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  • 1. Bitar, Christian
    et al.
    Krupic, Ferid
    Fellaender-Tsai, Li
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Wretenberg, Per
    Living with a recalled implant: a qualitative study of patients' experiences with ASR hip resurfacing arthroplasty2021Inngår i: Patient Safety in Surgery, E-ISSN 1754-9493, Vol. 15, nr 1, artikkel-id 2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundTotal hip arthroplasty is the traditional treatment for osteoarthritis in the hip joint. Hip resurfacing arthroplasty, with metal on metal bearing, is a modern concept initially developed mainly for young active people. The metal-on-metal hip arthroplasty implant, Articular Surface Replacement (ASR), was implanted in approximately 93,000 patients before it was recalled in 2010 due to a high complication rate. This study aimed to evaluate patients' own experiences living with an implant that they knew had a high complication rate and had been recalled from the market.MethodsA total of 14 patients, still living with the implant, of a cohort of 34 patients were available for follow-up. Qualitative semi-structured interviews were conducted with 14 patients where a majority actively sought for metal-on-metal hip resurfacing arthroplasty (HRA), and subsequently underwent HRA with an ASR prosthesis between 11/21/2006 and 09/28/2009. The responses were analyzed using content analysis described by Graneheim and Lundman to compress text and identify categories and subcategories.ResultsThe results showed that most patients had already decided that they wanted a metal-on-metal HRA implant before meeting the surgeon. They expressed that the implant made it possible to live an active life. A majority did not think about the fact that they had a hip implant, because they lacked subjective pain. Most of the patients were positive about the annual exams at the hospital and wanted them to continue. None of them felt that their trust towards the healthcare system had changed after the implant recall. They expressed a belief that they would need new surgery sooner than they first thought.ConclusionsDespite all the attention when the ASR prosthesis was recalled, patients with ASR-HRA did not report themselves negatively affected by the recall in this group of patients where a majority had actively sought for an HRA procedure. The healthcare system has an obligation to continue the annual exams, even if the implant provider does not continue reimbursement.

    Fulltekst (pdf)
    fulltext
  • 2.
    Bitar, Christian
    et al.
    Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden; Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden.
    Moberg, Ivan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Krupic, Ferid
    Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wretenberg, Per
    Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden; Department of Orthopaedics, School of Medical Sciences, Örebro University and Örebro University Hospital, Örebro, Sweden.
    Otten, Volker T C
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    11-Year outcomes in patients with metal-on-metal ASR hip arthroplasty2022Inngår i: Journal of Orthopaedics, ISSN 0972-978X, E-ISSN 2589-9082, Vol. 32, s. 98-103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We analysed the long-term revision rate, clinical outcomes and metal ion concentrations in blood over time in patients who had undergone metal-on-metal Articular Surface Replacement (ASR) hip arthroplasty. Methods: A total of 38 patients (43 hips) were included: 24 patients (28 hips) underwent large-head total hip arthroplasty (XL THA), and 14 patients (15 hips) underwent hip resurfacing arthroplasty (HRA). The median follow-up time was 11 (range 7-12) years. Results: None of 15 HRA implants were revised. Nine of 28 XL THA implants (32%) in 8 patients were revised. The Co ion levels significantly increased in the XL THA group (p=0.009) over a median time period of 84 (25-97) months. Conclusion: The levels of Co ions in blood were higher in the patients who had undergone XL THA and increased significantly over time.

  • 3.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordstrand, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases2018Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 50-50Artikkel i tidsskrift (Annet vitenskapelig)
  • 4.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Egevad, Lars
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response2017Inngår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, nr 5, s. 776-787Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.

    Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.

    Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.

    Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.

    Fulltekst (pdf)
    fulltext
  • 5.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer2021Inngår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 13, nr 1, artikkel-id 133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.

    Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.

    Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.

    Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

    Fulltekst (pdf)
    fulltext
  • 6.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Integrated DNA methylation and gene expression analysis of molecular heterogeneity in prostate cancer bone metastasisManuskript (preprint) (Annet vitenskapelig)
  • 7.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Metastatic spinal cord compression in prostate cancer: clinical and morphological studies2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Bone metastases occur in most patients with advanced hormone-refractory prostate cancer causing pain, pathologic fractures, and spinal cord compression. Few studies specifically address surgical treatment of metastatic spinal cord compression (MSCC) in prostate cancer. Criteria for identifying patients who may benefit from surgery are poorly defined. Most of the current knowledge regarding tumor biology in prostate cancer is based on studies of primary tumors or soft tissue metastases. The mechanisms regulating growth of bone metastases are not fully established.

    Aims: a) to evaluate outcome after surgery for MSCC in prostate cancer and to identify prognostic factors for survival and functional recovery; b) to evaluate current practice for referral of prostate cancer patients with MSCC; c) to analyze expression of androgen receptor (AR), cell proliferation, apoptosis, and prostate-specific antigen (PSA) in bone metastases with regard to survival after surgery for complications of bone metastases.

