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  • 1.
    Aasebö, Kristine Ö.
    et al.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Eide, Geir Egil
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Lifestyle Epidemiol Grp, Bergen, Norway;Haukeland Hosp, Ctr Clin Res, Bergen, Norway.
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sorbye, Halfdan
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients2019Ingår i: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, nr 7, s. 3623-3635Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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

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

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

  • 2.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laszlo, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Triumf, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hedström, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Biosci & Nutr, Novum, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients2016Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 9-10, s. 1126-1131Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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

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

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

  • 3.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 1, s. 106-109Artikel i tidskrift (Refereegranskat)
  • 4.
    Abouzayed, Ayman
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Yim, Cheng-Bin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer2019Ingår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, nr 7, artikel-id 358Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 5.
    Abramenkovs, Andris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikel-id e0209594Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 6. Adam, René
    et al.
    de Gramont, Aimery
    Figueras, Joan
    Kokudo, Norihiro
    Kunstlinger, Francis
    Loyer, Evelyne
    Poston, Graeme
    Rougier, Philippe
    Rubbia-Brandt, Laura
    Sobrero, Alberto
    Teh, Catherine
    Tejpar, Sabine
    Van Cutsem, Eric
    Vauthey, Jean-Nicolas
    Påhlman, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Managing synchronous liver metastases from colorectal cancer: A multidisciplinary international consensus2015Ingår i: Cancer Treatment Reviews, ISSN 0305-7372, E-ISSN 1532-1967, Vol. 41, nr 9, s. 729-741Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ⩽12months and >12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team.

  • 7.
    Adamo, Hanibal
    et al.
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Hammarsten, Peter
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Hägglöf, Christina
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Scherdin, Tove Dahl
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Egevad, Lars
    Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden.
    Stattin, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Bergström, Sofia Halin
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Bergh, Anders
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome2019Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, nr 5, s. 435-445Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

    Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

    Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

    Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

  • 8. Adams, Charleen
    et al.
    Richmond, Rebecca C
    Santos Ferreira, Diana L
    Spiller, Wes
    Tan, Vanessa Y
    Zheng, Jie
    Wurtz, Peter
    Donovan, Jenny L
    Hamdy, Freddie C
    Neal, David E
    Lane, J Athene
    Davey Smith, George
    Relton, Caroline L
    Eeles, Rosalind A
    Henderson, Brian E
    Haiman, Christopher A
    Kote-Jarai, Zsofia
    Schumacher, Fredrick R
    Amin Al Olama, Ali
    Benlloch, Sara
    Muir, Kenneth
    Berndt, Sonja I
    Conti, David V
    Wiklund, Fredrik
    Chanock, Stephen J
    Gapstur, Susan M
    Stevens, Victoria L
    Tangen, Catherine M
    Batra, Jyotsna
    Clements, Judith A
    Grönberg, Henrik
    Pashayan, Nora
    Schleutker, Johanna
    Albanes, Demetrius
    Wolk, Alicja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    West, Catharine M L
    Mucci, Lorelei A
    Cancel-Tassin, Geraldine
    Koutros, Stella
    Sørensen, Karina D
    Maehle, Lovise
    Travis, Ruth C
    Hamilton, Robert
    Ingles, Sue Ann
    Rosenstein, Barry S
    Lu, Yong-Jie
    Giles, Graham G
    Kibel, Adam S
    Vega, Ana
    Kogevinas, Manolis
    Penney, Kathryn L
    Park, Jong Y
    Stanford, Janet L
    Cybulski, Cezary
    Nordestgaard, Borge G
    Brenner, Hermann
    Maier, Christiane
    Kim, Jeri
    John, Esther M
    Teixeira, Manuel R
    Neuhausen, Susan L
    DeRuyck, Kim
    Razack, Azad
    Newcomb, Lisa F
    Lessel, Davor
    Kaneva, Radka P
    Usmani, Nawaid
    Claessens, Frank
    Townsend, Paul
    Gago Dominguez, Manuela
    Roobol, Monique J
    Menegaux, Florence
    Khaw, Kay-Tee
    Cannon-Albright, Lisa A
    Pandha, Hardev
    Thibodeau, Stephen N
    Martin, Richard M
    Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.2018Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, artikel-id cebp.0079.2018Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).

    MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

    RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

    CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

    IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

  • 9.
    Adde, Magdalena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Aggressive B-cell Lymphomas: Studies of Treatment, FDG-PET Evaluation and Prognostic Factors2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    To improve outcome in young, high-risk lymphoma patients, treatment was intensified, adding etoposide and rituximab to standard CHOP treatment. Granulocyte-colony stimulating factor (G-CSF) enabled treatment bi-weekly. Results were promising: overall (OS) and event-free survival (EFS) 79% and 60% respectively, median follow up 27 months. Single infusion Ara-C, contrary to expectations, did not prevent relapse in CNS.

    DLBCL were classified as germinal center (GC) or non-GC derived, using immunohistochemical markers, CD10, BCL6 and MUM1. We investigated the outcome for both phenotypes after adding rituximab to chemotherapy. For 106 patients treated with CHOP alone, the GC phenotype displayed significantly better OS and EFS. In contrast, GC phenotype did not predict outcome in 95 patients treated with immunochemotherapy . Thus, addition of rituximab seems to eliminate the prognostic value of immunohistochemically defined GC phenotypes in DLBCL.

    To improve evaluation and find non-responders, mid-treatment FDG-PET CT was incorporated into clinical routine for patients with high-risk aggressive lymphoma. For those with positive PET, biopsy followed by treatment intensification was recommended. Twenty-five patients were examined, five with positive PET. Two of these had lymphoma in the biopsy. Two had a negative biopsy, and one had a false positive investigation. Seven patients had increased uptake of uncertain significance. Two patients with uncertain PET, and two with negative PET have relapsed, giving a negative predictive value of 85%.

    In case of relapse of aggressive lymphoma or if not obtaining CR, high dose chemotherapy with autologous stem cell support (HDT) is standard treatment. HDT outcome for 38 patients with transformed follicular lymphoma was compared to outcome for 79 patients with de novo B-cell lymphoma. At median follow-up of 11.5 years both OS and EFS were superior in the transformed group, OS 67% and 33%, EFS 55% and 27% respectively. Treatment related mortality was less than reported in other studies.

    Delarbeten
    1. Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14).
    Öppna denna publikation i ny flik eller fönster >>Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14).
    Visa övriga...
    2006 (Engelska)Ingår i: Med Oncol, ISSN 1357-0560, Vol. 23, nr 2, s. 283-93Artikel i tidskrift (Refereegranskat) Published
    Nyckelord
    Adult, Aged, Antibodies; Monoclonal/administration & dosage, Antimetabolites; Antineoplastic, Antineoplastic Combined Chemotherapy Protocols/*administration & dosage, Central Nervous System Neoplasms/mortality/*prevention & control/secondary, Cyclophosphamide/administration & dosage, Cytarabine/administration & dosage, Disease-Free Survival, Doxorubicin/administration & dosage, Etoposide/administration & dosage, Female, Follow-Up Studies, Granulocyte Colony Stimulating Factor; Recombinant, Humans, Lymphoma; B-Cell/complications/*drug therapy/mortality, Male, Middle Aged, Prednisolone/administration & dosage, Recurrence, Retrospective Studies, Vincristine/administration & dosage
    Identifikatorer
    urn:nbn:se:uu:diva-25280 (URN)16720929 (PubMedID)
    Tillgänglig från: 2007-04-02 Skapad: 2007-04-02 Senast uppdaterad: 2011-01-11
    2. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy
    Öppna denna publikation i ny flik eller fönster >>Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy
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    2007 (Engelska)Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, nr 11, s. 4930-4935Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-10681 (URN)10.1182/blood-2006-09-047068 (DOI)000246946100053 ()17299093 (PubMedID)
    Tillgänglig från: 2007-04-20 Skapad: 2007-04-20 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    3. Little usefullness of mid-treatment FDG-PET and biopsy for treatment intensification in patients with aggressive lymphoma
    Öppna denna publikation i ny flik eller fönster >>Little usefullness of mid-treatment FDG-PET and biopsy for treatment intensification in patients with aggressive lymphoma
    Visa övriga...
    (Engelska)Manuskript (Övrigt vetenskapligt)
    Abstract [en]

    Purpose: To evaluate the experiences of introducing mid-treatment FDG-PET in patients with aggressive lymphoma, in a population based program with decentralized examinations, with emphasis on finding patients who would benefit from dose-escalation.

