveri, Leena-Maija
    Univ Helsinki, Dept Oncol, Haartmaninkatu 8, Helsinki 00290, Finland.;Joint Municipal Author Hlth Care & Social Serv Kes, Home Care, Sairaalakatu 1, Hyvinkaa 05850, Finland..
    Nordin, Arno
    Helsinki Univ Hosp, Dept Transplantat & Liver Surg, Haartmaninkatu 4, Helsinki 00290, Finland.;Univ Helsinki, Dept Surg, Haartmaninkatu 8, Helsinki 00290, Finland..
    Uutela, Aki
    Helsinki Univ Hosp, Dept Transplantat & Liver Surg, Haartmaninkatu 4, Helsinki 00290, Finland.;Univ Helsinki, Dept Surg, Haartmaninkatu 8, Helsinki 00290, Finland..
    Salminen, Tapio
    Tampere Univ Hosp, Tays Canc Ctr, Dept Oncol, Elamanaukio 2, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, Arvo Ylpon Katu 23, Tampere 33520, Finland..
    Stedt, Hanna
    Kuopio Univ Hosp, Dept Oncol, Puijonlaaksontie 2, Kuopio 70210, Finland.;Univ Eastern Finland, Fac Hlth Sci, Yliopistonranta 1A, Kuopio 70210, Finland..
    Lamminmäki, Annamarja
    Kuopio Univ Hosp, Dept Oncol, Puijonlaaksontie 2, Kuopio 70210, Finland.;Univ Eastern Finland, Fac Hlth Sci, Yliopistonranta 1A, Kuopio 70210, Finland..
    Muhonen, Timo
    Univ Helsinki, Dept Oncol, Haartmaninkatu 8, Helsinki 00290, Finland.;South Carel Cent Hosp, Dept Oncol, Valto Kakelan Katu 1, Lappeenranta 53130, Finland..
    Kononen, Juha
    Docrates Hosp, Docrates Canc Ctr, Saukonpaadenranta 2, Helsinki 00180, Finland.;Hosp Nova, Dept Oncol, Hoitajankatu 3, Jyvaskyla 40620, Finland..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Isoniemi, Helena
    Helsinki Univ Hosp, Dept Transplantat & Liver Surg, Haartmaninkatu 4, Helsinki 00290, Finland.;Univ Helsinki, Dept Surg, Haartmaninkatu 8, Helsinki 00290, Finland..
    Lehto, Juho T.
    Tampere Univ, Fac Med & Hlth Technol, TUNI Palliat Care Res Grp, Arvo Ylpon Katu 23, Tampere 33520, Finland.;Tampere Univ Hosp, Palliat Care Ctr, Elamanaukio 2, Tampere 33520, Finland..
    Lehtomäki, Kaisa
    Tampere Univ Hosp, Tays Canc Ctr, Dept Oncol, Elamanaukio 2, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, Arvo Ylpon Katu 23, Tampere 33520, Finland..
    Österlund, Pia
    Tampere Univ Hosp, Tays Canc Ctr, Dept Oncol, Elamanaukio 2, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, Arvo Ylpon Katu 23, Tampere 33520, Finland.;Helsinki Univ Hosp, Dept Oncol, Haartmaninkatu 4, Helsinki 00290, Finland.;Univ Helsinki, Dept Oncol, Haartmaninkatu 8, Helsinki 00290, Finland.;Karolinska Univ Sjukhuset, Dept Gastrointestinal Oncol, Eugeniavagen 3, S-17176 Solna, Sweden.;Karolinska Inst, Dept Oncol Pathol, Solnavagen 1, S-17177 Solna, Sweden..
    Impact of Primary Tumor Location on Demographics, Resectability, Outcomes, and Quality of Life in Finnish Metastatic Colorectal Cancer Patients (Subgroup Analysis of the RAXO Study)2024In: Cancers, ISSN 2072-6694, Vol. 16, no 5, article id 1052Article in journal (Refereed)
    Abstract [en]

    Simple Summary The location of the primary tumor in the right colon, left colon, or rectum affects the efficacy of biological drugs used in the treatment of metastatic colorectal cancer, but how? We examined how the primary tumor location affects disease characteristics, treatability, quality of life, and outcome in a real-life study population of 1080 Finnish patients in the RAXO study. The primary tumor location correlates with the location of metastases, the frequency of gene mutations, how often metastases can be operated upon, long-term survival after curative surgery or palliative chemotherapy, and the quality of life during the disease trajectory. The primary tumor location is a helpful surrogate for clinicians working with metastatic colorectal cancer patients in estimating the clinical course of the disease. This study cannot identify the reasons for the associations, i.e., whether it is the primary location per se, the different mutations, or other reasons.Abstract The primary tumor location (PTL) is associated with the phenotype, metastatic sites, mutations, and outcomes of metastatic colorectal cancer (mCRC) patients, but this has mostly been studied according to sidedness (right vs. left sided). We studied right colon vs. left colon vs. rectal PTL in a real-life study population (n = 1080). Health-related quality of life (HRQoL) was assessed multi-cross-sectionally with QLQ-C30, QLQ-CR29, EQ-5D, and 15D. A chi-square, Kaplan-Meier, and Cox regression were used to compare the groups. The PTL was in the right colon in 310 patients (29%), the left colon in 396 patients (37%), and the rectum in 375 patients (35%). The PTL was associated with distinct differences in metastatic sites during the disease trajectory. The resectability, conversion, and resection rates were lowest in the right colon, followed by the rectum, and were highest in the left colon. Overall survival was shortest for right colon compared with left colon or rectal PTL (median 21 vs. 35 vs. 36 months), with the same trends after metastasectomy or systemic therapy only. PTL also remained statistically significant in a multivariable model. The distribution of symptoms varied according to PTL, especially between the right colon (with general symptoms of metastases) and rectal PTL (with sexual- and bowel-related symptoms). mCRC, according to PTL, behaves differently regarding metastatic sites, resectability of the metastases, outcomes of treatment, and HRQoL.

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  • 2.
    Arce, Maximiliano
    et al.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile.
    Pinto, Mauricio P.
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Galleguillos, Macarena
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Munoz, Catalina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Lange, Soledad
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Ramirez, Carolina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Erices, Rafaela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Univ Mayor, Vicerrectoria Invest, Santiago 7510041, Chile.
    Gonzalez, Pamela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Velasquez, Ethel
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Comis Chilena Energia Nucl CCHEN, Santiago, Chile.
    Tempio, Fabian
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile.
    Lopez, Mercedes N.
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Salazar-Onfray, Flavio
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Cautivo, Kelly
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Kalergis, Alexis M.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Biomed Res Consortium Chile, Santiago 8331010, Chile.
    Cruz, Sebastian
    Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lladser, Alvaro
    Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lobos-Gonzalez, Lorena
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile;Univ Desarrollo, Fac Med, Regenerat Med Ctr, Clin Alemana, Santiago 7650568, Chile.
    Valenzuela, Guillermo
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Olivares, Nixa
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Saez, Claudia
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Koning, Tania
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Sanchez, Fabiola A.
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Fuenzalida, Patricia
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Godoy, Alejandro
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Roswell Pk Comprehens Canc Ctr, Dept Urol, Buffalo, NY 14203 USA.
    Contreras Orellana, Pamela
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Leyton, Lisette
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Lugano, Roberta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Quest, Andrew F. G.
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Owen, Gareth, I
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation2019In: Cancers, ISSN 2072-6694, Vol. 11, no 8, article id 1103Article in journal (Refereed)
    Abstract [en]

    Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

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  • 3.
    Arthur, Cecilia
    et al.
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden..
    Jylha, Cecilia
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden..
    de Stahl, Teresita Diaz
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden..
    Shamikh, Alia
    Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, S-17176 Stockholm, Sweden..
    Sandgren, Johanna
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, S-17176 Stockholm, Sweden..
    Rosenquist, Richard
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden..
    Nordenskjold, Magnus
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden..
    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.
    Barbany, Gisela
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden..
    Sandvik, Ulrika
    Karolinska Inst, Dept Clin Neurosci, Div Neurosurg, S-17177 Stockholm, Sweden..
    Tham, Emma
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden..
    Simultaneous Ultra-Sensitive Detection of Structural and Single Nucleotide Variants Using Multiplex Droplet Digital PCR in Liquid Biopsies from Children with Medulloblastoma2023In: Cancers, ISSN 2072-6694, Vol. 15, no 7, article id 1972Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma is one of the most common types of brain tumors in children. During and after treatment with surgery, chemotherapy, and/or radiotherapy, children with this disease are monitored with imaging and cerebrospinal fluid analysis for the detection of tumor cells. These methods are not always sensitive or specific enough to confirm or rule out residual disease. Here, we develop a laboratory test based on the genetic makeup of medulloblastomas in 12 children. We analyze liquid biopsies (cerebrospinal fluid and blood plasma) for specific genetic fragments leaking from the individual tumors and find molecular traces of disease in 75% (9/12) of children overall. None of the children had malignant cells in the cerebrospinal fluid. We propose that this test could open up new technical possibilities to track measurable residual disease in children with medulloblastoma in order to further risk-adapt treatment, but first, larger studies of the approach at standardized time points are warranted.Medulloblastoma is a malignant embryonal tumor of the central nervous system (CNS) that mainly affects infants and children. Prognosis is highly variable, and molecular biomarkers for measurable residual disease (MRD) detection are lacking. Analysis of cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) using broad genomic approaches, such as low-coverage whole-genome sequencing, has shown promising prognostic value. However, more sensitive methods are needed for MRD analysis. Here, we show the technical feasibility of capturing medulloblastoma-associated structural variants and point mutations simultaneously in cfDNA using multiplexed droplet digital PCR (ddPCR). Assay sensitivity was assessed with a dilution series of tumor in normal genomic DNA, and the limit of detection was below 100 pg of input DNA for all assays. False positive rates were zero for structural variant assays. Liquid biopsies (CSF and plasma, n = 47) were analyzed from 12 children with medulloblastoma, all with negative CSF cytology. MRD was detected in 75% (9/12) of patients overall. In CSF samples taken before or within 21 days of surgery, MRD was detected in 88% (7/8) of patients with localized disease and in one patient with the metastasized disease. Our results suggest that this approach could expand the utility of ddPCR and complement broader analyses of cfDNA for MRD detection.

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  • 4.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    The Role of Fast-Cycling Atypical RHO GTPases in Cancer2022In: Cancers, ISSN 2072-6694, Vol. 14, no 8, article id 1961Article, review/survey (Refereed)
    Abstract [en]

    For many years, cancer-associated mutations in RHO GTPases were not identified and observations suggesting roles for RHO GTPases in cancer were sparse. Instead, RHO GTPases were considered primarily to regulate cell morphology and cell migration, processes that rely on the dynamic behavior of the cytoskeleton. This notion is in contrast to the RAS proteins, which are famous oncogenes and found to be mutated at high incidence in human cancers. Recent advancements in the tools for large-scale genome analysis have resulted in a paradigm shift and RHO GTPases are today found altered in many cancer types. This review article deals with the recent views on the roles of RHO GTPases in cancer, with a focus on the so-called fast-cycling RHO GTPases. The RHO GTPases comprise a subfamily within the RAS superfamily of small GTP-hydrolyzing enzymes and have primarily been ascribed roles in regulation of cytoskeletal dynamics in eukaryotic cells. An oncogenic role for the RHO GTPases has been disregarded, as no activating point mutations were found for genes encoding RHO GTPases. Instead, dysregulated expression of RHO GTPases and their regulators have been identified in cancer, often in the context of increased tumor cell migration and invasion. In the new landscape of cancer genomics, activating point mutations in members of the RHO GTPases have been identified, in particular in RAC1, RHOA, and CDC42, which has suggested that RHO GTPases can indeed serve as oncogenes in certain cancer types. This review describes the current knowledge of these cancer-associated mutant RHO GTPases, with a focus on how their altered kinetics can contribute to cancer progression.

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    FULLTEXT01
  • 5.
    Aughton, Karen
    et al.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Elander, Nils O.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England.;Linköping Univ, Dept Oncol, SE-58183 Linköping, Sweden..
    Evans, Anthony
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Jackson, Richard
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Campbell, Fiona
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Costello, Eithne
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Halloran, Christopher M.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Mackey, John R.
    Univ Alberta, Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada..
    Scarfe, Andrew G.
    Univ Alberta, Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada..
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, England..
    Carter, Ross
    Glasgow Royal Infirm, Glasgow G4 0SF, Lanark, Scotland..
    Cunningham, David
    Royal Marsden Natl Hlth Serv NHS Fdn Trust, London SW3 6JJ, England..
    Tebbutt, Niall C.
    Austin Hlth, Melbourne, Vic 3084, Australia..
    Goldstein, David
    Univ New South Wales, Prince Wales Hosp & Clin Sch, Sydney, NSW 2052, Australia..
    Shannon, Jennifer
    Univ Sydney, Nepean Canc Ctr, Sydney, NSW 2747, Australia..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hackert, Thilo
    Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany..
    Charnley, Richard M.
    Freeman Rd Hosp, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England..
    Anthoney, Alan
    St James Univ Hosp, Leeds LS9 7TF, W Yorkshire, England..
    Lerch, Markus M.
    Univ Med Greifswald, Dept Med A, D-17489 Greifswald, Germany..
    Mayerle, Julia
    Univ Med Greifswald, Dept Med A, D-17489 Greifswald, Germany.;Klinikum LMU Munchen Grosshadern, Med Klin & Poliklin 2, D-81377 Munich, Germany..
    Palmer, Daniel H.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Büchler, Markus W.
    Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany..
    Ghaneh, Paula
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Neoptolemos, John P.
    Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany..
    Greenhalf, William
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA2021In: Cancers, ISSN 2072-6694, Vol. 13, no 22, article id 5758Article in journal (Refereed)
    Abstract [en]

    Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

    Simple Summary:

    Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.

