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  • 1.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Capodanno, Alessandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women2017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 54, p. 92134-92142Article in journal (Refereed)
    Abstract [en]

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

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  • 2.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Increased nutrient availability in dense breast tissue of postmenopausal women in vivo2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 42733Article in journal (Refereed)
    Abstract [en]

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

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  • 3.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Borga, Magnus
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lundberg, Peter
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo2016In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 10, article id e1229723Article in journal (Refereed)
    Abstract [en]

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

  • 4.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Vazquez Rodriguez, Gabriela
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dabrosin, Charlotta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen2020In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 20, p. 4487-4499Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Abramian, David
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Blystad, Ida
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Eklund, Anders
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning.
    Evaluation of inverse treatment planning for gamma knife radiosurgery using fMRI brain activation maps as organs at risk2023In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 50, no 9, p. 5297-5311Article in journal (Refereed)
    Abstract [en]

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

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  • 6.
    Abtahi, Jahan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Ajan, Aida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Malignant Transformation of Ossifying Fibroma into Parosteal Osteosarcoma with High-grade Component: Presentation of an Unusual Case and Review of the Literature2018In: The Open Dentistry Journal, E-ISSN 1874-2106, Vol. 12, p. 1059-1068Article in journal (Refereed)
    Abstract [en]

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

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  • 7.
    Abuhasanein, Suleiman
    et al.
    Univ Gothenburg, Sweden; NU Hosp Grp, Sweden.
    Jahnson, Staffan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Abdul-Sattar Aljabery, Firas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Gårdmark, Truls
    Karolinska Inst, Sweden.
    Jerlström, Tomas
    Örebro Univ, Sweden.
    Liedberg, Fredrik
    Skåne Univ Hosp, Sweden; Lund Univ, Sweden.
    Sherif, Amir
    Umeå Univ, Sweden.
    Ströck, Viveka
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Kjölhede, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Do not throw out the baby with the bath water2022In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 56, no 3, p. 235-236Article in journal (Other academic)
  • 8.
    Alickovic, Emina
    et al.
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, Faculty of Science & Engineering.
    Subasi, Abdulhamit
    Effat Univ, Saudi Arabia.
    Normalized Neural Networks for Breast Cancer Classification2020In: PROCEEDINGS OF THE INTERNATIONAL CONFERENCE ON MEDICAL AND BIOLOGICAL ENGINEERING, CMBEBIH 2019, SPRINGER , 2020, Vol. 73, p. 519-524Conference paper (Refereed)
    Abstract [en]

    In almost all parts of the world, breast cancer is one of the major causes of death among women. But at the same time, it is one of the most curable cancers if it is diagnosed at early stage. This paper tries to find a model that diagnose and classify breast cancer with high accuracy and help to both patients and doctors in the future. Here we develop a model using Normalized Multi Layer Perceptron Neural Network to classify breast cancer with high accuracy. The results achieved is very good (accuracy is 99.27%). It is very promising result compared to previous researches where Artificial Neural Networks were used. As benchmark test, Breast Cancer Wisconsin (Original) was used.

  • 9. Order onlineBuy this publication >>
    Aljabery, Firas
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.

    Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.

    Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.

    Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.

    List of papers
    1. PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.
    Open this publication in new window or tab >>PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.
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    2015 (English)In: BMC Urology, E-ISSN 1471-2490, Vol. 15, no 1, p. 87-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: We studied patients treated with radical cystectomy for locally advanced bladder cancer to compare the results of both preoperative positron emission tomography/computed tomography (PET/CT) and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes.

    METHODS: Patients who had bladder cancer and were candidates for cystectomy underwent preoperative PET/CT using 18-fluorodeoxyglucose (FDG) and conventional CT. The results regarding lymph node involvement were independently evaluated by two experienced radiologists and were subsequently compared with histopathology results, the latter of which were reassessed by an experienced uropathologist (HO).

    RESULTS: There were 54 evaluable patients (mean age 68 years, 47 [85 %] males and 7 [15 %] females) with pT and pN status as follows: < pT2-14 (26 %), pT2-10 (18 %), and > pT2-30 (56 %); pN0 37 (69 %) and pN+ 17 (31 %). PET/CT showed positive lymph nodes in 12 patients (22 %), and 7 of those cases were confirmed by histopathology; the corresponding results for conventional CT were 11 (20 %) and 7 patients (13 %), respectively. PET/CT had 41 % sensitivity, 86 % specificity, 58 % PPV, and 76 % NPV, whereas the corresponding figures for conventional CT were 41 %, 89 %, 64 %, and 77 %. Additional analyses of the right and left side of the body or in specified anatomical regions gave similar results.

    CONCLUSIONS: In this study, PET/CT and conventional CT had similar low sensitivity in detecting and localizing regional lymph node metastasis in bladder cancer.

    National Category
    Urology and Nephrology Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-120796 (URN)10.1186/s12894-015-0080-z (DOI)000359832000001 ()26294219 (PubMedID)
    Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2024-01-16
    2. Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.
    Open this publication in new window or tab >>Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.
    Show others...
    2017 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 120, no 3, p. 329-336Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field.

    PATIENTS AND METHODS: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides.

    RESULTS: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001).

    CONCLUSION: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2017
    Keywords
    #BladderCancer, #blcsm, cystectomy, lymph node metastasis, prognostic factors, sentinel node
    National Category
    Surgery
    Identifiers
    urn:nbn:se:liu:diva-136947 (URN)10.1111/bju.13700 (DOI)000407781500011 ()27797436 (PubMedID)
    Note

    Funding agencies: County Council of Ostergotland, Linkoping, Sweden

    Available from: 2017-05-01 Created: 2017-05-01 Last updated: 2022-09-28
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    Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
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  • 10.
    Aljabery, Firas
    et al.
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Lindblom, Gunnar
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Skoog, Susann
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.2015In: BMC Urology, E-ISSN 1471-2490, Vol. 15, no 1, p. 87-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We studied patients treated with radical cystectomy for locally advanced bladder cancer to compare the results of both preoperative positron emission tomography/computed tomography (PET/CT) and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes.

    METHODS: Patients who had bladder cancer and were candidates for cystectomy underwent preoperative PET/CT using 18-fluorodeoxyglucose (FDG) and conventional CT. The results regarding lymph node involvement were independently evaluated by two experienced radiologists and were subsequently compared with histopathology results, the latter of which were reassessed by an experienced uropathologist (HO).

    RESULTS: There were 54 evaluable patients (mean age 68 years, 47 [85 %] males and 7 [15 %] females) with pT and pN status as follows: < pT2-14 (26 %), pT2-10 (18 %), and > pT2-30 (56 %); pN0 37 (69 %) and pN+ 17 (31 %). PET/CT showed positive lymph nodes in 12 patients (22 %), and 7 of those cases were confirmed by histopathology; the corresponding results for conventional CT were 11 (20 %) and 7 patients (13 %), respectively. PET/CT had 41 % sensitivity, 86 % specificity, 58 % PPV, and 76 % NPV, whereas the corresponding figures for conventional CT were 41 %, 89 %, 64 %, and 77 %. Additional analyses of the right and left side of the body or in specified anatomical regions gave similar results.

    CONCLUSIONS: In this study, PET/CT and conventional CT had similar low sensitivity in detecting and localizing regional lymph node metastasis in bladder cancer.

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  • 11.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer2018In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, no 4, article id 159.e19Article in journal (Refereed)
    Abstract [en]

    Background

    Tumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer(UBC) is controversial.

    Methods

    We prospectively studied 103 patients with stage pT1–T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome.

    Results

    The mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02).

    Conclusions

    M2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact.

  • 12.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer2018In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, no 12, p. 530.e7-530.e18, article id 530.e7Article in journal (Refereed)
    Abstract [en]

    Purpose: We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy.

    Materials and methods: We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival.

    Results: The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P = 0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03).

    Conclusions: The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation.

  • 13.
    Alvez, Maria Bueno
    et al.
    KTH Royal Inst Technol, Sweden.
    Edfors, Fredrik
    KTH Royal Inst Technol, Sweden.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sweden.
    Zwahlen, Martin
    KTH Royal Inst Technol, Sweden.
    Mardinoglu, Adil
    KTH Royal Inst Technol, Sweden; Kings Coll London, England.
    Edqvist, Per-Henrik
    Uppsala Univ, Sweden.
    Sjoblom, Tobias
    Uppsala Univ, Sweden.
    Lundin, Emma
    Uppsala Univ, Sweden.
    Rameika, Natallia
    Uppsala Univ, Sweden.
    Enblad, Gunilla
    Uppsala Univ, Sweden.
    Lindman, Henrik
    Uppsala Univ, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    Hesselager, Goran
    Uppsala Univ, Sweden.
    Stalberg, Karin
    Uppsala Univ, Sweden.
    Enblad, Malin
    Uppsala Univ, Sweden.
    Simonson, Oscar E.
    Uppsala Univ, Sweden.
    Haggman, Michael
    Uppsala Univ, Sweden.
    Axelsson, Tomas
    Uppsala Univ, Sweden.
    Aberg, Mikael
    Uppsala Univ, Sweden.
    Nordlund, Jessica
    Uppsala Univ, Sweden.
    Zhong, Wen
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Max
    KTH Royal Inst Technol, Sweden.
    Gyllensten, Ulf
    Uppsala Univ, Sweden.
    Ponten, Fredrik
    Uppsala Univ, Sweden.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sweden.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Next generation pan-cancer blood proteome profiling using proximity extension assay2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    Comprehensive and scalable proteomic profiling of plasma samples can improve the screening and diagnosis of cancer patients. Here, the authors use the Olink Proximity Extension Assay technology to characterise the plasma proteomes of 1477 patients across twelve cancer types, and use machine learning to obtain a protein panel for cancer classification. A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature in blood across patients representing many of the major cancer types. Plasma profiles of 1463 proteins from more than 1400 cancer patients are measured in minute amounts of blood collected at the time of diagnosis and before treatment. An open access Disease Blood Atlas resource allows the exploration of the individual protein profiles in blood collected from the individual cancer patients. We also present studies in which classification models based on machine learning have been used for the identification of a set of proteins associated with each of the analyzed cancers. The implication for cancer precision medicine of next generation plasma profiling is discussed.

  • 14. Order onlineBuy this publication >>
    Andersson, Bengt-Åke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Department of Laboratory Medicine, Region Jönköping County.
    Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Head and neck cancer (HNC) is a collective name for heterogeneous tumors located in the head and neck regions for which smoking, alcohol and human papillomavirus (HPV) are documented risk factors. The survival of HNC patients has only improved marginally during the last decade. The most important prognostic factors are tumor size, local spread and distant metastases, tumor node metastasis (TNM) staging. Prognostic biomarkers are needed as a complement to TNM staging.

    The aim for this thesis was to investigate rapid and low cost blood based biomarkers which could indicate the risk of HNC, recurrence of the disease or the survival of HNC patients. Furthermore, the aim was to examine how cigarette smoking influences the levels of biomarkers.

    In paper I, a possible role of plasma cytokines or proteins associated with immune response or inflammation, as biomarkers for the survival of HNC patients was investigated. Higher levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) were detected in plasma of the patients compared with the levels in the controls. The elevated levels of these two biomarkers detected in patients were associated with decreased survival.

    In paper II, the influence of 45 single nucleotide polymorphisms (SNPs) located in 41 genes associated with cell cycle progression, cell death, DNA repair or immune response on cancer risk, tumor recurrence and survival in HNC patients were investigated. SNPs in immune response genes were associated with risk for HNC, an elevated risk for recurrence and a decreased survival in HNC patients.

    In paper III, the influence of cigarette smoking on levels of inflammatory cells, proteins or cytokines/chemokines, microRNAs (miRNAs) and SNPs was analysed in healthy smokers and non-smokers. Higher levels of total white blood cells (WBCs), neutrophils, monocytes, lymphocytes, neutrophil to lymphocyte ratio (NLR), CRP, monocyte chemoattractant protein- 1 (MCP-1) and interferon gamma (IFN-γ) were detected in smokers compared to non-smokers and indicate an inflammatory response. Also, a lower level of oncomiRNA miR-21was detected in smokers. This alteration, in combination with the elevated levels of IFN-γ in smokers could be a protective response to cigarette smoke. The higher levels of IFN-γ in smokers compared to non-smokers were however only detected in individuals with SNP rs2069705 genotype AG/GG. This indicates a genetic association of the levels of IFN-γ.

    In paper IV, the separate effects of cigarette smoking and HNC on inflammatory or immune biomarkers and the impact of high risk human papillomavirus, age and gender were investigated. Comparisons of circulating levels of WBCs and its subpopulations, plasma proteins or cytokines/chemokines between smoking and non-smoking patients, smoking and non-smoking controls and between the patient and control groups were analysed. Smoking had highest impact on elevated levels of WBCs, IFN-γ and MCP-1, and HNC had highest impact on elevated levels of neutrophils, monocytes, NLR, CRP, macrophage inflammatory protein 1 beta and TNF-α.

