Publications by authors named "Bodil Bjerkehagen"

94 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

Clinical and molecular implications of NAB2-STAT6 fusion variants in solitary fibrous tumour.

Pathology 2021 Mar 18. Epub 2021 Mar 18.

Department of Tumour Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. Electronic address:

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm characterised by pathognomonic NAB2-STAT6 gene fusions. The clinical implications and prognostic value of different fusion variants has not been clarified. In the current study, we explore the clinicopathological, prognostic and molecular differences between tumours with different fusions. Thirty-nine patients with localised, extrameningeal SFT were included, of whom 20 developed distant recurrence and 19 were without recurrence after long term follow-up. Capture-based RNA sequencing identified 12 breakpoint variants, which were categorised into two groups based on the STAT6 domain composition in the predicted chimeric proteins. Twenty-one of 34 (62%) sequenced tumours had fusions with most of the STAT6 domains intact and were classified as STAT6-Full. Thirteen tumours (38%) contained only the transactivation domain of STAT6 and were classified as STAT6-TAD. Tumours with STAT6-TAD fusions had a higher mitotic count (p=0.016) and were associated with inferior recurrence-free interval (p=0.004) and overall survival (p=0.012). Estimated 10-year recurrence-free survival was 25% for patients with STAT6-TAD tumours compared to 78% for the STAT6-Full group. Distinct transcriptional signatures between the fusion groups were identified, including higher expression of FGF2 in the STAT6-TAD group and IGF2, EGR2, PDGFRB, STAT6 and several extracellular matrix genes in STAT6-Full tumours. In summary, we demonstrate that NAB2-STAT6 fusion variants are associated with distinct clinicopathological and molecular characteristics and have prognostic significance in extrameningeal SFT.
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http://dx.doi.org/10.1016/j.pathol.2020.11.010DOI Listing
March 2021

Primary uterine ectomesenchymoma harboring a DICER1 mutation: case report with molecular analysis.

Virchows Arch 2021 Feb 17. Epub 2021 Feb 17.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway.

Ectomesenchymoma is an exceedingly rare biphasic malignant tumor characterized by the presence of mesenchymal and neuroectodermal elements. The majority of patients are infants or children. We describe the first case of this entity diagnosed as a primary uterine tumor. A 72-year-old female presented with post-menopausal bleeding. Dilatation and curettage showed irregular mesenchymal proliferation of uncertain nature. In the hysterectomy specimen, a myxoid spindle cell tumor with areas of skeletal muscle and neural differentiation was found in the uterus, with direct invasion of the small intestine, and biphasic differentiation into rhabdomyosarcoma and ganglioneuroblastoma was unequivocally seen in a lymph node metastasis. The morphological findings were validated by immunohistochemistry. Massive parallel sequencing identified TP53, PTEN, and DICER1 mutations in the tumor. This report describes the presence of ectomesenchymoma in an unusual primary organ and in an uncharacteristic age and presents novel data regarding the genetic characteristics of this tumor.
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http://dx.doi.org/10.1007/s00428-021-03057-xDOI Listing
February 2021

Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study.

Clin Sarcoma Res 2020 Nov 17;10(1):22. Epub 2020 Nov 17.

Department of Oncology, Skåne University Hospital, and Lund University, Lund, Sweden.

Background: We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B.

Methods: Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m) and ifosfamide (6 g/m), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks intervals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented.

Results: Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3-10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7-77.4). The median follow-up time was 5.4 years (range 0.3-10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8-89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed surgery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3).

Conclusions: Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing problems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39.
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http://dx.doi.org/10.1186/s13569-020-00145-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672981PMC
November 2020

Cytogenetic and Molecular Study of an Adult Sclerosing Rhabdomyosarcoma of the Extremity: -mutation and Clonal Evolution.

Cancer Genomics Proteomics 2020 Sep-Oct;17(5):563-569

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background: Spindle cell/sclerosing rhabdomyosarcoma is a genomically heterogeneous, uncommon subtype of rhabdomyosarcoma, particularly rare in adults. Its MYOD1-mutant variant is aggressive irrespective of age. Cytogenetic data on spindle cell/sclerosing rhabdomyosarcoma are sparse and disparate.