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  • 6.
    Banys-Paluchowski, Maggie
    et al.
    Univ Hosp Schleswig Holstein, Dept Gynecol & Obstet, Campus Lubeck, D-23538 Lubeck, Germany..
    Kühn, Thorsten
    Filderklin, Dept Gynecol & Obstet, D-70794 Filderstadt, Germany..
    Masannat, Yazan
    Aberdeen Royal Infirm, Aberdeen Breast Unit, Aberdeen AB25 2ZN, Scotland..
    Rubio, Isabel
    Clin Univ Navarra, Breast Surg Oncol, Madrid 28027, Spain..
    de Boniface, Jana
    Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.;Capio St Gorans Hosp, Dept Surg, Capio St, S-11219 Stockholm, Sweden..
    Ditsch, Nina
    Univ Hosp Augsburg, Canc Ctr 7Breast, D-86156 Augsburg, Germany..
    Karadeniz Cakmak, Güldeniz
    Zonguldak BEUN Sch Med, Gen Surg Dept, Breast & Endocrine Unit, TR-67600 Zonguldak, Turkey..
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Dave, Rajiv
    Univ Manchester, Manchester Univ NHS Fdn Trust, Fac Biol, Nightingale & Genesis Breast Canc Prevent Ctr, Manchester M13 9PL, England..
    Hahn, Markus
    Univ Tubingen, Dept Womens Hlth, D-72076 Tubingen, Germany. Bristol Populat Hlth Sci Inst, Bristol Med Sch THS, Bristol BS8 1QU, England. Guys & St Thomas NHS Fdn Trust, Kings Coll, London SE1 9RT, England..
    Potter, Shelley
    Kothari, Ashutosh
    Gentilini, Oreste Davide
    San Raffaele Univ & Res Hosp, Dept Breast Surg, I-20132 Milan, Italy. Marmara Univ, Sch Med, Breast Surg Unit, Dept Surg, TR-34854 Istanbul, Turkey..
    Gulluoglu, Bahadir M.
    SENATURK Turkish Acad Senol, TR-34854 Istanbul, Turkey..
    Lux, Michael Patrick
    St Louise Frauen & Kinderklin, Dept Gynecol & Obstet, D-33098 Paderborn, Germany..
    Smidt, Marjolein
    Maastricht Univ, Med Ctr, Dept Surg Oncol, NL-6229 HX Maastricht, Netherlands..
    Weber, Walter Paul
    Basel Univ Hosp, Dept Surg, Div Breast Surg, CH-4031 Basel, Switzerland. European Breast Canc Res Assoc Surg Trialists EUBR, D-73730 Esslingen, Germany..
    Aktas Sezen, Bilge
    Krawczyk, Natalia
    Heinrich Heine Univ Dusseldorf, Dept Gynecol & Obstet, D-40225 Dusseldorf, Germany..
    Hartmann, Steffi
    Univ Hosp Rostock, Dept Gynecol & Obstet, D-18059 Rostock, Germany..
    Di Micco, Rosa
    San Raffaele Univ & Res Hosp, Dept Breast Surg, I-20132 Milan, Italy. Marmara Univ, Sch Med, Breast Surg Unit, Dept Surg, TR-34854 Istanbul, Turkey..
    Nietz, Sarah
    Univ Witwatersrand, Fac Hlth Sci, Dept Surg, ZA-2000 Johannesburg, South Africa..
    Malherbe, Francois
    Univ Cape Town, Groote Schuur Hosp, Breast & Endocrine Surg Unit, ZA-7935 Cape Town, South Africa..
    Cabioglu, Neslihan
    Istanbul Univ, Istanbul Fac Med, Dept Gen Surg, TR-34093 Istanbul, Turkey..
    Canturk, Nuh Zafer
    Kocaeli Univ, Sch Med, Dept Gen Surg, TR-41001 Kocaeli, Turkey..
    Gasparri, Maria Luisa
    Osped Regionale Lugano EOC, Dept Gynecol & Obstet, CH-6900 Lugano, Switzerland.;Ente Osped Cantonale, Ctr Senol Svizzera Italiana CSSI, Via Pietro Capelli 1, CH-6900 Lugano, Switzerland..
    Murawa, Dawid
    Univ Svizzera Italiana USI, Fac Biomed Sci, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland..
    Harvey, James
    Univ Zielona Gora, Gen Surg & Surg Oncol Dept, Coll Medicum, PL-65417 Zielona Gora, Poland..
    Localization Techniques for Non-Palpable Breast Lesions: Current Status, Knowledge Gaps, and Rationale for the MELODY Study (EUBREAST-4/iBRA-NET, NCT 05559411)2023In: Cancers, ISSN 2072-6694, Vol. 15, no 4, article id 1173Article, review/survey (Refereed)
    Abstract [en]

    Background: Surgical excision of a non-palpable breast lesion requires a localization step. Among available techniques, wire-guided localization (WGL) is most commonly used. Other techniques (radioactive, magnetic, radar or radiofrequency-based, and intraoperative ultrasound) have been developed in the last two decades with the aim of improving outcomes and logistics.

    Methods: We performed a systematic review on localization techniques for non-palpable breast cancer.

    Results: For most techniques, oncological outcomes such as lesion identification and clear margin rate seem either comparable with or better than for WGL, but evidence is limited to small cohort studies for some of the devices. Intraoperative ultrasound is associated with significantly higher negative margin rates in meta-analyses of randomized clinical trials (RCTs). Radioactive techniques were studied in several RCTs and are non-inferior to WGL. Smaller studies show higher patient preference towards wire-free localization, but little is known about surgeons’ and radiologists’ attitudes towards these techniques.

    Conclusions: Large studies with an additional focus on patient, surgeon, and radiologist preference are necessary. This review aims to present the rationale for the MELODY (NCT05559411) study and to enable standardization of outcome measures for future studies.

    Simple summary

    Most breast cancers are small and can be treated using breast-conserving surgery. Since these tumors are non-palpable, they require a localization step that helps the surgeon to decide which tissue needs to be removed. The oldest localization technique is a guidewire placed into the tumor before surgery, usually using ultrasound or mammography. Afterwards, the surgeon removes the tissue around the wire tip. However, this technique has several disadvantages: It can cause the patient discomfort, requires a radiologist or another professional specialized in breast diagnostics to perform the procedure shortly before surgery, and 15–20% of patients need a second surgery to completely remove the tumor. Therefore, new techniques have been developed but most of them have not yet been examined in large, prospective, multicenter studies. In this review, we discuss all available techniques and present the MELODY study that will investigate their safety, with a focus on patient, surgeon, and radiologist preference.

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  • 7.
    Barnekow, Elin
    et al.
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Liu, Wen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Helgadottir, Hafdis T.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Michailidou, Kyriaki
    Cyprus Sch Mol Med, Cyprus Inst Neurol & Genet, Nicosia, Cyprus..
    Dennis, Joe
    Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England..
    Bryant, Patrick
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Chulalongkorn Univ, Fac Engn, Dept Comp Engn, Bangkok, Thailand..
    Wendt, Camilla
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hall, Per
    Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Margolin, Sara
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 162022In: Cancers, ISSN 2072-6694, Vol. 14, no 5, article id 1206Article in journal (Refereed)
    Abstract [en]

    Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility.

    Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls.

    Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68.

    Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

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  • 8.
    Beckmann, Kerri
    et al.
    Univ South Australia, Allied Hlth & Human Performance, Canc Epidemiol & Populat Hlth Res Grp, Adelaide, SA 5001, Australia; Kings Coll London, Sch Canc & Pharmaceut Studies, Translat Oncol & Urol Res, London SE1 9RT, England.
    Garmo, Hans
    Kings Coll London, Sch Canc & Pharmaceut Studies, Translat Oncol & Urol Res, London SE1 9RT, England; Uppsala Univ Hosp, Reg Canc Ctr, SE-75122 Uppsala, Sweden.
    Franck Lissbrant, Ingela
    Sahlgrenska Univ, Inst Clin Sci, Dept Oncol, SE-41345 Gothenburg, Sweden.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    The Value of Real-World Data in Understanding Prostate Cancer Risk and Improving Clinical Care: Examples from Swedish Registries2021In: Cancers, ISSN 2072-6694, Vol. 13, no 4, article id 875Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary

    Real-world data (RWD), i.e., data reflecting normal clinical practice collected outside the constraints of randomised controlled trials, provide important insights into our understanding of prostate cancer and its management. Clinical cancer registries are an important source of RWD. Depending on their scope and the potential linkage to other data sources, registry-based data can be utilised to address a variety of questions including risk factors, healthcare utilisation, treatment effectiveness, adverse effects, disparities in healthcare access, quality of care and healthcare economics. This review describes the various registry-based RWD sources for prostate cancer research in Sweden (namely the National Prostate Cancer Register, the Prostate Cancer data Base Sweden (PCBaSe) and the Patient-overview Prostate Cancer) and documents their utility for better understanding prostate cancer aetiology and improving clinical care.

    Abstract

    Real-world data (RWD), that is, data from sources other than controlled clinical trials, play an increasingly important role in medical research. The development of quality clinical registers, increasing access to administrative data sources, growing computing power and data linkage capacities have contributed to greater availability of RWD. Evidence derived from RWD increases our understanding of prostate cancer (PCa) aetiology, natural history and effective management. While randomised controlled trials offer the best level of evidence for establishing the efficacy of medical interventions and making causal inferences, studies using RWD offer complementary evidence about the effectiveness, long-term outcomes and safety of interventions in real-world settings. RWD provide the only means of addressing questions about risk factors and exposures that cannot be “controlled”, or when assessing rare outcomes. This review provides examples of the value of RWD for generating evidence about PCa, focusing on studies using data from a quality clinical register, namely the National Prostate Cancer Register (NPCR) Sweden, with longitudinal data on advanced PCa in Patient-overview Prostate Cancer (PPC) and data linkages to other sources in Prostate Cancer data Base Sweden (PCBaSe).

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  • 9.
    Bekkhus, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Martikainen, Teemu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olofsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Franzén Boger, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vasiliu Bacovia, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wärnberg, Fredrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Surg, S-41345 Gothenburg, Sweden..
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells2021In: Cancers, ISSN 2072-6694, Vol. 13, no 2, article id 211Article in journal (Refereed)
    Abstract [en]

    The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.

    Simple Summary

    Tumor draining lymph nodes (TDLNs) are the most common metastatic sites in human cancer but are also essential sites for induction of tumor immunity. How different types of primary tumors affect the anti-tumor immune response in the LNs is not fully understood. By analyzing biobank tissue from breast cancer patients, we demonstrate that invasive breast cancer induce dramatic pre-metastatic LN changes affecting the structure and function of the specialized LN vasculature and associated stromal cells, required for recruitment of T-lymphocytes into the LNs. These changes could not be seen in patients with non-invasive breast cancer and provide new insights of how invasive tumors can disrupt essential functions within the immune system. The data also shows promise of LN stromal and vascular changes as possible future biomarkers for prediction of disease progression in human cancer.

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  • 10.
    Bendahl, Par-Ola
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Gezelius, Emelie
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Longitudinal Assessment of Circulating Tumor Cells and Outcome in Small Cell Lung Cancer: A Sub-Study of RASTEN-A Randomized Trial with Low Molecular Weight Heparin2023In: Cancers, ISSN 2072-6694, Vol. 15, no 12, article id 3176Article in journal (Refereed)
    Abstract [en]

    Simple Summary Small cell lung cancer (SCLC) is an aggressive lung cancer subtype associated with an overall poor prognosis but a variable response rate to chemotherapy. The measurement of circulating tumor cells (CTCs) offers a non-invasive method to monitor the disease and may provide prognostic information as potential guidance to clinicians in the management of SCLC. However, the value of CTCs during and after chemotherapy appears inconclusive. Here, we show that the detection of CTCs at baseline correlates to overall survival in SCLC, and that persistently detectable CTCs after completion of treatment adds further prognostic value. This suggests that repetitive analysis of CTCs during and after the course of treatment may have a role in the management of SCLC, warranting further studies. Circulating tumor cells (CTCs) may provide a liquid biopsy approach to disease monitoring in small cell lung cancer (SCLC), a particularly aggressive tumor subtype. Yet, the prognostic role of CTCs during and after treatment in relation to baseline remains ill-defined. Here, we assessed the value of longitudinal CTC analysis and the potential of low-molecular-weight heparin (LMWH) to reduce CTC abundance in SCLC patients from a randomized trial (RASTEN). Blood samples were collected at baseline, before chemotherapy Cycle 3, and at 2-month follow-up from 42 patients in total, and CTCs were quantified using the FDA-approved CellSearch system. We found a gradual decline in CTC count during and after treatment, independently of the addition of LMWH to standard therapy. Detectable CTCs at baseline correlated significantly to reduced survival compared to undetectable CTCs (unadjusted hazard ratio (HR) of 2.75 (95% CI 1.05-7.20; p = 0.040)). Furthermore, a persistent CTC count at 2-month follow-up was associated with a HR of 4.22 (95% CI 1.20-14.91; p = 0.025). Our findings indicate that persistently detectable CTCs during and after completion of therapy offer further prognostic information in addition to baseline CTC, suggesting a role for CTC in the individualized management of SCLC.