    In conclusion, host immune response associated parameters could be suitable as biomarkers for the risk of HNC, risk of recurrence or in predicting survival of HNC patients. This thesis show that HNC are associated with systemic inflammatory response and upregulated CRP and TNF-α is related to shorter survival in HNC patients. Additionally, SNPs in immune response genes such as rs1800629 in the TNF-α gene indicates a risk for HNC or an elevated risk for recurrence and a decreased survival in HNC patients. These rapid and low cost blood based biomarkers could be used in combination or as a supplement to established biomarkers in the clinic for a more personalized treatment modality.

    List of papers
    1. Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma.
    Open this publication in new window or tab >>Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma.
    Show others...
    2014 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 140, no 3, p. 515-519Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Tumor TNM staging is the main basis for prognosis and treatment decision for head and neck squamous cell carcinoma (HNSCC) despite significant heterogeneity in terms of outcome among patients with the same clinical stage. In this study, a possible role of plasma interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) as biomarkers for survival of HNSCC patients was investigated.

    METHODS: In this prospective study, plasma levels of IL-2, IL-6, GM-CSF, TNF-α and CRP in patients (n = 100) and controls (n = 48) were analyzed.

    RESULTS: Significantly elevated levels of CRP and TNF-α (p < 0.001) were found in the patients. Combination of upregulated CRP and TNF-α in the patient plasma was significantly related to shorter patient survival, independent of clinical stage.

    CONCLUSIONS: Our findings indicate that CRP and TNF-α might be suitable as biomarkers in combination with tumor TNM staging for predicting survival and individualized treatment of HNSCC patients. Plasma CRP and TNF-α analysis are simple, rapid, cost effective and suitable for clinical practice.

    Keywords
    Head and neck squamous cell carcinoma, Biomarkers, Survival, CRP, TNF-α
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-162092 (URN)10.1007/s00432-014-1592-8 (DOI)24481866 (PubMedID)
    Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2019-11-19Bibliographically approved
    2. Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients
    Open this publication in new window or tab >>Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients
    Show others...
    2017 (English)In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 92, no 3, p. 161-169Article in journal (Refereed) Published
    Abstract [en]

    Objective: This paper aims at studying the influence of single-nucleotide polymorphisms (SNPs) on cancer risk, tumor recurrence, and survival in head and neck (Hamp;N) cancer patients. Methods: A total of 45 SNPs in 41 genes were investigated. A total of 174 Caucasian Hamp;N cancer patients and 245 healthy blood donors were enrolled in the study. Results: Ten SNPs were associated with Hamp;N cancer risk, but the identified SNPs differed among males and females. Some of the SNPs were related to immune response genes. The immune response gene SNPs were also related to survival. In particular, we noted that the tumor necrosis factor alpha (TNF alpha) rs1800629 could have an influence on cancer risk; tumor recurrence as well as survival. Conclusion: Genetic variation of the TNFa rs1800629 might be useful as a biomarker in clinical decision-making since it was found to be related to cancer risk, tumor recurrence, and survival of Hamp;N cancer patients. (C) 2016 S. Karger AG, Basel

    Place, publisher, year, edition, pages
    KARGER, 2017
    Keywords
    Head and neck cancer; Tumor recurrence; Survival time; Single-nucleotide polymorphisms
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-136217 (URN)10.1159/000452278 (DOI)000395366800005 ()27997918 (PubMedID)
    Note

    Funding Agencies|Jonkoping Clinical Cancer Research Foundation; Futurum; FORSS; Swedish Laryngeal Foundation

    Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2019-11-19
    3. Cigarette smoking affects microRNAs and inflammatory biomarkers in healthy individuals and an association to single nucleotide polymorphisms is indicated
    Open this publication in new window or tab >>Cigarette smoking affects microRNAs and inflammatory biomarkers in healthy individuals and an association to single nucleotide polymorphisms is indicated
    Show others...
    2019 (English)In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 24, no 2, p. 180-185Article in journal (Refereed) Published
    Abstract [en]

    Background: Cigarette smoke induces inflammation and remodels immune response. Genetic and epigenetic alterations might be involved in the pathogenesis of smoking related diseases. In this study, we investigated the effect of smoking on systemic inflammation biomarkers and epigenetic changes at microRNA (miRNA) expression level. We also examined if the levels of inflammatory biomarkers were associated with selected single nucleotide polymorphisms (SNPs). Method: From 39 smokers and 101 non-smokers, levels of total white blood cells (WBCs) and its subpopulations, plasma cytokines/chemokines/proteins and miRNAs were analysed. For three biomarkers, C-reactive protein (CRP), MCP-1 and IFN-gamma that were affected by smoking, the influence of SNPs was analyzed. Result: Elevated levels of total WBCs, neutrophils, monocytes, lymphocytes, CRP, MCP-1, IFN-gamma and lower levels of miR-21 were detected in smokers. The elevated levels of IFN-gamma in smokers was only statistically significantly associated with rs2069705 AG/GG SNP-genotype. Conclusions: A lower level of oncomir miRNA-21 and a higher level of immune modelling cytokine IFN-gamma detected in smokers could be a protective immune response to cigarette smoke. The higher level of IFN-gamma in smokers with a specific SNP genotype also suggests that a genetic interaction with smoking might predict the pathobiology of smoking related disease.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2019
    Keywords
    Immune respons; single nucleotide polymorphism; microRNA; smoking related diseases; cigarette smoking
    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:liu:diva-157272 (URN)10.1080/1354750X.2018.1539764 (DOI)000465158700011 ()30375257 (PubMedID)
    Note

    Funding Agencies|Forskningsradet i Sydostra Sverige; Futurum-Academy of HealthCare at Jonkoping County Council [477461, 490031, 669631]; Foundation of Clinical Cancer Research in Jo nkoping [110426-1]; Medical Research Council of Southeast Sweden (FORSS) [567001]

    Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-11-19
    4. Impact of Cigarette Smoking and Head and Neck Squamous Cell Carcinoma on Circulating Inflammatory Biomarkers
    Open this publication in new window or tab >>Impact of Cigarette Smoking and Head and Neck Squamous Cell Carcinoma on Circulating Inflammatory Biomarkers
    Show others...
    2020 (English)In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 98, no 1, p. 42-47Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Smoking induces inflammation and an immune response. A cancer-related inflammatory response has been seen in smoking and nonsmoking head and neck squamous cell carcinoma (HNSCC) patients.

    OBJECTIVES: The aim of this study was to analyze the possible separated effects of smoking or HNSCC on 18 inflammatory or immune regulatory biomarkers.

    METHODS: Fifty-one nonsmoking and 36 smoking pretreated HNSCC patients and 101 nonsmoking and 39 smoking controls were included in this study. The levels of 18 inflammatory or immune regulatory biomarkers were analyzed. A multivariable linear regression model was used to predict the impact of smoking and HNSCC on the levels of the biomarkers.

    RESULTS: Smoking had the highest impact on total WBC, IFN-γ, and MCP-1 levels. The highest impact of HNSCC was found on neutrophils, neutrophil-to-lymphocyte ratio, HsCRP, MIP-1b, and TNF-α levels.

    CONCLUSION: Identifying HNSCC or smoking-related inflammatory biomarkers might contribute to the understanding of the immune response in HNSCC patients. This study could provide information of inflammatory biomarkers in HNSCC patients.

    Place, publisher, year, edition, pages
    S. Karger, 2020
    Keywords
    Biomarkers, Head and neck squamous cell carcinoma, Immune response, Inflammation, Smoking
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-162093 (URN)10.1159/000502651 (DOI)000522873100007 ()31437849 (PubMedID)
    Note

    Funding agencies: 

    Futurum-Academy of HealthCare at Jonkoping County Council [696261]; Foundation of Clinical Cancer Research in Jonkoping [110426]

    Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2022-10-04Bibliographically approved
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  • 15.
    Andersson, Bengt-Åke
    et al.
    Microbiology Laboratory, Division of Medical Services, Department of Laboratory Services, Ryhov County Hospital, Jönköping.
    Lewin, Freddi
    Department of Oncology, Ryhov County Hospital, Jönköping.
    Lundgren, Jan
    Department of ENT, Karolinska University Hospital, Stockholm.
    Nilsson, Mats
    Futurum - The Academy for Healthcare, County Council, Ryhov County Hospital, Jönköping.
    Rutqvist, Lars-Erik
    Department of Scientific Affairs, Swedish Match AB, Stockholm.
    Löfgren, Sture
    Microbiology Laboratory, Division of Medical Services, Department of Laboratory Services, Ryhov County Hospital, Jönköping.
    Laytragoon-Lewin, Nongnit
    Microbiology Laboratory, Division of Medical Services, Department of Laboratory Services, Ryhov County Hospital, Jönköping.
    Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma.2014In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 140, no 3, p. 515-519Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Tumor TNM staging is the main basis for prognosis and treatment decision for head and neck squamous cell carcinoma (HNSCC) despite significant heterogeneity in terms of outcome among patients with the same clinical stage. In this study, a possible role of plasma interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) as biomarkers for survival of HNSCC patients was investigated.

    METHODS: In this prospective study, plasma levels of IL-2, IL-6, GM-CSF, TNF-α and CRP in patients (n = 100) and controls (n = 48) were analyzed.

    RESULTS: Significantly elevated levels of CRP and TNF-α (p < 0.001) were found in the patients. Combination of upregulated CRP and TNF-α in the patient plasma was significantly related to shorter patient survival, independent of clinical stage.

    CONCLUSIONS: Our findings indicate that CRP and TNF-α might be suitable as biomarkers in combination with tumor TNM staging for predicting survival and individualized treatment of HNSCC patients. Plasma CRP and TNF-α analysis are simple, rapid, cost effective and suitable for clinical practice.

  • 16.
    Andersson, Bengt-Åke
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences. Department of Laboratory Medicine, Region Jönköping County.
    Löfgren, Sture
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Department of Laboratory Medicine, Region Jönköping County.
    Lewin, Freddi
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Department of Oncology, Region Jönköping County.
    Nilsson, Mats
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Futurum, Academy for Health and Care, Jönköping.
    Laytragoon-Lewin, Nongnit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences. Department of Laboratory Medicine, Region Jönköping County.
    Impact of Cigarette Smoking and Head and Neck Squamous Cell Carcinoma on Circulating Inflammatory Biomarkers2020In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 98, no 1, p. 42-47Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Smoking induces inflammation and an immune response. A cancer-related inflammatory response has been seen in smoking and nonsmoking head and neck squamous cell carcinoma (HNSCC) patients.

    OBJECTIVES: The aim of this study was to analyze the possible separated effects of smoking or HNSCC on 18 inflammatory or immune regulatory biomarkers.

    METHODS: Fifty-one nonsmoking and 36 smoking pretreated HNSCC patients and 101 nonsmoking and 39 smoking controls were included in this study. The levels of 18 inflammatory or immune regulatory biomarkers were analyzed. A multivariable linear regression model was used to predict the impact of smoking and HNSCC on the levels of the biomarkers.

    RESULTS: Smoking had the highest impact on total WBC, IFN-γ, and MCP-1 levels. The highest impact of HNSCC was found on neutrophils, neutrophil-to-lymphocyte ratio, HsCRP, MIP-1b, and TNF-α levels.

    CONCLUSION: Identifying HNSCC or smoking-related inflammatory biomarkers might contribute to the understanding of the immune response in HNSCC patients. This study could provide information of inflammatory biomarkers in HNSCC patients.

  • 17.
    Andersson, Nadine G.
    et al.
    Lund Univ, Sweden; Skåne Univ Hosp, Sweden.
    Rathe, Mathias
    Odense Univ Hosp, Denmark.
    Molle, Ingolf
    Univ Hosp Aarhus, Denmark.
    Jarvis, Kirsten Brunswig
    Oslo Univ Hosp, Norway.
    Hoffmann, Marianne
    Univ Hosp Copenhagen, Denmark.
    Huurre, Anu
    Turku Univ Hosp, Finland; Turku Univ, Finland.
    Joelsson, Joel
    Karolinska Univ Hosp, Sweden.
    Albertsen, Birgitte Klug
    Aarhus Univ Hosp, Denmark; Aarhus Univ, Denmark.
    Lohi, Olli
    Tampere Univ, Finland; Tampere Univ Hosp, Finland.
    Långström, Satu
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Overgaard, Ulrik
    Univ Hosp Copenhagen, Denmark.
    Trakymiene, Sonata Saulyte
    Vilnius Univ, Lithuania.
    Vepsäläinen, Kaisa
    Kuopio Univ Hosp, Finland.
    Vogt, Hartmut
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Linköping University, Department of Biomedical and Clinical Sciences.
    Ranta, Susanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management2022In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 199, no 1, p. 117-121Article in journal (Refereed)
    Abstract [en]

    Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.

