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  • 1.
    Abrahamsson, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Capodanno, Alessandra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rzepecka, Anna
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 54, s. 92134-92142Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Abrahamsson, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rzepecka, Anna
    Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Increased nutrient availability in dense breast tissue of postmenopausal women in vivo2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 42733Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Abrahamsson, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rzepecka, Anna
    Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Romu, Thobias
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Borga, Magnus
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dahlqvist Leinhard, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Lundberg, Peter
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Kihlberg, Johan
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo2016Ingår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, nr 10, artikel-id e1229723Artikel i tidskrift (Refereegranskat)
    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.
    Abtahi, Jahan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Käkkliniken US.
    Ajan, Aida
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Käkkliniken US.
    Malignant Transformation of Ossifying Fibroma into Parosteal Osteosarcoma with High-grade Component: Presentation of an Unusual Case and Review of the Literature2018Ingår i: The Open Dentistry Journal, E-ISSN 1874-2106, Vol. 12, s. 1059-1068Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Alickovic, Emina
    et al.
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Subasi, Abdulhamit
    Effat Univ, Saudi Arabia.
    Normalized Neural Networks for Breast Cancer Classification2020Ingår i: PROCEEDINGS OF THE INTERNATIONAL CONFERENCE ON MEDICAL AND BIOLOGICAL ENGINEERING, CMBEBIH 2019, SPRINGER , 2020, Vol. 73, s. 519-524Konferensbidrag (Refereegranskat)
    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.

  • 6.
    Aljabery, Firas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.
    Öppna denna publikation i ny flik eller fönster >>PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.
    Visa övriga...
    2015 (Engelska)Ingår i: BMC urology, ISSN 1471-2490, Vol. 15, nr 1, s. 87-Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Urologi och njurmedicin Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-120796 (URN)10.1186/s12894-015-0080-z (DOI)000359832000001 ()26294219 (PubMedID)
    Tillgänglig från: 2015-08-25 Skapad: 2015-08-25 Senast uppdaterad: 2017-05-17
    2. Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.
    Öppna denna publikation i ny flik eller fönster >>Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.
    Visa övriga...
    2017 (Engelska)Ingår i: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 120, nr 3, s. 329-336Artikel i tidskrift (Refereegranskat) 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.

    Ort, förlag, år, upplaga, sidor
    Wiley-Blackwell Publishing Inc., 2017
    Nyckelord
    #BladderCancer, #blcsm, cystectomy, lymph node metastasis, prognostic factors, sentinel node
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:liu:diva-136947 (URN)10.1111/bju.13700 (DOI)000407781500011 ()27797436 (PubMedID)
    Anmärkning

    Funding agencies: County Council of Ostergotland, Linkoping, Sweden

    Tillgänglig från: 2017-05-01 Skapad: 2017-05-01 Senast uppdaterad: 2018-05-03
  • 7.
    Aljabery, Firas
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Lindblom, Gunnar
    Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Skoog, Susann
    Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Shabo, Ivan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Jahnson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.2015Ingår i: BMC urology, ISSN 1471-2490, Vol. 15, nr 1, s. 87-Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    Aljabery, Firas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Gimm, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Jahnson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Shabo, Ivan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer2018Ingår i: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, nr 4, artikel-id 159.e19Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Aljabery, Firas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Shabo, Ivan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gimm, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Jahnson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    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 cancer2018Ingår i: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, nr 12, s. 530.e7-530.e18, artikel-id 530.e7Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    Andersson, Bengt-Åke
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Department of Laboratory Medicine, Region Jönköping County.
    Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Huvud- och halscancer (HH-cancer) innefattar tumörer belägna i huvud och halsområdet. Tobaksrökning ökar risken dramatiskt för olika sjukdomar. Knappt hälften av rökande patienter dör i de av rökning orsakade sjukdomarna. Cancer är orsaken till en tredjedel av de rökrelaterade dödsfallen av vilka HH-cancer är en. En andel av patienterna med HH-cancer dör på grund av att tumören varit för stor redan vid diagnos eller att tumören har spridit sig till övriga delar av kroppen. Men för många patienter är det mycket oklart vad som bestämmer behandlingsresultatet. Tumörerna är till synes lika och behandlingen standardiserad.

    Målet med denna doktorsavhandling var att undersöka billiga och lättillgängliga biologiska markörer som kan indikera risk för att drabbas av HH-cancer eller om dessa markörer kan förutspå behandlingsresultat och överlevnad hos de drabbade patienterna. Dessutom undersöktes hur cigarettrökning påverkade nivåerna av markörerna.

    I studie I, undersöktes om molekyler i blodet (biomarkörer), förknippade med immunförsvaret, kunde förutsäga överlevnaden hos HH-cancerpatienter. I jämförelse med friska individer sågs högre nivåer av molekylerna TNF-α och CRP hos patienterna och dessa förhöjningar var relaterade till förkortad överlevnad hos patienterna.

    I studie II, var målet att undersöka om variationer i gener, förknippade med immunförsvaret, celldelning, celldöd eller enzymer som reparerar skadat DNA, kunde påverka risk och prognos för HH-cancer. Resultatet visade framför allt att små ärftliga variationer i gener som reglerar immunförsvaret kunde påverkade risk för HH-cancer, risk för återfall i sjukdomen samt överlevnaden hos patienterna.

    I studie III, jämfördes inflammatoriska och immunförknippade biomarkörer som kunde påverkas av cigarettrökning mellan friska rökare och friska icke-rökare. Rökarna hade en högre inflammatorisk aktivitet med högre nivåer av totalt antal vita blodkroppar och tre av dess olika undergrupper (neutrofiler, monocyter och lymfocyter) samt av biomarköerna CRP, MCP-1 och IFN-γ. De funna lägre nivåerna av den cancerförknippade biomarkören miR-21 och högre nivåer av den förmodat skyddande biomarkören IFN-γ hos rökarna, kan vara ett uttryck för kroppens försvar mot den cancerframkallade cigarettröken. Ärftliga faktorer tycks kunna påverka de högre nivåerna av IFN-γ hos rökarna, eftersom ökningen endast fanns i en grupp individer med viss typ av genetisk uppsättning.

    Eftersom både rökning och HH-cancer ger upphov till inflammation, undersöktes i studie IV hur dessa var för sig påverkade nivåerna av inflammatoriska biomarkörer. Detta för en bättre förståelse hur immunförsvaret reagerar på rökning och HH-cancer. Jämförelser av inflammatoriska markörer från rökande och icke-rökande patienter, och rökande och ickerökande friska individer genomfördes. Rökning hade störst påverkan på de högre nivåerna av totalt antal vita blodkroppar och signalmolekylerna MCP-1 och IFN-γ. HH-cancer hade störst påverkan på högre nivåerna av neutrofiler, monocyter, kvoten mellan neutrofiler och lymfocyter, CRP, MIP-1b och TNF-α.

    Uppkomsten av HH-cancer, behandlingsresultat och överlevnad bland patienterna kan antas inte bara bero på tumörens egenskaper, utan även på värdfaktorer hos patienten. Dessa kan vara ärftliga, eller bero på reglering av gener eller tumörens omgivning av t.ex. immunceller och inflammatoriska molekyler och hur dessa samverkar med miljöfaktorer som tobaksrökning. I denna avhandling presenteras biomarkörer som kan bidra med information om risk och prognos för HH-cancer samt hur tobaksrökning påverkar dessa markörer.