    Patients and Methods: Twenty-five patients with aggressive lymphoma were included. Twenty-four (95%) of these having an aggressive B-cell lymphoma (84% diffuse large B-cell lymphoma) were treated with CHOP-like treatment given at two week intervals + rituximab. One patient having an anaplastic T-cell lymphoma was treated with CHOEP-14. Mid-treatment FDG-PET was performed and assessed as positive, uncertain or negative for remaining lymphoma. The intention was to perform a biopsy in those with a positive FDG-PET, and, to change to a platina-containing therapy and consolidate with high-dose therapy if viable lymphoma was found. Retrospective review of the PET investigations was done. Living patients were followed for a median of 22 months.

    Results: At primary analysis five patients (20%) had positive uptake on FDG-PET. Two of them had biopsy-proven viable tumor but did not complete the planned salvage treatment, one due to chemotherapy toxicity and one due to progressive disease during salvage therapy. Two patients had a negative biopsy and one patient had no biopsy due to technical difficulties at diagnosis. These three patients remain in remission after standard treatment. Out of seven patients (28%) having “uncertain” uptake two relapsed. Thirteen patients (52%) were negative,two of whom relapsed giving a negative predictive value of 85%.

    Conclusion: Mid-treatment FDG PET-CT in order to find patients with biopsy-proven aggressive lymphoma, who can be salvaged with dose escalation, was not feasible in clinical routine.

    Identifikatorer
    urn:nbn:se:uu:diva-100255 (URN)
    Tillgänglig från: 2009-03-29 Skapad: 2009-03-29 Senast uppdaterad: 2010-01-14
    4. Superior outcome in transformed follicular lymphoma compared to de novo aggressive B-cell lymphoma treated with high-dose therapy and autologous stem-cell support
    Öppna denna publikation i ny flik eller fönster >>Superior outcome in transformed follicular lymphoma compared to de novo aggressive B-cell lymphoma treated with high-dose therapy and autologous stem-cell support
    Visa övriga...
    (Engelska)Manuskript (Övrigt vetenskapligt)
    Abstract [en]

    Purpose: To assess the outcome of high–dose therapy with autologous stem cell support (HDT) in patients with transformed follicular lymphoma compared to patients with de novo aggressive B-cell lymphoma, in a retrospective analysis of patients treated at two Swedish university hospitals.

    Patients and Methods: 117 patients, mean age 48 years (21-65), 79 with de novo aggressive B-cell lymphoma and 38 with transformed follicular lymphoma, were treated with high-dose-therapy (HDT) as consolidation. Thirteen patients with transformed follicular lymphoma had been treated with a single alkylating agent and 25 were chemonaive at transformation. After transformation, nine patients had HDT as part of first line aggressive therapy, and a further eight failed to obtain CR and had HDT upfront. Twenty-one patients received more than one treatment regimen before HDT. In the de novo aggressive lymphoma group five patients with high risk criteria, and 16 patients who failed to obtain CR, received HDT upfront (CR1), Fifty-eight patients received more than one regimen before HDT because of relapse. Rituximab was given as a single dose to five patients for in vivo purging of the stem cell graft.

    Results: With a median follow up of 11.5 years (8-20), event free survival (EFS) and overall survival (OS) were 35% and 44% respectively. When comparing the two groups, the ten- year EFS rates were 27% in the de novo group and 55% in the transformed group and the ten-year OS was 33 % and 67% respectively. Treatment related mortality was acceptable with 4% early and 3.5% late mortality. In a multivariate analysis, “transformed vs de novo aggressive” histopathology was the only factor significantly related to outcome.

    Conclusion: Both EFS and OS were much better in patients with transformed follicular lymphoma compared to patients with de novo aggressive B-cell lymphoma Although the introduction of rituximab certainly has improved the outcome in both groups, HDT should still be considered as a salvage strategy not only in cases of de novo aggressive B-cell lymphoma and especially in transformed follicular lymphoma relapsing after first line treatment..

    Identifikatorer
    urn:nbn:se:uu:diva-100257 (URN)
    Tillgänglig från: 2009-03-29 Skapad: 2009-03-29 Senast uppdaterad: 2010-01-14
  • 10.
    Afshari, Kevin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Chabok, Abbas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Naredi, Peter
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Surg, Gothenburg, Sweden.
    Smedh, Kennet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Nikberg, Maziar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Prognostic factors for survival in stage IV rectal cancer: A Swedish nationwide case-control study2019Ingår i: Surgial oncology, ISSN 0960-7404, E-ISSN 1879-3320, Vol. 29, s. 102-106Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: The aim was to identify patient-, tumor- and treatment-related prognostic factors for five-year survival in rectal cancer patients with synchronous stage IV disease. Material and methods: This nationwide case-control study was based on the Swedish Colorectal Cancer Registry with supplementary information from medical records and the Swedish Inpatient Registry during the period 2000-2008. All resected rectal cancer patients with synchronous metastases that survived more than five years were included as cases. The control group consisted of corresponding patients who lived less than five years, matched in a 1:2 based on gender, age, resection of the rectal tumor, and the study period. Results: A total of 405 patients were identified; 99 long-term survivors (LTS) and 182 short-term survivors (STS). Patient-related factors of symptoms and comorbidity did not differ between LTS and STS. Among the treatment-related factors, multiple site metastases (p = 0.007), bilobar liver metastasis (p = 0.002), and increasing number of liver metastasis (p < 0.001) were associated with STS. Prognostic treatment-related factors were preoperative radiotherapy (p = 0.001), metastasectomy (p < 0.001), and radical resection of the primary tumor (p = 0.014). In the multivariable analysis, the single most important factor for becoming a LTS was a metastasectomy (hazard ratio: 8.474, 95% confidence interval: 4.098-17.543). Conclusions: The most important prognostic factor for long-term survival in patients with stage IV rectal cancer was metastasectomy, especially liver surgery. With thorough selection of patients for metastasectomy more patients with metastasized rectal cancer may survive beyond five years.

  • 11.
    Aftab, Obaid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Engskog, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Haglöf, Jakob
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Elmsjö, Albert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Hammerling, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes2014Ingår i: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 54, nr 11, s. 3251-3258Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

  • 12.
    Aftab, Obaid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Hassan, Saadia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Hammerling, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Label free quantification of time evolving morphologies using time-lapse video microscopy enables identity control of cell lines and discovery of chemically induced differential activity in iso-genic cell line pairs2015Ingår i: Chemometrics and Intelligent Laboratory Systems, ISSN 0169-7439, E-ISSN 1873-3239, Vol. 141, s. 24-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Label free time-lapse video microscopy based monitoring of time evolving cell population morphology has potential to offer a simple and cost effective method for identity control of cell lines. Such morphology monitoring also has potential to offer discovery of chemically induced differential changes between pairs of cell lines of interest, for example where one in a pair of cell lines is normal/sensitive and the other malignant/resistant. A new simple algorithm, pixel histogram hierarchy comparison (PHHC), for comparison of time evolving morphologies (TEM) in phase contrast time-lapse microscopy movies was applied to a set of 10 different cell lines and three different iso-genic colon cancer cell line pairs, each pair being genetically identical except for a single mutation. PHHC quantifies differences in morphology by comparing pixel histogram intensities at six different resolutions. Unsupervised clustering and machine learning based classification methods were found to accurately identify cell lines, including their respective iso-genic variants, through time-evolving morphology. Using this experimental setting, drugs with differential activity in iso-genic cell line pairs were likewise identified. Thus, this is a cost effective and expedient alternative to conventional molecular profiling techniques and might be useful as part of the quality control in research incorporating cell line models, e.g. in any cell/tumor biology or toxicology project involving drug/agent differential activity in pairs of cell line models.

  • 13.
    Aftab, Obaid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nazir, Madiha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Hammerling, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gustafsson, Mats G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing2014Ingår i: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 19, nr 9, s. 1411-1418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Label free time-lapse microscopy has opened a new avenue to the study of time evolving events in living cells. When combined with automated image analysis it provides a powerful tool that enables automated large-scale spatiotemporal quantification at the cell population level. Very few attempts, however, have been reported regarding the design of image analysis algorithms dedicated to the detection of apoptotic cells in such time-lapse microscopy images. In particular, none of the reported attempts is based on sufficiently fast signal processing algorithms to enable large-scale detection of apoptosis within hours/days without access to high-end computers. Here we show that it is indeed possible to successfully detect chemically induced apoptosis by applying a two-dimensional linear matched filter tailored to the detection of objects with the typical features of an apoptotic cell in phase-contrast images. First a set of recorded computational detections of apoptosis was validated by comparison with apoptosis specific caspase activity readouts obtained via a fluorescence based assay. Then a large screen encompassing 2,866 drug like compounds was performed using the human colorectal carcinoma cell line HCT116. In addition to many well known inducers (positive controls) the screening resulted in the detection of two compounds here reported for the first time to induce apoptosis.