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  • 18. Order onlineBuy this publication >>
    Andersson, Patiyan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Molecular Genetic Studies on Prostate and Penile Cancer2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is comprised of two parts. In the first part we study the influence of four frequently disputed genes on the susceptibility for developing prostate cancer, and in the second part we attempt to establish a basic understanding of the molecular genetic events in penile cancer.

    In a prostate cancer cohort we have investigated the relation of prostate cancer risk and single nucleotide polymorphisms (SNPs) in four different genes coding for the androgen receptor (AR), the vitamin D receptor (VDR), insulin (INS) and insulin receptor substrate 1 (IRS1). Despite strong biological indications of an involvement of these genes in prostate carcinogenesis, the results from different studies are contradictory and inconclusive.

    The action of the AR varies between individuals in part owing to a repetitive CAG sequence (polyglutamine) in the first exon of the AR gene. The results presented in this thesis show that in our cohort of prostate cancer patients the average number of repeats is 20.1, which is significantly (p<0.001) fewer repeats compared to healthy control individuals, where the average is 22.5 repeats. We find a 4.94 fold (p=0.00003) increased risk of developing prostate cancer associated with having short repeat lengths (≤19 repeats), compared with long repeats (≥23 repeats). In paper I we also study the TaqI polymorphism in the VDR gene, and find that it does not modify the risk of prostate cancer.

    In the INS gene we study the +1127 PstI polymorphism and find no overall effect on the risk of prostate cancer. However, we do find that the CC genotype is associated with low grade disease defined as having a Gleason score ≤6 (OR=1.46; p=0.018). In the IRS1 gene we study the G972R polymorphism and observe that the R allele is significantly associated with a 2.44 fold increased prostate cancer risk (p=0.010).

    The knowledge of molecular genetic events in penile cancer is very scarce and to date very few genes have been identified to be involved in penile carcinogenesis. We chose therefore to analyse the penile cancer samples using genome-wide high-density SNP arrays. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses are 3p, 4q, 11p and 13q. We suggest four candidate genes residing in these areas, the PIK3CA gene (3q26.32), the hTERT gene (5p15.33), the MYC gene (8q24.21) and the FHIT gene (3p14.2).

    The mutational status of the PIK3CA and PTEN genes in the PI3K/AKT pathway and the HRAS, KRAS, NRAS and BRAF genes in the RAS/MAPK pathway was assessed in the penile cancer samples. We find the PIK3CA, HRAS and KRAS genes to be mutated in 29%, 7% and 3% of the cases, respectively. All mutations are mutually exclusive. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

    List of papers
    1. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
    Open this publication in new window or tab >>Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
    2006 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, no 16, p. 2833-2837Article in journal (Refereed) Published
    Abstract [en]

    We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p < 0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (19, 20–22, 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p = 0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.

    Place, publisher, year, edition, pages
    Elsevier, 2006
    Keywords
    Androgen receptor; Vitamin D receptor; Prostate cancer; CAG repeat
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15097 (URN)10.1016/j.ejca.2006.06.030 (DOI)
    Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2021-12-28Bibliographically approved
    2. Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
    Open this publication in new window or tab >>Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
    2008 (English)In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Article in journal (Refereed) Submitted
    Abstract [en]

    We study the G972R polymorphism in the Insulin receptor substrate 1 gene (IRS1) and the +1127 PstI polymorphism of the Insulin gene (INS), in 120 and 151, respectively, incidentally discovered, histologically verified prostate cancers, and in 185 healthy control subjects. The number of IRS1 R allele was found to be significantly associated with increased risk of prostate cancer. Analysis of the INS +1127 PstI polymorphism shows no significant differences between cases and controls. We conclude that subjects carrying one or two R-alleles at the IRS1 G972R polymorphic site are at an elevated risk of developing prostate cancer.

    Keywords
    IRS1, G972R, INS, Insulin, prostate cancer
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15098 (URN)
    Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2021-12-28
    3. PIK3CA, HRAS and KRAS gene mutations in human penile cancer
    Open this publication in new window or tab >>PIK3CA, HRAS and KRAS gene mutations in human penile cancer
    Show others...
    2008 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, p. 2030-2034 Article in journal (Refereed) Published
    Abstract [en]

    Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

    Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

    Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

    Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

    Keywords
    Penis, penile neoplasms, mutation, 1-phosphatidylinositol 3-kinase, carcinoma, squamous cell
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15099 (URN)10.1016/j.juro.2007.12.040 (DOI)
    Note
    On the day of the defence date the status of article III was: In Press.Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2021-12-28Bibliographically approved
    4. Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
    Open this publication in new window or tab >>Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
    Show others...
    (English)Manuscript (Other academic)
    Abstract [en]

    The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

    Keywords
    SNP array, penile cancer, PIK3CA, Myc, TERT, FHIT
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-15100 (URN)
    Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2021-12-28Bibliographically approved
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  • 19.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kolaric, Aleksandra
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Mats G.
    Departments of b Pathology, Örebro University Hospital, Örebro, Sweden.
    PIK3CA, HRAS and KRAS gene mutations in human penile cancer2008In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, p. 2030-2034 Article in journal (Refereed)
    Abstract [en]

    Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

    Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

    Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

    Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

  • 20.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kolaric, Aleksandra
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Departments of Urology, Örebro University Hospital, Örebro, Sweden..
    Andrén, Ove
    Departments of Urology, Örebro University Hospital, Örebro, Sweden..
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Karlsson, Mats G
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arraysManuscript (Other academic)
    Abstract [en]

    The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

  • 21.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Clinical and Experimental Medicine, Urology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk2008In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Article in journal (Refereed)
    Abstract [en]

    We study the G972R polymorphism in the Insulin receptor substrate 1 gene (IRS1) and the +1127 PstI polymorphism of the Insulin gene (INS), in 120 and 151, respectively, incidentally discovered, histologically verified prostate cancers, and in 185 healthy control subjects. The number of IRS1 R allele was found to be significantly associated with increased risk of prostate cancer. Analysis of the INS +1127 PstI polymorphism shows no significant differences between cases and controls. We conclude that subjects carrying one or two R-alleles at the IRS1 G972R polymorphic site are at an elevated risk of developing prostate cancer.

  • 22.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Clinical and Experimental Medicine, Urology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk2006In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, no 16, p. 2833-2837Article in journal (Refereed)
    Abstract [en]

    We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p < 0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (19, 20–22, 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p = 0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.

  • 23.
    Ansell, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Farnebo, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head & Neck Surgery, and Medical Biochemistry, University of Turku, Finland.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer2009In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, no 1, p. 23-29Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the predisposition of the FGFR4 Gly/Arg polymorphism for development of head and neck squamous cell carcinoma (HNSCC) and, furthermore, to examine if the FGFR4 Arg(388) allele can be associated with resistance to chemo-and radiotherapy.

    When analysing 110 tumour biopsies a significant 1.7-fold increased risk to develop HNSCC in individuals carrying the Gly(388) allele (p = 0.026) was found. Moreover a 2-fold increased risk for mates harbouring the Gly(388) allele (p = 0.031) to develop HNSCC was detected. In 39 HNSCC cell lines the role of the Arg(388) allele for radiation and cisplatin sensitivity was investigated. Our results show no rote of the Arg(388) allele for the radiosensitivity (p = 0.996) but indicate a tendency to increased cisplatin sensitivity (p = 0.141). When screening the transmembrane and kinase domains in the FGFR4 gene a novel mutation, probably generating a truncated protein lacking exons 14-18, was found in six of eight selected cell lines.

    Taken together, we have here identified a marker that predicts the risk to develop HNSCC and possibly the sensitivity to cisplatin as well as a novel. mutation in the FGFR4 gene.

  • 24.
    Ansell, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Jedlinski, Adam
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Roberg, Karin
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science.
    Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells2016In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 45, no 1, p. 9-16Article in journal (Refereed)
    Abstract [en]

    Background: Epidermal growth factor receptor (EGFR) is a target for treatment in tongue cancer. Here, EGFR ligands were evaluated for their potential uses as predictive biomarkers of cetuximab treatment response.

    Methods: In three tongue cancer cell lines the influences of epidermal growth factor (EGF), amphiregulin (AR), and epiregulin (EPR) on tumour cell proliferation and cetuximab response were evaluated by the addition of recombinant human (rh) proteins or the siRNA-mediated downregulation of endogenous ligand production.

    Results: EGF or AR downregulation suppressed the proliferation of all investigated cell lines. Furthermore, all cell lines displayed increased cetuximab resistance upon the addition of rhEGF, whereas EGF silencing resulted in an improved cetuximab response in one cell line.

    Conclusions: Our data suggest that EGF and AR are critical components of the EGFR signalling network required for full proliferative potential. Moreover, EGF is a potential predictive biomarker of poor cetuximab response and a possible treatment target.

  • 25.
    Ansell, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Ceder, Rebecca
    Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland
    VTT Technical Research Centre of Finland.
    Grénman, Reidar
    VTT Technical Research Centre of Finland.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.2009In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, no 10, p. 866-871Article in journal (Refereed)
    Abstract [en]

    Concomitant chemoradiotherapy is a common treatment for advanced head and neck squamous cell carcinomas (HNSCC). Cisplatin is the backbone of chemotherapy regimens used to treat HNSCC. Therefore, the aim of this study was to identify predictive markers for cisplatin treatment outcome in HNSCC. The intrinsic cisplatin sensitivity (ICS) was determined in a panel of tumour cell lines. From this panel, one sensitive and two resistant cell lines were selected for comparative transcript profiling using microarray analysis. The enrichment of Gene Ontology (GO) categories in sensitive versus resistant cell lines were assessed using the Gene Ontology Tree Machine bioinformatics tool. In total, 781 transcripts were found to be differentially expressed and 11 GO categories were enriched. Transcripts contributing to this enrichment were further analyzed using Ingenuity Pathway Analysis (IPA) for identification of key regulator genes. IPA recognized 20 key regulator genes of which five were differentially expressed in sensitive versus resistant cell lines. The mRNA level of these five genes was further assessed in a panel of 25 HNSCC cell lines using quantitative real-time PCR. Among these key regulators, MMP-7 and MMP-13 are implicated as potential biomarkers of ICS. Taken together, genome-wide transcriptional analysis identified single genes, GO categories as well as molecular networks that are differentially expressed in HNSCC cell lines with different ICS. Furthermore, two novel predictive biomarkers for cisplatin resistance, MMP-7 and MMP-13, were identified.

  • 26.
    Antonovic, Laura
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences.
    Furusawa, Yoshiya
    National Institute of Radiological Sciences, Chiba, Japan.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Relative clinical effectiveness of carbon ion radiotherapy: theoretical modelling for H&N tumours2015In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 56, no 4, p. 639-645Article in journal (Refereed)
    Abstract [en]

    Comparison of the efficiency of photon and carbon ion radiotherapy (RT) administered with the same number of fractions might be of limited clinical interest, since a wide range of fractionation patterns are used clinically today. Due to advanced photon treatment techniques, hypofractionation is becoming increasingly accepted for prostate and lung tumours, whereas patients with head and neck tumours still benefit from hyperfractionated treatments. In general, the number of fractions is considerably lower in carbon ion RT. A clinically relevant comparison would be between fractionation schedules that are optimal within each treatment modality category. In this in silico study, the relative clinical effectiveness (RCE) of carbon ions was investigated for human salivary gland tumours, assuming various radiation sensitivities related to their oxygenation. The results indicate that, for hypoxic tumours in the absence of reoxygenation, the RCE (defined as the ratio of D50 for photons to carbon ions) ranges from 3.5 to 5.7, corresponding to carbon ion treatments given in 36 and 3 fractions, respectively, and 30 fractions for photons. Assuming that interfraction local oxygenation changes take place, results for RCE are lower than that for an oxic tumour if only a few fractions of carbon ions are used. If the carbon ion treatment is given in more than 12 fractions, the RCE is larger for the hypoxic than for the well-oxygenated tumour. In conclusion, this study showed that in silico modelling enables the study of a wide range of factors in the clinical considerations and could be an important step towards individualisation of RT treatments.

  • 27.
    Antonovic, Laura
    et al.
    Stockholm University, Sweden.
    Lindblom, Emely
    Stockholm University, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Bassler, Niels
    Aarhus University, Denmark.
    Furusawa, Yoshiya
    National Institute of Radiological Sciences, Chiba, Japan.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes2014In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, no 5, p. 902-911Article in journal (Refereed)
    Abstract [en]

    The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required  for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.