    Delarbeten
    1. Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma.
    Öppna denna publikation i ny flik eller fönster >>Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma.
    Visa övriga...
    2014 (Engelska)Ingår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 140, nr 3, s. 515-519Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Head and neck squamous cell carcinoma, Biomarkers, Survival, CRP, TNF-α
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-162092 (URN)10.1007/s00432-014-1592-8 (DOI)24481866 (PubMedID)
    Tillgänglig från: 2019-11-19 Skapad: 2019-11-19 Senast uppdaterad: 2019-11-19Bibliografiskt granskad
    2. Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients
    Öppna denna publikation i ny flik eller fönster >>Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients
    Visa övriga...
    2017 (Engelska)Ingår i: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 92, nr 3, s. 161-169Artikel i tidskrift (Refereegranskat) 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

    Ort, förlag, år, upplaga, sidor
    KARGER, 2017
    Nyckelord
    Head and neck cancer; Tumor recurrence; Survival time; Single-nucleotide polymorphisms
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-136217 (URN)10.1159/000452278 (DOI)000395366800005 ()27997918 (PubMedID)
    Anmärkning

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

    Tillgänglig från: 2017-03-31 Skapad: 2017-03-31 Senast uppdaterad: 2019-11-19
    3. Cigarette smoking affects microRNAs and inflammatory biomarkers in healthy individuals and an association to single nucleotide polymorphisms is indicated
    Öppna denna publikation i ny flik eller fönster >>Cigarette smoking affects microRNAs and inflammatory biomarkers in healthy individuals and an association to single nucleotide polymorphisms is indicated
    Visa övriga...
    2019 (Engelska)Ingår i: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 24, nr 2, s. 180-185Artikel i tidskrift (Refereegranskat) 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.

    Ort, förlag, år, upplaga, sidor
    TAYLOR & FRANCIS LTD, 2019
    Nyckelord
    Immune respons; single nucleotide polymorphism; microRNA; smoking related diseases; cigarette smoking
    Nationell ämneskategori
    Reumatologi och inflammation
    Identifikatorer
    urn:nbn:se:liu:diva-157272 (URN)10.1080/1354750X.2018.1539764 (DOI)000465158700011 ()30375257 (PubMedID)
    Anmärkning

    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]

    Tillgänglig från: 2019-06-12 Skapad: 2019-06-12 Senast uppdaterad: 2019-11-19
    4. Impact of Cigarette Smoking and Head and Neck Squamous Cell Carcinoma on Circulating Inflammatory Biomarkers
    Öppna denna publikation i ny flik eller fönster >>Impact of Cigarette Smoking and Head and Neck Squamous Cell Carcinoma on Circulating Inflammatory Biomarkers
    Visa övriga...
    2019 (Engelska)Ingår i: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, s. 1-6Artikel i tidskrift (Refereegranskat) Epub ahead of print
    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.

    Nyckelord
    Biomarkers, Head and neck squamous cell carcinoma, Immune response, Inflammation, Smoking
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-162093 (URN)10.1159/000502651 (DOI)31437849 (PubMedID)
    Tillgänglig från: 2019-11-19 Skapad: 2019-11-19 Senast uppdaterad: 2019-11-19Bibliografiskt granskad
  • 11.
    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.2014Ingår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 140, nr 3, s. 515-519Artikel i tidskrift (Refereegranskat)
    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.

  • 12.
    Andersson, Bengt-Åke
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa. Department of Laboratory Medicine, Region Jönköping County.
    Löfgren, Sture
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Department of Laboratory Medicine, Region Jönköping County.
    Lewin, Freddi
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Department of Oncology, Region Jönköping County.
    Nilsson, Mats
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Futurum, Academy for Health and Care, Jönköping.
    Laytragoon-Lewin, Nongnit
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Department of Laboratory Medicine, Region Jönköping County.
    Impact of Cigarette Smoking and Head and Neck Squamous Cell Carcinoma on Circulating Inflammatory Biomarkers2019Ingår i: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, s. 1-6Artikel i tidskrift (Refereegranskat)
    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.

  • 13.
    Andersson, Patiyan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Molecular Genetic Studies on Prostate and Penile Cancer2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
    Öppna denna publikation i ny flik eller fönster >>Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
    2006 (Engelska)Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, nr 16, s. 2833-2837Artikel i tidskrift (Refereegranskat) 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.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2006
    Nyckelord
    Androgen receptor; Vitamin D receptor; Prostate cancer; CAG repeat
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15097 (URN)10.1016/j.ejca.2006.06.030 (DOI)
    Tillgänglig från: 2008-10-15 Skapad: 2008-10-15 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    2. Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
    Öppna denna publikation i ny flik eller fönster >>Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
    2008 (Engelska)Ingår i: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    IRS1, G972R, INS, Insulin, prostate cancer
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15098 (URN)
    Tillgänglig från: 2008-10-15 Skapad: 2008-10-15 Senast uppdaterad: 2017-12-11
    3. PIK3CA, HRAS and KRAS gene mutations in human penile cancer
    Öppna denna publikation i ny flik eller fönster >>PIK3CA, HRAS and KRAS gene mutations in human penile cancer
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, nr 5, s. 2030-2034 Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Penis, penile neoplasms, mutation, 1-phosphatidylinositol 3-kinase, carcinoma, squamous cell
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15099 (URN)10.1016/j.juro.2007.12.040 (DOI)
    Anmärkning
    On the day of the defence date the status of article III was: In Press.Tillgänglig från: 2008-10-15 Skapad: 2008-10-15 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    4. Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
    Öppna denna publikation i ny flik eller fönster >>Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
    Visa övriga...
    (Engelska)Manuskript (Övrigt vetenskapligt)
    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.

    Nyckelord
    SNP array, penile cancer, PIK3CA, Myc, TERT, FHIT
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15100 (URN)
    Tillgänglig från: 2008-10-15 Skapad: 2008-10-15 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
  • 14.
    Andersson, Patiyan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Mats G.
    Departments of b Pathology, Örebro University Hospital, Örebro, Sweden.
    PIK3CA, HRAS and KRAS gene mutations in human penile cancer2008Ingår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, nr 5, s. 2030-2034 Artikel i tidskrift (Refereegranskat)
    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.

  • 15.
    Andersson, Patiyan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologiska patologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Mats G
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arraysManuskript (Övrigt vetenskapligt)
    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.

  • 16.
    Andersson, Patiyan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk2008Ingår i: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Artikel i tidskrift (Refereegranskat)
    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.

  • 17.
    Andersson, Patiyan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk2006Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, nr 16, s. 2833-2837Artikel i tidskrift (Refereegranskat)
    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.

  • 18.
    Ansell, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Farnebo, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head & Neck Surgery, and Medical Biochemistry, University of Turku, Finland.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer2009Ingår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, nr 1, s. 23-29Artikel i tidskrift (Refereegranskat)
    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.

  • 19.
    Ansell, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Jedlinski, Adam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Roberg, Karin
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap.
    Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells2016Ingår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 45, nr 1, s. 9-16Artikel i tidskrift (Refereegranskat)
    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.

  • 20.
    Ansell, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland
    VTT Technical Research Centre of Finland.
    Grénman, Reidar
    VTT Technical Research Centre of Finland.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.2009Ingår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, nr 10, s. 866-871Artikel i tidskrift (Refereegranskat)
    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.

  • 21.
    Antonovic, Laura
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet.
    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 tumours2015Ingår i: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 56, nr 4, s. 639-645Artikel i tidskrift (Refereegranskat)
    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.

  • 22.
    Antonovic, Laura
    et al.
    Stockholm University, Sweden.
    Lindblom, Emely
    Stockholm University, Sweden.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    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 changes2014Ingår i: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, nr 5, s. 902-911Artikel i tidskrift (Refereegranskat)
    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.

  • 23.
    Ardenfors, Oscar
    et al.
    Stockholm University, Stockholm, Sweden.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. 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 MCNP62017Ingår i: INTERNATIONAL NUCLEAR SCIENCE AND TECHNOLOGY CONFERENCE 2016, Institute of Physics (IOP), 2017, Vol. 860, artikel-id 012025Konferensbidrag (Refereegranskat)
    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.

  • 24.
    Ardenfors, Oscar
    et al.
    Stockholm University, Sweden.
    Gudowska, Irena
    Stockholm University, Sweden.
    Flejmer, Anna M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Impact of irradiation setup in proton spot scanning brain therapy on organ doses from secondary radiation2018Ingår i: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, nr 1-4, s. 261-266Artikel i tidskrift (Refereegranskat)
    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.

  • 25.
    Ardenfors, Oscar
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Stockholm University.
    Josefsson, Dan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Are IMRT treatments in the head and neck region increasing the risk of secondary cancers?2014Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 8, s. 1041-1047Artikel i tidskrift (Refereegranskat)
    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.