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  • 11.
    Bragina, Olga
    et al.
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Therapy & Diagnost, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Therapy & Diagnost, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Schulga, Alexey
    Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia..
    Konovalova, Elena
    Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia..
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, S-10044 Stockholm, Sweden..
    Deyev, Sergey
    Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia..
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Direct Intra-Patient Comparison of Scaffold Protein-Based Tracers, [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3, for Imaging of HER2-Positive Breast Cancer2023In: Cancers, ISSN 2072-6694, Vol. 15, no 12, article id 3149Article in journal (Refereed)
    Abstract [en]

    Previous Phase I clinical evaluations of the radiolabelled scaffold proteins [Tc-99m]Tc-ADAPT6 and DARPin [Tc-99m]Tc-(HE)(3)-G3 in breast cancer patients have demonstrated their safety and indicated their capability to discriminate between HER2-positive and HER2-negative tumours. The objective of this study was to compare the imaging of HER2-positive tumours in the same patients using [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3. Eleven treatment-naive female patients (26-65 years) with HER2-positive primary and metastatic breast cancer were included in the study. Each patient was intravenously injected with [Tc-99m]Tc-ADAPT6, followed by an [Tc-99m]Tc-(HE)(3)-G3 injection 3-4 days later and chest SPECT/CT was performed. All primary tumours were clearly visualized using both tracers. The uptake of [Tc-99m]Tc-ADAPT6 in primary tumours (SUVmax = 4.7 & PLUSMN; 2.1) was significantly higher (p < 0.005) than the uptake of [Tc-99m]Tc-(HE)(3)-G3 (SUVmax = 3.5 & PLUSMN; 1.7). There was no significant difference in primary tumour-to-contralateral site values for [Tc-99m]Tc-ADAPT6 (15.2 & PLUSMN; 7.4) and [Tc-99m]Tc-(HE)(3)-G3 (19.6 & PLUSMN; 12.4). All known lymph node metastases were visualized using both tracers. The uptake of [Tc-99m]Tc-ADAPT6 in all extrahepatic soft tissue lesions was significantly (p < 0.0004) higher than the uptake of [Tc-99m]Tc-(HE)(3)-G3. In conclusion, [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3 are suitable for the visualization of HER2-positive breast cancer. At the selected time points, [Tc-99m]Tc-ADAPT6 has a significantly higher uptake in soft tissue lesions, which might be an advantage for the visualization of small metastases.

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  • 12. Brandão, Andreia
    et al.
    Paulo, Paula
    Maia, Sofia
    Pinheiro, Manuela
    Peixoto, Ana
    Cardoso, Marta
    Silva, Maria P.
    Santos, Catarina
    Eeles, Rosalind A.
    Kote-Jarai, Zsofia
    Muir, Kenneth
    Ukgpcs Collaborators,
    Schleutker, Johanna
    Wang, Ying
    Pashayan, Nora
    Batra, Jyotsna
    Apcb BioResource,
    Grönberg, Henrik
    Neal, David E.
    Nordestgaard, Børge G.
    Tangen, Catherine M.
    Southey, Melissa C.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Albanes, Demetrius
    Haiman, Christopher A.
    Travis, Ruth C.
    Stanford, Janet L.
    Mucci, Lorelei A.
    West, Catharine M. L.
    Nielsen, Sune F.
    Kibel, Adam S.
    Cussenot, Olivier
    Berndt, Sonja I.
    Koutros, Stella
    Dalsgaard Sørensen, Karina
    Cybulski, Cezary
    Grindedal, Eli Marie
    Park, Jong Y.
    Ingles, Sue A.
    Maier, Christiane
    Hamilton, Robert J.
    Rosenstein, Barry S.
    Vega, Ana
    The Impact Study Steering Committee And Collaborators,
    Kogevinas, Manolis
    Wiklund, Fredrik
    Penney, Kathryn L.
    Brenner, Hermann
    John, Esther M.
    Kaneva, Radka
    Logothetis, Christopher J.
    Neuhausen, Susan L.
    De Ruyck, Kim
    Razack, Azad
    Newcomb, Lisa F.
    Canary PASS Investigators,
    Lessel, Davor
    Usmani, Nawaid
    Claessens, Frank
    Gago-Dominguez, Manuela
    Townsend, Paul A.
    Roobol, Monique J.
    The Profile Study Steering Committee,
    The PRACTICAL Consortium,
    Teixeira, Manuel R.
    The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor2020In: Cancers, ISSN 2072-6694, Vol. 12, no 11, article id 3254Article in journal (Refereed)
    Abstract [en]

    The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

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  • 13.
    Chelebian, Eduard
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Avenel, Christophe
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Kartasalo, Kimmo
    Marklund, Maja
    Tanoglidi, Anna
    Uppsala Univ Hosp, Dept Clin Pathol, S-75237 Uppsala, Sweden..
    Mirtti, Tuomas
    Colling, Richard
    Erickson, Andrew
    Lamb, Alastair D.
    Lundeberg, Joakim
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Morphological Features Extracted by AI Associated with Spatial Transcriptomics in Prostate Cancer2021In: Cancers, ISSN 2072-6694, ISSN 2072-6694, Vol. 13, no 19, article id 4837Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is a common cancer type in men, yet some of its traits are still under-explored. One reason for this is high molecular and morphological heterogeneity. The purpose of this study was to develop a method to gain new insights into the connection between morphological changes and underlying molecular patterns. We used artificial intelligence (AI) to analyze the morphology of seven hematoxylin and eosin (H & E)-stained prostatectomy slides from a patient with multi-focal prostate cancer. We also paired the slides with spatially resolved expression for thousands of genes obtained by a novel spatial transcriptomics (ST) technique. As both spaces are highly dimensional, we focused on dimensionality reduction before seeking associations between them. Consequently, we extracted morphological features from H & E images using an ensemble of pre-trained convolutional neural networks and proposed a workflow for dimensionality reduction. To summarize the ST data into genetic profiles, we used a previously proposed factor analysis. We found that the regions were automatically defined, outlined by unsupervised clustering, associated with independent manual annotations, in some cases, finding further relevant subdivisions. The morphological patterns were also correlated with molecular profiles and could predict the spatial variation of individual genes. This novel approach enables flexible unsupervised studies relating morphological and genetic heterogeneity using AI to be carried out.

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  • 14.
    Chernov, Vladimir
    et al.
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Rybina, Anastasiya
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Nucl Med, Tomsk 634009, Russia..
    Zelchan, Roman
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Medvedeva, Anna
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Nucl Med, Tomsk 634009, Russia..
    Bragina, Olga
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Lushnikova, Nadejda
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Gen Oncol, Tomsk 634009, Russia..
    Doroshenko, Artem
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Gen Oncol, Tomsk 634009, Russia..
    Usynin, Evgeniy
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Gen Oncol, Tomsk 634009, Russia..
    Tashireva, Liubov
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Gen & Mol Pathol, Tomsk 634009, Russia.;Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Lab Mol Therapy Canc, Tomsk 634028, Russia..
    Vtorushin, Sergey
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Dept Gen & Mol Pathol, Tomsk 634009, Russia.;Siberian State Med Univ, Pathol Dept, Tomsk 634050, Russia..
    Abouzayed, Ayman
    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.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Orlova, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.;Siberian State Med Univ, Pathol Dept, Tomsk 634050, Russia..
    Phase I Trial of [Tc-99m]Tc-maSSS-PEG(2)-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors2023In: Cancers, ISSN 2072-6694, Vol. 15, no 6, article id 1631Article in journal (Refereed)
    Abstract [en]

    The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [Tc-99m]Tc-maSSS-PEG(2)-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 mu g of [Tc-99m]Tc-maSSS-PEG(2)-RM26 (600-700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 +/- 0.0007 for male patients and 0.008 +/- 0.003 mSv/MBq for female patients. The accumulation of [Tc-99m]Tc-maSSS-PEG(2)-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was safe and well tolerated. [Tc-99m]Tc-maSSS-PEG(2)-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.

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  • 15.
    Christou, Constantina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Tiblom Ehrsson, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Westerbergh, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Longitudinal Changes in the Fatty Acid Profile in Patients with Head and Neck Cancer: Associations with Treatment and Inflammatory Response2022In: Cancers, ISSN 2072-6694, Vol. 14, no 15, article id 3696Article in journal (Refereed)
    Abstract [en]

    Simple Summary Cancer-associated malnutrition affects nutrient metabolism, including the metabolism of lipids. Toxicities associated with the treatment for head and neck cancer (HNC) may contribute to malnutrition through impaired oral intake and inflammation. Studies on lipid metabolism in patients with HNC are very limited. The anti-inflammatory effect of some fatty acids (FAs) is already proven in other cancers but the results of these studies in HNC are not consistent. This prospective study of 174 patients with HNC contributes to our knowledge of alterations in lipid metabolism following treatment for HNC and serves as basis for future research. Studies on fatty acids (FAs) in patients with head and neck cancer (HNC) are limited. We aimed to investigate the longitudinal changes of circulating FAs in patients with HNC and to examine potential correlations of FA changes with treatment. The secondary aims were to investigate correlations of FAs with cytokines and patient-related factors, and if any FAs correlated with disease recurrence or death. A total of 174 patients with HNC were included before treatment and followed-up at three time points after the start of the treatment through blood sampling and body weight measurements. Serum FA profiling was assessed by gas chromatography. The total follow-up time was 3 years. The levels of almost all FAs changed from baseline to 7 weeks. The change in FA 14:0 was associated with treatment and the change in 18:3n-6 was associated with the patients' pre-treatment BMI. FAs 14:0 and 18:0 were correlated with weight changes from baseline to 7 weeks. IL-6 was correlated with three FAs at 7 weeks and with two FAs at 1 year. Patients with higher levels 20:5n-3 at 3 months had a higher risk of all-cause death within 3 years (HR 2.75, 95% CI 1.22-6.21). Treatment, inflammation, and weight loss contributed in a complex manner to the altered FA profile in the studied cohort. The association between IL-6 and FAs in patients with HNC is in line with earlier studies and suggests the opportunity for regulating inflammation in HNC patients through modulation of FAs.

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  • 16.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10,Room 1E-3140, Bethesda, MD 20892 USA.
    Backman, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Taieb, David
    Aix Marseille Univ, Dept Nucl Med, La Timone Univ Hosp, European Ctr Res Med Imaging, F-13385 Marseille, France.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Pacak, Karel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10,Room 1E-3140, Bethesda, MD 20892 USA.
    RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective2018In: Cancers, ISSN 2072-6694, Vol. 10, no 12, article id 518Article in journal (Refereed)
    Abstract [en]

    Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features.

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  • 17.
    de Flon, Caroline Haglund
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pathol, CCK R8 02, S-17164 Stockholm, Sweden..
    Haeggblom, Linnea
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden..
    Holzhauser, Stefan
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden..
    Kostopoulou, Ourania N.
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden..
    Zupancic, Mark
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Head & Neck Surg, Med Unit Head Neck Lung & Skin Canc, S-17164 Stockholm, Sweden..
    Dalianis, Tina
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Head & Neck Surg, Med Unit Head Neck Lung & Skin Canc, S-17164 Stockholm, Sweden..
    Munck-Wikland, Eva
    Karolinska Univ Hosp, Dept Head & Neck Surg, Med Unit Head Neck Lung & Skin Canc, S-17164 Stockholm, Sweden.;Karolinska Inst, Univ Hosp, Dept Clin Sci Intervent & Technol CLINTEC, Div Ear Nose & Throat Dis, S-17164 Stockholm, Sweden..
    Marklund, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Karolinska Univ Hosp, Dept Head & Neck Surg, Med Unit Head Neck Lung & Skin Canc, S-17164 Stockholm, Sweden.;Karolinska Inst, Univ Hosp, Dept Clin Sci Intervent & Technol CLINTEC, Div Ear Nose & Throat Dis, S-17164 Stockholm, Sweden..
    Nasman, Anders
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Bioclin J6 20, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pathol, CCK R8 02, S-17164 Stockholm, Sweden..
    High Levels of FGF11 Correlate with Poor Survival in Patients with Human Papillomavirus (HPV)-Positive Oropharyngeal Squamous Cell Carcinoma2023In: Cancers, ISSN 2072-6694, Vol. 15, no 7, article id 1954Article in journal (Refereed)
    Abstract [en]

    To better identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) and a poor prognosis after treatment, we compared the gene expression in tumours from patients with a poor or a favourable prognosis in a case-control setting. The results were thereafter validated in two separate cohorts on the RNA and protein levels. High RNA or protein expression of FGF11 was correlated with a poor patient survival in all three cohorts. Taken together, the data imply that FGF11 may play a major role in the prognosis of patients and that FGF11 could serve as a prognostic marker in HPV-positive oropharyngeal cancer.Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this patient group. For this purpose, all patients diagnosed with HPV and p16-positive OPSCC in Stockholm 2000-2009, identified as having a partial/nonresponse to treatment and having viable tumour cells in their neck specimen with material available were categorized as cases. These were matched to controls (complete responders), and the differences in the gene expression were analysed. Two separate verification cohorts were identified including patients with HPV- and p16-positive OPSCC, and the data from the case-control study were verified by qPCR and immunohistochemistry (IHC) in the respective cohorts. A separation of gene expression in correlation with survival was observed in the case-control study, and FGF11 expression was identified as significantly differently expressed between the two groups. The prognostic role of FGF11 was validated in the two cohorts on the RNA and protein levels, respectively. Taken together, our findings suggest that FGF11 may indicate a poor prognosis in HPV-positive OPSCC and may serve as a prognostic biomarker.