    Download full text (pdf)
    fulltext
  • 28.
    Ardenfors, Oscar
    et al.
    Stockholm University, Stockholm, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. The Skandion Clinic, Uppsala, Sweden.
    Kopeć, Mariusz
    University of Science and Technology, Krakow, Poland.
    Gudowska, Irena
    Stockholm University, Stockholm, Sweden.
    Modelling of a proton spot scanning system using MCNP62017In: INTERNATIONAL NUCLEAR SCIENCE AND TECHNOLOGY CONFERENCE 2016, Institute of Physics (IOP), 2017, Vol. 860, article id 012025Conference paper (Refereed)
    Abstract [en]

    The aim of this work was to model the characteristics of a clinical proton spot scanning beam using Monte Carlo simulations with the code MCNP6. The proton beam was defined using parameters obtained from beam commissioning at the Skandion Clinic, Uppsala, Sweden. Simulations were evaluated against measurements for proton energies between 60 and 226 MeV with regard to range in water, lateral spot sizes in air and absorbed dose depth profiles in water. The model was also used to evaluate the experimental impact of lateral signal losses in an ionization chamber through simulations using different detector radii. Simulated and measured distal ranges agreed within 0.1 mm for R90 and R80, and within 0.2 mm for R50. The average absolute difference of all spot sizes was 0.1 mm. The average agreement of absorbed dose integrals and Bragg-peak heights was 0.9%. Lateral signal losses increased with incident proton energy with a maximum signal loss of 7% for 226 MeV protons. The good agreement between simulations and measurements supports the assumptions and parameters employed in the presented Monte Carlo model. The characteristics of the proton spot scanning beam were accurately reproduced and the model will prove useful in future studies on secondary neutrons.

    Download full text (pdf)
    fulltext
  • 29.
    Ardenfors, Oscar
    et al.
    Stockholm University, Sweden.
    Gudowska, Irena
    Stockholm University, Sweden.
    Flejmer, Anna M.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Impact of irradiation setup in proton spot scanning brain therapy on organ doses from secondary radiation2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 261-266Article in journal (Refereed)
    Abstract [en]

    A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 μGy.Gy−1 in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 μSv.Gy−1 for the paediatric patient and between 0.2 and 134 μSv.Gy−1 for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

  • 30.
    Ardenfors, Oscar
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Stockholm University.
    Josefsson, Dan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Are IMRT treatments in the head and neck region increasing the risk of secondary cancers?2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    Background: Intensity modulated radiation therapy (IMRT) has been increasingly employed for treating head and neck (H&N) tumours due to its ability to produce isodoses suitable for the complex anatomy of the region. The aim of this study was to assess possible differences between IMRT and conformal radiation therapy (CRT) with regard to risk of radiation-induced secondary malignancies for H&N tumours.

    Material and Methods: IMRT and CRT plans were made for 10 H&N adult patients and the resulting treatment planning data were used to calculate the risk of radiation-induced malignancies in four different tissues. Three risk models with biologically relevant parameters were used for calculations. The influence of scatter radiation and repeated imaging sessions has also been investigated.

    Results: The results showed that the total lifetime risks of developing radiation-induced secondary malignancies from the two treatment techniques, CRT and IMRT, were comparable and in the interval 0.9-2.5%. The risk contributions from the primary beam and scatter radiation were comparable, whereas the contribution from repeated diagnostic imaging was considerably smaller.

    Conclusion: The results indicated that the redistribution of the dose characteristic to IMRT leads to a redistribution of the risks in individual tissues. However, the total levels of risk were similar between the two irradiation techniques considered.

  • 31.
    Armuand, Gabriela
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Skoog-Svanberg, Agneta
    Uppsala University, Uppsala, Sweden.
    Correction: Reproductive Patterns Among Childhood and Adolescent Cancer Survivors in Sweden: A Population-Based Matched-Cohort Study (vol 35, pg 1577, 2018)2018In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 20Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 32.
    Arriola, Edurne
    et al.
    Hosp del Mar, Spain.
    Jaal, Jana
    Univ Tartu, Estonia.
    Edvardsen, Anne
    Akershus Univ Hosp, Norway.
    Silvoniemi, Maria
    Turku Univ Hosp, Finland.
    Araujo, Antonio
    Ctr Hosp Univ Santo Antonio, Portugal; Univ Porto, Portugal.
    Vikström, Anders
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Zairi, Eleni
    St Lukes Hosp, Greece.
    Rodriguez-Mues, Mari Carmen
    Hosp Clin Barcelona, Spain.
    Roccato, Marco
    Kaiku Hlth, Finland.
    Schneider, Sophie
    F Hoffmann La Roche Ltd, Switzerland.
    Ammann, Johannes
    F Hoffmann La Roche Ltd, Switzerland; F Hoffmann La Roche Ltd, Switzerland.
    Feasibility and User Experience of Digital Patient Monitoring for Real-World Patients With Lung or Breast Cancer2024In: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 29, no 4, p. e561-e569Article in journal (Refereed)
    Abstract [en]

    Background Digital patient monitoring (DPM) tools can facilitate early symptom management for patients with cancer through systematic symptom reporting; however, low adherence can be a challenge. We assessed patient/healthcare professional (HCP) use of DPM in routine clinical practice.Materials and Methods Patients with locally advanced/metastatic lung cancer or HER2-positive breast cancer received locally approved/reimbursed drugs alongside DPM, with elements tailored by F. Hoffmann-La Roche Ltd, on the Kaiku Health DPM platform. Patient access to the DPM tool was through their own devices (eg, laptops, PCs, smartphones, or tablets), via either a browser or an app on Apple iOS or Android devices. Coprimary endpoints were patient DPM tool adoption (positive threshold: 60%) and week 1-6 adherence to weekly symptom reporting (positive threshold: 70%). Secondary endpoints included experience and clinical impact.Results At data cutoff (June 9, 2022), adoption was 85% and adherence was 76%. Customer satisfaction and effort scores for patients were 76% and 82%, respectively, and 83% and 79% for HCPs. Patients spent approximately 10 minutes using the DPM tool and completed approximately 1.0 symptom questionnaires per week (completion time 1-4 minutes). HCPs spent approximately 1-3 minutes a week using the tool per patient. Median time to HCP review for alerted versus non-alerted symptom questionnaires was 19.6 versus 21.5 hours. Most patients and HCPs felt that the DPM tool covered/mostly covered symptoms experienced (71% and 75%), was educational (65% and 92%), and improved patient-HCP conversations (70% and 83%) and cancer care (51% and 71%).Conclusion The DPM tool demonstrated positive adoption, adherence, and user experience for patients with lung/breast cancer, suggesting that DPM tools may benefit clinical cancer care. Digital patient monitoring tools can facilitate early symptom monitoring and management for cancer through systematic symptom reporting; however, low adherence can be a challenge. This study assessed patient and healthcare professional use of such tools in routine clinical practice.

  • 33.
    Askling, Johan
    et al.
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    van Vollenhoven, Ronald F
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Granath, Fredrik
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Raaschou, Pauline
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Fored, C Michael
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Baecklund, Eva
    Uppsala University Hospital, Uppsala, Sweden.
    Dackhammar, Christina
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Feltelius, Nils
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden, and Medical Products Agency, Uppsala, Sweden.
    Cöster, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Geborek, Pierre
    Lund University Hospital, Lund, Sweden.
    Jacobsson, Lennart T
    Malmö University Hospital, Malmö, Sweden.
    Lindblad, Staffan
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Norrland University Hospital, Umeå, Sweden.
    Saxne, Tore
    Lund University Hospital, Lund, Sweden.
    Klareskog, Lars
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Cancer Risk in Patients With Rheumatoid Arthritis Treated With Anti-Tumor Necrosis Factor alpha Therapies Does the Risk Change With the Time Since Start of Treatment?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 11, p. 3180-3189Article in journal (Refereed)
    Abstract [en]

    Objective. To determine the short-term and medium-term risks of cancer in patients receiving antitumor necrosis factor alpha (anti-TNF alpha) therapies that have proven effective in the treatment of chronic inflammatory conditions. Methods. By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received. Results. During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed. Conclusion. During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

  • 34.
    Asklund, Thomas
    et al.
    Department of Radiation Sciences and Oncology, Umeå University, Sweden .
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Bergqvist, Michael
    Department of Radiology, Oncology and Radiation Sciences, Uppsala University Hospital, Sweden; Department of Radiation Sciences, Umeå University, Sweden .
    Björ, Ove
    Department of Radiation Sciences and Oncology, Umeå University, Sweden .
    Henriksson, Roger
    Department of Radiation Sciences and Oncology, Umeå University, Sweden: Regional Cancer Centre Stockholm, Gotland, Sweden .
    Brain tumors in Sweden: Data from a population-based registry 1999-2012.2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArticle in journal (Refereed)
    Abstract [en]

    Background. The Swedish brain tumor registry has, since it was launched in 1999, provided significant amounts of data on histopathological diagnoses and on important aspects of surgical and medical management of these patients. The purpose is mainly quality control, but also as a resource for research. Methods. Three Swedish healthcare regions, constituting 40% of the Swedish population, have had an almost complete registration. The following parameters are registered: diagnosis according to SNOMED/WHO classification, symptoms, performance status, pre- and postoperative radiology, tumor size and localization, extent of surgery and occurrence of postoperative complications, postoperative treatment, such as radiotherapy and/or chemotherapy, other treatments, complications and toxicity, occurrence of reoperation/s, participation in clinical trials, multidisciplinary conferences and availability of a contact nurse. Results. Surgical radicality has been essentially constant, whereas the use of early (within 72 hours) postoperative CT and MRI has increased, especially for high-grade glioma, which is a reflection of quality of surgery. Survival of patients with high-grade glioma has increased, especially in the age group 60-69. Patients aged 18-39 years had a five-year survival of 40%. Waiting times for the pathological report has been slightly prolonged. Geographical differences do exist for some of the variables. Conclusion. Population-based registration is valuable for assessment of clinical management, which could have impact on patient care. As a result of short survival and/or the propensity to affect cognitive functions this patient group has considerable difficulties to make their voices heard in society. We therefore believe that a report like the present one can contribute to the spread of knowledge and increase the awareness for this patient group among caregivers and policy makers.

  • 35.
    Asowed, Mustafa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pettersson, Linn
    Ryhov Cty Hosp, Sweden.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Papantoniou, Dimitrios
    Ryhov Cty Hosp, Sweden; Uppsala Univ, Sweden.
    Activity and safety of KEES-an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer2023In: BMC Cancer, E-ISSN 1471-2407, Vol. 23, no 1, article id 309Article in journal (Refereed)
    Abstract [en]

    BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule.MethodsA retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed.ResultsOne hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1-15.0) and 4.4 (3.8-5.5) months, respectively. Biochemical response, defined as &gt;= 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) &gt;= 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities.ConclusionsKEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0-1 and lower baseline ALP, and had an acceptable toxicity profile.

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  • 36.
    Aughton, Karen
    et al.
    Univ Liverpool, England.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Univ Liverpool, England.
    Evans, Anthony
    Univ Liverpool, England.
    Jackson, Richard
    Univ Liverpool, England.
    Campbell, Fiona
    Univ Liverpool, England.
    Costello, Eithne
    Univ Liverpool, England.
    Halloran, Christopher M.
    Univ Liverpool, England.
    Mackey, John R.
    Univ Alberta, Canada.
    Scarfe, Andrew G.
    Univ Alberta, Canada.
    Valle, Juan W.
    Univ Manchester, England.
    Carter, Ross
    Glasgow Royal Infirm, Scotland.
    Cunningham, David
    Royal Marsden Natl Hlth Serv NHS Fdn Trust, England.
    Tebbutt, Niall C.
    Austin Hlth, Australia.
    Goldstein, David
    Univ New South Wales, Australia.
    Shannon, Jennifer
    Univ Sydney, Australia.
    Glimelius, Bengt
    Uppsala Univ, Sweden.
    Hackert, Thilo
    Heidelberg Univ, Germany.
    Charnley, Richard M.
    Freeman Rd Hosp, England.
    Anthoney, Alan
    St James Univ Hosp, England.
    Lerch, Markus M.
    Univ Med Greifswald, Germany.
    Mayerle, Julia
    Univ Med Greifswald, Germany; Klinikum LMU Munchen Grosshadern, Germany.
    Palmer, Daniel H.
    Univ Liverpool, England.
    Buechler, Markus W.
    Heidelberg Univ, Germany.
    Ghaneh, Paula
    Univ Liverpool, England.
    Neoptolemos, John P.
    Heidelberg Univ, Germany.
    Greenhalf, William
    Univ Liverpool, England.
    hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA2021In: Cancers, ISSN 2072-6694, Vol. 13, no 22, article id 5758Article in journal (Refereed)
    Abstract [en]

    Simple Summary: Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

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  • 37.
    Aus, Gunnar
    et al.
    Department of Urology, Sahlgrens University Hospital, 413 45, Göteborg, Sweden.
    Nordenskjöld, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Robinson, David
    Department of Surgery, Höglandssjukhuset, Eksjö, Sweden.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Varenhorst, Eberhard
    Department of Urology and Surgery, Vrinnevisjukhuset, Norrköping, Sweden.
    Prognostic Factors and Survival in Node-Positive (N1) Prostate Cancer: A Prospective Study Based on Data from a Swedish Population-Based Cohort2003In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 43, no 6, p. 627-631Article in journal (Refereed)
    Abstract [en]

    Objective: At presentation of prostate cancer, patients with proven lymph node metastasis (N1) are comparatively rare. It is difficult to give prognostic information based on the present literature. The aim of this study was to evaluate the impact of known risk factors in patients with pelvic node involvement and without distant metastasis.

