Publications by authors named "Otte Brosjø"

50 Publications

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

Eur J Cancer 2021 Jul 11;151:150-158. Epub 2021 May 11.

Department of Orthopaedics and Orthopaedic Oncology, University of Padova, Padova, Italy.

Introduction: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study.

Materials And Methods: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models.

Results: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles.

Conclusions: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.
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http://dx.doi.org/10.1016/j.ejca.2021.04.017DOI Listing
July 2021

Loss of NF2 defines a genetic subgroup of non-FOS-rearranged osteoblastoma.

J Pathol Clin Res 2020 10 16;6(4):231-237. Epub 2020 Jun 16.

Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.

Osteoblastoma is a locally aggressive tumour of bone. Until recently, its underlying genetic features were largely unknown. During the past two years, reports have demonstrated that acquired structural variations affect the transcription factor FOS in a high proportion of cases. These rearrangements modify the terminal exon of the gene and are believed to stabilise both the FOS transcript and the encoded protein, resulting in high expression levels. Here, we applied in-depth genetic analyses to a series of 29 osteoblastomas, including five classified as epithelioid osteoblastoma. We found recurrent homozygous deletions of the NF2 gene in three of the five epithelioid cases and in one conventional osteoblastoma. These events were mutually exclusive from FOS mutations. Structural variations were determined by deep whole genome sequencing and the number of FOS-rearranged cases was less than previously reported (10/23, 43%). One conventional osteoblastoma displayed a novel mechanism of FOS upregulation; bringing the entire FOS gene under the control of the WNT5A enhancer that is itself activated by FOS. Taken together, we show that NF2 loss characterises a subgroup of osteoblastomas, distinct from FOS-rearranged cases. Both NF2 and FOS are involved in regulating bone homeostasis, thereby providing a mechanistic link to the excessive bone growth of osteoblastoma.
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http://dx.doi.org/10.1002/cjp2.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578308PMC
October 2020

[Synovial sarcoma - a rare and highly malignant, tumor with an ambiguous clinical picture at times].

Lakartidningen 2020 01 16;117. Epub 2020 Jan 16.

Ortopedkliniken - Falu lasaret Falun, Sweden - ortopedkliniken, Falu Lasarett Falun, Sweden.

A characteristic feature of soft tissue sarcomas is the absence of alarm symptoms such as pain or abnormal laboratory findings. We present two patients where the diagnostic difficulties delayed the definitive diagnosis, in one case with lethal outcome. The two patients highlight the difficulties a clinician may encounter with this particular disease. Even though synovial sarcoma represents around 0,1 % of all cancer forms, we recommend a high degree of awareness and - when in doubt - prompt contact with a Sarcoma center for consultation.
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January 2020

Genetic profiling of a chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumor of bone reveals a homozygous deletion of CDKN2A, intragenic deletion of DMD, and a targetable FN1-FGFR1 gene fusion.

Genes Chromosomes Cancer 2019 10 15;58(10):731-736. Epub 2019 May 15.

Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.

Conventional osteosarcoma is the most common primary malignancy of bone. This group of neoplasms is subclassified according to specific histological features, but hitherto there has been no correlation between subtype, treatment, and prognosis. By in-depth genetic analyses of a chondroblastoma-like osteosarcoma, we detect a genetic profile that is distinct from those previously reported in benign and malignant bone tumors. The overall genomic copy number profile was less complex than that typically associated with conventional osteosarcoma, and there was no activating point mutation in any of H3F3A, H3F3B, IDH1, IDH2, BRAF, or GNAS. Instead, we found a homozygous CDKN2A deletion, a DMD microdeletion and an FN1-FGFR1 gene fusion. The latter alteration has been described in phosphaturic mesenchymal tumor. This tumor type shares some morphological features with chondroblastoma-like osteosarcoma and we cannot rule out that the present case actually represents an FN1-FGFR1 positive malignant phosphaturic mesenchymal tumor of bone without osteomalacia.
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http://dx.doi.org/10.1002/gcc.22764DOI Listing
October 2019

Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas.

Br J Cancer 2019 02 12;120(4):435-443. Epub 2019 Feb 12.

Department of Breast cancer, Endocrine tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden.

Background: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs.

Methods: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations.

Results: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient.

Conclusions: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.
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http://dx.doi.org/10.1038/s41416-018-0359-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462037PMC
February 2019

Preoperative radiotherapy of soft-tissue sarcomas: surgical and radiologic parameters associated with local control and survival.

Clin Sarcoma Res 2018 5;8:19. Epub 2018 Oct 5.

2Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Background: Preoperative radiotherapy is often used to facilitate excision of soft-tissue sarcomas. We aimed define factors that affect local tumour control and patient survival.

Methods: A single institution registry study of 89 patients with non-metastatic soft-tissue sarcomas having preoperative radiotherapy between 1994 and 2014. Radiologic (presence of peritumoural oedema and volume change following radiotherapy) and histopathologic (tumour volume, grade and surgical margin) parameters were recorded. Outcomes were the events of local recurrence, amputation, metastasis and death.

Results: Local recurrence rate was low (12%) and marginal excision gave equal local control to wide excision. Pelvic localization was associated with a higher risk for amputation. The absence of peritumoural oedema on MRI defined a subgroup of tumours with more favourable oncologic outcome. Reduction of tumour volume following radiotherapy was also associated with better patient survival. Both these radiologic parameters were associated with lower tumour grade. Tumour necrosis was not significant for patient survival. The local complication rate, mainly wound healing problems and infection, was high (40%), but did not lead to any amputation.

Conclusion: Preoperative radiotherapy of high-risk soft-tissue sarcomas allows for good local control rate at the expense of local wound complications, which are however manageable. Marginal excision is sufficient for local control. Absence of peritumoural oedema on MRI, as well as tumour size reduction following radiotherapy are associated to superior patient survival and can be used ass early prognostic factors.
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http://dx.doi.org/10.1186/s13569-018-0106-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172791PMC
October 2018

Different patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years.

Nat Commun 2018 09 10;9(1):3662. Epub 2018 Sep 10.

Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.

To compare clonal evolution in tumors arising through different mechanisms, we selected three types of sarcoma-amplicon-driven well-differentiated liposarcoma (WDLS), gene fusion-driven myxoid liposarcoma (MLS), and sarcomas with complex genomes (CXS)-and assessed the dynamics of chromosome and nucleotide level mutations by cytogenetics, SNP array analysis and whole-exome sequencing. Here we show that the extensive single-cell variation in WDLS has minor impact on clonal key amplicons in chromosome 12. In addition, only a few of the single nucleotide variants in WDLS were present in more than one lesion, suggesting that such mutations are of little significance in tumor development. MLS displays few mutations other than the FUS-DDIT3 fusion, and the primary tumor is genetically sometimes much more complex than its relapses, whereas CXS in general shows a gradual increase of both nucleotide- and chromosome-level mutations, similar to what has been described in carcinomas.
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http://dx.doi.org/10.1038/s41467-018-06098-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131146PMC
September 2018

EURO-B.O.S.S.: A European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma.

Tumori 2018 Jan-Feb;104(1):30-36

2 Stuttgart Cancer Center, Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Stuttgart - Germany.

Introduction: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma.

Methods: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators' choice were also eligible for the study.

Results: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity.

Conclusions: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.
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http://dx.doi.org/10.5301/tj.5000696DOI Listing
May 2018

The effect of radiotherapy on fat content and fatty acids in myxoid liposarcomas quantified by MRI.

Magn Reson Imaging 2017 11 8;43:37-41. Epub 2017 Jul 8.

Department of Medical Radiation Physics, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Background: Myxoid liposarcomas are highly radiosensitive. Consequently radiotherapy is often used pre-operatively to reduce tumor volume and lessen the post-operative deficit. In soft-tissue sarcomas therapy response is mainly evaluated using magnetic resonance imaging (MRI) and the fundamental criterion for a positive response is decreased tumor size. In myxoid liposarcomas an increased fat content is also known to occur as a response to radiotherapy.

Objective: To highlight the difficulties of MRI for therapy response evaluation in irradiated myxoid liposarcomas, by using MRI Dixon techniques enabling objective quantification of proton density fat fraction (%) and the number of double bonds (ndb; unsaturation degree) of fatty acids. Secondly, to compare quantitative fat fraction measurements versus visual grading of fat content on T1-weighted images.

Case Descriptions: Prior to surgery, two patients with myxoid liposarcoma were treated with 50Gy. Following radiotherapy, both tumors on MRI showed reduced size, elevated fat fraction and transformed fat fraction histograms with diverse changes of ndb, while histopathological specimens showed discordant treatment effects; one case having good response and the other having poor response.

Conclusions: A decrease in tumor size and increase in fat content on MRI cannot be interpreted as positive therapy response in radiotherapy of myxoid liposarcomas. Our data also give further supporting evidence that differentiation and maturation of tumor cells is the cause for the lipoma-like areas seen after radiotherapy. Finally, quantitative MRI Dixon techniques are preferable to visual grading for estimating the fat content in lipomatous tumors.
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http://dx.doi.org/10.1016/j.mri.2017.07.005DOI Listing
November 2017

Improved Prognosis for Patients with Ewing Sarcoma in the Sacrum Compared with the Innominate Bones: The Scandinavian Sarcoma Group Experience.