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  • 18.
    Deyev, Sergey M.
    et al.
    Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.;Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia.;Natl Res Nucl Univ MEPhI, Inst Engn Phys Biomed PhysBio, Bionanophoton Lab, Moscow 115409, Russia..
    Xu, Tianqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Yongsheng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Schulga, Alexey
    Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.;Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia..
    Konovalova, Elena
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia..
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-11417 Stockholm, Sweden..
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Larkina, Maria
    Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.;Siberian State Med Univ SSMU, Dept Pharmaceut Anal, 2 Moscow Trakt, Tomsk 634050, Russia..
    Ding, Haozhong
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-11417 Stockholm, Sweden..
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-11417 Stockholm, Sweden..
    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 634050, 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 634050, Russia..
    Vorobyeva, Anzhelika
    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 634050, Russia..
    Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec12021In: Cancers, ISSN 2072-6694, Vol. 13, no 14, article id 3589Article in journal (Refereed)
    Abstract [en]

    Simple Summary Metastasis-targeting therapy might improve outcomes in oligometastatic prostate cancer. Epithelial cell adhesion molecule (EpCAM) is overexpressed in 40-60% of prostate cancer cases and might be used as a target for specific delivery of toxins and drugs. Radionuclide molecular imaging could enable non-invasive detection of EpCAM and stratification of patients for targeted therapy. Designed ankyrin repeat proteins (DARPins) are scaffold proteins, which can be selected for specific binding to different targets. The DARPin Ec1 binds strongly to EpCAM. To determine an optimal design of Ec1-based probes, we labeled Ec1 at two different positions with four different nuclides (Ga-68, In-111, Co-57 and I-125) and investigated the impact on Ec1 biodistribution. We found that the C-terminus is the best position for labeling and that In-111 and I-125 provide the best imaging contrast. This study might be helpful for scientists developing imaging probes based on scaffold proteins. The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40-60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and composition on the targeting and imaging properties of Ec1. Two variants, having an N- or C-terminal cysteine, were produced, site-specifically conjugated to a DOTA chelator and labeled with cobalt-57, gallium-68 or indium-111. Site-specific radioiodination was performed using ((4-hydroxyphenyl)-ethyl)maleimide (HPEM). Biodistribution of eight radiolabeled Ec1-probes was measured in nude mice bearing PCa DU145 xenografts. In all cases, positioning of a label at the C-terminus provided the best tumor-to-organ ratios. The non-residualizing [I-125]I-HPEM label provided the highest tumor-to-muscle and tumor-to-bone ratios and is more suitable for EpCAM imaging in early-stage PCa. Among the radiometals, indium-111 provided the highest tumor-to-blood, tumor-to-lung and tumor-to-liver ratios and could be used at late-stage PCa. In conclusion, label position and composition are important for the DARPin Ec1.

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  • 19.
    Ding, Haozhong
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjorn
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates2019In: Cancers, ISSN 2072-6694, Vol. 11, no 8, article id 1168Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderateto high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (Z(HER2:2891))(2) -ABD-MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-3-MC-DM1, or a hexaglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-6-MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (Z(HER2:2891))(2)-ABD-MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability.

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  • 20.
    Dubbelboer, Ilse R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pavlovic, Natasa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Heindryckx, Femke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile2019In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 1024Article in journal (Refereed)
    Abstract [en]

    Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 mu M doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

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  • 21.
    Ebrahimi, Sheida
    et al.
    Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA..
    Lundström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA.;Univ Uppsala Hosp, Ctr Med Imaging, S-75185 Uppsala, Sweden..
    Batasin, Summer J.
    Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA..
    Hedlund, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health.
    Ehman, Eric C.
    Dept Radiol, Mayo Clin, Rochester, MN 55905 USA..
    Sheth, Vipul R.
    Stanford Univ, Dept Radiol, Palo Alto, CA 94305 USA..
    Iranpour, Negaur
    Stanford Univ, Dept Radiol, Palo Alto, CA 94305 USA..
    Loubrie, Stephane
    Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA..
    Schlein, Alexandra
    Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA..
    Rakow-Penner, Rebecca
    Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA.;Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA..
    Application of PET/MRI in Gynecologic Malignancies2024In: Cancers, ISSN 2072-6694, Vol. 16, no 8, article id 1478Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary This article reviews the value of Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in evaluating female pelvic cancers. It also provides a comparative analysis of PET/MRI with other imaging modalities in the context of female pelvic malignancies and outlines their respective strengths and limitations. The aim of this narrative review is to introduce to clinicians up and coming technology and how it may be valuable to their assessment of female pelvic cancers.Abstract The diagnosis, treatment, and management of gynecologic malignancies benefit from both positron emission tomography/computed tomography (PET/CT) and MRI. PET/CT provides important information on the local extent of disease as well as diffuse metastatic involvement. MRI offers soft tissue delineation and loco-regional disease involvement. The combination of these two technologies is key in diagnosis, treatment planning, and evaluating treatment response in gynecological malignancies. This review aims to assess the performance of PET/MRI in gynecologic cancer patients and outlines the technical challenges and clinical advantages of PET/MR systems when specifically applied to gynecologic malignancies.

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  • 22.
    Ekström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Åkerrén Ögren, Jim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Exact Probability Distribution for the ROC Area under Curve2023In: Cancers, ISSN 2072-6694, Vol. 15, no 6, article id 1788Article in journal (Refereed)
    Abstract [en]

    Simple Summary This contribution allows for the computation of exact p-values and for conducting accurate statistical hypothesis tests of ROC AUC-values. As a result, the development of diagnostic tests is facilitated. This work is illustrated via simulated data and through the development of proteomic blood biomarkers for the early detection of cancer. The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development.

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  • 23.
    Eldh, Maria
    et al.
    Karolinska Inst, Dept Med Solna, Div Immunol & Allergy, S-17164 Stockholm, Sweden..
    Mints, Michael
    Karolinska Inst, Dept Med Solna, Div Immunol & Allergy, S-17164 Stockholm, Sweden.;Umeå Univ, Dept Surg & Perioperat Sci Urol & Androl, S-90736 Umeå, Sweden..
    Hiltbrunner, Stefanie
    Karolinska Inst, Dept Med Solna, Div Immunol & Allergy, S-17164 Stockholm, Sweden..
    Ladjevardi, Sam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. Akademiska Univ Hosp, Dept Urol, S-75185 Uppsala, Sweden..
    Alamdari, Farhood
    Vastmanland Hosp, Dept Urol, S-72189 Västerås, Sweden..
    Johansson, Markus
    Umeå Univ, Sundsvall Hosp, Dept Urol, S-90736 Umeå, Sweden..
    Jakubczyk, Tomasz
    Lanssjukhuset Ryhov, Dept Urol, S-55305 Jönköping, Sweden..
    Veerman, Rosanne E.
    Karolinska Inst, Dept Med Solna, Div Immunol & Allergy, S-17164 Stockholm, Sweden..
    Winqvist, Ola
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, S-17176 Solna, Sweden..
    Sherif, Amir
    Umeå Univ, Dept Surg & Perioperat Sci Urol & Androl, S-90736 Umeå, Sweden..
    Gabrielsson, Susanne
    Karolinska Inst, Dept Med Solna, Div Immunol & Allergy, S-17164 Stockholm, Sweden..
    Proteomic Profiling of Tissue Exosomes Indicates Continuous Release of Malignant Exosomes in Urinary Bladder Cancer Patients, Even with Pathologically Undetectable Tumour2021In: Cancers, ISSN 2072-6694, Vol. 13, no 13, article id 3242Article in journal (Refereed)
    Abstract [en]

    Simple Summary Urinary bladder cancer (UBC) has a high recurrence rate, and biomarkers for different treatment strategies are highly needed. This study investigated the release of nanovesicles called exosomes from urinary bladder tissue from tumour-proximal sites as well as tumour-distant sites in transurethrally resected (TUR-B) patients with or without preoperative neoadjuvant chemotherapy prior to ensuing radical cystectomy-all without remaining visible tumour after TUR-B. We show that cancer-promoting exosomes were detected from both sites, suggesting that the previous tumour has altered the whole bladder tissue into a cancer-supporting milieu. The exosomes may originate from remaining pathologically undetectable cancer cells or transformed epithelial cells, and the study supports the notion of exosomes as mediators of metastatic spread and as potential biomarkers. It also supports early and radical removal of the bladder in urinary bladder cancer patients. Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC.

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  • 24.
    Eltahir, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Isaksson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Karre, Klas
    Karolinska Inst, Dept Microbiol Cell & Tumor Biol, S-17177 Stockholm, Sweden..
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lord, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade2021In: Cancers, ISSN 2072-6694, Vol. 13, no 13, article id 3116Article in journal (Refereed)
    Abstract [en]

    Simple Summary Immunotherapy leads to highly variable responses in lung cancer patients. We assessed the value of a blood-based test to predict which patients would benefit from this new treatment modality. We determined that some patients have higher and lower levels of immune markers in their blood samples, and that this is related to better survival without tumor growth. The blood test has the potential to help select the optimal therapy for lung cancer patients. Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.

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  • 25.
    Enblad, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Ghanipour, Lana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Cashin, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    No Indication for Routine Resection of Surgical Scars during Cytoreductive Surgery and HIPEC2024In: Cancers, ISSN 2072-6694, Vol. 16, no 11, article id 2099Article in journal (Refereed)
    Abstract [en]

    Background: Careful macroscopic assessment of surgical scars is needed to avoid routine scar resection during cytoreductive surgery (CRS) for peritoneal metastases (PM). This study aimed to analyze the correlation between macroscopically suspected and microscopically confirmed scar metastases (SMs), and to analyze the prognostic impact of not undergoing routine scar resection.

    Method: All patients with previous surgery, treated with CRS and hyperthermic intraperitoneal chemotherapy, for colorectal PM or pseudomyxoma peritonei (PMP), at Uppsala University Hospital in 2013–2021, were included. Macroscopic SMs in surgical reports were compared with histopathological analyses.

    Results: In total, 227 patients were included. Among colorectal PM patients (n = 156), SM was macroscopically suspected in 41 (26%) patients, and 63 (40%) underwent scar resection. SM was confirmed in 19 (30%). Among patients with macroscopic suspicion, 45% had confirmed SM (positive predictive value, PPV). A total of 1 of 23 (4%) patients with no macroscopic suspicion had SM (negative predictive value, NPV = 96%). Among the PMP patients (n = 71), SM was macroscopically suspected in 13 (18%), and 28 (39%) underwent scar resection, of whom 12 (43%) had SM. The PPV was 77%. Occult SM was found in 1 of 14 (NPV = 93%). Not undergoing routine scar resection did not affect recurrence-free survival (RFS, p = 0.2) or overall survival (OS, p = 0.1) in colorectal PM patients or PMP patients (RFS p = 0.7, OS p = 0.7).

    Conclusion: Occult SM is uncommon and scar resection does not affect RFS or OS. Therefore, macroscopically benign-appearing scars can be left without resection, though resection should be performed upon suspicion or uncertainty.

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  • 26.
    Enblad, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pál Egerszegi, Péter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Folkesson, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Signet Ring Cell Colorectal and Appendiceal Cancer: A Small Signet Ring Cell Component Is Also Associated with Poor Outcome2023In: Cancers, ISSN 2072-6694, Vol. 15, no 9, article id 2497Article in journal (Refereed)
    Abstract [en]

    Background: Colorectal signet ring cell (SRC) carcinoma with ≥50% SRCs (SRC ≥ 50) has a poor prognosis, but the prognostic role of SRCs < 50% (SRC < 50) is unclear. The aim of this study was to provide a clinicopathological characterization of SRC colorectal and appendiceal tumours and analyse the importance of the SRC component size.

    Methods: All patients in the Swedish Colorectal Cancer Registry diagnosed with colorectal or appendiceal cancer in 2009–2020 at Uppsala University Hospital, Sweden, were included. The SRCs were verified, and the components estimated by a gastrointestinal pathologist.

    Results: Of the 2229 colorectal cancers, 51 (2.3%) had SRCs, with a median component size of 30% (interquartile range of 12.5–40) and 10 (0.45%) had SRC ≥ 50. The SRC tumours were primarily localized in the right colon (59%) and appendix (16%). No patients with SRCs had stage I disease, and 26 (51%) had stage IV, of whom, 18 (69%) had peritoneal metastases. The SRC tumours were often high grade with perineural and vascular invasion. The 5-year overall survival (OS) rate for patients with SRC ≥ 50 were 20% (95% confidence interval (CI) 6–70), for SRC < 50, 39% (95% CI 24–61); and for non-SRCs, 55% (95% CI 55–60). Among the patients with SRC < 50 and <50% extracellular mucin, the 5-year OS was 34% (95% CI 19–61), while those with ≥50% extracellular mucin had an OS of 50% (95% CI 25–99). The 5-year recurrence-free survival rates were 51% (95% CI 13–83) for patients with SRC tumours, as compared to 83% (95% CI 77–89) and 81% (95% CI 79–84) for mucinous and non-mucinous adenocarcinoma, respectively.