Materials And Methods: Cytogenetic and molecular analyses were performed on an adult sclerosing rhabdomyosarcoma.

Results: The karyotype of the sclerosing rhabdomyosarcoma displayed clonal evolution corresponding to two hyperdiploid clones: 48,XY,+i(19)(p10),+22/48,idem,der(9)t(2;9)(q21~22;p21). The changes were gain of chromosome 19 with the overrepresentation of 19p arm, gain of chromosome 22, gain of the 2q arm, and loss of 9p21. Mutation analysis revealed a homozygous c.T365G (p.L122R) mutation of the MYOD1 gene, but none of PIK3CA.

Conclusion: To our knowledge, this is the first adult MYOD1-mutant sclerosing rhabdomyosarcoma studied cytogenetically. The only other reported sclerosing rhabdomyosarcoma with MYOD1 mutation and abnormal karyotype was pediatric. Since these tumors are highly aggressive, further studies unravelling their cytogenetic and molecular characteristics are warranted.
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http://dx.doi.org/10.21873/cgp.20212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472446PMC
May 2021

Accurate 3-gene-signature for early diagnosis of liposarcoma progression.

Clin Sarcoma Res 2020 5;10. Epub 2020 Mar 5.

1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Ullernchausséen 70, 0379 Oslo, Norway.

Background: Well- and dedifferentiated liposarcoma (WD/DDLPS) are rare mesenchymal malignant tumors that account for 20% of all sarcomas in adults. The WD form is a low-grade malignancy with a favourable prognosis which may progress to DDLPS, a high-grade aggressive counterpart. WDLPS is referred to as atypical lipomatous tumour (ALT) when localised in extremities, due to its better prognosis. Currently the final differential diagnosis to distinguish between more aggressive and less aggressive form is based on post-surgical histological examination and no molecular biomarkers for early detection are available.

Methods: Quantitative polymerase chain reaction (qPCR) analysis of 11 metabolic genes involved in general and adipose tissue-specific metabolism, was performed on ALT (= 8), WDLPS (= 9) and DDLPS (= 20) samples. Subsequent statistical analysis was carried out to determine genes that most accurately can predict DDLPS differential diagnosis. Selected genes were further validated in a separate cohort by qPCR and the data statistically analysed. Deep sequencing was performed on DDLPS specimen from the metastatic patient and on five random WDLPS specimens.

Results: We established a three-gene signature based on and , which identified DDLPS with 100% sensitivity and 90% specificity, even in specimens from the WD component of DDLPS tumors. Interestingly, the gene is deleted in 45% of DDLPS samples analyzed under TCGA project, and the deletion is associated with significantly lower expression level. However, other mechanisms causing loss or downregulation of the expression of these three genes may be involved. Moreover, the significantly lower level of PNPLA2 is associated with R1 surgical margins, compare to R0 margins, which suggests the more invasive tumor phenotype in the absence of PNPLA2.

Conclusions: The identified metabolic signature allows highly accurate differential diagnosis between WD- and DDLPS even in samples containing lipid droplets, a marker of differentiation, which makes it very suitable for the use on biopsies. In respect to the pathogenesis of the disease, our results give a new insight into possible molecular mechanisms involved and support the recent observation that deletion of is a novel factor in liposarcoma progression.
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http://dx.doi.org/10.1186/s13569-020-0126-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057454PMC
March 2020

Risk stratification for central conventional chondrosarcoma of bone: A novel system predicting risk of metastasis and death in the Cancer Registry of Norway cohort.

J Surg Oncol 2020 Jun 5;121(7):1115-1125. Epub 2020 Mar 5.

Division of Orthopedic Surgery, Oslo University Hospital, Oslo, Norway.

Background And Objectives: Interobserver variability in histological grading of central conventional chondrosarcoma (CCCS) limits the quality of patient information and research progression. We aim to quantify known and new prognostic variables and propose a risk stratification model.

Method: We selected 149 cases from the Cancer Registry of Norway. Cox proportional hazard models were estimated. Based on these results a dichotomous risk classification was proposed and presented by Kaplan-Meier estimates for rates of local recurrence, metastasis, and disease-specific survival.