  • 26.
    Armuand, Gabriela
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Bladh, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Sydsjö, Gunilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i 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)2018Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, nr 20Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 27.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i 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?2009Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, nr 11, s. 3180-3189Artikel i tidskrift (Refereegranskat)
    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.

  • 28.
    Asklund, Thomas
    et al.
    Department of Radiation Sciences and Oncology, Umeå University, Sweden .
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, LAH 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 1999-2012.2014Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArtikel i tidskrift (Refereegranskat)
    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.

  • 29.
    Aus, Gunnar
    et al.
    Department of Urology, Sahlgrens University Hospital, 413 45, Göteborg, Sweden.
    Nordenskjöld, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Robinson, David
    Department of Surgery, Höglandssjukhuset, Eksjö, Sweden.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    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 Cohort2003Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 43, nr 6, s. 627-631Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    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 Sweden2005Ingår i: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 103, nr 5, s. 943- 951Artikel i tidskrift (Refereegranskat)
    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.

  • 31.
    Bagge, Ebba
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Beiron, Ulrica
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Malander, Susanne
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Åvall Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Pattern of endocrine treatment for epithelial ovarian cancer in the Southeast medical region of Sweden: a population-based study2019Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, nr 3, s. 320-325Artikel i tidskrift (Refereegranskat)
    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.

  • 32.
    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
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Radboud Univ Nijmegen, Netherlands.
    Deep learning assisted mitotic counting for breast cancer2019Ingår i: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 99, nr 11, s. 1596-1606Artikel i tidskrift (Refereegranskat)
    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.

  • 33.
    Banerjee, Debarshi
    et al.
    Columbia University Medical Center, USA.
    Cieslar-Pobuda, Artur
    University of Oslo, Norway.
    Zhu, Geyunjian Harry
    University of Cambridge, UK.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Patra, Hirak
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Chemical Engineering and Biotechnology, University of Cambridge, UK; Wolfson College, University of Cambridge, UK.
    Adding nanotechnology to the metastasis treatment arsenal2019Ingår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 40, nr 6, s. 403-418Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Metastasis is a major cause of cancer-related mortality, accounting for 90% of cancer deaths. The explosive growth of cancer biology research has revealed new mechanistic network information and pathways that promote metastasis. Consequently, a large number of antitumor agents have been developed and tested for their antimetastatic efficacy. Despite their exciting cytotoxic effects on tumor cells in vitro and antitumor activities in preclinical studies in vivo, only a few have shown potent antimetastatic activities in clinical trials. In this review, we provide a brief overview of current antimetastatic strategies that show clinical efficacy and review nanotechnology-based approaches that are currently being incorporated into these therapies to mitigate challenges associated with treating cancer metastasis.

    Publikationen är tillgänglig i fulltext från 2020-05-07 12:06
  • 34.
    Barczyk, K.
    et al.
    Department of Immunology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland; Institute of Experimental Dermatology, University of Münster, Münster, Germany.
    Kreuter, M.
    Department of Medicine/Hematology and Oncology, University of Münster, Münster, Germany.
    Pryjma, J.
    Department of Immunology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland.
    Booy, Evan P.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Ghavami, Saeid
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Berdel, W. E.
    Department of Medicine/Hematology and Oncology, University of Münster, Münster, Germany.
    Roth, J.
    Institute of Experimental Dermatology, University of Münster, Münster, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Münster, Münster, Germany Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Serum cytochrome c indicates in vivo apoptosis and can serve as a prognostic marker during cancer therapy2005Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 116, nr 2, s. 167-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite significant progress in cancer therapy, the outcome of the treatment is often unfavorable. Better treatment monitoring would not only allow an individual more effective, patient-adjusted therapy, but also it would eliminate some of the side effects. Using a cytochrome c ELISA that was modified to increase sensitivity, we demonstrate that serum cytochrome c is a sensitive apoptotic marker in vivo reflecting therapy-induced cell death burden. Furthermore, increased serum cytochrome c level is a negative prognostic marker. Cancer patients whose serum cytochrome c level was normal 3 years ago have a twice as high probability to be still alive, as judged from sera samples collected for years, analyzed recently and matched with survival data. Moreover, we show that serum cytochrome c and serum LDH-activity reflect different stages and different forms of cell death. Cellular cytochrome c release is specific for apoptosis, whereas increased LDH activity is an indicator of (secondary) necrosis. Whereas serum LDH activity reflects the "global" degree of cell death over a period of time, the sensitive cytochrome c-based method allows confirmation of the individual cancer therapy-induced and spontaneous cell death events. The combination of cytochrome c with tissue-specific markers may provide the foundation for precise monitoring of apoptosis in vivo, by "lab-on-the-chip" technology. (c) 2005 Wiley-Liss, Inc.

  • 35.
    Barlesi, Fabrice
    et al.
    Hop Marseille, AP HP, Marseille, France.
    Scherpereel, Arnaud
    Univ Lille, Ctr Hosp Reg, Hop A Calmette, Lille, France.
    Rittmeyer, Achim
    Lungenfachklin Immenhausen, Immenhausen, Germany.
    Pazzola, Antonio
    Osped Civile Santissima, Sassari, Italy.
    Ferrer Tur, Neus
    Hosp Son Llatzer, Palma De Mallorca, Spain.
    Kim, Joo-Hang
    Yonsei Univ, Coll Med, Seoul 120749, South Korea.
    Ahn, Myung-Ju
    Sungkyunkwan Univ, Sch Med, Seoul, South Korea.
    Aerts, Joachim G J V
    Amphia Hosp, Breda, Netherlands.
    Gorbunova, Vera
    NN Blokhin Canc Res Ctr Russia, Moscow, Russia.
    Vikström, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US.
    Wong, Elaine K
    F Hoffmann Roche, Basel, Switzerland.
    Perez-Moreno, Pablo
    F Hoffmann Roche, Basel, Switzerland.
    Mitchell, Lada
    F Hoffmann Roche, Basel, Switzerland.
    Groen, Harry J M
    Univ Med Ctr Groningen, Groningen, Netherlands.
    Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089).2013Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 31, nr 24, s. 3004-3011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment.

    PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m(2), and pemetrexed 500 mg/m(2) once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment.

    RESULTS: In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed.

    CONCLUSION: In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.

  • 36.
    Bartoszek, Krzysztof
    et al.
    Gdansk University of Technology.
    Izydorek, Bartosz
    Gdansk University of Technology.
    Ratajczak, Tadeusz
    Gdansk University of Technology, Poland.
    Skokowski, Jaroslaw
    Medical University of Gdansk, Poland.
    Szwaracki, Karol
    Gdansk University of Technology, Poland.
    Tomczak, Wiktor
    Gdansk University of Technology, Poland.
    Neural Network Breast Cancer Relapse Time Prognosis2006Ingår i: ASO Summer School 2006 abstract book Ostrzyce 30.06-2.07. 2006 / [ed] J. Skokowski and K. Drucis, 2006, s. 8-10Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    This paper is a result of a project at the Faculty of Electronics, Telecommunication and Computer Science (Technical University of Gdansk). The aim of the project was to create a neural network to predict the relapsetime of breast cancer. The neural network was to be trained on data collected over the past 20 years by dr. Jarosław Skokowski. The data includes 439 patient records described by about 40 parameters. For our neuralnetwork we only considered 6 medically most significant parameters the number of nodes showing evidence of cancer, size of tumour (in mm.), age, bloom score, estrogen receptors and proestrogen receptors and the relapsetime as the outcome. Our neural network was created in the MATLAB environment.