    Patients and Methods: We retrospectively evaluated the hospital records of 68 consecutive patients operated for metastatic spinal cord compression. Tumor tissue from bone metastases was obtained on spinal surgery (54 patients), fracture surgery (4 patients) and biopsy (2 patients), and analyzed by immunohistochemistry.

    Results:

    Study I: Mortality and complication rate after surgery was high. Patients with hormone-naïve disease and those with hormone-refractory disease with good performance status and without visceral metastases had more favorable survival. The ability to walk after surgery was related to better survival.

    Study II: A new score for prognosis of survival after surgery for spinal cord compression includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The score is simple, tumor specific, and easy to apply in clinical practice.

    Study III: Our results suggest that delays in diagnosis and treatment may have negative impact on functional outcome. Pretreatment ability to walk, hormone status of prostate cancer, and time from loss of ambulation influenced neurological recovery after surgery for spinal cord compression.

    Study IV: High nuclear AR immunostaining in bone metastases and high preoperative serum PSA were associated with a poor outcome after metastasis surgery in patients with hormone-refractory prostate cancer. Short-term effect of castration therapy disclosed that nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected.

    Conclusion:  Prostate cancer patients with metastatic spinal cord compression represent a heterogeneous group. We identified prognostic factors for survival and functional outcome, which may help clinicians in making decisions about treatment. Our results also implicate the need for development of local and regional guidelines for treatment of patients with spinal cord compression, as well as the importance of information to patients at risk.

    Fulltekst (pdf)
    fulltext
  • 8.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Metastatisk ryggmärgs­kompression får inte missas: ökad medvetenhet om tidiga symtom möjliggör snabb behandling2014Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, nr 7, s. 276-277Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
    Abstract [sv]

    Metastatisk ryggmärgskompression är ett akut tillstånd. Tidig diagnos och snabb behandling är avgörande för neurologisk restitution. Ökad medvetenhet om de tidiga symtomen vid tillståndet bland läkare, övrig sjukvårdspersonal och särskilt cancerpatienter är nödvändig för att öka möjligheten till tidig behandling. Regionala riktlinjer för handläggning av denna patientgrupp bör införas eller förbättras och – framför allt – efterlevas.

  • 9.
    Crnalic, Sead
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Hildingsson, Christer
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Svensson, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Löfvenberg, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Early diagnosis and treatment is crucial for neurological recovery after surgery for metastatic spinal cord compression in prostate cancer2013Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 4, s. 809-815Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Spinal cord compression is an oncological and surgical emergency. Delays in referral and diagnosis may influence functional outcome. It is therefore important to identify patients who will regain or maintain ability to walk after surgery. The aim of the present study was to examine current practice for referral and diagnosis of prostate cancer patients with spinal cord compression and to identify prognostic factors for neurological outcome after surgery.

    Patients and methods. The study includes 68 consecutive patients with prostate cancer who underwent surgery due to neurological compromise.  Intervals from onset of neurological symptoms to referral, diagnosis, and treatment were analyzed in relation to functional outcome. The prognostic significance of preoperative clinical parameters on gait function one month after surgery was evaluated.

    Results. Patients who were referred from local hospitals had longer delay to surgery than those who directly presented to the cancer centre (p=0.004). The rate of diagnosis with MRI increased through the week and peaked on Friday, with few patients being diagnosed during weekends. Ability to walk before surgery, hormone-naive prostate cancer, and/or shorter time from loss of ambulation were associated with more favorable neurological outcome. In patients with hormone-refractory disease who were unable to walk before surgery regaining of ambulation was associated with: duration of paresis <48 hours (p=0.005), good preoperative performance status (p=0.04), preoperative PSA serum level <200 ng/ml (p=0.03), and surgery with posterior decompression and stabilization (p=0.03).

    Conclusion. Early diagnosis and rapid treatment of spinal cord compression in prostate cancer patients is crucial for neurological recovery. Rising of awareness for the condition among patients at risk and among physicians is mandatory as well as improvement of local and regional guidelines for treatment.

  • 10.
    Crnalic, Sead
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Hildingsson, Christer
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Löfvenberg, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Outcome after surgery for metastatic spinal cord compression in 54 patients with prostate cancer2012Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, nr 1, s. 80-86Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose The criteria for selecting patients who may benefit from surgery of spinal cord compression in metastatic prostate cancer are poorly defined. We therefore studied patients operated for metastatic spinal cord compression in order to evaluate outcome of surgery and to find predictors of survival. Patients and methods We reviewed the records of 54 consecutive patients with metastatic prostate cancer who were operated for spinal cord compression at Umeå University Hospital. The indication for surgery was neurological deficit due to spinal cord compression. 41 patients had hormone-refractory cancer and 13 patients had previously untreated, hormone-naïve prostate cancer. 29 patients were operated with posterior decompression only, and in 25 patients posterior decompression and stabilization was performed. Results Preoperatively, 6/54 of patients were able to walk. 1 month after surgery, 33 patients were walking, 15 were non-ambulatory, and 6 had died. Mortality rate was 11% at 1 month, 41% at 6 months, and 59% at 1 year. In the hormone-naïve group, 8/13 patients were still alive with a median postoperative follow-up of 26 months. In the hormone-refractory group, median survival was 5 months. Patients with hormone-refractory disease and Karnofsky performance status (KPS) of ≤ 60% had median survival of 2.5 months, whereas those with KPS of 70% and KPS of ≥ 80% had a median survival of 7 months and 18 months, respectively (p < 0.001). Visceral metastases were present in 12/41 patients with hormone-refractory tumor at the time of spinal surgery, and their median survival was 4 months-as compared to 10 months in patients without visceral metastases (p = 0.003). Complications within 30 days of surgery occurred in 19/54 patients. Interpretation Our results indicate that patients with hormone-naive disease, and those with hormone-refractory disease with good performance status and lacking visceral metastases, may be helped by surgery for metastatic spinal cord compression.