Results: The influence of axial skeletal location (Hazard ratio [HR] = 19.06), a soft tissue component ≥1 cm (HR = 13.45), and histological grade 3 (HR = 16.46) are all significant in predicting the rate of metastasis. The creation of a variable combining axial skeletal location and a soft tissue component ≥1 cm strongly predicts the risk of metastasis (HR = 14.02; P < .001) and death (HR = 2.74; P = .030) at multivariate analysis, making the histological grade insignificant. Together with metastasis at diagnosis (HR = 285.65; P < .001), this forms the basis of our proposed risk stratification, producing a small high-risk group (39 cases with 33% risk of metastasis) and a large low-risk group (103 cases with 2% risk of metastasis) without a histological grade.

Conclusion: Axial skeletal location and a soft tissue component ≥1 cm combined divides a CCCS cohort into low- and high-risk groups without a histological grade.
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http://dx.doi.org/10.1002/jso.25883DOI Listing
June 2020

and Fusion Genes in Osteoblastoma.

Cancer Genomics Proteomics 2020 Mar-Apr;17(2):161-168

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background/aim: Osteoblastoma is a rare benign tumor of the bones in which recurrent rearrangements of FOS have been found. Our aim was to investigate two osteoblastomas for possible genetic aberrations.

Materials And Methods: Cytogenetic, RNA sequencing, and molecular analyses were performed.

Results: A FOS-ANKH transcript was found in the first tumor, whereas a FOS-RUNX2 was detected in the second. Exon 4 of FOS fused with sequences either from intron 1 of ANKH or intron 5 of RUNX2. The fusion events introduced a stop codon and removed sequences involved in the regulation of FOS.

Conclusion: Rearrangements and fusions of FOS show similarities with those of HMGA2 (a feature of leiomyomas and lipomas) and CSF1 (tenosynovial giant cell tumors). The replacement of a 3'-untranslated region, controlling the gene's expression, by a new sequence is thus a common pathogenetic theme shared by FOS, HMGA2, and CSF1 in many benign connective tissue tumors.
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http://dx.doi.org/10.21873/cgp.20176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078835PMC
September 2020

A novel risk score to predict early and late recurrence in solitary fibrous tumour.

Histopathology 2020 Jul;77(1):123-132

Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Aims: Solitary fibrous tumours (SFTs) are rare mesenchymal neoplasms with recurrence rates of 10-30%. Current risk stratification systems for extrameningeal SFTs are based on cohorts with limited follow-up and are not suitable for prediction of late recurrences. In this study we aimed to develop a prognostic model accounting for both early and late recurrences using a relatively large patient cohort with long-term follow-up.

Methods And Results: Clinicopathological factors were analysed in a cohort of 100 extrameningeal, STAT6-positive SFTs. Median follow-up for overall survival (OS) and recurrence-free interval (RFi) were 121 and 84 months, respectively. Disease relapse occurred in 31% of patients and median time to recurrence was 63 months. In univariate analysis mitotic count, necrosis, male gender and presence of severe atypia and pleomorphism were associated with inferior RFi. Mitotic count, necrosis and male gender were independent predictors of recurrence in multivariate analysis. Previously published risk models were also statistically associated with RFi in our cohort, but failed to reliably identify low-risk patients due to poor prediction of late recurrences. A novel risk score based on mitotic count, necrosis and gender was able to stratify patients into low-, intermediate- and high-risk groups for both early and late recurrences.

Conclusions: In this cohort of patients with extrameningeal SFT and long-term follow-up mitotic count, necrosis and gender were independent prognostic markers of recurrence. We propose a novel risk score based on these factors and accounting for late recurrences, which should be validated in external cohorts with sufficient follow-up time.
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http://dx.doi.org/10.1111/his.14078DOI Listing
July 2020

Chronic Expanding Hematoma with a t(11;19)(q13;q13) Chromosomal Translocation.

Anticancer Res 2020 Jan;40(1):97-100

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background/aim: Chronic expanding hematoma is defined as a hematoma that gradually expands over 1 month or longer, is without neoplastic features on histological sections, and does not occur in the setting of coagulopathy. The pathogenetic mechanism behind its development is unknown, nor is anything known about its genetic features.