  • 37.
    Bartoszek, Krzysztof
    et al.
    Mathematical Sciences, Chalmers University of Technology and the University of Gothenburg.
    Krzeminski, Michal
    Gdansk University of Technology.
    Skokowski, Jaroslaw
    Medical University of Gdansk.
    Survival time prognosis under a Markov model of cancer development2010Ingår i: Proceedings of the XVI National Conference Applications of Mathematics to Biology and Medicine, Krynica, Poland, September 14–18, 2010 / [ed] M. Ziółko, M. Bodnar and E. Kutafina, 2010, s. 6-11Konferensbidrag (Refereegranskat)
    Abstract [en]

    In this study we look at a breast cancer data set of women from the Pomerania region collected in the year 1987- 1992 in the Medical University of Gdansk.We analyze the clinical risk factors in conjunction with a Markov model of cancer development. We evaluate Artificial Neural Network (ANN) survival time prediction (which was done on this data set in a previous study) via a simulation study.

  • 38. Baust, H.
    et al.
    Schiessl, I.
    Mueller, B.
    Roedel, F.
    Distel, L.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Thomas, S.
    Rolf, S.
    Implications for the role of PKD2 in the radiotherapy of tumours2006Ingår i: Strahlentherapie und Onkologie (Print), ISSN 0179-7158, E-ISSN 1439-099X, Vol. 182, s. 81-81Artikel i tidskrift (Refereegranskat)
  • 39.
    Baust, H.
    et al.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Schoke, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Brey, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Gern, U.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, D-48149 Muenster, Germany.
    Schmid, R. M.
    2nd Department of Internal Medicine, University of Munich, D-81675 Munich, Germany.
    Röttinger, E. M.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Seufferlein, T.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappa B independent mechanisms2003Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, nr 54, s. 8786-8796Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radio-sensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.

  • 40.
    Belka, C.
    et al.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Marini, P.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Lepple-Wienhues, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Budach, W.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Jekle, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Los, Marek Jan
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Lang, F.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Schulze-Osthoff, K.
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Gulbins, E.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Bamberg, M.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation1999Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 18, nr 35, s. 4983-4992Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. The radiation induced cleavage pattern of procaspase-8 into mature caspase-8 resembled that following CD95 crosslinking and resulted in cleavage of the proapoptotic substrate BID. Overexpression of dominant-negative caspase-8 interfered with radiation-induced apoptosis, Caspase-8 activation by ionizing radiation was not observed in cells genetically defective for the Src-like tyrosine kinase Lck, Cells lacking Lck also displayed a marked resistance towards apoptosis induction upon ionizing radiation. After retransfection of Lck, caspase-8 activation and the capability to undergo apoptosis in response to ionizing radiation was restored. We conclude that radiation activates caspase-8 via an Lck-controlled pathway independently of CD95 ligand expression, This is a novel signaling event required for radiation induced apoptosis in T lymphoma cells.

  • 41.
    Bengtsson, Daniel
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Kalmar County Hospital, Sweden.
    Joost, Patrick
    Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik. Off Medical Serv, Sweden; Lund University, Sweden.
    Backman, Ann-Sofie
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    von Salome, Jenny
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Zagoras, Theofanis
    Sahlgrens University Hospital, Sweden.
    Gebre-Medhin, Samuel
    Lund University, Sweden; Karolinska University Hospital, Sweden.
    Burman, Pia
    Lund University, Sweden.
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 11, s. 3928-3932Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 42.
    Bennati, Paolo
    et al.
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Dasu, Alexandru
    The Skandion Clinic, Uppsala, Sweden.
    Colarieti-Tosti, Massimiliano
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Lönn, Gustaf
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Larsson, David
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Fabbri, Andrea
    INFN, National Institute for Nuclear Physics, Rome, Italy.
    Galasso, Matteo
    INFN, National Institute for Nuclear Physics, Rome, Italy.
    Cinti, Maria Nerina
    Sapienza University, Rome, Italy.
    Pellegrini, Rosanna
    Sapienza University, Rome, Italy.
    Pani, Roberto
    Sapienza University, Rome, Italy.
    Preliminary study of a new gamma imager for on-line proton range monitoring during proton radiotherapy2017Ingår i: Journal of Instrumentation, ISSN 1748-0221, E-ISSN 1748-0221, Vol. 12, nr 5, artikel-id C05009Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We designed and tested new concept imaging devices, based on a thin scintillating crystal, aimed at the online monitoring of the range of protons in tissue during proton radiotherapy. The proposed crystal can guarantee better spatial resolution and lower sensitivity with respect to a thicker one, at the cost of a coarser energy resolution. Two different samples of thin crystals were coupled to a position sensitive photo multiplier tube read out by 64 independent channels electronics. The detector was equipped with a knife-edge Lead collimator that defined a reasonable field of view of about 10 cm in the target. Geant4 Monte Carlo simulations were used to optimize the design of the experimental setup and assess the accuracy of the results. Experimental measurements were carried out at the Skandion Clinic, the recently opened proton beam facility in Uppsala, Sweden. PMMA and water phantoms studies were performed with a first prototype based on a round 6.0 mm thick Cry019 crystal and with a second detector based on a thinner 5 × 5 cm2, 2.0 mm thick LFS crystal. Phantoms were irradiated with mono-energetic proton beams whose energy was in the range between 110 and 160 MeV. According with the simulations and the experimental data, the detector based on LFS crystal seems able to identify the peak of prompt-gamma radiation and its results are in fair agreement with the expected shift of the proton range as a function of energy. The count rate remains one of the most critical limitations of our system, which was able to cope with only about 20% of the clinical dose rate. Nevertheless, we are confident that our study might provide the basis for developing a new full-functional system.

  • 43.
    Berntsen, Sveinung
    et al.
    Uppsala University, Sweden; University of Agder, Norway.
    Aaronson, Neil K.
    Netherlands Cancer Institute, Netherlands.
    Buffart, Laurien
    Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Demmelmaier, Ingrid
    Uppsala University, Sweden.
    Hellbom, Maria
    Lund University, Sweden.
    Hojman, Pernille
    Copenhagen University Hospital, Denmark.
    Igelstrom, Helena
    Uppsala University, Sweden.
    Johansson, Birgitta
    Uppsala University, Sweden.
    Pingel, Ronnie
    Uppsala University, Sweden.
    Raastad, Truls
    Norwegian School Sport Science, Norway.
    Velikova, Galina
    University of Leeds, England.
    Asenlof, Pernilla
    Uppsala University, Sweden.
    Nordin, Karin
    Uppsala University, Sweden; University of Agder, Norway.
    Design of a randomized controlled trial of physical training and cancer ( Phys-Can) the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome2017Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, artikel-id 218Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. Methods/design: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 x 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. Discussion: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated.

  • 44.
    Beskow, C
    et al.
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden..
    Kanter, L
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Holgersson, A
    Unit of Medical Radiation Biology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, B
    Department of Oncology and Pathology, Karolinska University Hospital, Stockholm, Sweden..
    Frankendal, B
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden..
    Åvall-Lundqvist, Elisabeth
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden..
    Lewensohn, R
    Unit of Medical Radiation Biology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB-IIA of cervical cancer.2006Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, nr 11, s. 1683-1689Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB-IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P=0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT.

  • 45.
    Bill-Axelson, Anna
    et al.
    University of Uppsala Hospital, Sweden .
    Holmberg, Lars
    University of Uppsala Hospital, Sweden Kings Coll London, England .
    Garmo, Hans
    University of Uppsala Hospital, Sweden Kings Coll London, England .
    Rider, Jennifer R.
    Brigham and Womens Hospital, MA USA Harvard University, MA USA Harvard University, MA 02115 USA .
    Taari, Kimmo
    University of Helsinki, Finland .
    Busch, Christer
    University of Uppsala Hospital, Sweden .
    Nordling, Stig
    University of Helsinki, Finland .
    Haggman, Michael
    University of Uppsala Hospital, Sweden .
    Andersson, Swen-Olof
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Spångberg, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Andren, Ove
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Palmgren, Juni
    Karolinska Institute, Sweden .
    Steineck, Gunnar
    Karolinska Institute, Sweden Sahlgrens Acad, Sweden .
    Adami, Hans-Olov
    Karolinska Institute, Sweden Harvard University, MA 02115 USA .
    Johansson, Jan-Erik
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer2014Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, nr 10, s. 932-942Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundRadical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain. MethodsBetween 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy. ResultsDuring 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04). ConclusionsExtended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.) The randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer diagnosed before the era of prostate-specific antigen (PSA) testing, showed a survival benefit of radical prostatectomy as compared with observation at 15 years of follow-up.(1) By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT), initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years.(2) PSA screening profoundly changes the clinical domain of study. Among other considerations, the substantial additional lead time ...