  • 11.
    Crnalic, Sead
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Hörnberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Tieva, Åse
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Svensson, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients2010Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 17, nr 4, s. 885-895Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Androgen receptors (ARs) are probably of importance during all phases of prostate cancer (PC) growth, but their role in bone metastases is largely unexplored. Bone metastases were therefore collected from hormone-naive (n=11), short-term castrated (n=7) and castration-resistant PC (CRPC, n=44) patients by biopsy (n=4) or at surgery to alleviate symptoms from metastases complications (metastasis surgery, n=58), and immunostained for nuclear ARs, Ki67, active caspase-3, prostate-specific antigen (PSA) and chromogranin A, and results were related to serum PSA, treatments and outcome. Nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected in metastases within a few days after surgical castration. In CRPC patients, nuclear AR staining of metastases was increased when compared to short-term castrated patients. The nuclear AR staining score was related to tumour cell proliferation, but it was not associated with other downstream effects of AR activation such as apoptosis and PSA staining, and it was only marginally related to the presence of neuroendocrine tumour cells. Serum PSA at metastasis surgery, although related to outcome, was not associated with AR staining, markers of metastasis growth or PSA staining in metastases. High nuclear AR immunostaining was associated with a particularly poor prognosis after metastasis surgery in CRPC patients, suggesting that such men may benefit from the potent AR blockers now tested in clinical trials.

  • 12.
    Crnalic, Sead
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Löfvenberg, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hildingsson, Christer
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Predicting survival for surgery of metastatic spinal cord compression in prostate cancer: a new score2012Inngår i: Spine, ISSN 0362-2436, E-ISSN 1528-1159, Vol. 37, nr 26, s. 2168-2176Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Study design. We retrospectively analyzed prognostic factors for survival in prostate cancer patients operated for metastatic spinal cord compression.

    Objective. The aim was to obtain a clinical score for prediction of survival after surgery.

    Summary of background data. Survival prognosis is important when deciding about treatment of patients with metastatic spinal cord compression. The criteria for identifying prostate cancer patients who may benefit from surgical treatment are unclear.

    Patients and methods The study comprised 68 consecutive patients with prostate cancer operated for metastatic spinal cord compression at Umeå University Hospital, Sweden. The indication for surgery was neurological deficit; 53 patients had hormone-refractory prostate cancer, and 15 patients had previously untreated, hormone-naïve prostate cancer. In 42 patients posterior decompression was performed and 26 patients were operated with posterior decompression and stabilization.

    Results A new score for prediction of survival was developed based on the results of survival analyses. The score includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The total scores ranged from 0 to 6. Three prognostic groups were formulated: group A (n = 32) with scores 0-1; group B (n = 23) with scores 2-4, and group C (n = 12) with scores 5-6. The median overall survival was 3 (0.3 - 20) months in group A, 16 (1.8 - 59) months in group B, and in group C more than half (7 of 12) of patients were still alive.

    Conclusion We present a new prognostic score for predicting survival of prostate cancer patients after surgery for metastatic spinal cord compression. The score is easy to apply in clinical practice and may be used as additional support when making decision about treatment.

  • 13.
    Djusberg, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lundberg, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases2017Inngår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, nr 6, s. 625-638Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