  • 14.
    Agarwal, Divyansh
    et al.
    Univ Penn, Dept Genom & Computat Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA..
    Nowak, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Zhang, Nancy R.
    Univ Penn, Dept Genom & Computat Biol, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA..
    Pusztai, Lajos
    Yale Univ, Yale Sch Med, Breast Med Oncol, Dept Med, New Haven, CT 06520 USA..
    Hatzis, Christos
    Yale Univ, Yale Sch Med, Breast Med Oncol, Dept Med, New Haven, CT 06520 USA..
    Functional germline variants as potential co-oncogenes2017Ingår i: NPJ BREAST CANCER, ISSN 2374-4677, Vol. 3, artikel-id 46Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.

  • 15.
    Agarwal, Prasoon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Alzrigat, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Párraga, Alba Atienza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Singh, Umashankar
    Ungerstedt, Johanna
    Österborg, Anders
    Brown, Peter J
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Öberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Jernberg-Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 6, s. 6809-6923Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

  • 16.
    Agathangelidis, Andreas
    et al.
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Ljungström, Viktor
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Gounari, Maria
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy;Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Pandzic, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, Kostas
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tonon, Giovanni
    IRCCS Ist Sci San Raffaele, Funct Genom Canc Unit, Div Expt Oncol, Milan, Italy.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations2018Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, nr 5, s. 865-873Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

  • 17. Agathangelidis, Andreas
    et al.
    Vardi, Anna
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Stereotyped B-cell receptors in chronic lymphocytic leukemia2014Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, nr 10, s. 2252-2261Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e. g. BcR reactivity and signaling; (ii) clonal genetic landscape, e. g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies.

  • 18.
    Ahlgren, Johan
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Studies on Prediction of Axillary Lymph Node Status in Invasive Breast Cancer2002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Breast cancer is the most common malignancy among females in Sweden. Axillary lymph-node dissection is a standard procedure in the management of breast cancer, aiming at obtaining prognostic information for adjuvant therapy decisions. Axillary dissection entails considerable morbidity. The aims of this study were to establish more selective surgical approaches and to investigate angiogenesis, a potential predictor for lymph-node metastases and prognosis.

    Clinical nodal status, tumour size and S-phase were associated with nodal metastases in cohort of 1145 women. The proportion of nodal metastases was 13% in the subgroup with the lowest risk.

    In a study from two registries, 675 and 1035 breast cancers ≤10 mm diagnosed by screening mammography had nodal metastases in 6,5% and 7%, respectively. Clinically detected cancers had a risk of 16% and 14%, respectively.

    In a study on 415 women, a 5-node biopsy of the axilla had a sensitivity of 97,3% and a false negative rate of 2,7% in comparison with axillary dissection.

    Six sections from 21 breast cancers were analysed for microvessel density (MVD). The inter-section variation contributed more to the total variance than inter-tumour variation, 45,0% and 37,3%, respectively.

    In a cohort of 315 women, breast cancers with high MVD more frequently had p53 mutations (27,1%) compared with cases with low MVD (18,4%). This difference was not statistically significant (p=0,075). p53 mutations were associated with a worse outcome, whereas MVD was not.

    In conclusion, women with screening detected ≤10 mm breast cancers have a low risk of lymph node metastases and some may not need axillary dissection in the future. The 5-node biopsy could be an alternative to axillary dissection. MVD is associated with methodological weaknesses and routine use is not recommended.

  • 19.
    Ahlgren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules: Preparation and Preclinical Evaluation2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours.

    Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection.

    Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial.

    Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule.

    It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

    Delarbeten
    1. Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Öppna denna publikation i ny flik eller fönster >>Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Visa övriga...
    2008 (Engelska)Ingår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, nr 1, s. 235-243Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Affibody molecules are a new class of small (7 kDa) scaffold affinity proteins, which demonstrate promising properties as agents for in vivo radionuclide targeting. The Affibody scaffold is cysteine-free and therefore independent of disulfide bonds. Thus, a single thiol group can be engineered into the protein by introduction of one cysteine. Coupling of thiol-reactive bifunctional chelators can enable site-specific labeling of recombinantly produced Affibody molecules. In this study, the use of 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for 111 In-labeling of anti-HER2 Affibody molecules His 6-Z HER2:342-Cys and Z HER2:2395-Cys has been evaluated. The introduction of a cysteine residue did not affect the affinity of the proteins, which was 29 pM for His 6-Z HER2:342-Cys and 27 pM for Z HER2:2395-Cys, comparable with 22 pM for the parental Z HER2:342. MMA-DOTA was conjugated to DTT-reduced Affibody molecules with a coupling efficiency of 93% using a 1:1 molar ratio of chelator to protein. The conjugates were labeled with 111 In to a specific radioactivity of up to 7 GBq/mmol, with preserved binding for the target HER2. In vivo, the non-His-tagged variant 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys demonstrated appreciably lower liver uptake than its His-tag-containing counterpart. In mice bearing HER2-expressing LS174T xenografts, 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys showed specific and rapid tumor localization, and rapid clearance from blood and nonspecific compartments, leading to a tumor-to-blood-ratio of 18 +/- 8 already 1 h p.i. Four hours p.i., the tumor-to-blood ratio was 138 +/- 8. Xenografts were clearly visualized already 1 h p.i.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-104530 (URN)10.1021/bc700307y (DOI)000252520300030 ()18163536 (PubMedID)
    Tillgänglig från: 2009-05-29 Skapad: 2009-05-28 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    Öppna denna publikation i ny flik eller fönster >>Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    2010 (Engelska)Ingår i: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 12, nr 1, s. 54-62Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    PURPOSE: Imaging using positron emission tomography (PET) in the field of nuclear medicine is becoming increasingly important. The aim of this study was to develop a method for labeling of affibody molecules with radiocobalt for PET applications. PROCEDURES: The human epidermal growth factor receptors type 2 (HER2) binding affibody molecule DOTA-Z(2395)-C was radiolabeled with (57)Co (used as a surrogate of (55)Co). The binding specificity and cellular processing of the labeled compound was studied in vitro followed by in vivo characterization in normal and tumor-bearing mice. Furthermore, a comparative biodistribution study was performed with a (111)In-labeled counterpart. RESULTS: DOTA-Z(2395)-C was successfully labeled with radiocobalt with nearly quantitative yield. The compound displayed good retention on cells over time and high tumor accumulation of radioactivity in animal studies. Imaging studies showed clear visualization of HER2-positive tumors. Furthermore, the radiocobalt label provided better tumor-to-organ ratios than (111)In. CONCLUSIONS: Radiocobalt is a promising label for affibody molecules for future PET applications.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-122173 (URN)10.1007/s11307-009-0238-8 (DOI)000273479300008 ()19557480 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    3. Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Öppna denna publikation i ny flik eller fönster >>Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Visa övriga...
    2009 (Engelska)Ingår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, nr 5, s. 781-789Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.

    Nyckelord
    Affibody molecule, technetium, imaging, HER2, C-terminal cysteine
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-122172 (URN)10.2967/jnumed.108.056929 (DOI)000272487900017 ()19372467 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    4. Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    Öppna denna publikation i ny flik eller fönster >>Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    2010 (Engelska)Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, nr 5, s. 539-546Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction: Molecular imaging of HER2-expression in malignant tumors provides potentially important information for patient management. Affibody molecules have shown to be suitable tracers for imaging applications using SPECT or PET. Results from an earlier evaluation of the application of site specific 99mTc-labeling on the Affibody molecule, ZHER2:2395-C, were favorable.

    Methods: As a preparation for clinical application of this tracer we have developed and evaluated a robust single-vial freeze-dried kit, allowing labeling of the Affibody molecule, ZHER2:2395-C, with 99mTc.

    Results: The composition of the kit (containing glucoheptonate, EDTA and tin(II)-chloride), as well as the protein amount and the pertechnetate volume were optimized for a high labeling yield (> 90 %) and minimal presence of reduced hydrolyzed technetium colloids (< 1 %). The specificity to HER2 receptors, the binding competence and the stability in PBS and murine serum were verified in vitro. The shelf-life was also evaluated in vitro, showing no reduction in labeling yield or binding capacity to HER2-expressing cells after over 400 days of storage of the single-vial freeze-dried kit.