    Methods: From the population-based, prospective prostate cancer tumour registry of the South–East Region in Sweden, we collected data on all 181 patients with N1, M0 prostate cancer diagnosed from January 1987 to October 2000 with a follow-up to December 2001. Mean follow-up was 62 months. Pre-operative risk factors as age, T-category, serum PSA, tumour grade and also primary treatment given was correlated to the outcome.

    Results: Median age at diagnosis was 65 years. Cancer-specific survival was highly variable with 5-year survival of 72%, a median of 8 years and the projected 13-year figure was 31%. T-category, age, PSA or treatment did not affect the outcome while poorly differentiated tumours had a tendency towards lower cancer-specific survival (p=0.0523) when compared to well and moderately differentiated tumours.

    Conclusions: This population-based cohort of prostate cancer patients with pelvic node involvement treated principally with non-curative intent had a median cancer-specific survival of 8 years. Preoperatively known risk factors seem to have but a modest impact on the prognosis for patients in this stage of the disease.

  • 38.
    Aus, Gunnar
    et al.
    Department of Urology, Sahlgrens University Hospital, Go¨ teborg, Sweden.
    Robinson, David
    Section of Urology, Ryhov County Hospital, Jönköping, Sweden.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Sandblom, Gabriel
    Department of Surgery, Akademiska Hospital, Uppsala, Sweden.
    Varenhorst, Eberhard
    Department of Surgery and Urology, Vrinnevi Hospital, Norrköping, Sweden..
    Survival in prostate carcinoma - Outcomes from a prospective, population-based cohort of 8887 men with up to 15 years of follow-up: Results from three counties in the population-based National Prostate Cancer Registry of Sweden2005In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 103, no 5, p. 943- 951Article in journal (Refereed)
    Abstract [en]

    BACKGROUND To decide on screening strategies and curative treatments for prostate carcinoma, it is necessary to determine the incidence and survival in a population that is not screened.

    METHODS The 15-year projected survival data were analyzed from a prospective, complete, population-based registry of 8887 patients with newly diagnosed prostate carcinoma from 1987 to 1999.

    RESULTS The median patient age at diagnosis was 75 years (range, 40-96 years), and 12% of patients were diagnosed before the age 65 years. The median follow-up was 80 months for patients who remained alive. In total, 5873 of 8887 patients (66.1%) had died, and 2595 of those patients (44.2%) died directly due to prostate carcinoma. The overall median age at death was 80 years (range, 41-100 years). The projected 15-year disease-specific survival rate was 44% for the whole population. In total, 18% of patients had metastases at diagnosis (M1), and their median survival was 2.5 years. Patients with nonmetastatic T1-T3 prostate carcinoma (age < 75 years at diagnosis; n = 2098 patients) had a 15-year projected disease-specific survival rate of 66%. Patients who underwent radical prostatectomy had a significantly lower risk of dying from prostate carcinoma (relative risk, 0.40) compared with patients who were treated with noncurative therapies or radiotherapy.

    CONCLUSIONS The disease-specific mortality was comparatively high, but it took 15 years to reach a disease-specific mortality rate of 56%. These data form a truly population-based baseline on how prostate carcinoma will affect a population when screening is not applied and can be used for comparison with other health care strategies. Cancer 2005. © 2005 American Cancer Society.

  • 39. Order onlineBuy this publication >>
    Ax, Anna-Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Exercise in patients with cancer: Effects on health-related quality of life, costs, and cost-effectiveness during oncological treatment2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Short and long-term side effects of oncological treatment negatively affect daily living and health-related quality of life (HRQoL) in patient with cancer. Exercise during treatment is beneficial for HRQoL, however evidence as to what exercise intensity is most optimal for improving HRQoL and cost-effectiveness is lacking. Cost-effectiveness is important information for decisionmakers when implementing healthcare interventions, such as exercise programmes. The overall aim of this thesis was to study functioning in daily life, HRQoL, costs, and cost-effectiveness of an exercise intervention of different exercise intensities in patients with cancer receiving oncological treatment. 

    Method: Study I was qualitative and explored how individuals with cancer receiving curative treatment and participating in an exercise intervention experienced their functioning in daily life. Semi-structured individual interviews (n =21) were performed and analysed with thematic analysis. Studies II–IV were quantitative and used data from a randomised controlled trial (RCT) of high-intensity (HI) and low-to-moderate-intensity (LMI) exercise of combined resistance and endurance training with or without self-regulatory behaviour change support. The RCT was preceded by a descriptive longitudinal study with usual care (UC). Participants were diagnosed with breast, prostate, or colon cancer and received (neo)adjuvant oncological treatment. Study II evaluated the effects on HRQoL of exercising at HI (n =288) and LMI (n =289) versus UC (n =89) up to 18 months after start of oncological treatment, using the EORTC QLQ-C30 questionnaire. Data were analysed using descriptive and multivariate statistics. Study III evaluated resource utilisation and societal costs of the exercise intervention in the RCT (n =534) versus UC (n =85), and of HI (n =269) versus LMI (n =265) exercise 18 months after start of oncological treatment. Societal costs included costs of healthcare resource utilisation (healthcare visits, hospitalisation, prescribed medication), productivity loss (disability pensions and sick leave), and the exercise intervention. Study IV evaluated the cost-effectiveness of the exercise intensities in the RCT (HI: n =99 and LMI: n =90) at 1-year follow-up post intervention. Cost data were retrieved from Study III and health outcome were collected using the EQ-5D-5L questionnaire and calculated for quality-adjusted life-years. Cost-effectiveness was evaluated as the incremental cost-effectiveness ratio (ICER). 

    Results: Participants experienced impairments from oncological treatment but strove to maintain function in daily life. The exercise programme improved physical and psychological wellbeing during treatment (Study I). There were no significant differences in HRQoL between exercise intensities up to 1 year after the exercise intervention. The exercise groups scored significant better HRQoL compared to UC over time (Study II). There was no significant difference in mean societal costs between the exercise intervention and UC, nor between the exercise intensities (Study III). There was no significant difference in cost or in effect between the exercise intensities. Although the mean ICER indicated that HI was cost-effective compared to LMI, the uncertainty was large (Study IV). 

    Conclusion: Participating in an exercise programme during oncological treatment was a positive and supportive experience that contributed to increase physical and psychological wellbeing. Exercise of HI and LMI during oncological treatment had similar effect on HRQoL and societal costs. In addition, the exercise group had beneficial effects on HRQoL and no significant difference in societal costs compared to UC, meaning the exercise programme did not save or add societal cost. Thus, based on cost-effectiveness we suggest decisionmakers and clinicians implement exercise programmes including both HI and LMI in cancer care and recommend exercise regardless of intensity according to the patient’s preferences to improve or to maintain aspects of HRQoL during oncological treatment. 

    List of papers
    1. Exercise: A positive feature on functioning in daily life during cancer treatment – Experiences from the Phys-Can study
    Open this publication in new window or tab >>Exercise: A positive feature on functioning in daily life during cancer treatment – Experiences from the Phys-Can study
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    2020 (English)In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Nursing, Vol. 44, article id 101713Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    Impaired functioning due to cancer treatment is a challenge for daily life. Exercise during treatment can improve functioning. However, research describing experiences of how exercise affects activities of daily life is limited. We aimed to explore how individuals with cancer receiving curative treatment and participating in an exercise intervention experienced their functioning in daily life.

    Methods

    Twenty-one participants were recruited from Phys-Can, an exercise intervention study. Semi-structured interviews were conducted after the intervention had finished, and data was analysed using thematic analysis.

    Results

    Two main themes evolved: “Striving to maintain a normal life in a new context” and “Struggling with impairments from side effects of cancer treatment”. The supervised group exercise proved popular, and participants reported positive effects on physical and psychological functioning, as well as social and informative support from other participants. Participants struggled with impaired cognitive and physical functioning and exhaustion. They strove to maintain a normal life by adjusting their activities.

    Conclusions

    Perceived physical and psychological benefits from exercise during cancer treatment suggest that exercise should be a part of cancer rehabilitation to facilitate activities and participation in daily life. Striving to maintain a normal life during cancer treatment is vital, and adjustments are needed to maintain activities and participation in daily life. Cancer nurses should motivate patients to engage in physical activity and encourage the introduction of exercise as part of their rehabilitation. They could also support patients in making adjustments to maintain functioning in daily life.

    Place, publisher, year, edition, pages
    Elsevier, 2020
    National Category
    Nursing
    Identifiers
    urn:nbn:se:liu:diva-162990 (URN)10.1016/j.ejon.2019.101713 (DOI)000523651500023 ()31877511 (PubMedID)
    Note

    Fulltext published under Creative Commons license CC BY-NC-ND 4.0

    https://creativecommons.org/licenses/by-nc-nd/4.0/

    Funding agencies: Department of Oncology, Linkoping University Hospital, Sweden; Region Ostergotland, Sweden; Swedish Cancer SocietySwedish Cancer Society; Swedish Research CouncilSwedish Research Council

    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2023-04-27Bibliographically approved
    2. Short- and long-term effect of high versus low-to-moderate intensity exercise to optimise health-related quality of life after oncological treatment - results from the Phys-Can project
    Open this publication in new window or tab >>Short- and long-term effect of high versus low-to-moderate intensity exercise to optimise health-related quality of life after oncological treatment - results from the Phys-Can project
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    2022 (English)In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 30, p. 5949-5963Article in journal (Refereed) Published
    Abstract [en]

    Purpose This study aimed to evaluate the effect of high intensity (HI) vs low-to-moderate intensity (LMI) exercise on health-related quality of life (HRQoL) up to 18 months after commencement of oncological treatment in patients with breast, colorectal or prostate cancer. In addition, we conducted a comparison with usual care (UC). Methods Patients scheduled for (neo)adjuvant oncological treatment (n = 577) were randomly assigned to 6 months of combined resistance and endurance training of HI or LMI. A longitudinal descriptive study (UC) included participants (n = 89) immediately before the RCT started. HRQoL was assessed by EORTC QLQ-C30 at baseline, 3, 6 and 18 months (1 year after completed exercise intervention) follow-up. Linear mixed models were used to study the groups over time. Results Directly after the intervention, HI scored significant (P = 0.02), but not clinically relevant, higher pain compared with LMI. No other significant difference in HRQoL was found between the exercise intensities over time. Clinically meaningful improvements in HRQoL over time were detected within both exercise intensities. We found favourable significant differences in HRQoL in both exercise intensities compared with UC over time. Conclusion This study adds to the strong evidence of positive effect of exercise and shows that exercise, regardless of intensity, can have beneficial effects on HRQoL during oncological treatment and also for a substantial time after completion of an exercise intervention. In this study, for one year after. Implications for cancer survivors Patients can be advised to exercise at either intensity level according to their personal preferences, and still benefit from both short-term and long-term improvements in HRQoL.