  • 46.
    Bisgin, Atil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Cukurova Univ, Turkey.
    Meng, Wen-Jian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Adell, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Interaction of CD200 Overexpression on Tumor Cells with CD200R1 Overexpression on Stromal Cells: An Escape from the Host Immune Response in Rectal Cancer Patients2019Ingår i: Journal of Oncology, ISSN 1687-8450, E-ISSN 1687-8469, Vol. 2019, artikel-id 5689464Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CD200 imparts an immunoregulatory signal through its receptor, CD200R1, leading to the suppression of tumor specific immunity. The mechanism of CD200:CD200R1 signaling pathway is still uncertain. Our aim was to investigate the expression and localization of CD200 and its receptor CD200R1 and their clinical significance in rectal cancer patients. We examined the immunohistochemical expressions and localizations of CD200 and CD200R1 in 140 rectal cancer patients. Among the patients, 79 underwent the preoperative radiotherapy and the others were untreated prior to the surgery. In addition, 121 matched normal rectal mucosa samples were evaluated. The results of immunohistochemical analysis showed a strikingly high level of CD200 in tumor cells (p=0.001) and CD200R1 expression in normal mucosal epithelium and stromal cells. Importantly, CD200R1 was overexpressed in stromal cells of the metastatic cancer patients compared to patients without metastases (p=0.002). More than that, 87% of metastatic patients had a phenotype of upregulated CD200 in tumor cells accompanied by overexpressed CD200R1 in stromal cells. In addition, low levels of CD200 were correlated with improved overall survival in untreated patients. We showed that tumor-stroma communication through CD200 and its receptor interaction is selected in patients with high risk of relapse. High levels of these molecules support instigation of the far and local metastatic nest that provides solid ground for metastasis. Our current data also disclose a mechanism by which CD200:CD200R1 affects tumor progression and may strengthen the feasibility of targeting CD200 or CD200R1 as anticancer strategy.

  • 47.
    Björn, Niclas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Pharmacogenetic biomarkers for chemotherapy-induced adverse drug reactions2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cancer is a serious disease expected to be the world-leading cause of death in the 21st century. The use of harsh chemotherapies is motivated and accepted but, unfortunately, is often accompanied by severe toxicity and adverse drug reactions (ADRs). These occur because the classical chemotherapies’ common modes of action effectively kill and/or reduce the growth rate not only of tumour cells, but also of many other rapidly dividing healthy cells in the body. There are also considerable interindividual differences in ADRs, even between patients with similar cancers and disease stage treated with equal doses; some experience severe to life-threatening ADRs after one dose, leading to treatment delays, adjustments, or even discontinuation resulting in suboptimal treatment, while others remain unaffected through all treatment cycles. Being able to predict which patients are at high or low risk of ADRs, and to adjust doses accordingly before treatment, would probably decrease toxicity and patient suffering while also increasing treatment tolerability and effects. In this thesis, we have used next-generation sequencing (NGS) and bioinformatics for the prediction of myelosuppressive ADRs in lung and ovarian cancer patients treated with gemcitabine/carboplatin and paclitaxel/carboplatin.

    Paper I shows that ABCB1 and CYP2C8 genotypes have small effects inadequate for stratification of paclitaxel/carboplatin toxicity. This supports the transition to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Papers II and IV, respectively, use WES and WGS, and demonstrate that genetic variation in or around genes involved in blood cell regulation and proliferation, or genes differentially expressed at chemotherapy exposure, can be used in polygenic prediction models for stratification of gemcitabine/carboplatininduced myelosuppression. Paper III reassuringly shows that WES and WGS are concordant and mostly yield comparable genotypes across the exome. Paper V proves that single-cell RNA sequencing of hematopoietic stem cells is a feasible method for elucidating differential transcriptional effects induced as a response to in vitro chemotherapy treatment.

    In conclusion, our results supports the transition to genome-wide approaches using WES, WGS, and RNA sequencing to establish polygenic models that combine effects of multiple pharmacogenetic biomarkers for predicting chemotherapy-induced ADRs. This approach could be applied to improve risk stratification and our understanding of toxicity and ADRs related to other drugs and diseases. We hope that our myelosuppression prediction models can be refined and validated to facilitate personalized treatments, leading to increased patient wellbeing and quality of life.

    Delarbeten
    1. ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
    Öppna denna publikation i ny flik eller fönster >>ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
    2018 (Engelska)Ingår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, nr 3, s. 277-287Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.

    Ort, förlag, år, upplaga, sidor
    WILEY, 2018
    Nationell ämneskategori
    Urologi och njurmedicin
    Identifikatorer
    urn:nbn:se:liu:diva-150852 (URN)10.1111/bcpt.12997 (DOI)000441237300009 ()29504705 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; ALF grants Region Ostergotland; Oasmia Pharmaceuticals AB, Uppsala, Sweden

    Tillgänglig från: 2018-09-06 Skapad: 2018-09-06 Senast uppdaterad: 2019-11-20
    2. Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
    Öppna denna publikation i ny flik eller fönster >>Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
    Visa övriga...
    2019 (Engelska)Ingår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150Artikel i tidskrift (Refereegranskat) Epub ahead of print
    Abstract [en]

    Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

    Nationell ämneskategori
    Cancer och onkologi Medicinsk genetik Farmakologi och toxikologi Läkemedelskemi
    Identifikatorer
    urn:nbn:se:liu:diva-162137 (URN)10.1038/s41397-019-0099-8 (DOI)
    Tillgänglig från: 2019-11-20 Skapad: 2019-11-20 Senast uppdaterad: 2019-11-20Bibliografiskt granskad
    3. Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
    Öppna denna publikation i ny flik eller fönster >>Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
    Visa övriga...
    2018 (Engelska)Ingår i: Journal of Next Generation Sequencing & Applications, ISSN 2469-9853, Vol. 5, nr 1, s. 1-8Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Whole exome sequencing (WES) has been extensively used in genomic research. As sequencing costs decline it is being replaced by whole genome sequencing (WGS) in large-scale genomic studies, but more comparative information on WES and WGS datasets would be valuable. Thus, we have extensively compared variant calls obtained from WGS and WES of matched germline DNA samples from 96 lung cancer patients. WGS provided more homogeneous coverage with higher genotyping quality, and identified more variants, than WES, regardless of exome coverage depth. It also called more reference variants, reflecting its power to call rare variants, and more heterozygous variants that met applied quality criteria, indicating that WGS is less prone to allelic drop outs. However, increasing WES coverage reduced the discrepancy between the WES and WGS results. We believe that as sequencing costs further decline WGS will become the method of choice even for research confined to the exome.