Case Report: A 49-year-old man noted a tender lump close to the right femoral trochanter. Examination of a core needle biopsy showed a fibrous capsule with fibrinoid material on one side. The patient underwent surgery with removal of a cystic, encapsulated structure with central bleeding and proliferating vessels in the fibrous capsule. The reactive fibroblasts were without any sign of atypia. Genetic analyses were performed on this chronic expanding hematoma.

Results: G-Banding analysis of short-term cultured cells from the chronic expanding hematoma yielded a karyotype with a single clonal chromosome abnormality: 46,XY,t(11;19)(q13;q13)[8]/46,XY[10]. RNA sequencing and examination of the sequencing data using five different programs did not identify fusion genes related to the translocation.

Conclusion: The acquired translocation t(11;19)(q13;q13) suggested that chronic expanding hematoma is a neoplastic lesion. Since the translocation did not lead to any fusion genes, one can speculate that it causes deregulation of gene expression.
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http://dx.doi.org/10.21873/anticanres.13930DOI Listing
January 2020

Fusion of the and Genes in Epithelioid Osteoblastoma.

Cancer Genomics Proteomics 2019 Sep-Oct;16(5):361-368

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background/aim: Epithelioid osteoblastoma is a rare benign tumor of the bone. Its pathogenesis is unknown and little is known regarding its genetic features.

Materials And Methods: Cytogenetic, RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), genomic PCR, and Sanger sequencing analyses were performed on an epithelioid osteoblastoma.

Results: G-banding analysis of short-term cultured tumor cells yielded a normal male karyotype in all examined metaphases. RNA sequencing detected a fusion of COL1A1 from 17q21 with FYN from 6q21. Both RT-PCR and genomic PCR together with Sanger sequencing verified the presence of a COL1A1-FYN fusion gene. In the COL1A1-FYN chimeric transcript, exon 43 of COL1A1 was fused to exon 2 of FYN. The genomic junction occurred in introns 43 and 1 of COL1A1 and FYN, respectively.

Conclusion: A COL1A1-FYN fusion gene was found in an epithelioid osteoblastoma resulting in deregulation of FYN. Whether COL1A1-FYN represents a consistent genetic feature of epithelioid osteoblastomas, remains to be seen.
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http://dx.doi.org/10.21873/cgp.20141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727071PMC
January 2020

Chondrosarcoma in Norway 1990-2013; an epidemiological and prognostic observational study of a complete national cohort.

Acta Oncol 2019 Mar 11;58(3):273-282. Epub 2019 Jan 11.

a Division of Orthopaedic Surgery , Oslo University Hospital , Oslo , Norway.

Background: Knowledge of chondrosarcoma (CS) of bone to date is based on institutional reports and registry publications with limits in reporting, detail and quality of data.

Method: We have performed a retrospective search of CS of bone in the National Cancer Registry in Norway from 1990-2013, cross checked against local tumor databases with further quality control and supplementation of all data from clinical files. The time period is defined by the routine use of axial imaging in clinical practice. A total of 311 cases are included. We performed 108 pathological reviews and 223 radiological reviews. The manuscript was prepared according to the STROBE checklist for strengthening of observational studies. We performed uni-/multivariate cox analyses to define independent prognostic variables from the main cohort of central CS of bone.

Results: The incidence of CS of bone in Norway is 2.85/million/yr. for both sexes overall, rising to 3.45/million/yr. in the last 5-year period. There is an increase in the most common central CS subtype, stronger for women than for men. Central CS had, in general 10-15% local recurrence rates, all evident by 5 years while metastasis rate increases with location and grade. Exceptions are extremity grade 1 CS which displayed no metastatic events and axial grade-3 disease with high rates (50%) of both local and metastatic relapse. Peripheral CS had limited metastatic potential (2%), but rates of local relapse (13%) continue to appear towards 10 years of follow up. Malignancy grade 3 independently predicts rate of metastasis and presence of soft tissue component predicts local recurrence, metastasis and survival.