J Bone Joint Surg Am 2016 Feb;98(3):199-210

Department of Orthopaedic Surgery, Karolinska University Hospital, Solna, Sweden

Background: Treatment of Ewing sarcoma of the pelvic bones remains one of the most difficult tasks in the treatment of bone sarcomas. Whether surgery or radiation therapy is the best local treatment is still a matter of debate. The aim of the present study was to compare sacral and nonsacral sites with regard to the treatment and outcome of pelvic Ewing sarcomas.

Methods: Patients with Ewing sarcoma of the osseous pelvis diagnosed between 1986 and 2011 were identified through the Scandinavian Sarcoma Group registry. Data regarding tumor size, local treatment (surgery or radiation therapy), metastatic disease, surgical margins, local recurrence, and overall survival were analyzed.

Results: Of the 117 patients examined, eighty-eight had tumors in the innominate bones and twenty-nine, in the sacrum. Radiation therapy was the sole local treatment for 40% of the innominate bone tumors in contrast to 79% of the sacral tumors. The five-year disease-free survival rate in the latter group (66%) was greater than that in the group with tumors in the innominate bones (40%) (p = 0.02 adjusted for size).

Conclusions: Disease-free survival among patients with Ewing sarcoma was improved when the tumor was localized in the sacrum compared with the innominate bones, where these tumors are generally larger. Local radiation therapy alone appears to result in good local tumor control and may be the treatment of choice for sacral tumors.
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http://dx.doi.org/10.2106/JBJS.O.00362DOI Listing
February 2016

Current Strategies for the Treatment of Aneurysmal Bone Cysts.

Orthop Rev (Pavia) 2015 Dec 28;7(4):6182. Epub 2015 Dec 28.

Department of Orthopedics, Karolinska University Hospital , Stockholm, Sweden.

Aneurysmal bone cysts are benign bone tumors that usually present in childhood and early adulthood. They usually manifest as expansile osteolytic lesions with a varying potential to be locally aggressive. Since their first description in 1942, a variety of treatment methods has been proposed. Traditionally, these tumors were treated with open surgery. Either intralesional surgical procedures or en bloc excisions have been described. Furthermore, a variety of chemical or physical adjuvants has been utilized in order to reduce the risk for local recurrence after excision. Currently, there is a shift to more minimally invasive procedures in order to avoid the complications of open surgical excision. Good results have been reported during percutaneous surgery, or the use of embolization. Recently, sclerotherapy has emerged as a promising treatment, showing effective consolidation of the lesions and functional results that appear to be superior to the ones of open surgery. Lastly, non-invasive treatment, such as pharmaceutical intervention with denosumab or bisphosphonates has been reported to be effective in the management of the disease. Radiotherapy has also been shown to confer good local control, either alone or in conjunction to other treatment modalities, but is associated with serious adverse effects. Here, we review the current literature on the methods of treatment of aneurysmal bone cysts. The indication for each type of treatment along reported outcome of the intervention, as well as potential complications are systematically presented. Our review aims to increase awareness of the different treatment modalities and facilitate decision-making regarding each individual patient.
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http://dx.doi.org/10.4081/or.2015.6182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703914PMC
December 2015

Femoral Metastasis from Penile Carcinoma: Report of 2 Cases.

Case Rep Urol 2015 22;2015:583851. Epub 2015 Oct 22.

Section of Orthopedics, Department of Molecular Medicine and Surgery, Karolinska Institute, 17176 Stockholm, Sweden ; Department of Orthopaedics, Karolinska University Hospital, 17176 Stockholm, Sweden.

Purpose. Penile cancer rarely gives symptomatic skeletal metastases. Methods. We present 2 patients with squamous carcinoma of the penis who were surgically treated for metastases in the femur. Results. Both patients had pathological fractures and were operated on. In one case, the skeletal metastasis preceded any lymphatic spread of the disease, suggesting early haematogenous dissemination. Conclusions. Endoprosthetic reconstruction resulted in pain relief and restored the ambulatory capacity. Clinicians should be aware of the possibility for symptomatic bone metastases with a risk for pathological fracture in patients with penile cancer.
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http://dx.doi.org/10.1155/2015/583851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633545PMC
November 2015

Reconstruction of metastatic acetabular defects using a modified Harrington procedure.

Acta Orthop 2015 28;86(6):690-4. Epub 2015 Jul 28.

a Section of Orthopaedics, Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Orthopaedics, Karolinska University Hospital , Stockholm, Sweden.