    Nyckelord
    Whole genome sequencing; Whole exome sequencing; Coverage; Depth; Genotyping quality; Discordant; Concordant; Variant calls; Single-nucleotide variants
    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:liu:diva-155840 (URN)
    Anmärkning

    DOI not working/activated: https://doi.org/10.4172/2469-9853.1000154

    Tillgänglig från: 2019-03-28 Skapad: 2019-03-28 Senast uppdaterad: 2019-11-20Bibliografiskt granskad
  • 48.
    Björn, Niclas
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Sigurgeirsson, Benjamín
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden / School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
    Svedberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Pradhananga, Sailendra
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden / Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden / Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Lewensohn, Rolf
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    de Petris, Luigi
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Apellániz-Ruiz, Maria
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Rodríguez-Antona, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Lundeberg, Joakim
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia2019Ingår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

  • 49.
    Blanco, Ignacio
    et al.
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Kuchenbaecker, Karoline
    University of Cambridge, England.
    Cuadras, Daniel
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Wang, Xianshu
    Mayo Clin, MN USA.
    Barrowdale, Daniel
    University of Cambridge, England.
    Ruiz de Garibay, Gorka
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Librado, Pablo
    University of Barcelona, Spain.
    Sanchez-Gracia, Alejandro
    University of Barcelona, Spain.
    Rozas, Julio
    University of Barcelona, Spain.
    Bonifaci, Nuria
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    McGuffog, Lesley
    University of Cambridge, England.
    Pankratz, Vernon S.
    Mayo Clin, MN USA.
    Islam, Abul
    University of Dhaka, Bangladesh.
    Mateo, Francesca
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Berenguer, Antoni
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Petit, Anna
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Catala, Isabel
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Brunet, Joan
    Hospital Josep Trueta, Spain.
    Feliubadalo, Lidia
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Tornero, Eva
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease, Spain.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease, Spain.
    Cajal, Teresa Ramon Y.
    Hospital Santa Creu and Sant Pau, Spain.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Aittomaki, Kristiina
    University of Helsinki, Finland.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Toland, Amanda E.
    Ohio State University, OH 43210 USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Walsh, Christine
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Greene, Mark H.
    National Cancer Institute, MD USA.
    Mai, Phuong L.
    National Cancer Institute, MD USA.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Andrulis, Irene L.
    University of Toronto, Canada; University of Toronto, Canada; University of Toronto, Canada.
    Domchek, Susan M.
    University of Penn, PA 19104 USA; University of Penn, PA 19104 USA.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA; University of Penn, PA 19104 USA.
    Rebbeck, Timothy R.
    University of Penn Perelman, PA 19104 USA; University of Penn Perelman, PA 19104 USA.
    Barkardottir, Rosa B.
    University of Iceland, Iceland; University of Iceland, Iceland.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Durda, Katarzyna
    Pomeranian Medical University, Poland.
    Jaworska-Bieniek, Katarzyna
    Pomeranian Medical University, Poland.
    Claes, Kathleen
    University of Ghent, Belgium.
    Van Maerken, Tom
    University of Ghent, Belgium.
    Diez, Orland
    Vall Hebron Research Institute VHIR, Spain; University of Autonoma Barcelona, Spain.
    Hansen, Thomas V.
    Copenhagen University Hospital, Denmark.
    Jonson, Lars
    Copenhagen University Hospital, Denmark.
    Gerdes, Anne-Marie
    Copenhagen University Hospital, Denmark.
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark.
    de la Hoya, Miguel
    San Carlos Research Institute IdISSC, Spain.
    Caldes, Trinidad
    San Carlos Research Institute IdISSC, Spain.
    Dunning, Alison M.
    University of Cambridge, England.
    Oliver, Clare
    University of Cambridge, England.
    Fineberg, Elena
    University of Cambridge, England.
    Cook, Margaret
    University of Cambridge, England.
    Peock, Susan
    University of Cambridge, England.
    McCann, Emma
    Glan Clwyd Gen Hospital, Wales.
    Murray, Alex
    Singleton Hospital, Wales.
    Jacobs, Chris
    Guys and St Thomas National Health Serv NHS Fdn Trust, England.
    Pichert, Gabriella
    Guys and St Thomas National Health Serv NHS Fdn Trust, England.
    Lalloo, Fiona
    Central Manchester University Hospital National Health Serv NHS Fdn, England.
    Chu, Carol
    Yorkshire Regional Genet Serv, England.
    Dorkins, Huw
    Kennedy Galton Centre, England.
    Paterson, Joan
    Addenbrookes Hospital, England.
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare National Health Serv, England.
    Teixeira, Manuel R.
    University of Porto, Portugal; University of Porto, Portugal.
    Teixeira,
    Netherlands Cancer Institute, The Netherlands.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, The Netherlands.
    van der Hout, Annemarie H.
    University of Groningen, Netherlands.
    Seynaeve, Caroline
    Erasmus University, Netherlands.
    van der Luijt, Rob B.
    University of Medical Centre Utrecht, Netherlands.
    Ligtenberg, Marjolijn J. L.
    Radboud University of Nijmegen, Netherlands; Radboud University of Nijmegen, Netherlands; Leiden University, Netherlands.
    Devilee, Peter
    Leiden University, Netherlands; Leiden University, Netherlands.
    Wijnen, Juul T.
    Leiden University, Netherlands; Leiden University, Netherlands.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands.
    Meijers-Heijboer, Hanne E. J.
    Vrije University of VJ University of Medical Centre, Netherlands.
    Blok, Marinus J.
    Maastricht University, Netherlands.
    van den Ouweland, Ans M. W.
    Erasmus University, Netherlands.
    Aalfs, Cora M.
    University of Amsterdam, Netherlands.
    Rodriguez, Gustavo C.
    University of Chicago, IL 60637 USA.
    Phillips, Kelly-Anne A.
    Peter MacCallum Cancer Centre, Australia.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY 14263 USA.
    Nerenstone, Stacy R.
    Hartford Hospital, CT USA.
    Bae-Jump, Victoria L.
    University of N Carolina, NC USA.
    OMalley, David M.
    Ohio State University, OH USA.
    Ratner, Elena S.
    Yale University, CT USA.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Engel, Christoph
    University of Leipzig, Germany.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Ditsch, Nina
    University of Munich, Germany.
    Arnold, Norbert
    University of Kiel, Germany.
    Plendl, Hansjoerg J.
    University of Kiel, Germany.
    Niederacher, Dieter
    University of Dusseldorf, Germany.
    Sutter, Christian
    University of Heidelberg Hospital, Germany.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Preisler-Adams, Sabine
    University of Munster, Germany.
    Kast, Karin
    Technical University of Dresden, Germany.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Gehrig, Andrea
    University of Wurzburg, Germany.
    Bojesen, Anders
    Vejle Hospital, Denmark.
    Sokilde Pedersen, Inge
    Aalborg University Hospital, Denmark.
    Sunde, Lone
    Aarhus University Hospital, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Kruse, Torben A.
    Odense University Hospital, Denmark.
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic.
    Peterlongo, Paolo
    Fdn Italiana Ric Cancro, Italy.
    Bernard, Loris
    Cogentech Cancer Genet Test Lab, Italy.
    Peissel, Bernard
    Fdn Ist Nazl Tumori INT, Italy.
    Scuvera, Giulietta
    Fdn Ist Nazl Tumori INT, Italy.
    Manoukian, Siranoush
    Fdn Ist Nazl Tumori INT, Italy.
    Radice, Paolo