  • 14.
    Gustafsson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crenshaw, Albert G.
    Edmundsson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Toolanen, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Muscle oxygenation in Type 1 diabetic and non-diabetic patients with and without chronic compartment syndrome2017Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 12, nr 10, artikkel-id e0186790Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Type 1 diabetic patients and non-diabetic patients were referred for evaluation for chronic exertional compartment syndrome (CECS) based on clinical examination and complaints of activity-related leg pain in the region of the tibialis anterior muscle. Previous studies using near-infrared spectroscopy (NIRS) showed greater deoxygenation during exercise for CECS patients versus healthy controls; however, this comparison has not been done for diabetic CECS patients. Methods: We used NIRS to test for differences in oxygenation kinetics for Type 1 diabetic patients diagnosed with (CECS-diabetics, n = 9) versus diabetic patients without (CON-diabetics, n = 10) leg anterior chronic exertional compartment syndrome. Comparisons were also made between non-diabetic CECS patients (n = 11) and healthy controls (CON, n = 10). The experimental protocol consisted of thigh arterial cuff occlusion (AO, 1-minute duration), and treadmill running to reproduce symptoms. NIRS variables generated were resting StO(2)%, and oxygen recovery following AO. Also, during and following treadmill running the magnitude of deoxygenation and oxygen recovery, respectively, were determined. Results: There was no difference in resting StO2% between CECS-diabetics (78.2 +/- 12.6%) vs. CON-diabetics (69.1 +/- 20.8%), or between CECS (69.3 +/- 16.2) vs. CON (75.9 +/- 11.2%). However, oxygen recovery following AO was significantly slower for CECS (1.8 +/- 0.8%/sec) vs. CON (3.8 +/- 1.7%/sec) (P = 0.002); these data were not different between the diabetic groups. StO2% during exercise was lower (greater deoxygenation) for CECS-diabetics (6.3 +/- 8.6%) vs. CON-diabetics (40.4 +/- 22.0%), and for CECS (11.3 +/- 16.8%) vs. CON (34.1 +/- 21.2%) (P<0.05 for both). The rate of oxygen recovery post exercise was faster for CECS-diabetics (3.5 +/- 2.6%/sec) vs. CON-diabetics (1.4 +/- 0.8%/sec) (P = 0.04), and there was a tendency of difference for CECS (3.1 +/- 1.4%/sec) vs. CON (1.9 +/- 1.3%/sec) (P = 0.05). Conclusion: The greater deoxygenation during treadmill running for the CECS-diabetics group (vs. CON-diabetics) is in line with previous studies (and with the present study) that compared non-diabetic CECS patients with healthy controls. Our findings could suggest that NIRS may be useful as a diagnostic tool for assessing Type 1 diabetic patients suspected of CECS.

    Fulltekst (pdf)
    fulltext
  • 15.
    Hedström, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Kullström, Antonia
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Waernbaum, Ingeborg
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Socioeconomic impact on the incidence of fractures in children and adolescents: a population-based study fron northern SwedenManuskript (preprint) (Annet vitenskapelig)
  • 16.
    Hedström, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Kullström, Antonia
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Waernbaum, Ingeborg
    Department of Statistics, Uppsala University, Uppsala, Sweden.
    Socioeconomic variables and fracture risk in children and adolescents: A population-based study from northern Sweden2021Inngår i: BMJ Open, E-ISSN 2044-6055, Vol. 11, nr 10, artikkel-id e053179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Previous studies have investigated the association between socioeconomic characteristics and fractures among children, producing different results. In a population-based study, we previously found an increased risk of fractures among children living in an urban municipality compared with rural municipalities. This study aimed to evaluate the importance of socioeconomic variables for the incidence of fractures among 0-17 year olds.

    Setting, design and outcome measure: We present a longitudinal, observational study of a population 0-17 years of age. Data from an injury database were linked with additional socioeconomic data for the population at risk. These were 55 758 individuals residing within the primary catchment area of a regional hospital in northern Sweden. Using the number of fractures as the outcome, we fitted a generalised linear mixed model for a Poisson response with socioeconomic variables at the family level as independent variables while controlling for age, sex and place of residence.

    Results: We found a significant association between higher levels of family income and the risk of fracture, rate ratio 1.40 (1.28-1.52) p<0.001 when comparing the highest income quintile to the lowest as well as the number of siblings and the risk of fracture. Children with one or two siblings had a rate ratio of 1.28 (1.19-1.38) p<0.001 when compared with children with no siblings. Parents' educational level and having a single parent showed no significant association with fractures. The previously observed association between municipalities and fracture risk was less pronounced when taking family-level socioeconomic variables into account.

    Conclusion: Our results indicate that children from families with higher income and with siblings are at greater risk of sustaining fractures.

    Fulltekst (pdf)
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  • 17. Henricson, Anders
    et al.
    Wojtowicz, Radek
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Nilsson, Kjell G
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Uncemented or cemented femoral components work equally well in total knee arthroplasty2019Inngår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 27, nr 4, s. 1251-1258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To study the pattern of migration and clinical results up to 10 years of uncemented versus cemented fixation of the femoral component in total knee arthroplasty.

    METHODS: Randomized controlled trial was conducted of 41 patients (23 women, 18 men) under the age of 60 years using radiostereometric analysis.

    RESULTS: About two-thirds of the cemented implants and half of the uncemented implants stabilized between 2 and 10 years, while the remainder displayed a small annual increase of maximum total point motion of 0.09-0.10 mm/year. At 10 years there were no statistically significant differences in migration or clinical results between the groups.

    CONCLUSION: Uncemented fixation with titanium fiber mesh coating of the femoral component in total knee arthroplasty works equally as well as cemented fixation up to 10 years. An annual migration of 0.1 mm seems compatible with excellent long-term performance.

    LEVEL OF EVIDENCE: I.

  • 18.
    Hörnberg, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival2011Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 6, nr 4, s. e19059-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote  the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.

    Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from  40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.

    Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

    Fulltekst (pdf)
    fulltext
  • 19. Iglesias-Gato, Diego
    et al.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mann, Matthias
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Flores-Morales, Amilcar
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    The proteome of prostate cancer bone metastases2018Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 91-92Artikkel i tidsskrift (Annet vitenskapelig)
  • 20. Iglesias-Gato, Diego
    et al.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tyanova, Stefka
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Santos, Alberto
    Lima, Thiago S.
    Geiger, Tamar
    Cox, Juergen
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Mann, Matthias
    Flores-Morales, Amilcar
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications2018Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, nr 21, s. 5433-5444Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.

    Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.

    Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid b-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.

    Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. (C) 2018 AACR.

  • 21.
    Jernberg, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lundberg, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Molecular features of prostate cancer bone metastases harboring androgen receptor gene amplificationManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The relation between AR amplification and other mechanisms behind castration-resistance in prostate cancer, such as increased expression of AR splice variants and steroid-converting enzymes in CRPC metastases, has been poorly examined. Specific aims of this study were therefore to examine AR amplification in hormone-naïve and castration-resistant prostate cancer (CRPC) bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying molecular targets for treatment of CRPC bone metastases. AR amplification was assessed by fluorescence in situ hybridization and verified in 16 (53 %) of the CRPC bone metastases (n=30), and in none of the untreated bone metastases (n=10). AR amplification was associated with increased expression of AR and its constitutively active AR-V7 splice variant as well as with co-amplification of genes in the AR proximity at Xq12, such as of YIPF6. Furthermore, gene expression pattern pointed at decreased osteoclast activity, and consequently decreased bone resorption and increased bone mineral density in AR amplified metastases. In conclusion, our results indicated a sclerotic phenotype in CRPC bone metastases with AR amplification that may be of both biological and clinical relevance. This is a novel hypothesis that requires to be thoroughly examined.

  • 22.
    Jernberg, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rudolfsson, Stina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants2013Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 11, s. e77407-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated withcastration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels ofsteroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation toexpression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.

    Methodology/Principal Findings: Untreated, hormone-naıve (HN, n = 9) and CRPC bone metastases samples (n = 45) wereobtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry andimmunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases.Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases thanin non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNAlevels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which wasnot due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only oneexception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with highAKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individualbone metastases.

    Conclusions/Significance: Induced capacity of converting adrenal-gland derived steroids into more potent androgens wasindicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage ofmetastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs,which might be of relevance for patient response to 2nd line androgen-deprivation therapy.

    Fulltekst (pdf)
    fulltext
  • 23.
    Järemo, Helena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Semenas, Julius
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Halin Bergström, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-43282023Inngår i: Cancers, ISSN 2072-6694, Vol. 15, nr 9, artikkel-id 2437Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MicroRNAs (miRNAs) are aberrantly expressed in prostate cancer (PC), but comprehensive knowledge about their levels and function in metastatic PC is lacking. Here, we explored the differential expression of miRNA profiles during PC progression to bone metastasis, and further focused on the downregulation of miRNA-23c and -4328 and their impact on PC growth in experimental models. Using microarray screening, the levels of 1510 miRNAs were compared between bone metastases (n = 14), localized PC (n = 7) and benign prostate tissue (n = 7). Differentially expressed miRNAs (n = 4 increased and n = 75 decreased, p < 0.05) were identified, of which miRNA-1, -23c, -143-3p, -143-5p, -145-3p, -205-5p, -221-3p, -222-3p and -4328 showed consistent downregulation during disease progression (benign > localized PC > bone metastases). The downregulation of miRNA-23c and -4328 was confirmed by reverse transcription and quantitative polymerase chain reaction analysis of 67 metastasis, 12 localized PC and 12 benign prostate tissue samples. The stable overexpression of miRNA-23c and -4328 in the 22Rv1 and PC-3 cell lines resulted in reduced PC cell growth in vitro, and in the secretion of high levels of miRNA-23c (but not -4328) in extracellular vesicles. However, no tumor suppressive effects were observed from miRNA-23c overexpression in PC-3 cells subcutaneously grown in mice. In conclusion, bone metastases display a profound reduction of miRNA levels compared to localized PC and benign disease. The downregulation of those miRNAs, including miRNA-23c and -4328, may lead to a loss of tumor suppressive effects and provide biomarker and therapeutic possibilities that deserve to be further explored.

    Fulltekst (pdf)
    fulltext
  • 24.
    Järemo, Helena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Semenas, Julius
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Halin Bergström, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Freyhult, Eva
    Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Welén, Karin
    Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    The microRNA landscape of prostate cancer bone metastases and the role of miRNA-375 in modulating phenotypic characteristics of metastatic cellsManuskript (preprint) (Annet vitenskapelig)
  • 25.
    Kristoffersson, Emelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Otten, Volker T C
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    The accuracy of digital templating in cementless total hip arthroplasty in dysplastic hips2021Inngår i: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 22, nr 1, artikkel-id 942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH) is a complex procedure due to associated anatomical abnormalities. We studied the extent to which preoperative digital templating is reliable when performing cementless THA in patients with DDH.

    Methods: We templated and compared the pre- and postoperative sizes of the acetabular and femoral components and the center of rotation (COR), and analysed the postoperative cup coverage, leg length discrepancy (LLD), and stem alignment in 50 patients (56 hips) with DDH treated with THA.