    Conclusions: ZHER2:2395-C labeled with 99mTc using the lyophilized kit was stable and resulted in a favorable biodistribution in an in vivo evaluation in normal NMRI mice.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-122175 (URN)10.1016/j.nucmedbio.2010.02.009 (DOI)000279412400002 ()20610158 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    5. Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Öppna denna publikation i ny flik eller fönster >>Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Visa övriga...
    2010 (Engelska)Ingår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 51, nr 7, s. 1131-1138Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Overexpression of HER2 in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a non-immunoglobulin scaffold have demon-strated high potential for in vivo molecular imaging of HER2-expressing tumors. Re-engineering of the molecular scaffold has led to a second generation of optimized Affibody molecules, having a surface distinctly different from the parental protein domain from staphylococcal protein A. The new tracer showed further increased melting point, stability and overall hydrophilicity compared to the parental molecule, and was shown to be more amenable for chemical peptide synthesis. The goal of this study was to assess potential effects of this extensive re-engineering on HER2 targeting, using ABY-025, a DOTA conjugated variant of the novel tracer.

    Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, in rats and in cynomolgus macaques.

    Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats and macaques. A highly specific tumor uptake of 16.7 ± 2.5 %IA/g was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h, 88 at 4 h, and increased up to 3 days after injection. Gamma camera imaging of tumors was already possible 0.5 h after injection. Furthermore, repeated i.v. administration of ABY-025 did not induce antibody formation in rats.

    Conclusions: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound re-engineering of the non-binding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor bearing mice, leading to high tumor-to-organ-ratios and high contrast imaging shortly after injection.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-122176 (URN)10.2967/jnumed.109.073346 (DOI)000279430900021 ()20554729 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
  • 20.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, nr 3, s. 667-678Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

  • 21.
    Ahlström, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ekström, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sjöholm, Therese
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Strand, Robin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Johansson, E.
    Antaros Med, Molndal, Sweden..
    Hagmar, P.
    Antaros Med, Molndal, Sweden..
    Malmberg, Filip
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Registration-based automated lesion detection and therapy evaluation of tumors in whole body PET-MR images2017Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, nr S5, artikel-id 78PArtikel i tidskrift (Övrigt vetenskapligt)
  • 22.
    Ahmadi, Zainab
    et al.
    Univ Lund Hosp, Div Resp Med & Allergol, Dept Clin Sci, SE-22100 Lund, Sweden..
    Lundstrom, Staffan
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala Univ, Dept Med Sci Resp Med & Allergol, Uppsala, Sweden..
    Strang, Peter
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Emtner, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysioterapi.
    Currow, David C.
    Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia..
    Ekström, Magnus
    Univ Lund Hosp, Div Resp Med & Allergol, Dept Clin Sci, SE-22100 Lund, Sweden.;Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia..
    End-of-life care in oxygen-dependent COPD and cancer: a national population-based study2015Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 46, nr 4, s. 1190-1193Artikel i tidskrift (Refereegranskat)
  • 23. Akeus, Paulina
    et al.
    Langenes, Veronica
    von Mentzer, Astrid
    Yrlid, Ulf
    Sjoling, Asa
    Saksena, Pushpa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Raghavan, Sukanya
    Quiding-Jarbrink, Marianne
    Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice2014Ingår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 63, nr 8, s. 807-819Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumor progression in the colon moves from aberrant crypt foci to adenomatous polyps to invasive carcinomas. The composition of the tumor-infiltrating leukocyte population affects the ability of the immune system to fight the tumor. T cell infiltration into colorectal adenocarcinomas, particularly T helper 1 (Th1) type T cells as well as increased regulatory T cell (Treg) frequencies, is correlated with improved prognosis. However, whether Th1 cells and Tregs are already present at the adenoma stage is not known. In this study, the APC(Min/+) mouse model of intestinal adenomatous polyposis was used to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas. Compared to unaffected tissue, adenomas accumulated CD4(+)FoxP3(+) putative Treg in parallel with lower frequencies of conventional T cells and B cells. The accumulation of Treg was also observed in human adenomatous polyps. Despite high Treg numbers, the function of conventional T cells present in the APC(Min/+) adenomas was not different from those in the unaffected tissue. Adenomas displayed an altered chemokine balance, with higher CCL17 and lower CXCL11 and CCL25 expression than in the unaffected tissue. In parallel, CXCR3(+) Tregs were largely absent from adenomas. The data indicate that already in early stages of tumor development, the balance of lymphocyte-recruiting chemokines is altered possibly contributing to the observed shift toward higher frequencies of Treg.

  • 24.
    Albertsen, Birgitte Klug
    et al.
    Aarhus Univ Hosp, Children & Adolescent Hlth, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark.
    Harila-Saari, Arja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland;Univ Helsinki, Cent Hosp, Helsinki, Finland.
    Lahteenmaki, Paivi
    Turku Univ Hosp, Dept Pediat & Adolescent Med, Turku, Finland;Turku Univ, Turku, Finland.
    Riikonen, Pekka
    Kuopio Univ Hosp, Dept Pediat, Kuopio, Finland.
    Mottonen, Merja
    Univ Oulu, PEDEGO Res Ctr, Oulu, Finland;Univ Oulu, Med Res Ctr Oulu, Oulu, Finland;Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland.
    Lausen, Birgitte
    Univ Hosp, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.
    Asparaginase treatment in infants with acute lymphoblastic leukemia; pharmacokinetics and asparaginase hypersensitivity in Interfant-062019Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 60, nr 6, s. 1469-1475Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac((R))) and PEG-asparaginase (Oncaspar((R))) as well as hypersensitivity reactions during treatment in Interfant-06 (www.clinicaltrials.gov: NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.

  • 25. Alcorn, S. R.
    et al.
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Dieckmann, K.
    McNutt, T. R.
    Chen, M. J.
    Ermoian, R. P.
    Ford, E. C.
    MacDonald, S.
    Nechesnyuk, A.
    Tryggestad, E. J.
    Smith, K.
    Villar, R. C.
    Winey, B.
    Terezakis, S. A.
    Predictors of Setup Accuracy in Image-Guided CNS Radiation Therapy: Prospective Data From a Multinational Pediatrics Consortium2014Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 90, nr S1, s. S723-S723Artikel i tidskrift (Övrigt vetenskapligt)
  • 26.
    Alcorn, Sara
    et al.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Rao, Avani D.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Ladra, Matthew M.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Ermoian, Ralph P.
    Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA.
    Villar, Rosangela C.
    Ctr Infantil Boldrini, Dept Radiat Oncol, Campinas, SP, Brazil.
    Chen, Michael J.
    Grp Apoio Adolescente & Crianca Canc, Dept Radiat, Sao Paulo, Brazil.
    Kobyzeva, Daria
    Fed Sci Clin Ctr Childrens Hematol Oncol & Immuno, Dept Radiotherapy, Moscow, Russia.
    Nechesnyuk, Alexey V.
    Fed Sci Clin Ctr Childrens Hematol Oncol & Immuno, Dept Radiotherapy, Moscow, Russia.
    Ford, Eric
    Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA.
    MacDonald, Shannon
    Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
    Winey, Brian
    Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
    Dieckmann, Karin
    Univ Klin Strahlentherapie & Strahlenbiol, Dept Radiat Oncol, Vienna, Austria.
    Terezakis, Stephanie A.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Practice Patterns of Stereotactic Radiotherapy in Pediatrics: Results From an International Pediatric Research Consortium2018Ingår i: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 40, nr 7, s. 522-526Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose/Objectives: There is little consensus regarding the application of stereotactic radiotherapy (SRT) in pediatrics. We evaluated patterns of pediatric SRT practice through an international research consortium. Materials and Methods: Eight international institutions with pediatric expertise completed a 124-item survey evaluating patterns of SRT use for patients 21 years old and younger. Frequencies of SRT use and median margins applied with and without SRT were evaluated. Results: Across institutions, 75% reported utilizing SRT in pediatrics. SRT was used in 22% of brain, 18% of spine, 16% of other bone, 16% of head and neck, and <1% of abdomen/pelvis, lung, and liver cases across sites. Of the hypofractionated SRT cases, 42% were delivered with definitive intent. Median gross tumor volume to planning target volume margins for SRT versus non-SRT plans were 0.2 versus 1.4 cm for brain, 0.3 versus 1.5 cm for spine/other bone, 0.3 versus 2.0 cm for abdomen/pelvis, 0.7 versus 1.5 cm for head and neck, 0.5 versus 1.7 cm for lung, and 0.5 versus 2.0 cm for liver sites. Conclusions: SRT is commonly utilized in pediatrics across a range of treatment sites. Margins used for SRT were substantially smaller than for non-SRT planning, highlighting the utility of this approach in reducing treatment volumes.