Background And Purpose: Metastases engaging the acetabulum result in significant disability. We investigated the outcome after curettage and reconstruction of the defect with a protrusio cage, retrograde screws, and a cemented total hip arthroplasty.

Patients And Methods: We retrospectively identified 70 consecutive patients who were surgically treated for metastatic disease of the acetabulum between 1995 and 2012 using the above technique. The type of primary tumor, extent of the disease, degree of acetabular erosion, and type of implant used were identified. Patient and implant survival, complications, and functional outcome were recorded.

Results: There were no mortalities in the perioperative period (30 days after surgery). Median overall patient survival was 12 months. Prosthesis survival was 92% at 1 year and 89% at 5 years. One third of the patients suffered a complication, the most frequent one being dislocation. The functional outcome was good. Multiple skeletal or visceral metastases and specific types of cancer were associated with poor patient survival.

Interpretation: Reconstruction of metastatic acetabular defects using a protrusio cage stabilized with retrograde screws and a cemented total hip arthroplasty is a safe procedure that provides efficient relief of symptoms. Patients with extensive disease, especially when diagnosed with specific types of cancer, have a very poor prognosis. The complication rate is substantial, the most frequent being dislocation. However, revision surgery is seldom required and prosthesis survival is high.
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http://dx.doi.org/10.3109/17453674.2015.1077308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750768PMC
April 2016

Prognostic factors and follow-up strategy for superficial soft-tissue sarcomas: Analysis of 622 surgically treated patients from the scandinavian sarcoma group register.

J Surg Oncol 2015 Jun 3;111(8):951-6. Epub 2015 Jun 3.

Section of Orthopaedics, Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden.

Background And Objectives: Our study aimed to describe the clinical outcome of patients with superficial soft-tissue sarcomas (SSTS), define prognostic factors and provide evidence for a rational surveillance scheme.

Methods: Data for 622 consecutive, surgically treated SSTS patients were retrieved from the Scandinavian Sarcoma Group Register. We assessed the rates of local recurrence (LR) and metastasis (M), as well as overall survival (OS), local recurrence free-survival (LRFS) and metastasis-free survival (MFS) of the cohort.

Results: The incidence of LR and M was 9% and 12%, respectively. OS at 5 years was 79%, LRFS was 74% and MFS 76%. Factors that affected OS, LRFS, and MFS were tumor size and patient age. Additionally, tumor grade was an independent prognostic factor for LRFS. The majority of LR and M events were observed the first 2 years of follow-up. Clear surgical margins were correlated to lower risk for LR. Selected patients benefited from adjuvant radiotherapy.

Conclusions: SSTS have a favourable prognosis, which is mainly determined by tumour-associated factors. Adequate surgical margins are important for local control, whereas radiotherapy has a secondary role. The data support current surveillance schemes, with a closer follow-up the first 2 years after surgery.
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http://dx.doi.org/10.1002/jso.23927DOI Listing
June 2015

Reconstruction with modular megaprostheses for sarcomas of the lower extremity.

Orthopedics 2015 May;38(5):e401-6

Limb-preserving surgery using modular megaprostheses for the reconstruction of large skeletal defects is currently the preferred treatment for sarcomas. The authors report the postoperative outcomes after skeletal resection for lower extremity sarcomas and the use of the METS cemented modular implant system (Stanmore Implants, Hertfordshire, United Kingdom) for reconstruction. They retrospectively studied 52 consecutive patients operated on from 2003 to 2012. There were 27 distal femur prostheses, 13 proximal femur, 11 proximal tibia, and 1 total femur implants. Patients were followed for a mean of 4.3 years. Overall patient survival, prosthesis survival, limb salvage rate, and secondary complications were documented. Five years postoperatively, prosthesis survival was 79%. Complications warranting implant revision surgery were documented in 15% of patients, whereas complications warranting surgery of any kind were observed in 27% of the patients. Nonmechanical complications, namely local relapse of the tumor and prosthetic infection, were the most common cause of prosthetic failure, accounting for 88% of major revision surgeries and 100% of amputations. Mechanical complications were rare, observed in only 6% of patients. No patients required secondary revision surgery. The limb salvage rate was 89%. Overall patient survival was 79% at 5 years and 71% at 10 years. The low risk for mechanical complications and the high limb salvage rate support the use of the METS modular megaprostheses for the reconstruction of skeletal defects following lower limb sarcoma surgery.
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http://dx.doi.org/10.3928/01477447-20150504-57DOI Listing
May 2015

Giant hydatid cyst of the pelvis, femur and retroperitoneal space: surgical treatment with extended hemipelvectomy.