Conclusion: Rates of local recurrence, metastasis and disease specific survival follow clear patterns depending on subtype, location and grade allowing better tailoring of follow-up regimes. Malignancy grade 3 and the presence of a soft tissue component independently predict behavior for central CS of bone.
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http://dx.doi.org/10.1080/0284186X.2018.1554260DOI Listing
March 2019

Multimodal kreftbehandling av gastrointestinal stromal tumor.

Tidsskr Nor Laegeforen 2018 10 1;138(15). Epub 2018 Oct 1.

Gastrointestinal stromal tumour (GIST) is a subtype of sarcoma that may occur in any part of the gastrointestinal system, most frequently in the stomach and small intestine. The most common symptoms are bleeding and abdominal pain. In this clinical review, we summarise the progress made with this condition and discuss the recommended diagnostics and treatment of GIST.
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http://dx.doi.org/10.4045/tidsskr.18.0200DOI Listing
October 2018

Noninvasive Detection of ctDNA Reveals Intratumor Heterogeneity and Is Associated with Tumor Burden in Gastrointestinal Stromal Tumor.

Mol Cancer Ther 2018 11 10;17(11):2473-2480. Epub 2018 Aug 10.

Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing tumor-specific aberrations through noninvasive sampling. In gastrointestinal stromal tumor (GIST), analysis of and mutations is important for therapeutic decisions, but the invasiveness of traditional biopsies limits the possibilities for repeated sampling. Using targeted next-generation sequencing, we have analyzed circulating cell-free DNA from 50 GIST patients. Tumor-specific mutations were detected in 16 of 44 plasma samples (36%) from treatment-naïve patients and in three of six (50%) patients treated with tyrosine kinase inhibitors. A significant association between detection of ctDNA and the modified National Institutes of Health risk classification was found. All patients with metastatic disease had detectable ctDNA, and tumor burden was the most important detection determinant. Median tumor size was 13.4 cm for patients with detectable mutation in plasma compared with 4.4 cm in patients without detectable mutation ( = 0.006). ctDNA analysis of a patient with disease progression on imatinib revealed that multiple resistance mutations were synchronously present, and detailed analysis of tumor tissue showed that these were spatially distributed in the primary tumor. Plasma samples taken throughout the course of treatment demonstrated that clonal evolution can be monitored over time. In conclusion, we have shown that detection of GIST-specific mutations in plasma is particularly feasible for patients with high tumor burden. In such cases, we have demonstrated that mutational analysis by use of liquid biopsies can capture the molecular heterogeneity of the whole tumor, and may guide treatment decisions during progression. .
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0174DOI Listing
November 2018

Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53.

Mod Pathol 2018 11 26;31(11):1694-1707. Epub 2018 Jun 26.

Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Malignant peripheral nerve sheath tumor is a rare and aggressive disease with poor treatment response, mainly affecting adolescents and young adults. Few molecular biomarkers are used in the management of this cancer type, and although TP53 is one of few recurrently mutated genes in malignant peripheral nerve sheath tumor, the mutation prevalence and the corresponding clinical value of the TP53 network remains unsettled. We present a multi-level molecular study focused on aberrations in the TP53 network in relation to patient outcome in a series of malignant peripheral nerve sheath tumors from 100 patients and 38 neurofibromas, including TP53 sequencing, high-resolution copy number analyses of TP53 and MDM2, and gene expression profiling. Point mutations in TP53 were accompanied by loss of heterozygosity, resulting in complete loss of protein function in 8.2% of the malignant peripheral nerve sheath tumors. Another 5.5% had MDM2 amplification. TP53 mutation and MDM2 amplification were mutually exclusive and patients with either type of aberration in their tumor had a worse prognosis, compared to those without (hazard ratio for 5-year disease-specific survival 3.5, 95% confidence interval 1.78-6.98). Both aberrations had similar consequences on the gene expression level, as analyzed by a TP53-associated gene signature, a property also shared with the copy number aberrations and/or loss of heterozygosity at the TP53 locus, suggesting a common "TP53-mutated phenotype" in as many as 60% of the tumors. This was a poor prognostic phenotype (hazard ratio = 4.1, confidence interval:1.7-9.8), thus revealing a TP53-non-aberrant patient subgroup with a favorable outcome. The frequency of the "TP53-mutated phenotype" warrants explorative studies of stratified treatment strategies in malignant peripheral nerve sheath tumor.
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http://dx.doi.org/10.1038/s41379-018-0074-yDOI Listing
November 2018

Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX).