    Conclusions: The presence of SRCs was strongly associated with aggressive clinicopathological features, peritoneal metastases, and poor prognosis, also when they make up <50% of a tumour.

    Simple Summary

    Signet ring cell (SRC) carcinoma of colorectal and appendiceal cancer is rare but is recognized as the histopathological subtype with the poorest prognosis. However, the prognostic relevance of a SRC component <50% is unclear. The aim of this study was to provide a clinicopathological characterization of all SRC-containing colorectal and appendiceal cancers, including those with <50% SRCs. The results showed that SRCs, both ≥50% and <50%, were associated with aggressive histopathological features, advanced stages, and, particularly, peritoneal metastases. Information about the presence of SRCs in tumour tissue, not only in the case of ≥50% SRCs, should be routinely registered in pathology reports and clinical registers to enable larger studies that can aid our understanding of SRCs in colorectal and appendiceal cancers.

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  • 27.
    Engstrand, Jennie
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Surg, S-14186 Stockholm, Sweden..
    Taflin, Helena
    Sahlgrens Univ Hosp, Sahlgrenska Acad Univ Gothenburg, Inst Clin Sci, Dept Surg, S-41345 Gothenburg, Sweden..
    Rystedt, Jenny Lundmark
    Lund Univ, Skane Univ Hosp, Dept Surg, S-22100 Lund, Sweden..
    Hemmingsson, Oskar
    Umeå Univ, Dept Surg & Perioperat Sci, S-90187 Umeå, Sweden.;Umeå Univ, Wallenberg Ctr Mol Med, S-90187 Umeå, Sweden..
    Urdzik, Jozef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Sandstrom, Per
    Linköping Univ, Dept Surg Linköping, S-58183 Linköping, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden..
    Bjornsson, Bergthor
    Linköping Univ, Dept Surg Linköping, S-58183 Linköping, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden..
    Hasselgren, Kristina
    Linköping Univ, Dept Surg Linköping, S-58183 Linköping, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden..
    The Resection Rate of Synchronously Detected Liver and Lung Metastasis from Colorectal Cancer Is Low-A National Registry-Based Study2023In: Cancers, ISSN 2072-6694, Vol. 15, no 5, article id 1434Article in journal (Refereed)
    Abstract [en]

    Population-based data on the incidence and surgical treatment of patients with colorectal cancer (CRC) and synchronous liver and lung metastases are lacking as are real-life data on the frequency of metastasectomy for both sites and outcomes in this setting. This is a nationwide population-based study of all patients having liver and lung metastases diagnosed within 6 months of CRC between 2008 and 2016 in Sweden identified through the merging of data from the National Quality Registries on CRC, liver and thoracic surgery and the National Patient Registry. Among 60,734 patients diagnosed with CRC, 1923 (3.2%) had synchronous liver and lung metastases, of which 44 patients had complete metastasectomy. Surgery of liver and lung metastases yielded a 5-year OS of 74% (95% CI 57–85%) compared to 29% (95% CI 19–40%) if liver metastases were resected but not the lung metastases and 2.6% (95% CI 1.5–4%) if non-resected, p < 0.001. Complete resection rates ranged from 0.7% to 3.8% between the six healthcare regions of Sweden, p = 0.007. Synchronous liver and lung CRC metastases are rare, and a minority undergo the resection of both metastatic sites but with excellent survival. The reasons for differences in regional treatment approaches and the potential of increased resection rates should be studied further.

    Simple summary: Real-life data on the occurrence and treatment of synchronously detected liver and lung metastases from colorectal cancer are lacking. Through the merging of several Swedish nationwide patient quality registries, we aimed to answer these questions. We found that synchronous liver and lung colorectal metastases are rare and that a minority undergo resection of both metastatic sites, but if they do, they have an excellent survival. It is likely that a larger proportion of patients could be offered treatment that leads to a prolonged overall survival. We also found differences in regional treatment approaches across Sweden, but the reasons for this are unknown, which warrants further studies.

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  • 28.
    Enlund, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland.
    Is It Definitely Clear That Long-Term Survival after Breast Cancer Surgery Is Not Affected by Anaesthetics?2021In: Cancers, ISSN 2072-6694, Vol. 13, no 14, article id 3390Article, review/survey (Refereed)
    Abstract [en]

    Retrospective studies indicate that cancer survival may be affected by the anaesthetic technique. Propofol seems to be a better choice than volatile anaesthetics, such as sevoflurane. The first two retrospective studies suggested better long-term survival with propofol, but not for breast cancer. Subsequent retrospective studies from Asia indicated the same. When data from seven Swedish hospitals were analysed, including 6305 breast cancer patients, different analyses gave different results, from a non-significant difference in survival to a remarkably large difference in favour of propofol, an illustration of the innate weakness in the retrospective design. The largest randomised clinical trial, registered on clinicaltrial.gov, with survival as an outcome is the Cancer and Anesthesia study. Patients are here randomised to propofol or sevoflurane. The inclusion of patients with breast cancer was completed in autumn 2017. Delayed by the pandemic, one-year survival data for the cohort were presented in November 2020. Due to the extremely good short-term survival for breast cancer, one-year survival is of less interest for this disease. As the inclusions took almost five years, there was also a trend to observe. Unsurprisingly, no difference was found in one-year survival between the two groups, and the trend indicated no difference either.

    Simple summary

    The choice of anaesthetic may affect long-term survival, as suggested in animal studies and in retrospective patient studies. Breast cancer seems to be an exception, according to results from retrospective patient studies. So far this has not been proven in randomised clinical trials. The current state of research is summarised in this overview. The conclusion is that today it seems that the choice of anaesthetic does not play a role in long-term survival after breast cancer surgery.

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  • 29.
    Enroth, Stefan
    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.
    Plasma Proteins and Cancer2021In: Cancers, ISSN 2072-6694, Vol. 13, no 5, article id 1062Article in journal (Other academic)
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  • 30.
    Gallus, Roberto
    et al.
    Mater Olbia Hosp, Otolaryngol, I-07026 Olbia, Italy..
    Nauta, Irene H.
    Vrije Univ Amsterdam, Amsterdam UMC, Canc Ctr, Otolaryngol Head & Neck Surg, NL-1081 Amsterdam, Netherlands..
    Marklund, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Karolinska Univ Hosp, Karolinska Inst, Dept Clin Sci Intervent & Technol, Dept Oto Rhinolaryngol Head & Neck Surg, S-17164 Stockholm, Sweden; Karolinska Univ Hosp, Med Unit Head Neck Lung & Skin Canc, S-17164 Stockholm, Sweden.
    Rizzo, Davide
    Univ Sassari, Dept Med Surg & Expt Sci, Otolaryngol Div, Viale San Pietro 43, I-07100 Sassari, Italy..
    Crescio, Claudia
    Azienda Osped Univ, Otolaryngol Div, I-07100 Sassari, Italy..
    Mureddu, Luca
    Univ Cagliari, Policlin Univ Duilio Casula, UOC Otorinolaringoiatria, I-09042 Monserrato, Italy..
    Tropiano, Paolo
    Azienda Osped Univ, Otolaryngol Div, I-07100 Sassari, Italy..
    Delogu, Giovanni
    Univ Cattolica Sacro Cuore, Dipartimento Sci Biotecnolog Base Clin Intensivol, Sez Microbiol, I-00168 Rome, Italy.;Mater Olbia Hosp, I-07026 Olbia, Italy..
    Bussu, Francesco
    Univ Sassari, Dept Med Surg & Expt Sci, Otolaryngol Div, Viale San Pietro 43, I-07100 Sassari, Italy..
    Accuracy of p16 IHC in Classifying HPV-Driven OPSCC in Different Populations2023In: Cancers, ISSN 2072-6694, Vol. 15, no 3, article id 656Article in journal (Refereed)
    Abstract [en]

    High-risk human papillomavirus (HPV) infection is a defined etiopathogenetic factor in oropharyngeal carcinogenesis with a clear prognostic value. The P16 IHC (immunohistochemistry) is a widely accepted marker for HPV-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC); in the present paper, we discuss its reliability as a standalone marker in different populations. The literature suggests that rates of p16 IHC false positive results are inversely correlated with the prevalence of HPV-driven carcinogenesis in a population. We propose a formula that can calculate such a false positive rate while knowing the real prevalence of HPV-driven OPSCCs in a given population. As it has been demonstrated that p16 positive/HPV negative cases (i.e., false positives at p16 IHC) have the same prognosis as p16 negative OPSCC, we conclude that despite the valuable prognostic value of p16 IHC, relying only on a p16 IHC positive result to recommend treatment de-intensification could be risky. For this aim, confirmation with an HPV nucleic acid detection system, especially in areas with a low prevalence of HPV-related OPSCCs, should be pursued.

    Simple summary

    p16 IHC is the HPV detection method suggested by the current version of the TNM (AJCC 8th edition) for oropharyngeal squamocellular carcinoma. However, its reliability has been extensively discussed, and its applicability in every context, especially the enrollment of patients in de-intensification protocols, is debatable. Here, we discuss its limits, especially in populations with a low prevalence of HPV-driven oropharyngeal squamocellular carcinoma, and suggest the possible actions to be taken to overcome such limitations.

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  • 31.
    Garbulowski, Mateusz
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-10691 Solna, Sweden..
    Smolinska Garbulowska, Karolina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cabuk, Ugur
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Helmholtz Ctr Polar & Marine Res, Alfred Wegener Inst, Polar Terr Environm Syst, D-14473 Potsdam, Germany.;Univ Potsdam, Inst Biochem & Biol, D-14469 Potsdam, Germany..
    Younes, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Celli, Ludovica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CNR, Inst Mol Genet Luigi Luca Cavalli Sforza, I-27100 Pavia, Italy.;Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy..
    Yaz, Esma Nur
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Istanbul Medipol Univ, Grad Sch Engn & Nat Sci, Dept Biomed Engn & Bioinformat, TR-34810 Istanbul, Turkey..
    Barrenäs, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Washington Natl Primate Res Ctr, Seattle, WA 98195 USA..
    Diamanti, Klev
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. 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.
    Wadelius, Claes
    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.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). Washington Natl Primate Res Ctr, Seattle, WA 98195 USA.;Swedish Coll Adv Study, S-75238 Uppsala, Sweden.;Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland..
    Machine Learning-Based Analysis of Glioma Grades Reveals Co-Enrichment2022In: Cancers, ISSN 2072-6694, Vol. 14, no 4, article id 1014Article in journal (Refereed)
    Abstract [en]

    Simple Summary Gliomas are heterogenous types of cancer, therefore the therapy should be personalized and targeted toward specific pathways. We developed a methodology that corrected strong batch effects from The Cancer Genome Atlas datasets and estimated glioma grade-specific co-enrichment mechanisms using machine learning. Our findings created hypotheses for annotations, e.g., pathways, that should be considered as therapeutic targets. Gliomas develop and grow in the brain and central nervous system. Examining glioma grading processes is valuable for improving therapeutic challenges. One of the most extensive repositories storing transcriptomics data for gliomas is The Cancer Genome Atlas (TCGA). However, such big cohorts should be processed with caution and evaluated thoroughly as they can contain batch and other effects. Furthermore, biological mechanisms of cancer contain interactions among biomarkers. Thus, we applied an interpretable machine learning approach to discover such relationships. This type of transparent learning provides not only good predictability, but also reveals co-predictive mechanisms among features. In this study, we corrected the strong and confounded batch effect in the TCGA glioma data. We further used the corrected datasets to perform comprehensive machine learning analysis applied on single-sample gene set enrichment scores using collections from the Molecular Signature Database. Furthermore, using rule-based classifiers, we displayed networks of co-enrichment related to glioma grades. Moreover, we validated our results using the external glioma cohorts. We believe that utilizing corrected glioma cohorts from TCGA may improve the application and validation of any future studies. Finally, the co-enrichment and survival analysis provided detailed explanations for glioma progression and consequently, it should support the targeted treatment.