BMJ Case Rep 2015 May 12;2015. Epub 2015 May 12.

Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden.

Hydatid disease of the bone is a very rare manifestation of the disease, and is often associated with debilitating symptoms. We present a rare case of skeletal hydatidosis in a 56-year-old man who had been misdiagnosed for many years. Massive involvement of the pelvic bones and soft tissues was evident. An extended hemipelvectomy was performed in order to achieve resection of the affected segments with a clear surgical margin. The patient recovered uneventfully and there are no signs of recurrence of the disease.
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http://dx.doi.org/10.1136/bcr-2015-209715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434284PMC
May 2015

RNA sequencing of sarcomas with simple karyotypes: identification and enrichment of fusion transcripts.

Lab Invest 2015 Jun 13;95(6):603-9. Epub 2015 Apr 13.

Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.

Gene fusions are neoplasia-associated mutations arising from structural chromosomal rearrangements. They have a strong impact on tumor development and constitute important diagnostic markers. Malignant soft tissue tumors (sarcomas) constitute a heterogeneous group of neoplasms with >50 distinct subtypes, each of which is rare. In addition, there is considerable morphologic overlap between sarcomas and benign lesions. Several subtypes display distinct gene fusions, serving as excellent biomarkers. The development of methods for deep sequencing of the complete transcriptome (RNA-Seq) has substantially improved the possibilities for detecting gene fusions. With the aim of identifying new gene fusions of biological and clinical relevance, eight sarcomas with simple karyotypes, ie, only one or a few structural rearrangements, were subjected to massively parallel paired-end sequencing of mRNA. Three different algorithms were used to identify fusion transcripts from RNA-Seq data. Three novel (KIAA2026-NUDT11, CCBL1-ARL1, and AFF3-PHF1) and two previously known fusions (FUS-CREB3L2 and HAS2-PLAG1) were found and could be verified by other methods. These findings show that RNA-Seq is a powerful tool for detecting gene fusions in sarcomas but also suggest that it is advisable to use more than one algorithm to analyze the output data as only two of the confirmed fusions were reported by more than one of the gene fusion detection software programs. For all of the confirmed gene fusions, at least one of the genes mapped to a chromosome band implicated by the karyotype, suggesting that sarcomas with simple karyotypes constitute an excellent resource for identifying novel gene fusions.
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http://dx.doi.org/10.1038/labinvest.2015.50DOI Listing
June 2015

[Most musculoskeletal soft tissue tumors are benign].

Lakartidningen 2014 Sep 17-23;111(38):1578-80

Most musculoskeletal soft tissue tumors are benign, lipoma being the most common. Malignant soft tissue tumors may be difficult to clinically distinguish from benign. Scandinavian recommendations are that all lesions suspicious for sarcoma be referred to a sarcoma center. This has led to improved tumor control and less post-operative functional deficits. Magnetic resonance imaging (MRI) can reliably diagnose lipomas, and further work-up is not necessary. Lipomas can be treated at the local hospital. All deep seated musculoskeletal tumors (under the muscle fascia) not unequivocally lipomas should be referred to a sarcoma center. All superficial (subcutaneous) musculoskeletal tumors larger than 5 cm and not unequivocally lipomas should be referred to a sarcoma center.
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February 2015

Treatment of an aggressive aneurysmal bone cyst with percutaneous injection of polidocanol: a case report.

J Med Case Rep 2014 Dec 20;8:450. Epub 2014 Dec 20.

Section of Orthopaedics, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm S-17176, Sweden.

Introduction: Aneurysmal bone cysts are benign tumours that usually present in childhood. Aggressive forms have been described, which are often treated with surgery that entails major resection and reconstruction. Polidocanol sclerotherapy has recently been reported to have excellent results and promises to replace operative treatments, but its efficacy in the case of aggressive aneurysmal bone cysts has not been documented.

Case Presentation: An 18-year-old woman from Sweden presented with pain in her shoulder and a rapidly progressing cystic bone lesion. The differential diagnosis was a rare, aggressive form of aneurysmal bone cyst or a sarcoma of the proximal humerus. She was successfully treated using sequential percutaneous injections of polidocanol after exclusion of malignancy.

Conclusions: Management of aggressive aneurysmal bone cysts has thus far relied on open surgery. We propose that non-operative treatment with polidocanol is efficient even in the aggressive form of the aneurysmal bone cyst.
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http://dx.doi.org/10.1186/1752-1947-8-450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307636PMC
December 2014

Recurrent PRDM10 gene fusions in undifferentiated pleomorphic sarcoma.

Clin Cancer Res 2015 Feb 16;21(4):864-9. Epub 2014 Dec 16.

Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.

Purpose: Undifferentiated pleomorphic sarcoma (UPS) is defined as a sarcoma with cellular pleomorphism and no identifiable line of differentiation. It is typically a high-grade lesion with a metastatic rate of about one third. No tumor-specific rearrangement has been identified, and genetic markers that could be used for treatment stratification are lacking. We performed transcriptome sequencing (RNA-Seq) to search for novel gene fusions.

Experimental Design: RNA-Seq, FISH, and/or various PCR methodologies were used to search for gene fusions and rearrangements of the PRDM10 gene in 84 soft tissue sarcomas.

Results: Using RNA-Seq, two cases of UPS were found to display novel gene fusions, both involving the transcription factor PRDM10 as the 3' partner and either MED12 or CITED2 as the 5' partner gene. Further screening of 82 soft tissue sarcomas for rearrangements of the PRDM10 locus revealed one more UPS with a MED12/PRDM10 fusion. None of these genes has been implicated in neoplasia-associated gene fusions before.

Conclusions: Our results suggest that PRDM10 fusions are present in around 5% of UPS. Although the fusion-positive cases in our series showed the same nuclear pleomorphism and lack of differentiation as other UPS, it is noteworthy that all three were morphologically low grade and that none of the patients developed metastases. Thus, PRDM10 fusion-positive sarcomas may constitute a clinically important subset of UPS.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2399DOI Listing
February 2015

Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma.

Int J Biochem Cell Biol 2014 Aug 8;53:475-81. Epub 2014 Apr 8.

Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden. Electronic address:

Benign fibrous histiocytoma (BFH) is a mesenchymal tumor that most often occurs in the skin (so-called dermatofibroma), but may also appear in soft tissues (so-called deep BFH) and in the skeleton (so-called non-ossifying fibroma). The origin of BFH is unknown, and it has been questioned whether it is a true neoplasm. Chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism arrays, RNA sequencing, RT-PCR and quantitative real-time PCR were used to search for recurrent somatic mutations in a series of BFH. BFHs were found to harbor recurrent fusions of genes encoding membrane-associated proteins (podoplanin, CD63 and LAMTOR1) with genes encoding protein kinase C (PKC) isoforms PRKCB and PRKCD. PKCs are serine-threonine kinases that through their many phosphorylation targets are implicated in a variety of cellular processes, as well as tumor development. When inactive, the amino-terminal, regulatory domain of PKCs suppresses the activity of their catalytic domain. Upon activation, which requires several steps, they typically translocate to cell membranes, where they interact with different signaling pathways. The detected PDPN-PRKCB, CD63-PRKCD and LAMTOR1-PRKCD gene fusions are all predicted to result in chimeric proteins consisting of the membrane-binding part of PDPN, CD63 or LAMTOR1 and the entire catalytic domain of the PKC. This novel pathogenetic mechanism should result in constitutive kinase activity at an ectopic location. The results show that BFH indeed is a true neoplasm, and that distorted PKC activity is essential for tumorigenesis. The findings also provide means to differentiate BFH from other skin and soft tissue tumors. This article is part of a Directed Issue entitled: Rare cancers.
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http://dx.doi.org/10.1016/j.biocel.2014.03.027DOI Listing
August 2014

Recurrent chromosome 22 deletions in osteoblastoma affect inhibitors of the Wnt/beta-catenin signaling pathway.

PLoS One 2013 13;8(11):e80725. Epub 2013 Nov 13.

Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.

Osteoblastoma is a bone forming tumor with histological features highly similar to osteoid osteoma; the discrimination between the tumor types is based on size and growth pattern. The vast majority of osteoblastomas are benign but there is a group of so-called aggressive osteoblastomas that can be diagnostically challenging at the histopathological level. The genetic aberrations required for osteoblastoma development are not known and no genetic difference between conventional and aggressive osteoblastoma has been reported. In order to identify recurrent genomic aberrations of importance for tumor development we applied cytogenetic and/or SNP array analyses on nine conventional and two aggressive osteoblastomas. The conventional osteoblastomas showed few or no acquired genetic aberrations while the aggressive tumors displayed heavily rearranged genomes. In one of the aggressive osteoblastomas, three neighboring regions in chromosome band 22q12 were homozygously deleted. Hemizygous deletions of these regions were found in two additional cases, one aggressive and one conventional. In total, 10 genes were recurrently and homozygously lost in osteoblastoma. Four of them are functionally involved in regulating osteogenesis and/or tumorigenesis. MN1 and NF2 have previously been implicated in the development of leukemia and solid tumors, and ZNRF3 and KREMEN1 are inhibitors of the Wnt/beta-catenin signaling pathway. In line with deletions of the latter two genes, high beta-catenin protein expression has previously been reported in osteoblastoma and aberrations affecting the Wnt/beta-catenin pathway have been found in other bone lesions, including osteoma and osteosarcoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080725PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827481PMC
July 2014

Sclerotherapy with polidocanol for treatment of aneurysmal bone cysts.