Eur J Cancer 2018 08 19;99:78-85. Epub 2018 Jun 19.

Department of Oncology, Skåne University Hospital and Lund University, Lund, Sweden. Electronic address:

Purpose: To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy.

Methods: High-risk STS was defined as high-grade morphology (according to the Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II-III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m) and ifosfamide (6 g/m) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4.

Results: For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2-8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1-78.4) with a local recurrence rate of 14.0% (95% CI: 7.8-20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2-8.7). The five-year OS was 76.1% (95% CI: 68.8-84.2). Tumour size, deep location and reduced dose intensity (<80%) had a negative impact on survival. Toxicity was moderate with no treatment-related death.

Conclusions: A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2018.05.011DOI Listing
August 2018

Evaluation of commercial DNA and RNA extraction methods for high-throughput sequencing of FFPE samples.

PLoS One 2018 17;13(5):e0197456. Epub 2018 May 17.

Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Nucleic acid material of adequate quality is crucial for successful high-throughput sequencing (HTS) analysis. DNA and RNA isolated from archival FFPE material are frequently degraded and not readily amplifiable due to chemical damage introduced during fixation. To identify optimal nucleic acid extraction kits, DNA and RNA quantity, quality and performance in HTS applications were evaluated. DNA and RNA were isolated from five sarcoma archival FFPE blocks, using eight extraction protocols from seven kits from three different commercial vendors. For DNA extraction, the truXTRAC FFPE DNA kit from Covaris gave higher yields and better amplifiable DNA, but all protocols gave comparable HTS library yields using Agilent SureSelect XT and performed well in downstream variant calling. For RNA extraction, all protocols gave comparable yields and amplifiable RNA. However, for fusion gene detection using the Archer FusionPlex Sarcoma Assay, the truXTRAC FFPE RNA kit from Covaris and Agencourt FormaPure kit from Beckman Coulter showed the highest percentage of unique read-pairs, providing higher complexity of HTS data and more frequent detection of recurrent fusion genes. truXTRAC simultaneous DNA and RNA extraction gave similar outputs as individual protocols. These findings show that although successful HTS libraries could be generated in most cases, the different protocols gave variable quantity and quality for FFPE nucleic acid extraction. Selecting the optimal procedure is highly valuable and may generate results in borderline quality specimens.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197456PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957415PMC
November 2018

Cytogenetics of Spindle Cell/Pleomorphic Lipomas: Karyotyping and FISH Analysis of 31 Tumors.

Cancer Genomics Proteomics 2018 May-Jun;15(3):193-200

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background: Spindle cell/pleomorphic lipomas are benign tumors. Here, we present our cytogenetic data on 31 such tumors.

Materials And Methods: G-banding chromosome analysis and (in selected cases) fluorescence in situ hybridization (FISH) using probes for FOXO1, RB1, and HMGA2 were performed.

Results: Rearrangements of chromosome 13 were found in 58% of tumors. Chromosomes 6, 1, 12, and 11 were also involved in 42%, 26%, 26%, and 23% of tumors, respectively. FISH analysis showed heterozygous deletion of RB1 in seven samples with chromosome 13 aberrations. In four of them, FOXO1 was also deleted. In two tumors with 12q15 rearrangements, FISH confirmed that HMGA2 was targeted.

Conclusion: Structural rearrangements of 13q or losses of an entire chromosome 13 are the most common cytogenetic aberrations in spindle cell/pleomorphic lipomas. However, cytogenetic variation exists similarly to what is found in other lipomas, suggesting that various pathways may be responsible for tumorigenesis.
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http://dx.doi.org/10.21873/cgp.20077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971011PMC
October 2018

Recurrence-Free Survival After Resection of Gastric Gastrointestinal Stromal Tumors Classified According to a Strict Definition of Tumor Rupture: A Population-Based Study.

Ann Surg Oncol 2018 May 12;25(5):1133-1139. Epub 2018 Feb 12.

Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.

Background: In gastrointestinal stromal tumors (GISTs), rupture is a high-risk feature and an indication for adjuvant treatment; however, the independent impact of rupture on prognosis is uncertain and the term is inconsistently defined. In the present study, a previously proposed definition of 'tumor rupture' was applied on a population-based cohort of gastric GISTs.

Methods: Patients undergoing surgery for non-metastatic gastric GISTs from 2000 to 2015 were identified in the regional sarcoma database of Oslo University Hospital. Tumor rupture included spillage or fracture, piecemeal resection, incisional biopsy, blood-tinged ascites, gastric perforation, and microscopic adjacent infiltration. Minor defects of tumor integrity were not considered rupture, i.e. core needle biopsy, peritoneal tumor penetration, superficial peritoneal rupture, and R1 resection. Risk was assessed according to the modified National Institutes of Health consensus criteria.

Results: Among 242 patients, tumor rupture occurred in 22 patients and minor defects of tumor integrity occurred in 81 patients. Five-year recurrence-free survival (RFS) for patients with tumor rupture, minor defects of tumor integrity, and no defect was 37, 91, and 96%, respectively (p < 0.001). In the high-risk group, 5 year RFS for patients with rupture was 37%, versus 77% without rupture (hazard ratio 3.56, 95% confidence interval 1.57-8.08, p = 0.001). On multivariable analysis, tumor rupture and mitotic index were independently associated with recurrence. Of 13 patients who received adjuvant imatinib after tumor rupture, 11 relapsed.

Conclusions: Tumor rupture according to the present definition was independently associated with recurrence. With tumor rupture, patients relapsed despite adjuvant treatment. Without rupture, prognosis was good, even in the high-risk group.
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http://dx.doi.org/10.1245/s10434-018-6353-5DOI Listing
May 2018

Consistent Involvement of Chromosome 13 in Angiolipoma.

Cancer Genomics Proteomics 2018 Jan-Feb;15(1):61-65

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background/aim: Angiolipoma is a rare benign soft tissue tumor composed of mature adipocytes and blood vessels. Genetic information on angiolipomas is scarce. With the single exception of one tumor which carried a t(X;2)(p22;p12), all angiolipomas hitherto investigated cytogenetically had normal karyotypes.

Materials And Methods: G-banding chromosome analysis was performed on three short-term cultured angiolipomas. Fluorescence in situ hybridization (FISH) analysis using a commercially available RB1 deletion probe was also done.

Results: All three angiolipomas had abnormal karyotypes with loss or structural rearrangement of chromosome 13. The first tumor had the karyotype 46,XY,-6,del(13)(q14),+mar[cp5], the second had 44~45,XY,t(1;10;15)(p21~22;q24;q24),-13[cp5], and the third karyotype was 43,XX,t(13;22;17) (q12;q13; q22~23)[14]. FISH analysis showed heterozygous and homozygous deletion of the RB1 probe in case 2 and 3, respectively. FISH analysis failed in case 1.

Conclusion: Chromosome 13 was consistently involved in all three angiolipomas.
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http://dx.doi.org/10.21873/cgp.20065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822184PMC
July 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

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Nat Commun 2017 06 23;8:15936. Epub 2017 Jun 23.

The Francis Crick Institute, London NW1 1AT, UK.

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.
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http://dx.doi.org/10.1038/ncomms15936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490007PMC
June 2017

Genetic heterogeneity in leiomyomas of deep soft tissue.