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  • 32.
    Garcia-Vicien, Gemma
    et al.
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain..
    Mezheyeuski, Artur
    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.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ruiz, Nuria
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain.;Hosp Univ Bellvitge, Dept Pathol, Barcelona 08908, Catalonia, Spain..
    Ruffinelli, Jose Carlos
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain.;Inst Catala Oncol, Dept Med Oncol, Barcelona 08908, Catalonia, Spain..
    Mils, Kristel
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain.;Hosp Univ Bellvitge, Dept Surg, Barcelona 08908, Catalonia, Spain..
    Banuls, Maria
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain..
    Molina, Natalia
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain..
    Losa, Ferran
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain.;Inst Catala Oncol, Dept Med Oncol, Barcelona 08908, Catalonia, Spain..
    Llado, Laura
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain.;Hosp Univ Bellvitge, Dept Surg, Barcelona 08908, Catalonia, Spain..
    Mollevi, David G.
    Inst Invest Biomed Bellvitge IDIBELL, Tumoral & Stromal Chemoresistance Grp, Oncobell Program, Gran Via 197-203, Barcelona 08908, Catalonia, Spain.;Inst Catala Oncol, Program Canc Therapeut Resistance ProCURE, Barcelona 08908, Catalonia, Spain..
    Spatial Immunology in Liver Metastases from Colorectal Carcinoma according to the Histologic Growth Pattern2022In: Cancers, ISSN 2072-6694, Vol. 14, no 3, article id 689Article in journal (Refereed)
    Abstract [en]

    Simple Summary In the era of immunotherapy, the tumor microenvironment (TME) has attracted special interest. However, colorectal liver metastases (CRC-LM) present histological peculiarities that could affect the interaction of immune and tumor cells such as fibrotic encapsulation and dense intratumoral stroma. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the histologic growth patterns using multispectral digital pathology providing data on three different scenarios, tumor periphery, invasive margin, and central tumoral areas. Our results illustrate a similar poor cell density of CD8(+) cells between different metastases subtypes in intratumoral regions. However, in encapsulated metastases, cytotoxic cells reach the tumor cells while remaining retained in stromal areas in non-encapsulating metastases. Some aspects are still unresolved, such as understanding the reason why most lymphocytes are largely retained in the capsule. Colorectal cancer liver metastases (CRC-LM) present differential histologic growth patterns (HGP) that determine the interaction between immune and tumor cells. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the HGP using multispectral digital pathology. We did not find statistically significant differences of immune cell densities in the central regions of desmoplastic ((d)HGP) and non-desmoplastic ((nd)HGP) metastases. The spatial evaluation reported that (d)HGP-metastases displayed higher infiltration by CD8(+) and CD20(+) cells in peripheral regions as well as CD4(+) and CD45RO(+) cells in (nd)HGP-metastases. However, the reactive stroma regions at the invasive margin (IM) of (nd)HGP-metastases displayed higher density of CD4(+), CD20(+), and CD45RO(+) cells. The antitumor status of the TIL infiltrates measured as CD8/CD4 reported higher values in the IM of encapsulated metastases up to 400 mu m towards the tumor center (p < 0.05). Remarkably, the IM of (d)HGP-metastases was characterized by higher infiltration of CD8(+) cells in the epithelial compartment parameter assessed with the ratio CD8(epithelial)/CD8(stromal), suggesting anti-tumoral activity in the encapsulating lesions. Taking together, the amount of CD8(+) cells is comparable in the IM of both HGP metastases types. However, in (d)HGP-metastases some cytotoxic cells reach the tumor nests while remaining retained in the stromal areas in (nd)HGP-metastases.

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  • 33.
    Gezelius, Emelie
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden..
    Bendahl, Paer-Ola
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden..
    Gallo, Widet
    Lund Univ, Clin Res Ctr, Hypertens & Cardiovasc Dis Grp, Dept Clin Sci,Skane Univ Hosp, Jan Waldenstroms Gata 35, SE-21428 Malmö, Sweden..
    de Oliveira, Kelin Goncalves
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden..
    Ek, Lars
    Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden..
    Bergman, Bengt
    Sahlgrens Univ Hosp, Dept Resp Med, SE-41345 Gothenburg, Sweden..
    Sundberg, Jan
    Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden..
    Melander, Olle
    Lund Univ, Clin Res Ctr, Hypertens & Cardiovasc Dis Grp, Dept Clin Sci,Skane Univ Hosp, Jan Waldenstroms Gata 35, SE-21428 Malmö, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden..
    Circulating Levels of the Cardiovascular Biomarkers ST2 and Adrenomedullin Predict Outcome within a Randomized Phase III Lung Cancer Trial (RASTEN)2022In: Cancers, ISSN 2072-6694, Vol. 14, no 5, article id 1307Article in journal (Refereed)
    Abstract [en]

    Simple Summary Cardiovascular disease is common in patients with small cell lung cancer, partly reflecting its high correlation with smoking. Cardiovascular comorbidities may limit patient tolerance to cytotoxic drugs, thereby influencing the choice and intensity of treatment and, ultimately, patient survival. In light of the challenges relating to assessing cardiovascular status clinically in newly diagnosed lung cancer, objective biomarkers of cardiovascular vulnerability are warranted. Here, we show that circulating levels of ST2, an established biomarker in heart failure, and adrenomedullin, a vasodilator peptide known to reflect several aspects of cardiovascular status, strongly correlate with survival in small cell lung cancer. Our data, which are based on a large, randomized trial cohort, suggest the potential use of cardiovascular biomarkers in guiding clinicians in making individualized treatment decisions. Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic peptide (MR-proANP), copeptin (surrogate for vasopressin) and suppression-of-tumorigenicity-2 (ST2), all known to correlate with various aspects of cardiovascular function, in a SCLC cohort (N = 252) from a randomized, controlled trial (RASTEN). For all measured biomarkers, protein levels were inversely associated with survival, particularly with ST2 and MR-proADM, where the top versus bottom quartile was associated with an adjusted hazard ratio of 2.40 (95% CI 1.44-3.98; p = 0.001) and 2.18 (95% CI 1.35-3.51; p = 0.001), respectively, in the entire cohort, and 3.43 (95% CI 1.73-6.79; p < 0.001) and 3.49 (95% CI 1.84-6.60; p < 0.001), respectively, in extensive disease patients. A high combined score of MR-proADM and ST2 was associated with a significantly reduced median OS of 7.0 months vs. 14.9 months for patients with a low combined score. We conclude that the cardiovascular biomarkers MR-proADM and ST2 strongly correlate with survival in SCLC, warranting prospective studies on the clinical utility of MR-proADM and ST2 for improved, individualized treatment decisions.

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  • 34.
    Gholiha, Alex R.
    et al.
    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.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hashemi, Jamileh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattson Ulfstedt, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Molin, Daniel
    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.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics. 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 Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Enblad, Gunilla
    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.
    Immune-Proteome Profiling in Classical Hodgkin Lymphoma Tumor Diagnostic Tissue2022In: Cancers, ISSN 2072-6694, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    In classical Hodgkin Lymphoma (cHL), immunoediting via protein signaling is key to evading tumor surveillance. We aimed to identify immune-related proteins that distinguish diagnostic cHL tissues (=diagnostic tumor lysates, n = 27) from control tissues (reactive lymph node lysates, n = 30). Further, we correlated our findings with the proteome plasma profile between cHL patients (n = 26) and healthy controls (n = 27). We used the proximity extension assay (PEA) with the OlinkTM multiplex Immuno-Oncology panel, consisting of 92 proteins. Univariate, multivariate-adjusted analysis and Benjamini–Hochberg’s false discovery testing (=Padj) were performed to detect significant discrepancies. Proteins distinguishing cHL cases from controls were more numerous in plasma (30 proteins) than tissue (17 proteins), all Padj < 0.05. Eight of the identified proteins in cHL tissue (PD-L1, IL-6, CCL17, CCL3, IL-13, MMP12, TNFRS4, and LAG3) were elevated in both cHL tissues and cHL plasma compared with control samples. Six proteins distinguishing cHL tissues from controls tissues were significantly correlated to PD-L1 expression in cHL tissue (IL-6, MCP-2, CCL3, CCL4, GZMB, and IFN-gamma, all p ≤0.05). In conclusion, this study introduces a distinguishing proteomic profile in cHL tissue and potential immune-related markers of pathophysiological relevance

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  • 35.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Osterman, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Gävle Cent Hosp, Dept Surg, SE-80187 Gävle, Region Gävleborg, Sweden.
    Adjuvant Chemotherapy in Elderly Colorectal Cancer Patients2020In: Cancers, ISSN 2072-6694, Vol. 12, no 8, article id 2289Article, review/survey (Refereed)
    Abstract [en]

    The value of adjuvant chemotherapy in elderly patients has been the subject of many overviews, with opinions varying from "not effective", since randomized trials have not been performed, to "as effective as in young individuals", based upon many retrospective analyses of randomized trials that have included patients of all ages. In the absence of randomized trials performed specifically with elderly patients, retrospective analyses demonstrate that the influence on the time to tumour recurrence (TTR) may be the same as in young individuals, but that endpoints that include death for any reason, such as recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS), are poorer in the elderly. This is particularly true if oxaliplatin has been part of the treatment. The need for adjuvant chemotherapy after colorectal cancer surgery in elderly patients is basically the same as that in younger patients. The reduction in recurrence risks may be similar, provided the chosen treatment is tolerated but survival gains are less. Adding oxaliplatin to a fluoropyrimidine is probably not beneficial in individuals above a biological age of approximately 70 years. If an oxaliplatin combination is administered to elderly patients, three months of therapy is in all probability the most realistic goal.

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  • 36.
    Graf, Wilhelm
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala Univ, Akad Sjukhuset, Inst Surg Sci, Dept Surg, SE-75185 Uppsala, Sweden..
    Ghanipour, Lana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala Univ, Akad Sjukhuset, Inst Surg Sci, Dept Surg, SE-75185 Uppsala, Sweden..
    Birgisson, Helgi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala Univ, Akad Sjukhuset, Inst Surg Sci, Dept Surg, SE-75185 Uppsala, Sweden..
    Cashin, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala Univ, Akad Sjukhuset, Inst Surg Sci, Dept Surg, SE-75185 Uppsala, Sweden..
    Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases from Colorectal Cancer-An Overview of Current Status and Future Perspectives2024In: Cancers, ISSN 2072-6694, Vol. 16, no 2, article id 284Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary The concept of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy perfusion for the treatment of colorectal cancer peritoneal metastases has been debated based on the results of recent controlled trials. In this review, we describe the development of this "package" treatment and discuss various aspects of the selection and indications, as well as future fields of research.Abstract Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored.

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  • 37.
    Gyllensten, Ulf B.
    et al.
    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.
    Bosdotter Enroth, Sofia
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Sundfeldt, Karin
    Enroth, Stefan
    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.
    Preoperative Fasting and General Anaesthesia Alter the Plasma Proteome2020In: Cancers, ISSN 2072-6694, Vol. 12, no 9, article id 2439Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Blood plasma collected at time of surgery is an excellent source of patient material for investigations into disease aetiology and for the discovery of novel biomarkers. Previous studies on limited sets of proteins and patients have indicated that pre-operative fasting and anaesthesia can affect protein levels, but this has not been investigated on a larger scale. These effects could produce erroneous results in case-control studies if samples are not carefully matched.

    METHODS: The proximity extension assay (PEA) was used to characterize 983 unique proteins in a total of 327 patients diagnosed with ovarian cancer and 50 age-matched healthy women. The samples were collected either at time of initial diagnosis or before surgery under general anaesthesia.

    RESULTS: 421 of the investigated proteins (42.8%) showed statistically significant differences in plasma abundance levels comparing samples collected at time of diagnosis or just before surgery under anaesthesia.

    CONCLUSIONS: The abundance levels of the plasma proteome in samples collected before incision, i.e., after short-time fasting and under general anaesthesia differs greatly from levels in samples from awake patients. This emphasizes the need for careful matching of the pre-analytical conditions of samples collected from controls to cases at time of surgery in the discovery as well as clinical use of protein biomarkers.

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  • 38.
    Gyllensten, Ulf B.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Hedlund-Lindberg, Julia
    Svensson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Manninen, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öst, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ramsell, Jon
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åslin, Matilda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ivansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lomnytska, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health.
    Lycke, Maria
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik D
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sjöblom, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Uhlén, Mathias
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health.
    Sundfeldt, Karin
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer.2022In: Cancers, ISSN 2072-6694, Vol. 14, no 7, article id 1757Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers.

    METHODS: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37).

    RESULTS: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers.

    CONCLUSIONS: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.

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  • 39.
    Hammarström, Klara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Imam, Israa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ekström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    A Comprehensive Evaluation of Associations Between Routinely Collected Staging Information and The Response to (Chemo)Radiotherapy in Rectal Cancer2021In: Cancers, ISSN 2072-6694, Vol. 13, no 1, article id 16Article in journal (Refereed)
    Abstract [en]

    Simple Summary Rectal cancer patients are often treated with radiotherapy, either alone or combined with chemotherapy, prior to surgery to enable radical surgery on a non-resectable tumor or to lower the recurrence risk. For some patients, the tumor disappears completely after preoperative treatment, while others experience little or no benefit. Accurate prediction of therapy response before treatment is of great importance for a personalized treatment approach and intentional organ preservation. We performed a comprehensive evaluation of the predictive capacity of all routinely collected staging information at diagnosis in a population-based, completely staged patient material of 383 patients representing a real-life clinical situation. Size or stage of the rectal tumor were independent predictors of excellent response irrespective of preoperative treatment, with small/early-stage tumors being significantly more likely to reach a complete response. Levels of the tumor marker carcinoembryonic antigen (CEA) above upper normal limit halved the chance of response. Radiotherapy (RT) or chemoradiotherapy (CRT) are frequently used in rectal cancer, sometimes resulting in complete tumor remission (CR). The predictive capacity of all clinical factors, laboratory values and magnetic resonance imaging parameters performed in routine staging was evaluated to understand what determines an excellent response to RT/CRT. A population-based cohort of 383 patients treated with short-course RT (5 x 5 Gy in one week, scRT), CRT, or scRT with chemotherapy (scRT+CT) and having either had a delay to surgery or been entered into a watch-and-wait program were included. Complete staging according to guidelines was performed and associations between investigated variables and CR rates were analyzed in univariate and multivariate analyses. In total, 17% achieved pathological or clinical CR, more often after scRT+CT and CRT than after scRT (27%, 18% and 8%, respectively, p < 0.001). Factors independently associated with CR included clinical tumor stage, small tumor size (<3 cm), tumor level, and low CEA-value (<3.8 mu g/L). Size or stage of the rectal tumor were associated with excellent response in all therapy groups, with small or early stage tumors being significantly more likely to reach CR (p = 0.01 (scRT), p = 0.01 (CRT) and p = 0.02 (scRT+CT). Elevated level of carcinoembryonic antigen (CEA) halved the chance of response. Extramural vascular invasion (EMVI) and mucinous character may indicate less response to RT alone.