    Fdn Ist Nazl Tumori INT, Italy.
    Ottini, Laura
    University of Roma La Sapienza, Italy.
    Montagna, Marco
    IRCCS, Italy.
    Agata, Simona
    IRCCS, Italy.
    Maugard, Christine
    Hop University of Strasbourg, France.
    Simard, Jacques
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Soucy, Penny
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Berger, Andreas
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Singer, Christian F.
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Rappaport, Christine
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Geschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Tea, Muy-Kheng
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Pfeiler, Georg
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    John, Esther M.
    Cancer Prevent Institute Calif, CA USA.
    Miron, Alex
    Dana Farber Cancer Institute, MA 02115 USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA USA.
    Beth Terry, Mary
    Columbia University, NY USA.
    Chung, Wendy K.
    Columbia University, NY USA.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Goldgar, David E.
    University of Utah, UT USA.
    Janavicius, Ramunas
    Vilnius University, Lithuania.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    van Rensburg, Elisabeth J.
    University of Pretoria, South Africa.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Garber, Judy
    Harvard University, MA USA.
    Godwin, Andrew K.
    University of Kansas, KS 66103 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Narod, Steven A.
    University of Toronto, Canada.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel; B Rappaport Fac Med, Israel.
    Shimon Paluch, Shani
    Chaim Sheba Medical Centre, Israel.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel; Tel Aviv University, Israel.
    Liljegren, Annelie
    Karolinska University Hospital, Sweden.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Loman, Niklas
    University of Lund Hospital, Sweden.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Spurdle, Amanda B.
    Queensland Institute Medical Research, Australia.
    Healey, Sue
    Queensland Institute Medical Research, Australia.
    Weitzel, Jeffrey N.
    City Hope National Medical Centre, CA USA.
    Herzog, Josef
    City Hope National Medical Centre, CA USA.
    Margileth, David
    Care City Hope Clin Cancer Genet Commun Research Network, CA USA.
    Gorrini, Chiara
    University of Health Network, Canada.
    Esteller, Manel
    IDIBELL, Spain; University of Barcelona, Spain; Catalan Institute Research and Adv Studies ICREA, Spain.
    Gomez, Antonio
    IDIBELL, Spain.
    Sayols, Sergi
    IDIBELL, Spain.
    Vidal, Enrique
    IDIBELL, Spain.
    Heyn, Holger
    IDIBELL, Spain.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; Institute Curie, France; University of Paris 05, France.
    Leone, Melanie
    Hospital Civils Lyon, France.
    Barjhoux, Laure
    University of Lyon 1, France.
    Fassy-Colcombet, Marion
    Institute Curie, France.
    de Pauw, Antoine
    Institute Curie, France.
    Lasset, Christine
    University of Lyon 1, France; Centre Leon Berard, France.
    Fert Ferrer, Sandra
    Hop Hotel Dieu, France.
    Castera, Laurent
    Institute Curie, France.
    Berthet, Pascaline
    Centre Francois Baclesse, France.
    Cornelis, Francois
    Avicenne Hospital, France; Sud Francilien Hospital, France; University Hospital, France.
    Bignon, Yves-Jean
    University of Clermont Ferrand, France.
    Damiola, Francesca
    University of Lyon 1, France.
    Mazoyer, Sylvie
    University of Lyon 1, France.
    Sinilnikova, Olga M.
    Hospital Civils Lyon, France; University of Lyon 1, France.
    Maxwell, Christopher A.
    University of British Columbia, Canada.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Corines, Marina J.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Villano, Danylko
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Cunningham, Julie
    Mayo Clin, MN USA; Mayo Clin, MN USA.
    Lee, Adam
    Mayo Clin, MN USA.
    Lindor, Noralane
    Mayo Clin Scottsdale, AZ USA.
    Lazaro, Conxi
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Easton, Douglas F.
    University of Cambridge, England.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research, Australia.
    Couch, Fergus J.
    Mayo Clin, MN USA; Mayo Clin, MN USA.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Angel Pujana, Miguel
    Bellvitge Institute Biomed Research IDIBELL, Spain.
    Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 4, artikel-id e0120020Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values greater than 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  • 50.
    Block, Keith I.
    et al.
    Block Centre Integrat Cancer Treatment, IL 60077 USA.
    Gyllenhaal, Charlotte
    Block Centre Integrat Cancer Treatment, IL 60077 USA; National Cancer Centre, South Korea.
    Lowe, Leroy
    Getting Know Canc, Canada; University of Lancaster, England.
    Amedei, Amedeo
    University of Florence, Italy.
    Ruhul Amin, A. R. M.
    University of Florence, Italy.
    Amin, Amr
    University of Florence, Italy.
    Aquilano, Katia
    United Arab Emirates University, U Arab Emirates.
    Arbiser, Jack
    Atlanta Vet Adm Medical Centre, GA USA; Emory University, GA USA.
    Arreola, Alexandra
    University of Roma Tor Vergata, Italy.
    Arzumanyan, Alla
    University of N Carolina, NC 27599 USA.
    Salman Ashraf, S.
    Temple University, PA 19122 USA.
    Azmi, Asfar S.
    United Arab Emirates University, U Arab Emirates.
    Benencia, Fabian
    Wayne State University, MI USA.
    Bhakta, Dipita
    Ohio University, OH 45701 USA.
    Bilsland, Alan
    SASTRA University, India.
    Bishayeen, Anupam
    University of Glasgow, Scotland.
    Blain, Stacy W.
    Larkin Health Science Institute, FL USA.
    Block, Penny B.
    Block Centre Integrat Cancer Treatment, IL 60077 USA.
    Boosani, Chandra S.
    Suny Downstate Medical Centre, NY USA.
    Carey, Thomas E.
    Creighton University, NE 68178 USA.
    Carnero, Amancio
    University of Michigan, MI USA.
    Carotenuto, Marianeve
    CSIC, Spain; Centre Ingn Genet and Biotecnol Avanzate, Italy.
    Casey, Stephanie C.
    University of Naples Federico II, Italy.
    Chakrabarti, Mrinmay
    Stanford University, CA 94305 USA.
    Chaturvedi, Rupesh
    University of S Carolina, SC USA.
    Zhuo Chen, Georgia
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Chenx, Helen
    Jawaharlal Nehru University, India.
    Chen, Sophie
    University of British Columbia, Canada.
    Charlie Chen, Yi
    Ovarian and Prostate Cancer Research Lab, England; Alderson Broaddus University, PA USA.
    Choi, Beom K.
    National Cancer Centre, South Korea.
    Rosa Ciriolo, Maria
    United Arab Emirates University, U Arab Emirates.
    Coley, Helen M.
    University of Surrey, England.
    Collins, Andrew R.
    University of Oslo, Norway.
    Connell, Marisa
    Jawaharlal Nehru University, India.
    Crawford, Sarah
    So Connecticut State University, CT 06515 USA.
    Curran, Colleen S.
    University of Wisconsin, WI USA.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Damia, Giovanna
    Ist Ric Farmacol Mario Negri, Italy.
    Dasgupta, Santanu
    University of Texas Health Science Centre Tyler, TX USA.
    DeBerardinis, Ralph J.
    University of Texas SW Medical Centre Dallas, TX 75390 USA.
    Decker, William K.
    Baylor Coll Med, TX 77030 USA.
    Dhawan, Punita
    Vanderbilt University, TN 37212 USA.
    Diehl, Anna Mae E.
    Duke University, NC 27710 USA.
    Dong, Jin-Tang
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Ping Dou, Q.
    United Arab Emirates University, U Arab Emirates.
    Drew, Janice E.
    University of Aberdeen, Scotland.
    Elkord, Eyad
    United Arab Emirates University, U Arab Emirates.
    El-Rayes, Bassel
    Emory University, GA 30322 USA.
    Feitelson, Mark A.
    University of N Carolina, NC 27599 USA.
    Felsher, Dean W.
    University of Naples Federico II, Italy.
    Ferguson, Lynnette R.
    University of Auckland, New Zealand.
    Fimognari, Carmela
    University of Auckland, New Zealand.
    Firestone, Gary L.
    University of Bologna, Italy.
    Frezza, Christian
    University of Calif Berkeley, CA 94720 USA.
    Fujii, Hiromasa
    University of Cambridge, England.