    Results: The implant size exactly matched the template size in 42.9% of cases for the acetabular component and in 38.2% of cases for the femoral component, whereas the templated ±1 size was used in 80.4 and 81.8% of cases for the acetabular and femoral components, respectively. There were no statistically significant differences between templated and used component sizes among different DDH severity levels (acetabular cup: p = 0.30 under the Crowe classification and p = 0.94 under the Hartofilakidis classification; femoral stem: p = 0.98 and p = 0.74, respectively). There were no statistically significant differences between the planned and postoperative COR (p = 0.14 horizontally and p = 0.52 vertically). The median postoperative LLD was 7 (range 0–37) mm.

    Conclusion: Digital preoperative templating is reliable in the planning of cementless THA in patients with DDH.

    Fulltekst (pdf)
    fulltext
  • 26.
    Kruse, Mark
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mohammed, Jabbar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Sayed-Noor, Arkan
    Wolf, Olof
    Holmgren, Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Nordström, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Sköldenberg, Olof
    Mukka, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Peri-implant femoral fractures in hip fracture patients treated with osteosynthesis: a retrospective cohort study of 1965 patients2022Inngår i: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 48, s. 293-298Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE: There are few studies on incidence rates, treatment and outcomes for peri-implant femoral fractures (PIFF) in the proximity of osteosynthesis. The purpose of this study was to investigate the incidence of PIFF following osteosynthesis of proximal femoral fractures.

    PATIENTS AND METHODS: This retrospective cohort study comprised a consecutive series of hip fracture patients aged 50 years or older and operated with osteosynthesis between 2003 and 2015. Patients were followed-up until 2018, removal of implants or death, for a mean of 4 years (range 0-15). Data on age, sex, housing, hip complications, and reoperations were recorded. The risk of PIFFs was assessed using Cox proportional hazards regression analysis. In patients with two fractures during the study period, only the first fracture was included.

    RESULTS: A total of 1965 osteosynthesis procedures were performed, of which 382 were cephalomedullary nails (CMN), 933 sliding hip devices (SHD) and 650 pins. Mean age was 80 years (range 50-104), 65% of patients were women. A total of 41 PIFFs occurred during the study period. The cumulative incidence of peri-implant fractures was 0.8% for CMN, 2.7% (HR 2.995% CI, 0.87-9.6, p = 0.08) for SHD and 2.0% (HR 2.3 95% CI, 0.6-8.1, p = 0.2) for pins. PIFFs occurred after a mean of 27 months (range 0-143). The 1-year mortality was 34% following PIFF. The majority was treated surgically (66%, 27/41) and the reoperation rate was 15% (4/27).

    CONCLUSION: In this retrospective cohort study, in contrast to previous reports, we found a tendency to a higher cumulative incidence of PIFFs for SHD compared to modern CMN. Our results show cumulative incidences of PIFFs comparable to those described for periprosthetic femur fractures after hip arthroplasty for femoral neck fracture.

  • 27.
    Mahmood, Sarwar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Sundsvall and Norrland University Hospitals.
    Mukka, Sebastian S
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Sundsvall and Norrland University Hospitals.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Sundsvall and Norrland University Hospitals.
    Sayed-Noor, Arkan S
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Sundsvall and Norrland University Hospitals.
    The Influence of Leg Length Discrepancy after Total Hip Arthroplasty on Function and Quality of Life: a Prospective Cohort Study2015Inngår i: The Journal of Arthroplasty, ISSN 0883-5403, E-ISSN 1532-8406, Vol. 30, nr 9, s. 1638-1642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated whether patients with lengthening (> 9 mm), restoration (between 9 mm lengthening and 5 mm shortening) or shortening (> 5 mm) of the operated leg after total hip arthroplasty (THA) had different function (WOMAC score), quality of life (EQ-5D), residual hip pain, use of shoe lift and walking aid and leg length discrepancy (LLD) awareness, 12-15 months postoperatively. All patients had a significant postoperative improvement in WOMAC and EQ-5D regardless the LLD. However, the lengthening group showed less improvement in WOMAC, more use of shoe lift, residual hip pain and LLD awareness compared with the other two groups. No differences in EQ-5D were found. In spite of the improvement in function and quality of life, lengthening had adverse effects and should therefore be avoided.

  • 28.
    Mahmood, Sarwar S.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mukka, Sebastian S.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi. Sundsvall and Norrland University Hospitals.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Wretenberg, Per
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Sayed-Noor, Arkan S.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi. Sundsvall and Norrland University Hospitals.
    Association between changes in global femoral offset after total hip arthroplasty and function, quality of life, and abductor muscle strength: A prospective cohort study of 222 patients2016Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 87, nr 1, s. 36-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose - There is no consensus on the association between global femoral offset (FO) and outcome after total hip arthroplasty (THA). We assessed the association between FO and patients? reported hip function, quality of life, and abductor muscle strength.