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  • 40.
    Hellbacher, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Expression of PD-1, PD-L1 and PD-L2 in Lymphomas in Patients with Pre-Existing Rheumatic Diseases-A Possible Association with High Rheumatoid Arthritis Disease Activity2022In: Cancers, ISSN 2072-6694, Vol. 14, no 6, article id 1509Article in journal (Refereed)
    Abstract [en]

    Simple Summary Immunotherapy blocking programmed cell death protein 1 (PD-1) and its ligands (PD-L1, PD-L2) is less effective in non-Hodgkin lymphoma (NHL) than classical Hodgkin lymphoma. However, NHL is a heterogeneous group and current research seeks to identify subgroups of NHL patients responsive to PD-1 blocking agents. Whether patients with pre-existing rheumatic diseases might constitute such a subgroup is unknown. We investigated the expression of PD-1 and its ligands in lymphoma patients with pre-existing rheumatic diseases. Our key findings include that in patients with pre-existing rheumatoid arthritis (RA) and subsequent diffuse large B-cell lymphoma, an association between RA disease severity and increased expression of PD-L1 in tumor cells was seen. This warrants further studies of the PD-1 pathway in lymphoma in other chronic inflammatory conditions. Current research seeks to identify subgroups of non-Hodgkin lymphoma (NHL) patients responsive to PD-1 blocking agents. Whether patients with pre-existing rheumatic diseases might constitute such a subgroup is unknown. We determined intratumoral expression of PD-1 and its ligands in lymphoma patients with pre-existing rheumatic diseases. We included 215 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or Sjogren's syndrome with subsequent lymphoma and 74 diffuse large B-cell lymphoma (DLBCL) controls without rheumatic disease. PD-1 and PD-ligand immunohistochemical markers were applied on tumor tissue microarrays. The number of PD-1+ tumor infiltrating leukocytes (TILs) and proportions of PD-L1+ and PD-L2+ tumor cells and TILs were calculated and correlated with clinical data. Expression of PD-L1 in tumor cells and TILs was highest in classical Hodgkin lymphoma and DLBCL. In DLBCLs, expression of PD-1 in TILs and PD-L1 in tumor cells was similar in RA, SLE and controls. In RA-DLBCL, high expression of PD-L1 in tumor cells was significantly more common in patients with the most severe RA disease and was associated with inferior overall survival in multivariable analysis.

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  • 41.
    Herrera, Mercedes
    et al.
    Karolinska Inst, Oncol & Pathol Dept, S-17164 Stockholm, Sweden..
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Villabona, Lisa
    Karolinska Inst, Oncol & Pathol Dept, S-17164 Stockholm, Sweden..
    Corvigno, Sara
    Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA..
    Strell, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Klein, Christian
    Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev pRED, CH-8952 Schlieren, Switzerland..
    Holzlwimmer, Gabriele
    Roche Innovat Ctr Munich, Roche Pharma Res & Early Dev pRED, Dept Pathol & Tissue Analyt, D-82377 Penzberg, Germany..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Masucci, Giuseppe
    Karolinska Inst, Oncol & Pathol Dept, S-17164 Stockholm, Sweden..
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ostman, Arne
    Karolinska Inst, Oncol & Pathol Dept, S-17164 Stockholm, Sweden..
    Prognostic Interactions between FAP plus Fibroblasts and CD8a+T Cells in Colon Cancer2020In: Cancers, ISSN 2072-6694, Vol. 12, no 11, article id 3238Article in journal (Refereed)
    Abstract [en]

    Simple Summary In addition to malignant cells, tumors are composed also of other cell types including immune cells and fibroblasts. These cell types interact with each other and with the malignant cells. Prognosis associations have previously been demonstrated for CD8-positive immune cells. Recent studies suggest that fibroblasts can affect the function of immune cells. The aim of this study was to investigate if the fibroblast composition of tumors affected the prognosis association of CD8 immune cells. This study demonstrated that in colon cancer, CD8 prognosis associations was restricted to the group of tumors with high expression the FAP fibroblast marker. Our findings suggest continued mechanistic studies regarding crosstalk between FAP-positive fibroblasts and the different immune cell types; and also support the investigation of fibroblast/T-cell interactions for therapeutic purposes. Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

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  • 42.
    Hersi, Abdi-Fatah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala Univ, Ctr Clin Res, Reg Vastmanland, S-72189 Västerås, Sweden.;Vastmanlands Hosp, Dept Surg, S-72189 Västerås, Sweden..
    Pistiolis, Lida
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Surg,Sahlgrenska Acad, S-41345 Gothenburg, Sweden..
    Luberth, Carlos Dussan
    Linköping Univ Hosp, Dept Surg, S-58185 Linköping, Sweden..
    Vikhe-Patil, Eva
    Linköping Univ Hosp, Dept Surg, S-58185 Linköping, Sweden..
    Nilsson, Fredrik
    Umeå Univ Hosp, Dept Surg & Perioperat Sci, S-90187 Umeå, Sweden..
    Mohammed, Imad
    Kalmar Cty Hosp, Dept Surg, S-39185 Kalmar, Sweden..
    Bagge, Roger Olofsson
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Surg,Sahlgrenska Acad, S-41345 Gothenburg, Sweden..
    Warnberg, Fredrik
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Surg,Sahlgrenska Acad, S-41345 Gothenburg, Sweden.;Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden..
    Eriksson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala Univ, Ctr Clin Res, Reg Vastmanland, S-72189 Västerås, Sweden.;Vastmanlands Hosp, Dept Surg, S-72189 Västerås, Sweden..
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Optimizing Dose and Timing in Magnetic Tracer Techniques for Sentinel Lymph Node Detection in Early Breast Cancers: The Prospective Multicenter SentiDose Trial2021In: Cancers, ISSN 2072-6694, Vol. 13, no 4, article id 693Article in journal (Refereed)
    Abstract [en]

    Simple Summary Superparamagnetic iron oxide (SPIO) nanoparticles have comparable performance to the combination of radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) biopsy in breast cancer. In this multicenter prospective study, lower SPIO doses (undiluted 1.5 vs. 1.0 mL) in different timeframes (perioperative vs. 1-7 days preoperative) and injection sites (subareolar vs. peritumoral) were compared to the previous standard (diluted 2.0 mL perioperatively) from the earlier Nordic trial. RI + BD were co-administered as background. In total, 534 patients were analyzed. SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and respectively non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 mL and the Nordic cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Thus, SPIO at 1.5 and 1.0 mL was non-inferior to both Sienna+(R) and the dual technique for SLN detection. Superparamagnetic iron oxide nanoparticles (SPIO) are non-inferior to radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) detection. Previously, 2 mL SPIO (Sienna+(R)) in 3 mL NaCl was used. In this dose-optimizing study, lower doses of a new refined SPIO solution (Magtrace(R)) (1.5 vs. 1.0 mL) were tested in different timeframes (0-24 h perioperative vs. 1-7 days preoperative) and injections sites (subareolar vs. peritumoral). Two consecutive breast cancer cohorts (n = 328) scheduled for SLN-biopsy were included from 2017 to 2019. All patients received isotope +/- blue dye as back-up. SLNs were identified primarily with the SentiMag(R) probe and thereafter a gamma-probe. The primary endpoint was SLN detection rate with SPIO. Analyses were performed as a one-step individual patient-level meta-analysis using patient-level data from the previously published Nordic Trial (n = 206) as a third, reference cohort. In 534 patients, the SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 and the 2.0 mL cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Lower SPIO volumes injected up to 7 days before the operation have comparable efficacy to standard SPIO dose and RI + BD for SLN detection.

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  • 43.
    Holmberg Olausson, Karl O.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Borgenvik, Anna
    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giraud, Géraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Uppsala Univ, Dept Pediat Hematol & Oncol, Childrens Hosp, S-75185 Uppsala, Sweden..
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies2024In: Cancers, ISSN 2072-6694, Vol. 16, no 9, article id 1752Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

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  • 44.
    Huang, Dan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Damdimopoulos, Anastasios
    Karolinska Inst, Dept Biosci & Nutr, Bioinformat & Express Core Facil, SE-14183 Huddinge, Sweden..
    Antonson, Per
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma-Possible Estrogen Effects2023In: Cancers, ISSN 2072-6694, Vol. 15, no 4, article id 1298Article in journal (Refereed)
    Abstract [en]

    Simple Summary Females show a favorable sex difference in incidence as well as in survival for many cancer types, so also in lymphoma. The reasons for this are unknown. We have therefore analyzed global gene expression in a large cohort of the most common lymphoma type, diffuse large B-cell lymphoma. We show that many genes are differentially expressed between males and females. Furthermore, the results demonstrate sex-dependent differences in gene expression between DLBCL subtypes. In addition, gene expression differs in pre- vs. postmenopausal women suggesting that estrogen regulation of genes is involved. Thus, estrogens may contribute to the sex and female age differences in incidence and prognosis observed. For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene expression data from a publicly available cohort (EGAD00001003600) of 746 DLBCL samples based on RNA sequencing. We found 1293 genes to be differentially expressed between males and females (adj. p-value < 0.05). Few autosomal genes and pathways showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. Analysis of differentially expressed genes between pre- vs. postmenopausal females identified 208 GCB and 345 ABC genes, with only 5 being shared. When combining the differentially expressed genes between females vs. males and pre- vs. postmenopausal females, nine putative estrogen-regulated genes were identified in ABC DLBCL. Two of them, NR4A2 and MUC5B, showed induced and repressed expression, respectively. Interestingly, NR4A2 has been reported as a tumor suppressor in lymphoma. We show that ABC DLBCL females with a high NR4A2 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. NR4A2 and MUC5B were confirmed to be estrogen-regulated when the ABC cell line U2932 was grafted to mice. The results demonstrate sex- and female reproductive age-dependent differences in gene expression between DLBCL subtypes, likely due to estrogens. This may contribute to the sex differences in incidence and prognosis.

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  • 45.
    Imam, Israa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Hammarström, Klara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Determinants of Pre-Surgical Treatment in Primary Rectal Cancer: A Population-Based Study2023In: Cancers, ISSN 2072-6694, Vol. 15, no 4, article id 1154Article in journal (Refereed)
    Abstract [en]

    Simple Summary Preoperative radiotherapy has an established role in the treatment of rectal cancer, alone or with chemotherapy, but the use varies considerably. Many scientists have strived to reduce the use of radiation while maintaining high local control rates, partly counterbalanced by an ambition to preserve the organ. Besides patient-related factors, stage as defined by magnetic resonance imaging (MRI) is most important for the decision at multidisciplinary team (MDT) conferences to recommend direct surgery or any treatment prior to (eventual) surgery. In a large prospective, unselected and properly staged patient cohort, MRI characteristics were most important for treatment selection, but patient-related factors were also relevant. Changes over time, reflecting changed national guidelines that were striving to reduce the use of radiation, were seen; however, they were probably interpreted differently in the two analysed regions. The accuracy of MRI evaluated by specially trained radiologists, during an MDT conference in real life, was poor. When preoperative radiotherapy (RT) is best used in rectal cancer is subject to discussions and guidelines differ. To understand the selection mechanisms, we analysed treatment decisions in all patients diagnosed between 2010-2020 in two Swedish regions (Uppsala with a RT department and Dalarna without). Information on staging and treatment (direct surgery, short-course RT, or combinations of RT/chemotherapy) in the Swedish Colorectal Cancer Registry were used. Staging magnetic resonance imaging (MRI) permitted a division into risk groups, according to national guidelines. Logistic regression explored associations between baseline characteristics and treatment, while Cohen's kappa tested congruence between clinical and pathologic stages. A total of 1150 patients without synchronous metastases were analysed. Patients from Dalarna were older, had less advanced tumours and were pre-treated less often (52% vs. 63%, p < 0.001). All MRI characteristics (T-/N-stage, MRF, EMVI) and tumour levels were important for treatment choice. Age affected if chemotherapy was added. The correlation between clinical and pathological T-stage was fair/moderate and poor for N-stage. The MRI-based risk grouping influenced treatment choice the most. Since the risk grouping was modified to diminish the pre-treated proportion, fewer patients were irradiated with time. MRI staging is far from optimal. A stronger wish to decrease irradiation may explain why fewer patients from Dalarna were irradiated, but inequality in health care cannot be ruled out.

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  • 46.
    Jahn, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ilan, Ezgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Garske-Román, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Medical Imaging Centre, Uppsala University Hospital.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Medical Imaging Centre, Uppsala University Hospital.
    Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE: Differences in Tumor Dosimetry, Vascularity and Lesion Metrics in Pancreatic and Small Intestinal Neuroendocrine Neoplasms2021In: Cancers, ISSN 2072-6694, Vol. 13, no 5, article id 962Article in journal (Refereed)
    Abstract [en]

    Dosimetry during peptide receptor radionuclide therapy (PRRT) has mainly focused on normal organs and less on the tumors. The absorbed dose in one target tumor per patient and several response related factors were assessed in 23 pancreatic neuroendocrine neoplasms (P-NENs) and 25 small-intestinal NEN (SI-NENs) during PRRT with 177Lu-DOTATATE. The total administered activity per patient was (mean ± standard error of mean (SEM) 31.8 ± 1.9 GBq for P-NENs and 36 ± 1.94 GBq for SI-NENs. The absorbed tumor dose was 143.5 ± 2 Gy in P-NENs, 168.2 ± 2 Gy in SI-NENs. For both NEN types, a dose-response relationship was found between the absorbed dose and tumor shrinkage, which was more pronounced in P-NENs. A significant drop in the absorbed dose per cycle was shown during the course of PRRT. Tumor vascularization was higher in P-NENs than in SI-NENs at baseline but equal post-PRRT. The time to progression (RECIST 1.1) was similar for patients with P-NEN (mean ± SEM 30 ± 1 months) and SI-NEN (33 ± 1 months). In conclusion, a dose response relationship was established for both P-NENs and SI-NENs and a significant drop in the absorbed dose per cycle was shown during the course of PRRT, which warrants further investigation to understand the factors impacting PRRT to improve personalized treatment protocol design.