  • 27. Alcorn, Sara R
    et al.
    Chen, Michael J
    Claude, Line
    Dieckmann, Karin
    Ermoian, Ralph P
    Ford, Eric C
    Malet, Claude
    MacDonald, Shannon M
    Nechesnyuk, Alexey V
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Villar, Rosangela C
    Winey, Brian A
    Tryggestad, Erik J
    Terezakis, Stephanie A
    Practice patterns of photon and proton pediatric image guided radiation treatment: results from an International Pediatric Research consortium2014Ingår i: Practical radiation oncology, ISSN 1879-8500, Vol. 4, nr 5, s. 336-341Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Image guided radiation therapy (IGRT) has become common practice for both photon and proton radiation therapy, but there is little consensus regarding its application in the pediatric population. We evaluated clinical patterns of pediatric IGRT practice through an international pediatrics consortium comprised of institutions using either photon or proton radiation therapy.

    METHODS AND MATERIALS: Seven international institutions with dedicated pediatric expertise completed a 53-item survey evaluating patterns of IGRT use in definitive radiation therapy for patients ≤21 years old. Two institutions use proton therapy for children and all others use IG photon therapy. Descriptive statistics including frequencies of IGRT use and means and standard deviations for planning target volume (PTV) margins by institution and treatment site were calculated.

    RESULTS: Approximately 750 pediatric patients were treated annually across the 7 institutions. IGRT was used in tumors of the central nervous system (98%), abdomen or pelvis (73%), head and neck (100%), lung (83%), and liver (69%). Photon institutions used kV cone beam computed tomography and kV- and MV-based planar imaging for IGRT, and all proton institutions used kV-based planar imaging; 57% of photon institutions used a specialized pediatric protocol for IGRT that delivers lower dose than standard adult protocols. Immobilization techniques varied by treatment site and institution. IGRT was utilized daily in 45% and weekly in 35% of cases. The PTV margin with use of IGRT ranged from 2 cm to 1 cm across treatment sites and institution.

    CONCLUSIONS: Use of IGRT in children was prevalent at all consortium institutions. There was treatment site-specific variability in IGRT use and technique across institutions, although practices varied less at proton facilities. Despite use of IGRT, there was no consensus of optimum PTV margin by treatment site. Given the desire to restrict any additional radiation exposure in children to instances where the exposure is associated with measureable benefit, prospective studies are warranted to optimize IGRT protocols by modality and treatment site.

  • 28.
    Alexandersson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clinical data analyses of T-DM1, an anitbody drug conjugate for metastatic breast cancer2013Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Användningen av Socialstyrelsens ”Indikatorer för god

     läkemedelsterapi hos äldre” i Värmland

    Erika Markberg

    Handledare: Anna Karin Lidehäll. Examinator: Margareta Hammarlund-Udenaes.

     Institutionen för farmaceutisk biovetenskap. Avdelningen för farmakokinetik och läkemedelsterapi. 30 hp.

    Introduktion: Andelen äldre personer blir allt större, vilket gör det viktigare att de äldres läkemedel uppmärksammas. För att hjälpa förskrivarna i detta arbete har Socialstyrelsen tagit fram indikatorer som skall ge god läkemedelsterapi hos de äldre.

    Syfte: Att utvärdera vetskapen om och följsamheten till Socialstyrelsens indikatorer för äldre personer hos läkare verksamma vid vårdcentralen respektive på sjukhuset samt att utvärdera om läkemedelsförskrivningen vid ett särskilt boende i Värmland är anpassad efter Socialstyrelsens indikatorer för läkemedelsförskrivning till äldre personer.

    Material och metoder: En enkät skickades ut till ett sjukhus och en vårdcentral där förskrivarna fick svara på denna. Läkemedelslistor hämtades ifrån ett särskilt boende och utvärderades.

    Resultat: Alla förskrivarna på vårdcentralen men endast 18 % av förskrivarna vid sjukhuset hade kännedom om indikatorerna. Förskrivarna på sjukhuset ville ha mer information om Socialstyrelsens indikatorer. Läkemedelslistorna till 15 % av de totalt 47 personerna innehöll ett eller flera läkemedel som klassades som olämpliga. De olämpliga läkemedel som förekom var propiomazin, långverkande bensodiazepin eller läkemedel med antikolinerga effekter. Slutsats: Förskrivarnas kännedom om Socialstyrelsens indikatorer skiljer sig beroende på om de jobbar på vårdcentral eller på sjukhus. Läkemedelslistorna följde Socialstyrelsens indikatorer i stor utsträckning.

  • 29.
    Alexandersson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clinical data analyses of T-DM1, an antibody drug conjugate for metastatic breast cancer2013Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 30.
    Alfonzo, Emilia
    et al.
    Sahlgrens Univ Hosp, Dept Obstet & Gynaecol, SE-41345 Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Obstet & Gynaecol, Med Gatan 3, S-41390 Gothenburg, Sweden.
    Wallin, Emelie
    Karolinska Univ Hosp, Div Obstet & Gynaecol, Dept Womens & Childrens Hlth, K 57, S-14186 Stockholm, Sweden;Karolinska Inst, K 57, S-14186 Stockholm, Sweden.
    Ekdahl, Linnea
    Skane Univ Hosp, Div Gynaecol Oncol, Dept Obstet & Gynaecol, S-22185 Lund, Sweden;Lund Univ, Fac Med, Dept Clin Sci Obstet & Gynaecol, S-22185 Lund, Sweden.
    Staf, Christian
    Sahlgrens Univ Hosp, Reg Canc Ctr Western Sweden, S-41345 Gothenburg, Sweden.
    Radestad, Angelique Floter
    Karolinska Univ Hosp, Div Obstet & Gynaecol, Dept Womens & Childrens Hlth, K 57, S-14186 Stockholm, Sweden;Karolinska Inst, K 57, S-14186 Stockholm, Sweden.
    Reynisson, Petur
    Skane Univ Hosp, Div Gynaecol Oncol, Dept Obstet & Gynaecol, S-22185 Lund, Sweden;Lund Univ, Fac Med, Dept Clin Sci Obstet & Gynaecol, S-22185 Lund, Sweden.
    Stålberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Falconer, Henrik
    Karolinska Univ Hosp, Div Obstet & Gynaecol, Dept Womens & Childrens Hlth, K 57, S-14186 Stockholm, Sweden;Karolinska Inst, K 57, S-14186 Stockholm, Sweden.
    Persson, Jan
    Skane Univ Hosp, Div Gynaecol Oncol, Dept Obstet & Gynaecol, S-22185 Lund, Sweden;Lund Univ, Fac Med, Dept Clin Sci Obstet & Gynaecol, S-22185 Lund, Sweden.
    Dahm-Kahler, Pernilla
    Sahlgrens Univ Hosp, Dept Obstet & Gynaecol, SE-41345 Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Obstet & Gynaecol, Med Gatan 3, S-41390 Gothenburg, Sweden;Sahlgrens Univ Hosp, Reg Canc Ctr Western Sweden, S-41345 Gothenburg, Sweden.
    No survival difference between robotic and open radical hysterectomy for women with early-stage cervical cancer: results from a nationwide population-based cohort study2019Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 116, s. 169-177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: The aim of the study was to compare overall survival (OS) and diseasefree survival (DFS) after open and robotic radical hysterectomy for early-stage cervical cancer. Patients and methods: This was a nationwide population-based cohort study on all women with cervical cancer stage IA1-IB of squamous, adenocarcinoma or adenosquamous histological subtypes, from January 2011 to December 2017, for whom radical hysterectomy was performed. The Swedish Quality Register of Gynaecologic Cancer was used for identification. To ensure quality and conformity of data and to disclose patients not yet registered, hospital registries were reviewed and validated. Cox and propensity score regression analysis and univariable and multivariable regression analysis were performed in regard to OS and DFS. Results: There were 864 women (236 open and 628 robotic) included in the study. The 5-year OS was 92% and 94% and DFS was 84% and 88% for the open and robotic cohorts, respectively. The recurrence pattern was similar in both groups. Using propensity score analysis and matched cohorts of 232 women in each surgical group, no significant differences were seen in survival: 5-year OS of 92% in both groups (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.50-2.01) and DFS of 85% vs 84% in the open and robotic cohort, respectively (HR, 1.08; 95% CI, 0.66-1.78). In univariable and multivariable analysis with OS as the end-point, no significant factors were found, and in regard to DFS, tumour size (p < 0.001) and grade 3 (p = 0.02) were found as independent significant risk factors. Conclusion: In a complete nationwide population-based cohort, where radical hysterectomy for early-stage cervical cancer is highly centralised, neither long-term survival nor pattern of recurrence differed significantly between open and robotic surgery. (C) 2019 The Authors. Published by Elsevier Ltd.