    Patients and methods - We included 250 patients with unilateral hip osteoarthritis who underwent a THA. Before the operation, the patient?s reported hip function was evaluated with the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and quality of life was evaluated with EQ-5D. At 1-year follow-up, the same scores and also hip abductor muscle strength were measured. 222 patients were available for follow-up. These patients were divided into 3 groups according to the postoperative global FO of the operated hip compared to the contralateral hip, as measured on plain radiographs: the decreased FO group (more than 5 mm reduction), the restored FO group (within 5 mm restoration), and the increased FO group (more than 5 mm increment).

    Results - All 3 groups improved (p < 0.001). The crude results showed that the decreased FO group had a worse WOMAC index, less abductor muscle strength, and more use of walking aids. When we adjusted these results with possible confounding factors, only global FO reduction was statistically significantly associated with reduced abductor muscle strength. The incidence of residual hip pain and analgesics use was similar in the 3 groups.

    Interpretation - A reduction in global FO of more than 5 mm after THA appears to have a negative association with abductor muscle strength of the operated hip, and should therefore be avoided.

    Fulltekst (pdf)
    fulltext
  • 29.
    Morberg, Per
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Paradowski, Przemyslaw
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Röding, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Juto, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Sayed-Noor, Arkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Knutsson, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Wadsten, Mats
    Buttazzoni, Christian
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Nilsson, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Svensson, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Olofsson, Birgitta
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Häger, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering.
    Mukka, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Otten, Volker
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bobinski, Lukas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Åkerstedt, Josefin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Wänman, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Hedström, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bergström, Ulrica
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Toolanen, Göran
    Löfvenberg, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Edmundsson, David
    Hildingsson, Christer
    Elmqvist, Lars-Gunnar
    Ortopedisk forskning vid Umeå universitet2023Inngår i: Ortopediskt magasin, nr 1, s. 22-25Artikkel i tidsskrift (Fagfellevurdert)
  • 30.
    Nordstrand, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity2018Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 19, nr 4, artikkel-id 1223Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

    Fulltekst (pdf)
    fulltext
  • 31.
    Nordstrand, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bovinder-Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastasesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histological evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST), we found high osteoblast activity to be coupled to a high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2 positive osteoblasts and TRAP (ACP5) positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity within the tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histological evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserve further exploration.

  • 32.
    Otten, Volker T C
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Röhrl, Stephan M
    Nivbrant, Bo
    Nilsson, Kjell G
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Stability of Uncemented Cups - Long-Term Effect of Screws, Pegs and HA Coating: A 14-Year RSA Follow-Up of Total Hip Arthroplasty2016Inngår i: The Journal of Arthroplasty, ISSN 0883-5403, E-ISSN 1532-8406, Vol. 31, nr 1, s. 156-161Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Screws, pegs and hydroxyapatite-coating are used to enhance the primary stability of uncemented cups. We present a 14-year follow-up of 48 hips randomized to four groups: press-fit only, press-fit plus screws, press-fit plus pegs and hydroxyapatite-coated cups. Radiostereometric migration measurements showed equally good stability regardless cup augmentation. The mean wear rate was high, 0.21mm/year, with no differences between the groups. Seven hips had radiographical osteolysis but only in hips with augmented cups. Cups without screw-holes compared with cups with screw-holes resulted in better clinical outcome at the 14-year follow-up. Thus, augmentation of uncemented cups with screws, pegs, or hydroxyapatite did not appear to improve the long-term stability compared with press-fit only.

  • 33.
    Otten, Volker T C
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mukka, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Nilsson, Kjell G
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Kärrholm, Johan
    Uncemented cups with and without screw holes in primary THA: a Swedish Hip Arthroplasty Register study with 22,725 hips2019Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 90, nr 3, s. 258-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose — Uncemented cups in total hip arthroplasty (THA) are often augmented with additional screws to enhance their primary stability. We investigated whether there is a difference in the risk for revision between cups with screw holes and cups without screw holes.

    Patients and methods — We analyzed the risk for cup revision of uncemented cups registered in the Swedish Hip Arthroplasty Register (SHAR) between 2000 and 2017 with respe ct to the presence of screw holes. Only patients with primary osteoarthritis (OA) were included. 22,725 cups, including 12,354 without screw holes and 10,371 with screw holes, were evaluated. Revision rates at 2 and 10 years after the primary operation were analyzed.

    Results — At a median follow-up time of 3.4 years (0–18), 459 cup revisions were reported. The main reasons for cup revision during the whole observation time were infection, 52% of all cup revisions, and dislocation, 26% of all cup revisions. The survival rate with cup revision due to aseptic loosening as endpoint was 99.9% (95% CI 99.8–99.9) at 2 years for both cups with and cups without screw holes, and the survival rates at 10 years were 99.5% (CI 99.3–99.7) and 99.1% (CI 98.6–99.5), respectively. Cups without screw holes showed a decreased risk of revision due to any reason at both 2 years (adjusted hazard ratio [HR] 0.6, CI 0.5–0.8) and 10 years (HR 0.7, CI 0.5–0.9).