    Place, publisher, year, edition, pages
    Heidelberg, Germany: Springer, 2022
    Keywords
    Cancer; Oncological treatment; Exercise; HRQoL
    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:liu:diva-184562 (URN)10.1007/s00520-022-07016-3 (DOI)000779224400002 ()35391574 (PubMedID)2-s2.0-85127637021 (Scopus ID)
    Note

    Funding Agencies: Linköping University; Swedish Cancer Society; Swedish Research Council, European Commission; Region Östergötland, Sweden; Oncology Department Foundations Research Fund in Linköping, Sweden

    Available from: 2022-05-03 Created: 2022-05-03 Last updated: 2023-04-27Bibliographically approved
    3. Long-term resource utilisation and associated costs of exercise during (neo)adjuvant oncological treatment: the Phys-Can project
    Open this publication in new window or tab >>Long-term resource utilisation and associated costs of exercise during (neo)adjuvant oncological treatment: the Phys-Can project
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    2022 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, no 7, p. 888-896Article in journal (Refereed) Published
    Abstract [en]

    Background Exercise during oncological treatment is beneficial to patient health and can counteract the side effects of treatment. Knowledge of the societal costs associated with an exercise intervention, however, is limited. The aims of the present study were to evaluate the long-term resource utilisation and societal costs of an exercise intervention conducted during (neo)adjuvant oncological treatment in a randomised control trial (RCT) versus usual care (UC), and to compare high-intensity (HI) versus low-to-moderate intensity (LMI) exercise in the RCT. Methods We used data from the Physical Training and Cancer (Phys-Can) project. In the RCT, 577 participants were randomised to HI or to LMI of combined endurance and resistance training for 6 months, during oncological treatment. The project also included 89 participants with UC in a longitudinal observational study. We measured at baseline and after 18 months. Resource utilisation and costs of the exercise intervention, health care, and productivity loss were compared using analyses of covariance (RCT vs. UC) and t test (HI vs. LMI). Results Complete data were available for 619 participants (RCT HI: n = 269, LMI: n = 265, and UC: n = 85). We found no difference in total societal costs between the exercise intervention groups in the RCT and UC. However, participants in the RCT had lower rates of disability pension days (p < .001), corresponding costs (p = .001), and pharmacy costs (p = .018) than the UC group. Nor did we find differences in resource utilisation or costs between HI and LMI exercise int the RCT. Conclusion Our study showed no difference in total societal costs between the comprehensive exercise intervention and UC or between the exercise intensities. This suggests that exercise, with its well-documented health benefits during oncological treatment, produces neither additional costs nor savings.

    Place, publisher, year, edition, pages
    Taylor & Francis Ltd, 2022
    Keywords
    Cancer; exercise; health care costs; sick leave; costs; cost analysis
    National Category
    Health Care Service and Management, Health Policy and Services and Health Economy
    Identifiers
    urn:nbn:se:liu:diva-185605 (URN)10.1080/0284186X.2022.2075238 (DOI)000799825800001 ()35607981 (PubMedID)
    Note

    Funding Agencies|Swedish Cancer Society; Swedish Research Council; Region Ostergotland, Sweden

    Available from: 2022-06-09 Created: 2022-06-09 Last updated: 2023-05-04Bibliographically approved
    4. Cost-effectiveness of different exercise intensities during oncological treatment in the Phys-Can RCT
    Open this publication in new window or tab >>Cost-effectiveness of different exercise intensities during oncological treatment in the Phys-Can RCT
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    2023 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 62, no 4, p. 414-421Article in journal (Refereed) Published
    Abstract [en]

    Background

    Cost-effectiveness is important in the prioritisation between interventions in health care. Exercise is cost-effective compared to usual care during oncological treatment; however, the significance of exercise intensity to the cost-effectiveness is unclear. In the present study, we aimed to evaluate the long-term cost-effectiveness of the randomised controlled trial Phys-Can, a six-month exercise programme of high (HI) or low-to-moderate intensity (LMI) during (neo)adjuvant oncological treatment.

    Methods

    A cost-effectiveness analysis was performed, based on 189 participants with breast, colorectal, or prostate cancer (HI: n = 99 and LMI: n = 90) from the Phys-Can RCT in Sweden. Costs were estimated from a societal perspective, and included cost of the exercise intervention, health care utilisation and productivity loss. Health outcomes were assessed as quality-adjusted life-years (QALYs), using EQ-5D-5L at baseline, post intervention and 12 months after the completion of the intervention.

    Results

    At 12-month follow-up after the intervention, the total cost per participant did not differ significantly between HI (€27,314) and LMI exercise (€29,788). There was no significant difference in health outcome between the intensity groups. On average HI generated 1.190 QALYs and LMI 1.185 QALYs. The mean incremental cost-effectiveness ratio indicated that HI was cost effective compared with LMI, but the uncertainty was large.

    Conclusions

    We conclude that HI and LMI exercise have similar costs and effects during oncological treatment. Hence, based on cost-effectiveness, we suggest that decision makers and clinicians can consider implementing both HI and LMI exercise programmes and recommend either intensity to the patients with cancer during oncological treatment to facilitate improvement of health.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2023
    Keywords
    Cancer, exercise, health, cost-effectiveness
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-193277 (URN)10.1080/0284186X.2023.2200149 (DOI)000971022300001 ()37074759 (PubMedID)
    Note

    Funding agencies: This work was supported by grants from the Swedish Cancer Society; the Swedish Research Council, and the Region Östergötland, Sweden.

    Available from: 2023-04-27 Created: 2023-04-27 Last updated: 2024-05-02Bibliographically approved
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  • 40.
    Ax, Anna-Karin
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Husberg, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Johansson, Birgitta
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Demmelmaier, Ingrid
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Department of Sport Science and Physical Education, University of Agder, Kristiansand, Norway.
    Berntsen, Sveinung
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Department of Sport Science and Physical Education, University of Agder, Kristiansand, Norway.
    Sjövall, Katarina
    Faculty of Health Sciences, Kristianstad University, Kristianstad, Sweden.
    Börjeson, Sussanne
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences.
    Nordin, Karin
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Davidson, Thomas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Cost-effectiveness of different exercise intensities during oncological treatment in the Phys-Can RCT2023In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 62, no 4, p. 414-421Article in journal (Refereed)
    Abstract [en]

    Background

    Cost-effectiveness is important in the prioritisation between interventions in health care. Exercise is cost-effective compared to usual care during oncological treatment; however, the significance of exercise intensity to the cost-effectiveness is unclear. In the present study, we aimed to evaluate the long-term cost-effectiveness of the randomised controlled trial Phys-Can, a six-month exercise programme of high (HI) or low-to-moderate intensity (LMI) during (neo)adjuvant oncological treatment.

    Methods

    A cost-effectiveness analysis was performed, based on 189 participants with breast, colorectal, or prostate cancer (HI: n = 99 and LMI: n = 90) from the Phys-Can RCT in Sweden. Costs were estimated from a societal perspective, and included cost of the exercise intervention, health care utilisation and productivity loss. Health outcomes were assessed as quality-adjusted life-years (QALYs), using EQ-5D-5L at baseline, post intervention and 12 months after the completion of the intervention.

    Results

    At 12-month follow-up after the intervention, the total cost per participant did not differ significantly between HI (€27,314) and LMI exercise (€29,788). There was no significant difference in health outcome between the intensity groups. On average HI generated 1.190 QALYs and LMI 1.185 QALYs. The mean incremental cost-effectiveness ratio indicated that HI was cost effective compared with LMI, but the uncertainty was large.

    Conclusions

    We conclude that HI and LMI exercise have similar costs and effects during oncological treatment. Hence, based on cost-effectiveness, we suggest that decision makers and clinicians can consider implementing both HI and LMI exercise programmes and recommend either intensity to the patients with cancer during oncological treatment to facilitate improvement of health.

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    fulltext
  • 41.
    Bady, Pierre
    et al.
    Swiss Inst Bioinformat SIB, Switzerland; Lausanne Univ Hop, Switzerland; Univ Lausanne, Switzerland.
    Marosi, Christine
    Univ Vienna, Austria.
    Weller, Michael
    Univ Hosp, Switzerland; Univ Zurich, Switzerland.
    Gronberg, Bjorn H.
    Norwegian Univ Sci & Technol, Norway; St Olays Hosp, Norway.
    Schultz, Henrik
    Aarhus Univ Hosp, Denmark.
    Taphoorn, Martin J. B.
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Gijtenbeek, Johanna M. M.
    Radboud Univ Nijmegen, Netherlands.
    van den Bent, Martin J.
    Erasmus MC, Netherlands.
    von Deimling, Andreas
    Heidelberg Univ, Germany; German Canc Ctr DKFZ, Germany.
    Stupp, Roger
    Northwestern Med, IL USA; Northwestern Med, IL USA; Northwestern Univ, IL 60611 USA.
    Malmström, Annika
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Närvårdskliniken.
    Hegi, Monika E.
    Lausanne Univ Hop, Switzerland; Univ Lausanne, Switzerland; Univ Lausanne UNIL, Switzerland; Swiss Canc Ctr Leman SCCL, Switzerland.
    DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients2022In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 10, no 1, article id 39Article in journal (Refereed)
    Abstract [en]

    Elderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. We aimed at identifying age-related molecular differences that would justify and guide distinct treatment decisions in elderly glioblastoma patients. The combined DNA methylome (450 k) of four IDH wild-type glioblastoma datasets, comprising two clinical trial cohorts, was interrogated for differences based on the patients age, DNA methylation (DNAm) age acceleration (DNAm age "Horvath-clock" minus patient age), DNA methylation-based tumor classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes. Age dependent methylation included 19 CpGs (p-value &lt;= 0.1, Bonferroni corrected), comprising a CpG located in the ELOVL2 gene that is part of a 13-gene forensic age predictor. Most of the age related CpGs (n = 16) were also associated with age acceleration that itself was associated with a large number of CpGs (n = 50,551). Over 70% age acceleration-associated CpGs (n = 36,348) overlapped with those associated with the DNA methylation based tumor classification (n = 170,759). Gene set enrichment analysis identified associated pathways, providing insights into the biology of DNAm age acceleration and respective commonalities with glioblastoma classification. Functional methylation of several DDR genes, defined as correlation of methylation with gene expression (r &lt;= -0.3), was associated with age acceleration (n = 8), tumor classification (n = 12), or both (n = 4), the latter including MGMT. DNAm age acceleration was significantly associated with better outcome in both clinical trial cohorts, whereof one comprised only elderly patients. Multivariate analysis included treatment (RT, RT/TMZ -&gt; TMZ; TMZ, RT), MGMT promoter methylation status, and interaction with treatment. In conclusion, DNA methylation features of age acceleration are an integrative part of the methylation-based tumor classification (RTK I, RTK II, MES), while patient age seems hardly reflected in the glioblastoma DNA methylome. We found no molecular evidence justifying other treatments in elderly patients, not owing to frailty or co-morbidities.

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  • 42.
    Bagge, Ebba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Beiron, Ulrica
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Malander, Susanne
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Rosenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pattern of endocrine treatment for epithelial ovarian cancer in the Southeast medical region of Sweden: a population-based study2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 3, p. 320-325Article in journal (Refereed)
    Abstract [en]

    Aim of the study: Endocrine treatment (ET) is an alternative as salvage therapy in epithelial ovarian cancer (EOC) but the usage in routine care is unknown. We evaluated the treatment patterns and outcome of patients receiving ET for EOC in the Southeast medical region in Sweden.Method: Patients were identified through the population-based Southeast Quality Registry for gynaecological cancer. Inclusion criteria were: age 18 years, histologically verified EOC diagnosed 2000-2013, ET for 4 weeks. Coverage compared with the Swedish National Cancer Registry was 100%. Data extracted from medical records was collected by means of a study-specific Case Report Form. Last date of follow-up was February 1st, 2018. All statistics were descriptive.Results: Altogether 248 (18%) of 1414 patients were treated with ET. Most (49%) had received only one, and 34% two previous lines of chemotherapy. Time from last chemotherapy to ET was 4 months, range 0-55months. The reason for initiating ET was tumor progression (66%), chemotherapy related toxicity (29%) and maintenance (4%). Tamoxifen was prescribed in 94% of cases. Best response was partial (amp;lt; 5%) and stable disease (50%). No patient had a complete response. 194 (78%) patients received subsequent chemotherapy, of these 27% had 3-7 lines of chemotherapy. Duration of ET was a median 4 months (range 1-80 months). Median time from ET to subsequent chemotherapy was 5 months (range 0-79). The median overall survival was 45 months (range 9-173).Conclusion: In the Southeast region of Sweden, endocrine treatment for EOC was prescribed inconsistently and in various settings, usually initiated by a rising CA-125 level. Poorer documentation and irregular tumor response assessment were observed for endocrine treatment compared to chemotherapy.