  • 31.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Federspiel, Birgitte
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Scoazec, Jean-Yves
    Inst Gustave Roussy, Villejuif, France.
    Hjortland, Geir Olav
    Univ Oslo, Oslo, Norway.
    Gronbaek, Henning
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ladekarl, Morten
    Aarhus Univ Hosp, Aarhus, Denmark.
    Langer, Seppo W.
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Vestermark, Lene Weber
    Odense Univ Hosp, Odense, Denmark.
    Arola, Johanna
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland.
    Osterlund, Pia
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland; Tampere Univ Hosp, Tampere, Finland.
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Bergen, Norway; Univ Bergen, Bergen, Norway.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala Univ, Sect Endocrine Oncol, Dept Med Sci, Uppsala, Sweden..
    Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikel-id e0187667Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

  • 32.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Langer, Seppo W.
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark.;Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark..
    Ladekarl, Morten
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    Hjortland, Geir Olav
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Vestermark, Lene Weber
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Österlund, Pia
    Tampere Univ Hosp, Dept Oncol, Tampere, Finland.;Tampere Univ, Tampere, Finland.;Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Gronbaek, Henning
    Aarhus Univ Hosp, Dept Hepatol, Aarhus, Denmark.;Aarhus Univ Hosp, Dept Gastroenterol, Aarhus, Denmark..
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark.;Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Janson, Eva Tiensuu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)2018Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, nr 4, artikel-id 47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter-and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan-Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy.

  • 33.
    Ali, Dina
    et al.
    Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Mohammad, Dara K.
    Karolinska Inst, Karolinska Hosp Huddinge, Clin Res Ctr, Dept Lab Med, Stockholm, Sweden..
    Mujahed, Huthayfa
    Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Jonson-Videsater, Kerstin
    Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden..
    Nore, Beston
    Karolinska Inst, Karolinska Hosp Huddinge, Clin Res Ctr, Dept Lab Med, Stockholm, Sweden..
    Paul, Christer
    Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Lehmann, Sören
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi. Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells2016Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, nr 1, s. 117-126Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.

  • 34.
    Alit, Abir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, s. 43-43Artikel i tidskrift (Refereegranskat)
  • 35.
    Aljaderi, Russil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Behandling av CNS-metastaserad bröstcancer i Uppsala2014Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Bröstcancer är den näst mest vanliga orsaken till hjärnmetastering. Ungefär 20-40% av bröstcancer patienterna utvecklar någon form av CNS-metastasering. Bröstcancern kan delas in i tre olika subtyper; HER2-positiva, luminala och trippelnegativa. Studier har visat en förlängd överlevnad främst hos subtypen HER2-positiva patienter. Syfte: Att belysa förekomsten av CNS-metastaser bland bröstcancerpatienterna på onkologikliniken i Uppsala sedan 2009-2013, samt att göra en praktisk indelning av patienterna med CNS-spridning beroende av tumörtyp och spridningsmönster av metastaserna samt få en överblick av vilka behandlingar som givits och effekten av dessa. Material och metoder: En retrospektiv kohortstudie baserad på patientdatabas och granskning av patientjournaler för tiden 2009-2013. Materialet bestod av 48 patienter med diagnostiserade CNS-metastaser. Genom onkologiklinikens behandlingsdatabas RealQ® identifierades patienterna. Kompletterande information hämtades från journalgranskning i Cosmic. Patienterna följdes upp efter diagnosen fram till april 2014. Resultat: 33 av de 48 patienterna (83 %) hade strålbehandlats, varav 3 av dessa 33 patienter (4 %) strålbehandlats med boost. 4 av 48 patienter (8 %) opererades i kombination med strålbehandling.  2 patienter (4 %) hade stereotaktiskt strålbehandlats och 9 patienter (19 %) fick inte någon behandling. Genomsnittlig ålder i studiepopulationen var 55 år. Medianen var 56. Högsta ålder var 80 år och lägsta ålder var 34 år. 8 patienter (17 %) utav totala populationen som bestod av 48 patienter överlevde, resterande 40 patienter (83 %) avled. Primärtumör subtyper bland studiepopulationen var (24 %) HER2, (40 %) Luminal och (38 %) trippelnegativ. Det hittades en signifikant skillnad för en längre överlevnad från första metastasen (p=0,001) och från CNS-metastasen (p=0,04). Däremot hittades inte någon signifikant överlevnads skillnad från CNS-metastasen och meningeal metastasen (p=0,11). Dessvärre hade patienterna med meningal metastasen en kortare överlevnad. Konklusion: HER2 och trippelnegativa subtyperna var de vanligaste subtyperna inom studiepopulationen. Patienterna med HER2 positiva subtypen hade en bättre överlevnad i jämförelse med de andra två subtyperna. Detta kan sannolikt förklaras av att mer effektiva läkemedelsbehandlingar är tillgängliga för patienter med denna subtyp. Förklaringen till detta måste vara skadad blodhjärnbarriär vid hjärnmetastasering då dessa läkemedel normalt ej passerar blodhjärnbarriären

  • 36.
    Al-Jebari, Yahia
    et al.
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Div Clin Epidemiol, Dept Med, Stockholm, Sweden.
    Nord, Carina Berglund
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Cohn-Cedermark, Gabriella
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Stahl, Olof
    Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Tandstad, Torgrim
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Fac Med & Hlth Sci, Trondheim, Norway;St Olavs Univ Hosp, Canc Clin, Trondheim, Norway.
    Jensen, Allan
    Danish Canc Soc Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark.
    Haugnes, Hege Sagstuen
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway;UiT Arctic Univ Norway, Inst Clin Med, Tromso, Norway.
    Daugaard, Gedske
    Rigshosp, Dept Oncol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Rylander, Lars
    Lund Univ, Div Occupat & Environm Med, Lund, Sweden.
    Giwercman, Aleksander
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study2019Ingår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, nr 6, artikel-id e1002816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. Methods and findings In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. Conclusions No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

  • 37.
    Almquist, M.
    et al.
    Skane Univ Hosp, Dept Surg, Lund, Sweden..
    Myrenfors, P.
    IPSEN, Stockholm, Sweden..
    Strom, T.
    IPSEN, Stockholm, Sweden..
    Kozlovacki, Gordana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    STREET - Somatostatin Treatment Experience Trial2017Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, s. 191-191Artikel i tidskrift (Övrigt vetenskapligt)
  • 38.
    Al-Ramadan, Afkar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mortensen, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nestor, Marika V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Analysis of radiation effects in two irradiated tumor spheroid models2018Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 15, nr 3, s. 3008-3016Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multicellular spheroids have proven suitable as three-dimensional in vivo-like models of non-vascularized micrometastases. Unlike monolayer-based models, spheroids mirror the cellular milieu and the pathophysiological gradients inside tumor nodules. However, there is limited knowledge of the radiation effects at the molecular level in spheroids of human origin. The present study is a presentation of selected cell biological processes that may easily be analyzed with methods available at routine pathology laboratories. Using gamma irradiated pancreatic neuroendocrine BON1 and colonic adenocarcinoma HCT116 spheroids as model systems, the present study assessed the radiobiological response in these models. Spheroid growth after irradiation was followed over time and molecular responses were subsequently assessed with immunohistochemistry (IHC) staining for descriptive analyses and semi-automatic grading of apoptosis, G(2)-phase and senescence in thin sections of the spheroids. Growth studies demonstrated the BON1 spheroids were slower growing and less sensitive to radiation compared with the HCT116 spheroids. IHC staining for G2-phase was primarily observed in the outer viable P-cell layers of the spheroids, with the 6 Gy irradiated HCT116 spheroids demonstrating a very clear increase in staining intensity compared with unirradiated spheroids. Apoptosis staining results indicated increased apoptosis with increasing radiation doses. No clear association between senescence and radiation exposure in the spheroids were observed. The present results demonstrate the feasibility of the use of multicellular spheroids of human origin in combination with IHC analyses to unravel radiobiological responses at a molecular level. The present findings inspire further investigations, including other relevant IHC-detectable molecular processes in time-and radiation dose-dependent settings.