Acta Orthop 2013 Oct 31;84(5):502-5. Epub 2013 Oct 31.

Orthopaedics Section, Department of Molecular Medicine and Surgery , Karolinska Institute and Department of Orthopaedics, Karolinska University Hospital, Stockholm , Sweden.

Background And Purpose: Recent data suggest that percutaneous sclerotherapy is a safe alternative to surgery for treatment of aneurysmal bone cysts (ABCs). We present our experience of this method.

Methods: We retrospectively analyzed data from 38 consecutive patients treated with repeated injections of polidocanol. Each injection consisted of 2-4 mg polidocanol per kg body weight. Radiological and clinical assessments were performed until healing.

Results: All cycts except 1 healed after a median of 4 (1-11) injections. A lesion failed to heal in 1 patient, who was operated. 3 patients experienced minor local inflammatory reactions.

Interpretation: Our results show that percutaneus sclerotherapy with polidocanol has high efficacy in the treatment of ABCs, with a low frequency of side effects. Our findings corroborate data presented in previous publications. We believe that the method will be especially valuable in ABCs of the pelvis and sacrum, where surgery is associated with considerable morbidity.
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http://dx.doi.org/10.3109/17453674.2013.850013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822137PMC
October 2013

Integrative genome and transcriptome analyses reveal two distinct types of ring chromosome in soft tissue sarcomas.

Hum Mol Genet 2014 Feb 26;23(4):878-88. Epub 2013 Sep 26.

Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, 221 84 Lund, Sweden.

Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of ring chromosomes. Such structures are mitotically unstable and during tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many ring-containing tumors remains poorly characterized. Ring chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization (FISH), global genomic copy number and gene expression data on ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of ring chromosome: MDM2-positive and MDM2-negative rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative rings commonly show complete loss of either CDKN2A or RB1 -both known to be important for genome integrity. Sarcomas with MDM2-positive rings instead show co-amplification of a variety of potential driver oncogenes. More than 100 different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets.
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http://dx.doi.org/10.1093/hmg/ddt479DOI Listing
February 2014

Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor.

Genes Chromosomes Cancer 2013 Oct 12;52(10):873-86. Epub 2013 Jun 12.

Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.

Solitary fibrous tumor (SFT) is a mesenchymal neoplasm displaying variable morphologic and clinical features. To identify pathogenetically important genetic rearrangements, 44 SFTs were analyzed using a variety of techniques. Chromosome banding and fluorescence in situ hybridization (FISH) showed recurrent breakpoints in 12q13, clustering near the NAB2 and STAT6 genes, and single nucleotide polymorphism array analysis disclosed frequent deletions affecting STAT6. Quantitative real-time PCR revealed high expression levels of the 5'-end of NAB2 and the 3'-end of STAT6, which at deep sequencing of enriched DNA corresponded to NAB2/STAT6 fusions. Subsequent reverse-transcriptase PCR (RT-PCR) analysis identified a NAB2/STAT6 fusion in 37/41 cases, confirming that this fusion gene underlies the pathogenesis of SFT. The hypothesis that the NAB2/STAT6 fusions will result in altered properties of the transcriptional co-repressor NAB2--a key regulator of the early growth response 1 (EGR1) transcription factor - was corroborated by global gene expression analysis; SFTs showed deregulated expression of EGR1 target genes, as well as of other, developmentally important genes. We also identified several nonrandom secondary changes, notably loss of material from 13q and 14q. As neither chromosome banding nor FISH analysis identify more than a minor fraction of the fusion-positive cases, and because multiple primer combinations are required to identify all possible fusion transcripts by RT-PCR, alternative diagnostic markers might instead be found among deregulated genes identified at global gene expression analysis. Indeed, using immunohistochemistry on tissue microarrays, the top up-regulated gene, GRIA2, was found to be differentially expressed also at the protein level.
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http://dx.doi.org/10.1002/gcc.22083DOI Listing
October 2013

Megaprosthetic reconstruction for periprosthetic or highly comminuted fractures of the hip and knee.

Eur J Orthop Surg Traumatol 2014 May 21;24(4):553-7. Epub 2013 May 21.

Department of Orthopaedic Surgery, Sundsvall Teaching Hospital, 85186, Sundsvall, Sweden.