    Fuster, Mark M.
    Nara Medical University, Japan.
    Generali, Daniele
    University of Calif San Diego, CA 92103 USA; University of Calif San Diego, CA 92103 USA.
    Georgakilas, Alexandros G.
    University of Trieste, Italy.
    Gieseler, Frank
    Azienda Osped Ist Ospitalieri Cremona, Italy.
    Gilbertson, Michael
    National Technical University of Athens, Greece.
    Green, Michelle F.
    University Hospital Schleswig Holstein, Germany.
    Grue, Brendan
    Getting Know Canc, Canada.
    Guha, Gunjan
    Ohio University, OH 45701 USA.
    Halicka, Dorota
    Duke University, NC USA.
    Helferich, William G.
    Dalhousie University, Canada.
    Heneberg, Petr
    New York Medical Coll, NY 10595 USA.
    Hentosh, Patricia
    University of Illinois, IL 61820 USA.
    Hirschey, Matthew D.
    University Hospital Schleswig Holstein, Germany.
    Hofseth, Lorne J.
    Charles University of Prague, Czech Republic.
    Holcombe, Randall F.
    Old Domin University, VA USA.
    Honoki, Kanya
    Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan.
    Hsu, Hsue-Yin
    University of S Carolina, SC 29208 USA.
    Huang, Gloria S.
    Mt Sinai School Med, NY USA.
    Jensen, Lasse D.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Jiang, Wen G.
    Cardiff University, Wales.
    Jones, Lee W.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Karpowicz, Phillip A.
    University of Windsor, Canada.
    Nicol Keith, W.
    SASTRA University, India.
    Kerkar, Sid P.
    Mayo Clin, MN USA.
    Khan, Gazala N.
    Henry Ford Hospital, MI 48202 USA.
    Khatami, Mahin
    National Institute Heatlh, MD USA.
    Ko, Young H.
    University of Maryland BioPark, MD USA.
    Kucuk, Omer
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Kulathinal, Rob J.
    University of N Carolina, NC 27599 USA.
    Kumar, Nagi B.
    University of S Florida, FL USA.
    Kwon, Byoung S.
    National Cancer Centre, South Korea; Tulane University, LA 70118 USA.
    Le, Anne
    Johns Hopkins University, MD USA.
    Lea, Michael A.
    Rutgers State University, NJ USA.
    Lee, Ho-Young
    Seoul National University, South Korea.
    Lichtor, Terry
    Rush University, IL 60612 USA.
    Lin, Liang-Tzung
    Taipei Medical University, Taiwan.
    Locasale, Jason W.
    Cornell University, NY 14853 USA.
    Lokeshwar, Bal L.
    Georgia Regents University, GA USA.
    Longo, Valter D.
    University of So Calif, CA USA.
    Lyssiotis, Costas A.
    University of Michigan, MI USA; University of Michigan, MI USA.
    MacKenzie, Karen L.
    Childrens Cancer Institute Australia, Australia.
    Malhotra, Meenakshi
    McGill University, Canada.
    Marino, Maria
    University of Rome Tre, Italy.
    Martinez-Chantar, Maria L.
    Technology Pk Bizkaia, Spain.
    Matheu, Ander
    Biodonostia Institute, Spain.
    Maxwell, Christopher
    Jawaharlal Nehru University, India.
    McDonnell, Eoin
    University Hospital Schleswig Holstein, Germany.
    Meeker, Alan K.
    Johns Hopkins University, MD 21205 USA.
    Mehrmohamadi, Mahya
    Cornell University, NY USA.
    Mehta, Kapil
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Michelotti, Gregory A.
    Duke University, NC 27710 USA.
    Mohammad, Ramzi M.
    United Arab Emirates University, U Arab Emirates.
    Mohammed, Sulma I.
    Purdue University, IN 47907 USA.
    James Morre, D.
    Mor NuCo Inc, IN USA.
    Muqbil, Irfana
    United Arab Emirates University, U Arab Emirates.
    Muralidhar, Vinayak
    Harvard University, MA USA; MIT, MA 02139 USA.
    Murphy, Michael P.
    MRC Mitochondrial Biol Unit, England.
    Purnachandra Nagaraju, Ganji
    Emory University, GA 30322 USA.
    Nahta, Rita
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Niccolai, Elena
    University of Florence, Italy.
    Nowsheen, Somaira
    Mayo Clin, MN USA.
    Panis, Carolina
    State University of West Parana, Brazil.
    Pantano, Francesco
    University of Campus Bio Med, Italy.
    Parslow, Virginia R.
    University of Auckland, New Zealand.
    Pawelec, Graham
    University of Tubingen, Germany.
    Pedersen, Peter L.
    Johns Hopkins University, MD USA.
    Poore, Brad
    Johns Hopkins University, MD USA.
    Poudyal, Deepak
    Charles University of Prague, Czech Republic.
    Prakash, Satya
    McGill University, Canada.
    Prince, Mark
    University of Michigan, MI USA.
    Raffaghello, Lizzia
    Ist Giannina Gaslini, Italy.
    Rathmell, Jeffrey C.
    University Hospital Schleswig Holstein, Germany.
    Kimryn Rathmell, W.
    University of Roma Tor Vergata, Italy.
    Ray, Swapan K.
    Stanford University, CA 94305 USA.
    Reichrath, Joerg
    Saarland University Hospital, Germany.
    Rezazadeh, Sarallah
    University of Rochester, NY 14627 USA.
    Ribatti, Domenico
    University of Bari, Italy.
    Ricciardiello, Luigi
    National Cancer Institute Giovanni Paolo II, Italy.
    Brooks Robey, R.
    University of Bologna, Italy; White River Junct Vet Affairs Medical Centre, VT USA.
    Rodier, Francis
    Geisel School Medical Dartmouth, NH USA; University of Montreal, Canada.
    Vasantha Rupasinghe, H. P.
    Institute Cancer Montreal, Canada.
    Luigi Russo, Gian
    University of Montreal, Canada.
    Ryan, Elizabeth P.
    Dalhousie University, Canada.
    Samadi, Abbas K.
    Sanus Biosciences, San Diego, CA, United States.
    Sanchez-Garcia, Isidro
    CNR, Italy.
    Sanders, Andrew J.
    Cardiff University, Wales.
    Santini, Daniele
    University of Campus Bio Med, Italy.
    Sarkar, Malancha
    Colorado State University, CO 80523 USA.
    Sasada, Tetsuro
    Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
    Saxena, Neeraj K.
    University of Salamanca, Spain.
    Shackelford, Rodney E.
    University of Miami, FL USA.
    Shantha Kumara, H. M. C.
    St Lukes Roosevelt Hospital, NY 10025 USA.
    Sharma, Dipali
    Kurume University, Japan.
    Shin, Dong M.
    Winship Cancer Institute of Emory University, Atlanta, GA, United States.
    Sidransky, David
    University of Maryland, MD 21201 USA.
    David Siegelin, Markus
    Louisiana State University, LA 71105 USA.
    Signori, Emanuela
    Johns Hopkins University, MD 21205 USA; Johns Hopkins University, MD USA.
    Singh, Neetu
    Johns Hopkins University, MD USA; King Georges Medical University, India.
    Sivanand, Sharanya
    Columbia University, NY USA; University of Penn, PA 19104 USA.
    Sliva, Daniel
    Institute Translat Pharmacol, Italy; Purdue Research Pk, IN USA.
    Smythe, Carl
    University of Sheffield, England.
    Spagnuolo, Carmela
    University of Montreal, Canada.
    Stafforini, Diana M.
    University of Utah, UT USA.
    Stagg, John
    University of Utah, UT USA.
    Subbarayan, Pochi R.
    University of Montreal, Canada.
    Sundin, Tabetha
    University of Miami, FL USA.
    Talib, Wamidh H.
    Sentara Healthcare, VA USA.
    Thompson, Sarah K.
    Appl Science University, Jordan.
    Tran, Phuoc T.
    Royal Adelaide Hospital, Australia.
    Ungefroren, Hendrik
    Azienda Osped Ist Ospitalieri Cremona, Italy.
    Vander Heiden, Matthew G.
    MIT, MA 02139 USA.
    Venkateswaran, Vasundara
    Johns Hopkins University, MD USA; University of Toronto, Canada.
    Vinay, Dass S.
    Tulane University, LA USA.
    Vlachostergios, Panagiotis J.
    Johns Hopkins University, MD USA; New York University, NY USA.
    Wang, Zongwei
    Johns Hopkins University, MD USA; Harvard University, MA USA.
    Wellendx, Kathryn E.
    Columbia University, NY USA; University of Penn, PA 19104 USA.
    Whelan, Richard L.
    St Lukes Roosevelt Hospital, NY 10025 USA.
    Yang, Eddy S.
    University of Alabama Birmingham, AL USA.
    Yang, Huanjie
    Harbin Institute Technology, Peoples R China.
    Yang, Xujuan
    Dalhousie University, Canada.
    Yaswen, Paul
    Lawrence Berkeley National Lab, CA USA.
    Yedjou, Clement
    Jackson State University, MS USA.
    Yin, Xin
    Nara Medical University, Japan.
    Zhu, Jiyue
    Washington State University, WA USA.
    Zollo, Massimo
    CSIC, Spain; Centre Ingn Genet and Biotecnol Avanzate, Italy.
    Designing a broad-spectrum integrative approach for cancer prevention and treatment2015Ingår i: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 35, s. S276-S304Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.

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