  • 39.
    Altai, Mohamed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Leitao, Charles Dahlsson
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Atterby, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs2018Ingår i: CELLS, ISSN 2073-4409, Vol. 7, nr 10, artikel-id 164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD 035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

  • 40.
    Altai, Mohamed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 49, nr 3, s. 1185-1194Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 41. Alvegård, T A
    et al.
    Bauer, H
    Blomqvist, Carl
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Enheten för onkologi.
    Rydholm, A
    Smeland, S
    The Scandinavian Sarcoma Group--background, organization and the SSG Register--the first 25 years.2004Ingår i: Acta Orthop Scand Suppl, ISSN 0300-8827, Vol. 75, nr 311, s. 1-7Artikel i tidskrift (Övrigt vetenskapligt)
  • 42.
    Alzrigat, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.

    In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples.  These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.

    Delarbeten
    1. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
    Öppna denna publikation i ny flik eller fönster >>Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
    Visa övriga...
    2016 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 6, s. 6809-6923Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    Nyckelord
    multiple myeloma; Polycomb; EZH2; H3K27me3; UNC1999
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-289186 (URN)10.18632/oncotarget.6843 (DOI)000376123100032 ()26755663 (PubMedID)
    Forskningsfinansiär
    CancerfondenVetenskapsrådetNIH (National Institute of Health), R01GM103893
    Tillgänglig från: 2016-04-29 Skapad: 2016-04-29 Senast uppdaterad: 2019-04-14Bibliografiskt granskad
    2. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
    Öppna denna publikation i ny flik eller fönster >>EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
    Visa övriga...
    2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 6, s. 10213-10224Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-312396 (URN)10.18632/oncotarget.14378 (DOI)000394181800106 ()28052011 (PubMedID)
    Tillgänglig från: 2017-01-09 Skapad: 2017-01-09 Senast uppdaterad: 2019-04-14Bibliografiskt granskad
    3. The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Öppna denna publikation i ny flik eller fönster >>The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Visa övriga...
    2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 61, s. 103731-103743Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

    Nyckelord
    Multiple Myeloma, Epigenetics, Polycomb, BMI-1, PTC-209
    Nationell ämneskategori
    Cancer och onkologi
    Forskningsämne
    Medicinsk vetenskap; Molekylär medicin
    Identifikatorer
    urn:nbn:se:uu:diva-313562 (URN)10.18632/oncotarget.21909 (DOI)000419562500079 ()29262596 (PubMedID)
    Forskningsfinansiär
    CancerfondenVetenskapsrådet
    Tillgänglig från: 2017-01-20 Skapad: 2017-01-20 Senast uppdaterad: 2019-04-14Bibliografiskt granskad
  • 43.
    Alzrigat, Mohammad
    et al.
    Univ Florida, Hlth Canc Ctr, Div Hematol & Oncol, Dept Med, Gainesville, FL 32610 USA.
    Jernberg Wiklund, Helena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Licht, Jonathan D.
    Univ Florida, Hlth Canc Ctr, Div Hematol & Oncol, Dept Med, Gainesville, FL 32610 USA.
    Targeting EZH2 in Multiple Myeloma-Multifaceted Anti-Tumor Activity2018Ingår i: EPIGENOMES, ISSN 2075-4655, Vol. 2, nr 3, artikel-id 16Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM.

  • 44.
    Alzrigat, Mohammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Párraga, Alba Atienza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jernberg-Wiklund, Helena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Epigenetics in multiple myeloma: From mechanisms to therapy2018Ingår i: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, s. 101-115Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of antibody producing plasmablasts/plasma cells that resides within the bone marrow (BM). In addition to the well-established role of genetic lesions and tumor-microenvironment interactions in the development of MM, deregulated epigenetic mechanisms are emerging as important in MM pathogenesis. Recently, MM sequencing and expression projects have revealed that mutations and copy number variations as well as deregulation in the expression of epigenetic modifiers are characteristic features of MM. In the past decade, several studies have suggested epigenetic mechanisms via DNA methylation, histone modifications and non-coding RNAs as important contributing factors in MM with impacts on disease initiation, progression, clonal heterogeneity and response to treatment. Herein we review the present view and knowledge that has accumulated over the past decades on the role of epigenetics in MM, with focus on the interplay between epigenetic mechanisms and the potential use of epigenetic inhibitors as future treatment modalities for MM.

  • 45.
    Alzrigat, Mohammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala University.
    Párraga, Alba Atienza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Majumder, Muntasir
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Ma, Anqi
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Jin, Jian
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Heckman, Caroline
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Öberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Jernberg Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 61, s. 103731-103743Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

  • 46.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Hodgkin Lymphoma: Studies of Advanced Stages, Relapses and the Relation to Non-Hodgkin Lymphomas2002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The relationship between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is not entirely elucidated and a clonal relation may be present more often than previously believed. Mechanisms of tumour progression and resistance to therapy are poorly understood.

    Between 1974 and 1994 all individuals in Sweden with both HL and NHL were identified. Thirty-two cases were studied using clinical, histopathological and immunohistochemical methods. The second lymphoma often appeared in an aggressive clinical form and a significant correlation between the expression of p53 and LMP-1 in the first and second lymphoma was demonstrated.

    The treatment outcome for 307 patients with advanced stages of HL, in an unselected population was in accordance with the treatment results of large centres world-wide. Some patients were successfully selected for a shorter chemotherapy-regimen without inferior treatment results.

    In 124 patients with relapse, the survival of those primarily treated with radiotherapy according to the National guidelines was in accordance with the survival of patients of initially advanced stages. A worse outcome was found for those who received both chemotherapy and radiotherapy initially, probably because of a higher frequency of bulky disease in this group.

    Immunohistochemical analysis of the tumour suppressor protein p53 and retinoblastoma protein (Rb) of paired samples at diagnosis and at relapse in 81 patients did not reveal any specific staining pattern affecting survival.

    A novel B-cell line (U-2932) was established from a patient with a diffuse large B-cell lymphoma previously treated for advanced stage and subsequent relapses of HL. An identical rearranged IgH gene was demonstrated in tumour cells from the patient and in U-2932. A p53 point mutation was detected and over-expression of the p53 protein was found. A complex karyotype with high-level amplifications of the chromosomal regions 18q21 and 3q27, i.e. the loci for bcl-2 and bcl-6 were demonstrated.

    Delarbeten
    1. Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients
    Öppna denna publikation i ny flik eller fönster >>Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients
    1997 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, nr 4, s. 510-516Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89775 (URN)10.1002/(SICI)1097-0215(19970516)71:4<510::AID-IJC2>3.0.CO;2-X (DOI)9178801 (PubMedID)
    Tillgänglig från: 2002-04-05 Skapad: 2002-04-05 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience
    Öppna denna publikation i ny flik eller fönster >>Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience
    Visa övriga...
    2000 (Engelska)Ingår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 65, nr 6, s. 379-389Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Despite improved treatment results achieved in Hodgkin's disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB-IVB) of HD in younger patients in an unselected population-based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post-CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected.

    PATIENTS AND METHODS: Between 1985-92, 307 patients between 17-59 yr of age (median 36) were diagnosed with HD in stages IIB-IVB in 5/6 health care regions in Sweden. Median follow-up time was 7.8 yr (1.3-13). Retrospectively, laboratory parameters were collected.

    RESULTS: In total, 267 (87%) patients had a complete response (CR). The overall and disease-free 10-yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT + RT. In univariate analyses survival was affected by age, stage IVB, bone-marrow involvement, B-symptoms, S-LDH, S-Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant.

    CONCLUSIONS: The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89776 (URN)10.1034/j.1600-0609.2000.065006379.x (DOI)11168495 (PubMedID)
    Tillgänglig från: 2002-04-05 Skapad: 2002-04-05 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma
    Öppna denna publikation i ny flik eller fönster >>A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma
    Visa övriga...
    2002 (Engelska)Ingår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 68, nr 4, s. 225-232Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND:

    Our aims were to evaluate the response to salvage treatment in relation to initial treatment and to evaluate prognostic factors at the time of relapse in an unselected population of relapsing patients with Hodgkin's lymphoma (HL).

    PATIENTS AND METHODS:

    In total, 124 patients younger than 60 yr of age with initial diagnosis of HL in Sweden relapsed between 1985 and 1995.