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  • 47.
    Javadi, Joman
    et al.
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden..
    Heidari-Hamedani, Ghazal
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden..
    Schmalzl, Angelika
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden..
    Szatmari, Tunde
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden..
    Metintas, Muzaffer
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden.;Eskisehir Osmangazi Univ, Fac Med, Dept Chest, TR-26040 Eskisehir, Turkey..
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hjerpe, Anders
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden..
    Dobra, Katalin
    Karolinska Inst, Div Pathol, Dept Lab Med, SE-14157 Stockholm, Sweden..
    Syndecan-1 Overexpressing Mesothelioma Cells Inhibit Proliferation, Wound Healing, and Tube Formation of Endothelial Cells2021In: Cancers, ISSN 2072-6694, Vol. 13, no 4, article id 655Article in journal (Refereed)
    Abstract [en]

    Simple Summary The transmembrane proteoglycan syndecan-1 (SDC-1) is an important mediator of cell-matrix interactions. The heparan sulfate side-chains of SDC-1 can bind to a multitude of growth factors, cytokines, and chemokines, thereby regulating a plethora of physiological and pathological processes, including angiogenesis. The extracellular region of SDC-1 can be released from the cell surface by the action of sheddases including matrix metalloproteinase-7 and 9, resulting in a soluble protein that is still active and can act as a competitive activator or inhibitor of the cell surface receptor. Accelerated shedding and loss of cell surface SDC-1 is associated with epithelial to mesenchymal transition (EMT) and achievement of a more invasive phenotype in malignant mesothelioma (MM). Transfection with SDC-1 reverts the morphology in epithelioid direction and inhibits the proliferation and migration of MM cells. This study aimed to investigate the role of SDC-1 in angiogenesis. We demonstrate that overexpression and silencing of SDC-1 alters the secretion of angiogenic proteins in MM cells. Upon SDC-1 overexpression, several factors collectively inhibit the proliferation, wound closure, and tube formation of endothelial cells, whereas SDC-1 silencing only affects wound healing. Malignant mesothelioma (MM) is an aggressive tumor of the serosal cavities. Angiogenesis is important for mesothelioma progression, but so far, anti-angiogenic agents have not improved patient survival. Our hypothesis is that better understanding of the regulation of angiogenesis in this tumor would largely improve the success of such a therapy. Syndecan-1 (SDC-1) is a transmembrane heparan sulfate proteoglycan that acts as a co-receptor in various cellular processes including angiogenesis. In MM, the expression of SDC-1 is generally low but when present, SDC-1 associates to epithelioid differentiation, inhibition of tumor cell migration and favorable prognosis, meanwhile SDC-1 decrease deteriorates the prognosis. In the present study, we studied the effect of SDC-1 overexpression and silencing on MM cells ability to secrete angiogenic factors and monitored the downstream effect of SDC-1 modulation on endothelial cells proliferation, wound healing, and tube formation. This was done by adding conditioned medium from SDC-1 transfected and SDC-1 silenced mesothelioma cells to endothelial cells. Moreover, we investigated the interplay and molecular functional changes in angiogenesis in a co-culture system and characterized the soluble angiogenesis-related factors secreted to the conditioned media. We demonstrated that SDC-1 over-expression inhibited the proliferation, wound healing, and tube formation of endothelial cells. This effect was mediated by a multitude of angiogenic factors comprising angiopoietin-1 (Fold change +/- SD: 0.65 +/- 0.07), FGF-4 (1.45 +/- 0.04), HGF (1.33 +/- 0.07), NRG1-beta 1 (1.35 +/- 0.08), TSP-1 (0.8 +/- 0.02), TIMP-1 (0.89 +/- 0.01) and TGF-beta 1 (1.35 +/- 0.01). SDC-1 silencing increased IL8 (1.33 +/- 0.06), promoted wound closure, but did not influence the tube formation of endothelial cells. Pleural effusions from mesothelioma patients showed that Vascular Endothelial Growth Factor (VEGF) levels correlate to soluble SDC-1 levels and have prognostic value. In conclusion, SDC-1 over-expression affects the angiogenic factor secretion of mesothelioma cells and thereby inhibits endothelial cells proliferation, tube formation, and wound healing. VEGF could be used in prognostic evaluation of mesothelioma patients together with SDC-1.

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  • 48.
    Jazrawi, Allan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala Univ, Ctr Clin Res, S-72189 Västerås, County Vastmanl, Sweden.;Vastmanlands Cty Hosp, Dept Surg, S-72189 Västerås, Sweden..
    Pantiora, Eirini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden.;Uppsala Univ Hosp, Dept Surg, Sect Endocrine & Breast Surg, S-75185 Uppsala, Sweden..
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden.;Aleris Mammog Unit, S-75320 Uppsala, Sweden..
    Vasiliu-Bacovia, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Eriksson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala Univ, Ctr Clin Res, S-72189 Västerås, County Vastmanl, Sweden.;Vastmanlands Cty Hosp, Dept Surg, S-72189 Västerås, Sweden..
    Leonhardt, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Radiol, S-41343 Gothenburg, Sweden..
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden.;Uppsala Univ Hosp, Dept Surg, Sect Endocrine & Breast Surg, S-75185 Uppsala, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Surg, S-41345 Gothenburg, Sweden..
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden.;Uppsala Univ Hosp, Dept Surg, Sect Endocrine & Breast Surg, S-75185 Uppsala, Sweden..
    Magnetic-Guided Axillary UltraSound (MagUS) Sentinel Lymph Node Biopsy and Mapping in Patients with Early Breast Cancer. A Phase 2, Single-Arm Prospective Clinical Trial2021In: Cancers, ISSN 2072-6694, Vol. 13, no 17, article id 4285Article in journal (Refereed)
    Abstract [en]

    Simple Summary Superparamagnetic iron oxide nanoparticles (SPIO) have been shown to identify sentinel lymph nodes (SLNs) in patients with breast cancer. This study investigated whether a minimally invasive approach with MRI-LG after SPIO injection in the breast followed by a magnetic guided axillary ultrasound and core biopsy of the SLN (MagUS) could accurately stage the axilla. The study included not only patients planned for primary surgery but also patients with recurrent cancer after previous surgery, but also patients scheduled for neoadjuvant treatment (NAT). The latter underwent minimally invasive SLNB prior to treatment and had their SLN clipped; surgery in the axilla was performed after NAT. In 79 included patients, MagUS detected all patients with macrometastasis and performed comparably with surgical sentinel lymph node dissection (SLND). It also allowed for marking of the SLN in patients planned for PST and enabled tailored decision making in breast cancer recurrence. Lymph Node Dissection (SLND) is standard of care for diagnosing sentinel lymph node (SLN) status in patients with early breast cancer. Study aim was to determine whether the combination of Superparamagnetic iron oxide nanoparticles (SPIO) MRI-lymphography (MRI-LG) and a Magnetic-guided Axillary UltraSound (MagUS) with biopsy can allow for minimally invasive, axillary evaluation to de-escalate surgery. Patients were injected with 2 mL of SPIO and underwent MRI-LG for SN mapping. Thereafter MagUS and core needle biopsy (CNB) were performed. Patients planned for neoadjuvant treatment, the SLN was clipped and SLND was performed after neoadjuvant with the addition of isotope. During surgery, SLNs were controlled for signs of previous biopsy or clip. The primary endpoint was MagUS SLN detection rate, defined as successful SLN detection of at least one SLN of those retrieved in SLND. In 79 patients, 48 underwent upfront surgery, 12 received neoadjuvant and 19 had recurrent cancer. MagUS traced the SLN in all upfront and neoadjuvant cases, detecting all patients with macrometastases (n = 10). MagUS missed only one micrometastasis, outperforming baseline axillary ultrasound AUS (AUC: 0.950 vs. 0.508, p < 0.001) and showing no discordance to SLND (p = 1.000). MagUS provides the niche for minimally invasive axillary mapping that can reduce diagnostic surgery.

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  • 49.
    Jazrawi, Allan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Vastmanlands Cty Hosp, Dept Surg, S-72189 Västerås, Sweden..
    Wärnberg, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hersi, Abdi-Fatah
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Plast Surg, S-41345 Gothenburg, Sweden..
    Obondo, Christine
    Soder Sjukhuset, Dept Surg, S-11883 Stockholm, Sweden..
    Pistioli, Lida
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Surg, S-41345 Gothenburg, Sweden..
    Eriksson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Vastmanlands Cty Hosp, Dept Surg, S-72189 Västerås, Sweden..
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ Hosp, Dept Surg, Sect Endocrine & Breast Surg, Akadem Sjukhuset, S-75185 Uppsala, Sweden..
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Surg, S-41345 Gothenburg, Sweden.;Uppsala Univ Hosp, Dept Surg, Sect Endocrine & Breast Surg, Akadem Sjukhuset, S-75185 Uppsala, Sweden..
    A Comparison of Skin Staining after Sentinel Lymph Node Biopsy in Women Undergoing Breast Cancer Surgery Using Blue Dye and Superparamagnetic Iron Oxide Nanoparticle (SPIO) Tracers2022In: Cancers, ISSN 2072-6694, Vol. 14, no 23, article id 6017Article in journal (Refereed)
    Abstract [en]

    Simple Summary Both superparamagnetic iron oxide nanoparticles (SPIO) and blue dye (BD) have been reported to cause skin staining after breast-conserving surgery. SPIO is a novel tracer that has been shown to identify sentinel lymph nodes (SLNs) in patients with breast cancer. Our study was the first to compare the incidence and size of skin staining between the two tracers. We reported on these outcomes in a preplanned secondary analysis of a prospective clinical trial in which women received both SPIO and BD. This study investigated whether there was a difference in the incidence and size of skin staining between SPIO and BD after SLN-dissection. In all, 270 women were operated on with breast-conserving surgery and received SPIO, and 204 of these women also received BD. After 24 months of follow up, there was no statistically significant difference between the two tracers with regard to the size and incidence of skin staining. Superparamagnetic iron oxide nanoparticles (SPIO) are a tracer for sentinel lymph node (SLN) detection. In a preplanned secondary analysis of a prospective clinical trial (SentiDose) we reported on skin staining after SPIO and blue dye (BD) injections. For SPIO, either a 1.5 mL retroareolar injection on the day of surgery or a 1.0 mL peritumoral/retroareolar injection 1-7 days before surgery was given. A 1.0 mL sub-/intradermal periareolar injection of BD was also administered to all these women. Staining was then assessed at 6, 12 and 24 months after surgery. A total of 270 women received SPIO and were operated on with breast-conserving surgery. Of these, 204 women also received BD. A total of 58 (21.5%) women had an SPIO stain 6 months postoperatively with a median size of 6.8 cm(2) (p = 0.56), while 51 (25.0%) had a BD stain with a median size of 8.5 cm(2) (p = 0.93). The incidence and size of SPIO and BD staining decreased over time reciprocally. At 24 months, the incidence and median size of SPIO was 23 (8.6%) and 4 cm(2), respectively. For BD, the incidence was 14 (6.3%, p = 0.13), and the median size was 3.5 cm(2) (p = 0.18). There was, therefore, no statistically significant difference in the incidence or size of skin staining between SPIO and BD over time.

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  • 50.
    Jin, Yi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jakobsson, Lars
    The dynamics of developmental and tumor angiogenesis-a comparison.2012In: Cancers, ISSN 2072-6694, Vol. 4, no 2, p. 400-419Article in journal (Refereed)
    Abstract [en]

    The blood vasculature in cancers has been the subject of intense interest during the past four decades. Since the original ideas of targeting angiogenesis to treat cancer were proposed in the 1970s, it has become evident that more knowledge about the role of vessels in tumor biology is needed to fully take advantage of such strategies. The vasculature serves the surrounding tissue in a multitude of ways that all must be taken into consideration in therapeutic manipulation. Aspects of delivery of conventional cytostatic drugs, induction of hypoxia affecting treatment by radiotherapy, changes in tumor cell metabolism, vascular leak and trafficking of leukocytes are affected by interventions on vascular function. Many tumors constitute a highly interchangeable milieu undergoing proliferation, apoptosis, and necrosis with abundance of growth factors, enzymes and metabolites. These aspects are reflected by the abnormal tortuous, leaky vascular bed with detached mural cells (pericytes). The vascular bed of tumors is known to be unstable and undergoing remodeling, but it is not until recently that this has been dynamically demonstrated at high resolution, facilitated by technical advances in intravital microscopy. In this review we discuss developmental genetic loss-of-function experiments in the light of tumor angiogenesis. We find this a valid comparison since many studies phenocopy the vasculature in development and tumors.

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