  • 43.
    Bajbouj, Khuloud
    et al.
    Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.
    Shafarin, Jasmin
    Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.
    Allam, Hilda
    Department of Medical Laboratory Sciences, College of Health Sciences.
    Madkour, Mohamed
    Department of Medical Laboratory Sciences, College of Health Sciences.
    Awadallah, Samir
    Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE; Department of Medical Laboratory Sciences, College of Health Sciences.
    El-Serafi, Ahmed Taher
    Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE; College of Medicine, University of Sharjah, Sharjah, UAE.
    Sandeep, Divyasree
    Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.
    Hamad, Mawieh
    Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE; Department of Medical Laboratory Sciences, College of Health Sciences.
    Elevated Levels of Estrogen Suppress Hepcidin Synthesis and Enhance Serum Iron Availability in Premenopausal Women2018In: Experimental and clinical endocrinology & diabetes, ISSN 0947-7349, E-ISSN 1439-3646, Vol. 126, no 07, p. 453-459Article in journal (Refereed)
    Abstract [en]

    Clinical and experimental observations have long suggested that elevated levels of estrogen associate with increased serum iron availability. Additionally, recent work has shown that estrogen can downregulate hepcidin synthesis in vitro. This study aims at assessing whether the ability of estrogen to downregulate hepcidin synthesis translates into changes in serum iron status. Hepcidin synthesis was evaluated in MCF-7, Hep-G2 and SKOV-3 cells treated with increasing concentrations of estrogen and cultured for up to 24 h post treatment. The correlation between levels of serum estrogen, hepcidin and iron was assessed using serum samples collected from 153 premenopausal women at random and samples collected from 6 women at days 1, 5, 10, 16, 21 and 28 of the monthly cycle. Estrogen-treated MCF-7 cells showed a significant reduction in hepcidin synthesis, especially at 20 nM/24 h E2 treatment. Hepcidin synthesis was also significantly reduced in Hep-G2 and SKOV-3 cells at 20 nM/24 h E2 treatment. In serum samples collected at random, estrogen (P=0.022; R=-0.213) and iron (P=0.028; R=-0.316) correlated negatively with hepcidin and positively with each other (P=0.033; R=0.319). An overall similar pattern was also observed in monthly cycle-timed samples. These findings suggest that elevated levels of estrogen reduce hepcidin synthesis as means of enhancing serum iron content in menstruating women.

  • 44. Order onlineBuy this publication >>
    Balian, Alien
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Nuclease Activity as a Biomarker in Cancer Detection2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Nucleases are a group of enzymes that cleave the phosphodiester bonds in nucleic acids. As such, nucleases act as biological scissors that exhibit a plethora of fundamental roles, in prokaryotes and eukaryotes, dependent or non-dependent on their catalytic capability. Thus, differential status of nucleases between healthy and disease conditions might not be surprising, and can be deployed in disease detection. Specifically, there is growing body of research demonstrating the potential of nucleases as diagnostic biomarkers in several types of cancer. Biomarkers for early diagnosis are an immense need in the diagnostic landscape of cancer. In this sense, nucleases are promising biomolecules, and they possess a unique feature of catalytic activity that could be deployed for diagnosis and future therapeutic strategies.    

    In this thesis we aim to demonstrate the use of nucleases as biomarkers associated to cancer, and the capability of oligonucleotide substrates for targeting a specific nuclease.  

    The thesis work begins with comprehensive review of nucleases as promising biomarkers in cancer diagnosis (paper I). Then, we provide a methodological study in paper II, in which we propose a flexible approach for detection of disease associated nuclease activity using oligonucleotides as substrates. The probes utilized here are flanked with fluorophore at the 5’-end and a quencher at the 3’-end. Upon cleavage by nucleases, the fluorescent signal is increased in a proportional fashion to nuclease activity. This platform is suitable to implement in detection of any disease in which nuclease activity is altered.   

    We have applied this method in paper III, by using 75 probes as substrates to screen breast cancer cells, along with controls, for nuclease activity. We have identified a probe (DNA PolyAT) that discriminates between BT-474 breast cancer cells and healthy cells based on nuclease activity profile associated with cell membrane. Next, we screened tissue samples from breast tumors for nuclease activity, and we have identified a set of probes with the capability to discriminate breast tumor and healthy tissues in 89% of the cases (paper IV). To achieve a step forward towards non-invasive diagnosis, we have developed an activatable magnetic resonance imaging (MRI)-probe (paper V). The MRI-probe is oligonucleotide-based that works like a contrast agent, and it is activated only in presence of a specific nuclease. MRI-probes provide advantages over fluorescent probes, such as high spatial resolution and unlimited tissue penetration. 

    In conclusion, our findings suggest the utility of nuclease activity as a biomarker in cancer detection. Moreover, we demonstrate the applicability of nuclease activity-based approaches in imaging modalities, such as MRI. Our future aim is to translate our findings into non-invasive detection of breast cancer by utilizing breast cancer activatable MRI-probes. 

    List of papers
    1. Nucleases as molecular targets for cancer diagnosis
    Open this publication in new window or tab >>Nucleases as molecular targets for cancer diagnosis
    2021 (English)In: Biomarker Research, E-ISSN 2050-7771, Vol. 9, no 1, article id 86Article, review/survey (Refereed) Published
    Abstract [en]

    Early cancer diagnosis is a crucial element to improved treatment options and survival. Great research efforts have been made in the search for better performing cancer diagnostic biomarkers. However, the quest continues as novel biomarkers with high accuracy for an early diagnosis remain an unmet clinical need. Nucleases, which are enzymes capable of cleaving nucleic acids, have been long considered as potential cancer biomarkers. The implications of nucleases are key for biological functions, their presence in different cellular counterparts and catalytic activity led the enthusiasm towards investigating the role of nucleases as promising cancer biomarkers. However, the most essential feature of these proteins, which is their enzymatic activity, has not been fully exploited. This review discusses nucleases interrogated as cancer biomarkers, providing a glimpse of their physiological roles. Moreover, it highlights the potential of harnessing the enzymatic activity of cancer-associated nucleases as a novel diagnostic biomarker using nucleic acid probes as substrates.

    Place, publisher, year, edition, pages
    BMC, 2021
    Keywords
    Nuclease; Nuclease activity; cancer biomarkers; cancer diagnostics; Nucleic acid probes; novel diagnostics
    National Category
    Bioengineering Equipment
    Identifiers
    urn:nbn:se:liu:diva-181677 (URN)10.1186/s40364-021-00342-4 (DOI)000721961300001 ()34809722 (PubMedID)
    Note

    Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009-00971]; Linkoping University

    Available from: 2021-12-07 Created: 2021-12-07 Last updated: 2023-02-17
    2. Kinetic Screening of Nuclease Activity using Nucleic Acid Probes
    Open this publication in new window or tab >>Kinetic Screening of Nuclease Activity using Nucleic Acid Probes
    Show others...
    2019 (English)In: Journal of Visualized Experiments, E-ISSN 1940-087X, no 153, article id e60005Article in journal (Refereed) Published
    Abstract [en]

    Nucleases are a class of enzymes that break down nucleic acids by catalyzing the hydrolysis of the phosphodiester bonds that link the ribose sugars. Nucleases display a variety of vital physiological roles in prokaryotic and eukaryotic organisms, ranging from maintaining genome stability to providing protection against pathogens. Altered nuclease activity has been associated with several pathological conditions including bacterial infections and cancer. To this end, nuclease activity has shown great potential to be exploited as a specific biomarker. However, a robust and reproducible screening method based on this activity remains highly desirable. Herein, we introduce a method that enables screening for nuclease activity using nucleic acid probes as substrates, with the scope of differentiating between pathological and healthy conditions. This method offers the possibility of designing new probe libraries, with increasing specificity, in an iterative manner. Thus, multiple rounds of screening are necessary to refine the probes design with enhanced features, taking advantage of the availability of chemically modified nucleic acids. The considerable potential of the proposed technology lies in its flexibility, high reproducibility, and versatility for the screening of nuclease activity associated with disease conditions. It is expected that this technology will allow the development of promising diagnostic tools with a great potential in the clinic.

    Place, publisher, year, edition, pages
    United States: JOURNAL OF VISUALIZED EXPERIMENTS, 2019
    Keywords
    Biochemistry; Issue 153; Screening method; nucleases; biomarkers; nucleic acids; probes; nuclease activity; diagnostic tool; substrate
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-162891 (URN)10.3791/60005 (DOI)000500362600024 ()31736483 (PubMedID)2-s2.0-85075114874 (Scopus ID)
    Note

    Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University [2009-00971]

    Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2024-01-17Bibliographically approved
    3. Discovery and Proof-of-Concept Study of Nuclease Activity as a Novel Biomarker for Breast Cancer Tumors
    Open this publication in new window or tab >>Discovery and Proof-of-Concept Study of Nuclease Activity as a Novel Biomarker for Breast Cancer Tumors
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    2021 (English)In: Cancers, ISSN 2072-6694, Vol. 13, no 2, article id 276Article in journal (Refereed) Published
    Abstract [en]

    Simple Summary A diagnostic biomarker for the detection of breast cancer remains an unmet clinical need despite decades of intensive research efforts. Herein, we describe, for the first time, the use of nuclease activity as a biomarker to discriminate between healthy and cancer biopsy samples. We have identified a panel of three nucleic acid probes able to target nucleases derived from breast cancer tumors with high sensitivity and specificity. These results are in good agreement with histopathological analysis as the diagnostic gold standard. Moreover, these findings support nuclease activity as a potential adjacent diagnostic tool and shed light on the use of nuclease activity as a detection biomarker in breast cancer. Breast cancer is one of the most common pathologies diagnosed in the clinical practice. Despite major advancements in diagnostic approaches, there is no widely accepted biomarker in the clinical practice that can diagnose breast malignancy. Confirmatory diagnosis still relies on the pathological assessment of tissue biopsies by expert pathologists. Thus, there is an unmet need for new types of biomarkers and novel platform technologies that can be easily and robustly integrated into the clinic and that can assist pathologists. Herein, we show that nuclease activity associated to malignant tumors can be used as a novel biomarker in breast cancer, which can be detected via specific degradation of nucleic acid probes. In this study we have identified a set of three chemically modified nucleic acid probes that can diagnose malignancy in biopsy samples with high accuracy (89%), sensitivity (82%) and specificity (94%). This work represents a breakthrough for the potential clinical use of nuclease activity as biomarker, which can be detected via nucleic acids probes, for the clinical diagnosis of malignancy in breast tissue biopsies. This platform technology could be readily implemented into the clinic as adjunct to histopathological diagnostic.

    Place, publisher, year, edition, pages
    MDPI, 2021
    Keywords
    breast cancer; nucleic acid probes; cancer diagnostics; nuclease activity; biomarkers
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-173418 (URN)10.3390/cancers13020276 (DOI)000611111100001 ()33451046 (PubMedID)
    Note

    Funding Agencies|Wallenberg Centre for Molecular Medicine (WCMM) Linkoping, Sweden; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009-00971]; program Torres Quevedo (MINECO); industrial doctorate program (MINECO)

    Available from: 2021-02-20 Created: 2021-02-20 Last updated: 2022-12-30
    4. Activatable MRI probes for the specific detection of bacteria
    Open this publication in new window or tab >>Activatable MRI probes for the specific detection of bacteria
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    2021 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 413, no 30, p. 7353-7362Article in journal (Refereed) Published
    Abstract [en]

    Activatable fluorescent probes have been successfully used as molecular tools for biomedical research in the last decades. Fluorescent probes allow the detection of molecular events, providing an extraordinary platform for protein and cellular research. Nevertheless, most of the fluorescent probes reported are susceptible to interferences from endogenous fluorescence (background signal) and limited tissue penetration is expected. These drawbacks prevent the use of fluorescent tracers in the clinical setting. To overcome the limitation of fluorescent probes, we and others have developed activatable magnetic resonance probes. Herein, we report for the first time, an oligonucleotide-based probe with the capability to detect bacteria using magnetic resonance imaging (MRI). The activatable MRI probe consists of a specific oligonucleotide that targets micrococcal nuclease (MN), a nuclease derived from Staphylococcus aureus. The oligonucleotide is flanked by a superparamagnetic iron oxide nanoparticle (SPION) at one end, and by a dendron functionalized with several gadolinium complexes as enhancers, at the other end. Therefore, only upon recognition of the MRI probe by the specific bacteria is the probe activated and the MRI signal can be detected. This approach may be widely applied to detect bacterial infections or other human conditions with the potential to be translated into the clinic as an activatable contrast agent.