    RESULTS:

    Fifty-eight patients relapsed after initial treatment with radiotherapy (RT) only, 62 after combination chemotherapy (CT), of whom 30 had received additional involved-field RT, and four after a short course of CT followed by extended-field RT. For 37 patients among the 58 relapsers after initial RT treated according to the recommendations of the National guidelines, the 5-yr Hodgkin-specific survival (HLS) was 85%, overall survival (OS) 73% and event-free survival (EFS) 62%, which is not inferior to survival in patients with primarily advanced stages. It was poorer in the 21 patients who initially had received RT only, even though they had been recommended for more extensive treatment. For patients initially treated with a full course (6-8 cycles) of CT the 5-yr HLS was 60%, OS 58% and EFS 22%. Bulky disease and age at diagnosis strongly affected survival in a multivariate analysis.

    CONCLUSIONS:

    Patients initially treated with RT who relapse have a favourable outcome, provided they have been treated according to the recommendations of the guidelines at the time of diagnosis. Initially bulky disease and, as a consequence, additional RT as part of the initial treatment negatively affect survival at relapse in patients initially treated with a full course of CT.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89777 (URN)10.1034/j.1600-0609.2002.01565.x (DOI)12071938 (PubMedID)
    Tillgänglig från: 2002-04-05 Skapad: 2002-04-05 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival
    Öppna denna publikation i ny flik eller fönster >>Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival
    Visa övriga...
    2002 (Engelska)Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, nr 6, s. 1253-1260Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Patients with relapsing Hodgkin's lymphoma (HL) have a rather poor prognosis and mechanisms that lead to resistance to therapy are poorly understood. Our aims were to investigate the immunohistochemical staining patterns of Rb (retinoblastoma protein) and the p53 tumour suppressor protein in HL at initial presentation and at relapse in order to elucidate a possible role in disease progression and resistance to therapy. Further to evaluate the presence and prognostic importance of Epstein-Barr virus (EBV) and anaplastic lymphoma kinase (ALK). Eighty-one cases of relapsing HL were reexamined histopathologically and immunostained for the expression of p53, Rb, ALK and CD30. EBV was detected with LMP-1 stainings and in situ hybridisation for EBER. Clinical data were extracted from the Swedish National Health Care Programme for HL. Median follow-up time was six years (range 0-12) from the date of relapse. The majority of cases were positive for p53 and Rb both at presentation and at relapse, though to a different extent. Both an increase and a decrease in the proportion of stained tumour cells were observed. None of our cases was ALK-positive and 44% were EBV-positive. No specific staining pattern was directly correlated to survival. In 12 patients a switch in HL subtype from diagnosis to relapse was observed and the five-year Hodgkin-specific survival (HLS) was statistically significantly inferior, 37 vs 81% (p = 0.002), in those patients. We found a significant relation between the expression of p53 and EBV at diagnosis and relapse, indicating a clonal relationship. We were unable to find any specific staining pattern of p53 or Rb, affecting survival.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89778 (URN)10.1080/10428190290026303 (DOI)12152993 (PubMedID)
    Tillgänglig från: 2002-04-05 Skapad: 2002-04-05 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
    Öppna denna publikation i ny flik eller fönster >>A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
    Visa övriga...
    2002 (Engelska)Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, nr 11, s. 2179-2189Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89779 (URN)10.1080/1042819021000032917 (DOI)12533045 (PubMedID)
    Tillgänglig från: 2002-04-05 Skapad: 2002-04-05 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
  • 47.
    Amini, Rose-Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laszlo, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eriksson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Gustafsson, Kristin Ayoola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Loskog, Angelica S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Lokon Pharma, AB,Uppsala, Sweden.
    Thörn, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients2019Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, artikel-id 316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome. Methods: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome. Results: The percentage of CD3-positive T-cells was lower (p=0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p=0.2) nor the T-cell/monocyte ratio (p=0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7(+)/CD3(-)/CD56(bright)/CD16(dim/-)) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p=0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p=0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p=0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p=0.04). Conclusions: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

  • 48.
    Amoroso, Vito
    et al.
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    Pavel, Marianne
    Friedrich Alexander Univ Erlangen Nurnberg, Div Endocrinol, Dept Med, D-91012 Erlangen, Germany.
    Claps, Melanie
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    Roca, Elisa
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    Ravanelli, Marco
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Radiol Unit, I-25123 Brescia, Italy.
    Maroldi, Roberto
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Radiol Unit, I-25123 Brescia, Italy.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Berruti, Alfredo
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    IFN-alpha in advanced well-differentiated neuroendocrine tumors: the neglected drug?2018Ingår i: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 14, nr 10, s. 897-899Artikel i tidskrift (Övrigt vetenskapligt)
  • 49.
    Anandavadivelan, Poorna
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Surg Care Sci, Stockholm, Sweden.
    Wikman, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Johar, Asif
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Surg Care Sci, Stockholm, Sweden.
    Lagergren, Pernilla
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Surg Care Sci, Stockholm, Sweden.
    Profiles of patient and tumour characteristics in relation to health-related quality of life after oesophageal cancer surgery2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 4, artikel-id e0196187Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Strong deterioration in health-related quality of life (HRQOL) is a major concern in a sub-group of long-term oesophageal cancer survivors. This study aimed to identify potential clustering of patients and tumour variables that predicts such deterioration. Patient and tumour variables were collected in a prospective cohort of patients who underwent surgery for oesophageal cancer in Sweden 2001–2005. Latent cluster analysis identified statistically significant clustering of these variables. Multivariable logistic regression adjusted for age, BMI, tumour stage and marital status was used to determine odds ratios (ORs) with 95% confidence intervals (CIs) between patient profiles and HRQOL at 3 and 5 years from surgery. Among 155 included patients at 3 years, three patient profiles were identified: 1) ‘reference profile’ (males, younger age, employed, upper secondary education, co-habitating, urban dwellers, adenocarcinoma and advanced tumour stage) (n = 47;30%), 2) ‘adenocarcinoma profile’ (middle age, unemployed/retired, males, low education, co-habitating, adenocarcinoma, advanced tumour stage, tumour in lower oesophagus/cardia, and co-morbidities (n = 79;51%), and 3) ‘squamous-cell carcinoma profile’ (unemployed/retired, middle-age, males, low BMI, urban dwellers, squamous-cell carcinoma, tumour in upper/middle oesophagus (n = 29;19%). These profiles did not differ regarding most HRQOL measures. Exceptions were the squamous-cell carcinoma profile, reporting more constipation (OR = 5.69; 95%CI: 1.34–24.28) and trouble swallowing saliva (OR = 4.87; 95%CI: 1.04–22.78) and the adenocarcinoma profile reporting more dyspnoea (OR = 2.60; 95%CI: 1.00–6.77) and constipation (OR = 3.31; 95%CI: 1.00–10.97) compared to the reference profile. Three distinct patient profiles were identified but these could not explain the substantial deterioration in HRQOL observed in the sub-sample of survivors.

  • 50.
    Anastasopoulou, Stavroula
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Eriksson, Mats A.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Heyman, Mats
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Wang, Chen
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Niinimäki, Riitta
    Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland;Univ Oulu, PEDEGO Res Unit, Oulu, Finland.
    Mikkel, Sirje
    Univ Tartu, Dept Hematol & Oncol, Tartu, Estonia.
    Vaitkeviciene, Goda E.
    Vilnius Univ Hosp Santaros Klin, Childrens Hosp, Vilnius, Lithuania;Vilnius Univ, Vilnius, Lithuania.
    Johannsdottir, Inga Maria
    Oslo Univ Hosp, Dept Pediat Hematol Oncol, Oslo, Norway.
    Myrberg, Ida Hed
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Jonsson, Olafur Gisli
    Univ Iceland, Dept Pediat, Reykjavik, Iceland.
    Als-Nielsen, Bodil
    Rigshosp, Univ Hosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark.
    Schmiegelow, Kjeld
    Rigshosp, Univ Hosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark.
    Banerjee, Joanna
    Univ Helsinki, Childrens Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Harila-Saari, Arja H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Ranta, Susanna
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease2019Ingår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 66, nr 5, artikel-id e27594Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL).

    Procedure: Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records.

    Results: The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1-2.5) and at one year 3.7% (95% CI, 2.9-4.9). Older age (hazard ratios [HR] for each one-year increase in age 1.1; 95% CI, 1.0-1.2, P = 0.001) and T-cell immunophenotype (HR, 2.9; 95% CI, 1.6-5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios [OR] = 2.8; 95% CI, 1.2-6.5, P = 0.015) was associated with early PRES and high-risk block treatment (HR = 2.63; 95% CI, 1.1-6.4, P = 0.033) with late PRES. At follow-up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties.

    Conclusion: PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long-term morbidity. Older age, T-cell leukemia, CNS involvement and high-risk block treatment are risk factors for PRES.

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