    Interpretation — We found a very low revision rate for aseptic loosening with modern, uncemented cup designs. Cups with screw holes had an increased risk of revision due to any reason in patients with primary OA

    Fulltekst (pdf)
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  • 34.
    Otten, Volker T C
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mukka, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Nilsson, Kjell G
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Kärrholm, Johan
    Uncemented cups with and without screw holes in primary THA: a Swedish Hip Arthroplasty Register study with 22725 hipsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background and purpose: Uncemented cups in total hip arthroplasty (THA) are often augmented with additional screws to enhance their primary stability. We investigated whether there is a difference in the risk for revision between cups with screw holes and cups without screw holes.

    Patients and methods: We analyzed the risk for cup revision of uncemented cups registered in the Swedish Hip Arthroplasty Register (SHAR) between 2000 and 2017 with respect to the presence of screw holes. Only patients with primary osteoarthritis (OA) were included. 22725 cups, including 12354 without screw holes and 10371 with screw holes, were evaluated. Revision rates at 2 and 10 years after the primary operation were analyzed.

    Results: At a median follow-up time of 3.4 (0-18) years, 459 cup revisions were reported. The main reasons for cup revision during the whole observations time were infection, 52% of all cup revisions, and dislocation, 26% of all cup revisions. The survival rate with cup revision due to aseptic loosening as endpoint was 99.9% (95% CI 99.8-99.9) at 2 years for both cups with and cups without screw holes, and the survival rates at 10 years were 99.5% (CI 99.3-99.7) and 99.1% (CI 98.6-99.5), respectively. Cups without screw holes showed a decreased risk of revision due to any reason at both 2 years (adjusted hazard ratio [HR] 0.6, CI 0.5-0.8) and 10 years (HR 0.7, CI 0.5-0.9).

    Interpretation: We found a very low revision rate for aseptic loosening with modern, uncemented cup designs. Cups with screw holes had an increased risk for revision due to any reason in patients with primary OA.

  • 35.
    Otten, Volker T C
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Stamenkov, Roumen
    Callary, Stuart A.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Howie, Donald W.
    Nilsson, Kjell G
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Osteolysis around uncemented cups withand without screw holes: Analysis of osteolytic lesions on CT images in 48 hips at a 14-year follow-upManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Osteolysis around uncemented cups is a major complication for THA. We present a 14-year follow-up of 48 hips previously randomized to four groups of cup fixation – sealed cups with press-fit only, cups with hydroxyapatite coating, cups with screws, and cups with pegs. CT scans revealed three types of osteolytic lesions – Type 1A (absence of trabecular bone and a sclerotic border), Type 1B (absence of trabecular bone without a sclerotic border), and Type 2 (reductions in radiodensity and trabeculae). Cups with screw-holes were surrounded with larger osteolytic lesions that were predominantly Type 1A. Unsealed screw holes in uncemented cups appeared to be a risk factor for osteolysis development. Modern CT scans reveal three types of osteolytic lesions. Distinction between types is important for comparability between studies.

  • 36.
    Otten, Volker
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Wästerlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Lindbjörn, John
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mertens, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Mukka, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Nilsson, Kjell G.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Evaluation of a new cemented highly cross-linked all-polyethylene cup: a prospective and randomised study assessing wear and fixation characteristics using radiostereometric analysis2022Inngår i: HIP International, ISSN 1120-7000, E-ISSN 1724-6067, Vol. 32, nr 6, s. 779-786Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE: The aim of this prospective, randomised and controlled study was to evaluate the wear and fixation properties of a new cemented highly cross-linked all-polyethylene (HXLPE) cup in comparison with a conventional cemented ultra-high molecular weight polyethylene (ConvPE) cup using radiostereometric analysis (RSA).

    PATIENTS AND METHODS: A total of 58 patients (58 hips) with primary osteoarthritis (OA) were enrolled in a randomised controlled trial to receive either a ConvPE cup (control) or HXLPE cup (intervention) with identical geometry. The subjects were randomised in a 1:1 ratio. The primary endpoint was proximal wear measured as femoral head penetration into the cup, secondary outcomes were 3D-wear and annual proximal wear from 1 to 5 years. Cup fixation was measured as movement of the cup in relation to the acetabular bone with proximal migration being the primary outcome measure, 3D-migration and change in inclination as secondary outcomes. The patients were followed for 5 years with RSA performed postoperatively, at 3, 12, 24, and 60 months.

    RESULTS: The HXLPE displayed a lower median proximal femoral head penetration compared to ConvPE, with a median difference at 2 years of -0.07 mm (95% CI, -0.10 to -0.04 mm), and -0.19 mm (95% CI, -0.27 to -0.15 mm) at 5 years. Annual proximal wear between 1 and 5 years was 0.03 mm/year for HXLPE and 0.06 mm/year for ConvPE (mean difference 0.05 mm, [95% CI, 0.03-0.07 mm]). Proximal migration, 3D migration and change in inclination was numerically slightly higher for HXLPE, albeit not statistically significant.

    CONCLUSIONS: Compared to ConvPE, the HXLPE cup displayed significantly lower polyethylene wear. Cup migration was not statistically significant different.

    CLINICALTRIALS.GOV IDENTIFIER: NCT04322799.