Objectives: To present the experience of a tertiary referral hospital in the management of a case series with hip or knee fractures by using modular megaprosthesis.

Patients And Methods: Seventeen consecutive patients with highly comminuted fractures of the knee (n = 2), periprosthetic fractures of knee (n = 10) or hip (n = 5) were included. Fractures were managed with modular megaprosthesis (including total hip in 2 cases). Postoperative complications like infection and instability and outcome measures like return to previous mobility and living were recorded.

Results: The mean age at time of surgery was 77 years (25-91), and mean follow-up was 44 months (13-98). We had no intra-operative complications. There were 3 deep periprosthetic infections, 1 hip and 2 knee. In the hip group, including total femur patients, we had 2 dislocations (2/7), both managed with closed reduction. No aseptic loosening was seen. 15/17 patients regained walking ability, and 16 were discharged to independent living. Nine patients have died at the time of follow-up.

Conclusions: In these often old and physically compromised patients with highly comminuted fractures or complicated periprosthetic fractures, modular megaprosthesis could be a good surgical option. It can provide immediate stability and allow early mobilization.
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http://dx.doi.org/10.1007/s00590-013-1237-7DOI Listing
May 2014

A benign vascular tumor with a new fusion gene: EWSR1-NFATC1 in hemangioma of the bone.

Am J Surg Pathol 2013 Apr;37(4):613-6

Department of Clinical Genetics, University Hospital, Lund, Sweden.

The EWSR1 gene in chromosome band 22q12 is a promiscuous fusion partner involved in a vast array of tumors characterized by gene fusions. In this study, we report the finding of a new fusion gene, EWSR1-NFATC1, in a hemangioma of the bone; genetic rearrangements have not previously been described in this tumor type. Chromosome banding analysis showed a t(18;22)(q23;q12) translocation as the sole change. Fluorescence in situ hybridization mapping suggested the involvement of each of the 2 partner genes, and reverse transcriptase polymerase chain reaction revealed an in-frame EWSR1-NFATC1 transcript. NFATC1 has not previously been shown to be involved in a fusion chimera. However, NFATC2, encoding another member of the same protein family, is known to be a fusion partner for EWSR1 in a subgroup of Ewing sarcoma. Thus, our findings further broaden the spectrum of neoplasms associated with EWSR1 fusion genes, add a new partner to the growing list of EWSR1 chimeras, and suggest that chromosomal rearrangements of pathogenetic, and possibly also diagnostic, significance can be present in benign vascular bone tumors.
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http://dx.doi.org/10.1097/PAS.0b013e31827ae13bDOI Listing
April 2013

[Hemicorporectomy can give life back].

Lakartidningen 2013 Jan 16-22;110(3):90-1

Karolinska universitetssjukhuset i Solna.

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April 2013

SNP array and FISH findings in two pleomorphic hyalinizing angiectatic tumors.

Cancer Genet 2012 Dec 22;205(12):673-6. Epub 2012 Nov 22.

Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare soft tissue tumor of intermediate malignancy and uncertain cellular origin and lineage of differentiation. Although PHAT is still poorly characterized at the genetic level, there is a potential genetic overlap with two other soft tissue tumors: myxoinflammatory fibroblastic sarcoma (MIFS) and hemosiderotic fibrolipomatous tumor (HFLT); MIFS and HFLT share a characteristic t(1;10)(p22;q24) with breakpoints in the TGFBR3 locus on chromosome 1 and near the MGEA5 locus on chromosome 10. Recently, a PHAT with a similar t(1;10) was reported, suggesting a genetic link between MIFS/HFLT and PHAT. To ascertain whether PHAT is also associated with this translocation, two cases were subjected to single nucleotide polymorphism (SNP) array and fluorescence in situ hybridization analyses. Neither PHAT showed a t(1;10) or other types of rearrangement of the TGFBR3 or MGEA5 loci. Both tumors showed imbalances in the SNP array analysis, but none was shared. Thus, the results indicate that PHAT is genetically distinguishable from MIFS and HFLT, but further studies are needed to identify the salient genetic pathways involved in PHAT development.
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http://dx.doi.org/10.1016/j.cancergen.2012.10.008DOI Listing
December 2012

Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma.

Neoplasia 2012 Sep;14(9):807-12

Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.

Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2% to 0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, single-nucleotide polymorphism (SNP) array, and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21, and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels; disomic chromosomes showed higher gene expression levels than monosomic chromosomes, a finding that has not previously been reported for hyperhaploid tumors. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression achieved through massive loss of other chromosomes are essential features of ILMS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459276PMC
http://dx.doi.org/10.1593/neo.12930DOI Listing
September 2012