    Place, publisher, year, edition, pages
    Springer Heidelberg, 2021
    Keywords
    MRI; Bacteria; Nucleic acid probes; Detection system; Nucleases; Activatable MRI contrast agents
    National Category
    Other Medical Engineering
    Identifiers
    urn:nbn:se:liu:diva-180905 (URN)10.1007/s00216-021-03710-z (DOI)000711292000001 ()34704109 (PubMedID)
    Note

    Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009-00971]

    Available from: 2021-11-09 Created: 2021-11-09 Last updated: 2022-12-30
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  • 45.
    Balkenhol, Maschenka C. A.
    et al.
    Radboud Univ Nijmegen, Netherlands.
    Ciompi, Francesco
    Radboud Univ Nijmegen, Netherlands.
    Swiderska-Chadaj, Zaneta
    Radboud Univ Nijmegen, Netherlands; Warsaw Univ Technol, Poland.
    van de Loo, Rob
    Radboud Univ Nijmegen, Netherlands.
    Intezar, Milad
    Radboud Univ Nijmegen, Netherlands.
    Otte-Holler, Irene
    Radboud Univ Nijmegen, Netherlands.
    Geijs, Daan
    Radboud Univ Nijmegen, Netherlands.
    Lotz, Johannes
    Fraunhofer Inst Image Comp MEVIS, Germany.
    Weiss, Nick
    Fraunhofer Inst Image Comp MEVIS, Germany.
    de Bel, Thomas
    Radboud Univ Nijmegen, Netherlands.
    Litjens, Geert
    Radboud Univ Nijmegen, Netherlands.
    Bult, Peter
    Radboud Univ Nijmegen, Netherlands.
    van der Laak, Jeroen
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Radboud Univ Nijmegen, Netherlands.
    Optimized tumour infiltrating lymphocyte assessment for triple negative breast cancer prognostics2021In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 56, p. 78-87Article in journal (Refereed)
    Abstract [en]

    The tumour microenvironment has been shown to be a valuable source of prognostic information for different cancer types. This holds in particular for triple negative breast cancer (TNBC), a breast cancer subtype for which currently no prognostic biomarkers are established. Although different methods to assess tumour infiltrating lymphocytes (TILs) have been published, it remains unclear which method (marker, region) yields the most optimal prognostic information. In addition, to date, no objective TILs assessment methods are available. For this proof of concept study, a subset of our previously described TNBC cohort (n = 94) was stained for CD3, CD8 and FOXP3 using multiplex immunohistochemistry and subsequently imaged by a multispectral imaging system. Advanced whole-slide image analysis algorithms, including convolutional neural networks (CNN) were used to register unmixed multispectral images and corresponding H&E sections, to segment the different tissue compartments (tumour, stroma) and to detect all individual positive lymphocytes. Densities of positive lymphocytes were analysed in different regions within the tumour and its neighbouring environment and correlated to relapse free survival (RFS) and overall survival (OS). We found that for all TILs markers the presence of a high density of positive cells correlated with an improved survival. None of the TILs markers was superior to the others. The results of TILs assessment in the various regions did not show marked differences between each other. The negative correlation between TILs and survival in our cohort are in line with previous studies. Our results provide directions for optimizing TILs assessment methodology. (C) 2021 The Author(s). Published by Elsevier Ltd.

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  • 46.
    Balkenhol, Maschenka C. A.
    et al.
    Radboud Univ Nijmegen, Netherlands.
    Tellez, David
    Radboud Univ Nijmegen, Netherlands.
    Vreuls, Willem
    Canisius Wilhelmina Hosp, Netherlands.
    Clahsen, Pieter C.
    Haaglanden Med Ctr, Netherlands.
    Pinckaers, Hans
    Radboud Univ Nijmegen, Netherlands.
    Ciompi, Francesco
    Radboud Univ Nijmegen, Netherlands.
    Bult, Peter
    Radboud Univ Nijmegen, Netherlands.
    van der Laak, Jeroen
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Radboud Univ Nijmegen, Netherlands.
    Deep learning assisted mitotic counting for breast cancer2019In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 99, no 11, p. 1596-1606Article in journal (Refereed)
    Abstract [en]

    As part of routine histological grading, for every invasive breast cancer the mitotic count is assessed by counting mitoses in the (visually selected) region with the highest proliferative activity. Because this procedure is prone to subjectivity, the present study compares visual mitotic counting with deep learning based automated mitotic counting and fully automated hotspot selection. Two cohorts were used in this study. Cohort A comprised 90 prospectively included tumors which were selected based on the mitotic frequency scores given during routine glass slide diagnostics. This pathologist additionally assessed the mitotic count in these tumors in whole slide images (WSI) within a preselected hotspot. A second observer performed the same procedures on this cohort. The preselected hotspot was generated by a convolutional neural network (CNN) trained to detect all mitotic figures in digitized hematoxylin and eosin (Hamp;E) sections. The second cohort comprised a multicenter, retrospective TNBC cohort (n = 298), of which the mitotic count was assessed by three independent observers on glass slides. The same CNN was applied on this cohort and the absolute number of mitotic figures in the hotspot was compared to the averaged mitotic count of the observers. Baseline interobserver agreement for glass slide assessment in cohort A was good (kappa 0.689; 95% CI 0.580-0.799). Using the CNN generated hotspot in WSI, the agreement score increased to 0.814 (95% CI 0.719-0.909). Automated counting by the CNN in comparison with observers counting in the predefined hotspot region yielded an average kappa of 0.724. We conclude that manual mitotic counting is not affected by assessment modality (glass slides, WSI) and that counting mitotic figures in WSI is feasible. Using a predefined hotspot area considerably improves reproducibility. Also, fully automated assessment of mitotic score appears to be feasible without introducing additional bias or variability.

  • 47.
    Balkenhol, Maschenka C. A.
    et al.
    Radboud Univ Nijmegen, Netherlands.
    Vreuls, Willem
    Canisius Wilhelmina Hosp, Netherlands.
    Wauters, Carla A. P.
    Canisius Wilhelmina Hosp, Netherlands.
    Mol, Suzanne J. J.
    Jeroen Bosch Hosp, Netherlands.
    van der Laak, Jeroen
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Radboud Univ Nijmegen, Netherlands.
    Bult, Peter
    Radboud Univ Nijmegen, Netherlands.
    Histological subtypes in triple negative breast cancer are associated with specific information on survival2020In: Annals of Diagnostic Pathology, ISSN 1092-9134, E-ISSN 1532-8198, Vol. 46, article id 151490Article in journal (Refereed)
    Abstract [en]

    Much research has focused on finding novel prognostic biomarkers for triple negative breast cancer (TNBC), whereas only scattered information about the relation between histopathological features and survival in TNBC is available. This study aims to explore the prognostic value of histological subtypes in TNBC. A multicenter retrospective TNBC cohort was established from five Dutch hospitals. All non-neoadjuvantly treated, stage I-III patients with estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 negative breast cancer diagnosed between 2006 and 2014 were included. Clinical and follow-up data (overall survival; OS, relapse free survival; RFS) were retrieved and a central histopathological review was performed. Of 597 patients included (median follow up 62.8 months, median age at diagnosis 56.0 years), 19.4% developed a recurrence. The most prevalent histological subtypes were carcinoma of no special type (NST) (88.4%), metaplastic carcinoma (4.4%) and lobular carcinoma (3.4%). Collectively, tumors of special type were associated with a worse RFS and OS compared to carcinoma NST (RFS HR 1.89; 95% CI 1.18-3.03; p = 0.008; OS HR 1.94; 95% CI 1.28-2.92; p = 0.002). Substantial differences in survival, however, were present between the different histological subtypes. In the presented TNBC cohort, special histological subtype was in general associated with less favorable survival. However, within the group of tumors of special type there were differences in survival between the different subtypes. Accurate histological examination can provide specific prognostic information that may potentially enable more personalized treatment and surveillance regimes for TNBC patients.

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  • 48.
    Balla, Hajnal Zsuzsanna
    et al.
    Orebro Univ, Sweden.
    Cao, Yang
    Orebro Univ, Sweden; Karolinska Inst, Sweden.
    Ström, Jakob O.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Orebro Univ, Sweden.
    Effect of Beta-Blockers on Stroke Outcome: A Meta-Analysis2021In: Clinical Epidemiology, E-ISSN 1179-1349, Vol. 13, p. 225-236Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Cardiovascular events and infections are common in the acute phase after stroke. It has been suggested that these complications may be associated with excessive sympathetic activation due to the stroke, and that beta-adrenergic antagonists (beta-blockers) therefore may be beneficial. Aim: The aim of the current meta-analysis was to investigate the association between beta-blocker treatment in acute stroke and the three outcomes: mortality, functional outcome and post-stroke infections. Methods: A literature search was performed using the keywords stroke, cerebrovascular disorders, adrenergic beta-antagonists, treatment outcome and mortality. Randomized clinical trials and observational studies were eligible for data extraction. Heterogeneity was investigated using I-2 statistics. Random effect model was used when heterogeneity presented among studies; otherwise, a fixed-effect model was used. Publication bias was assessed using Eggers test and by visually inspecting funnel plots. Results: A total of 20 studies were eligible for at least one of the three outcomes. Two of the included studies were randomized controlled trials and 18 were observational studies. Quality assessments indicated that the risk of bias was moderate. The meta-analysis found no significant association between treatment with beta-blockers and any of the three outcomes. The studies analyzed for the outcomes mortality and infection were heterogeneous, while studies analyzed for functional outcome were homogeneous. The articles analyzed for mortality showed signs of publication bias. Conclusion: The lack of significant effects in the current meta-analysis, comprising more than 100,000 patients, does not support the proposed beneficial effects of beta-blockers in the acute phase of stroke.

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  • 49.
    Banerjee, Antara
    et al.
    Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE) and Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu, India.
    Chabria, Yashna
    Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE) and Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu, India.
    Kanna N. R., Rajesh
    Department of Pathology, Faculty of Medicine, Chettinad Academy of Research & Education, Kelambakkam, Tamil Nadu, India.
    Gopi, Janani
    Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE) and Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu, India.
    Rowlo, Praveen
    Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE) and Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu, India.
    Sun, Xiao-Feng
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine.
    Pathak, Surajit
    Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE) and Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu, India.
    Role of Tumor Specific niche in Colon Cancer Progression and Emerging Therapies by Targeting Tumor Microenvironment2021In: Cell Biology and Translational Medicine, Volume 13: Stem Cells in Development and Disease / [ed] Kursad Turksen, Springer, 2021, 1, p. 177-192Chapter in book (Refereed)
    Abstract [en]

    Colorectal cancer is the third most common form of cancer worldwide leading to escalating mortality rates and mainly includes hereditary, sporadic and colitis-associated cancer development. The escalated mortality rates is due to the limited treatment options as this form of cancer is usually not easy to diagnose in its early stages and are highly invasive leading to rapid metastasis of the malignant cells to the neighbouring tissue. In order to combat this limitation several chemotherapeutic regimens are now being combined with targeted therapies after the knowledge acquired on the inevitable effects of the tumor microenvironment on the colon cancer growth and progress. The colon tumor niche mainly consists of a large mass of tumor cells along with various immune cells, inflammatory cells, tumor macrophages and fibroblasts that infiltrate the tumor as it is a site of predominant inflammation. Among cells of the microenvironment, mesenchymal stem cells (MSCs) exhibiting ability to evolve into cancer associated fibroblasts (CAFs) have recently generated a major interest in the field. The physiological state of the tumor microenvironment is closely connected to discrete steps of tumorigenesis. The colon cancer cells elicit various factors with their direct interaction with MSCs or via paracrine fashion, which modulate these cells to promote cancer instead of performing their innate function of abating cancer progression. This review intends to highlight the necessity to exploit the cellular landscape of tumor microenvironment of colon cancer and a detailed understanding of the interactions between tumor epithelial cells and their stromal/inflammatory elements will aid in future perspectives for designing therapeutic regimens targeting tumor microenvironment to improve the clinical outcome of colon cancer.

  • 50.
    Banerjee, Antara
    et al.
    Chettinad Hosp & Res Inst CHRI, India.
    Deka, Dikshita
    Chettinad Hosp & Res Inst CHRI, India.
    Muralikumar, Makalakshmi
    Chettinad Hosp & Res Inst CHRI, India.
    Sun-Zhang, Alexander
    Karolinska Inst, Sweden.
    Bisgin, Atil
    Cukurova Technopolis, Turkey; Cukurova Univ, Turkey.
    Christopher, Cynthia
    Chettinad Hosp & Res Inst CHRI, India.
    Zhang, Hong
    Orebro Univ, Sweden.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pathak, Surajit
    Chettinad Hosp & Res Inst CHRI, India.
    A concise review on miRNAs as regulators of colon cancer stem cells and associated signalling pathways2023In: Clinical and Translational Oncology, ISSN 1699-048X, E-ISSN 1699-3055, Vol. 25, p. 3345-3356Article, review/survey (Refereed)
    Abstract [en]

    Despite recent therapy advances and a better understanding of colon cancer biology, it remains one of the major causes of death. The cancer stem cells, associated with the progression, metastasis, and recurrence of colon cancer, play a major role in promoting the development of tumour and are found to be chemo resistant. The stroma of the tumour, which makes up the bulk of the tumour mass, is composed of the tumour microenvironment. With the advent of theranostic and the development of personalised medicine, miRNAs are becoming increasingly important in the context of colon malignancies. A holistic understanding of the regulatory roles of miRNAs in cancer cells and cancer stem cells will allow us to design effective strategies to regulate miRNAs, which could lead to improved clinical translation and creating a potent colon cancer treatment strategy. In this review paper, we briefly discuss the history of miRNA as well as the mechanisms of miRNA and cancer stem cells that contribute to the tumour growth, apoptosis, and advancement of colon cancer. The usefulness of miRNA in colorectal cancer theranostic is further concisely reviewed. We conclude by holding a stance in addressing the prospects and possibilities for miRNA by the disclosure of recent theranostic approaches aimed at eradicating cancer stem cells and enhancing overall cancer treatment outcomes.

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