Oncotarget 2017 Jul;8(30):48769-48781

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Leiomyoma of deep soft tissue is a rare type of benign smooth muscle tumor that mostly occurs in the retroperitoneum or abdominal cavity of women, and about which very little genetic information exists. In the present study, eight leiomyomas of deep soft tissue were genetically analyzed. G-banding showed that three tumors carried rearrangements of the long arm of chromosome 12, three others had 8q rearrangements, the 7th tumor had deletion of the long arm of chromosome 7, del(7)(q22), and the 8th had aberrations of chromosome bands 3q21~23 and 11q21~22. The target genes of the 12q and 8q aberrations were HMGA2 and PLAG1, respectively. In the leiomyomas with 12q rearrangements, both HMGA2 and PLAG1 were expressed whereas in the tumors with 8q aberrations, only PLAG1 was expressed. In the cases without 12q or 8q aberrations, the expression of HMGA2 was very low and PLAG1 was expressed only in the case with del(7)(q22). All eight leiomyomas of deep soft tissue expressed MED12 but none of them had mutation in exon 2 of that gene. In two tumors with 12q rearrangements, RPSAP52 on 12q14.3 was fused with non-coding RNA (accession number XR_944195) from 14q32.2 or ZFP36L1 from14q24.1. In a tumor with inv(12), exon 3 of HMGA2 was fused to a sequence in intron 1 of the CRADD gene from 12q22. The present data together with those of our two previous studies in which the fusions KAT6B-KANSL1 and EWSR1-PBX3 were described in two retroperitoneal leiomyomas carrying a t(10;17)(q22;q21) and a t(9;22)(q33;q12) translocation, respectively, show that leiomyomas of deep soft tissue are genetically heterogenous but have marked similarities to uterine leiomyomas.
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http://dx.doi.org/10.18632/oncotarget.17953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564723PMC
July 2017

Identification of SETD2-NF1 fusion gene in a pediatric spindle cell tumor with the chromosomal translocation t(3;17)(p21;q12).

Oncol Rep 2017 Jun 4;37(6):3181-3188. Epub 2017 May 4.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Spindle cell tumors are clinically heterogeneous but morphologically similar neoplasms. The term refers to the tumor cells' long and slender microscopic appearance. Distinct subgroups of spindle cell tumors are characterized by chromosomal translocations and also fusion genes. Other spindle cell tumors exist that have not yet been found to have characteristic, let alone pathognomonic, genetic or pathogenetic features. Continuous examination of spindle cell tumors is likely to reveal other subgroups that may, in the future, be seen to correspond to meaningful clinical differences and may even be therapeutically decisive. We analyzed genetically a pediatric spindle cell tumor. Karyotyping showed the tumor cells to carry a t(3;17)(p21;q12) chromosomal translocation whereas RNA sequencing identified a SETD2-NF1 fusion gene caused by the translocation. RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript. Interphase FISH analysis confirmed the existence of the chimeric gene and showed that there was no reciprocal fusion. The fusion transcript codes for a protein in which the last 114 amino acids of SETD2, i.e., the entire Set2 Rpb1 interacting (SRI) domain of SETD2, are replaced by 30 amino acids encoded by the NF1 sequence. The result would be similar to that seen with truncating SETD2 mutations in leukemias. Absence of the SRI domain would result in inability to recruit SETD2 to its target gene locus through binding to the phosphor-C-terminal repeat domain of elongating RNA polymerase II and may affect H3K36 methylation. Alternatively, loss of one of two functional SETD2 alleles might be the crucial tumorigenic factor.
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http://dx.doi.org/10.3892/or.2017.5628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442398PMC
June 2017

Cytogenetic Analysis of a Pseudoangiomatous Pleomorphic/Spindle Cell Lipoma.

Anticancer Res 2017 05;37(5):2219-2223

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background: Pseudoangiomatous pleomorphic/spindle cell lipoma is a rare subtype of pleomorphic/spindle cell lipoma. Only approximately 20 such tumors have been described. Genetic information on pseudoangiomatous pleomorphic/spindle cell lipoma is restricted to a single case in which deletion of the forkhead box O1 (FOXO1) gene was found, using fluorescence in situ hybridization (FISH).

Materials And Methods: G-banding and FISH analyses were performed on a pseudoangiomatous pleomorphic/spindle cell lipoma.

Results: G-banding of tumor cells showed complex karyotypic changes including loss of chromosome 13. FISH analysis revealed that the deleted region contained the RB1 gene (13q14.2) and the part of chromosome arm 13q (q14.2-q14.3) in which spans the TRIM13 gene, the two non-coding RNA genes, DLEU1 and DLEU2, and the genetic markers RH44686 and D13S25.

Conclusion: Several acquired genomic aberrations were found in the tumor. Among them was loss of chromosome 13 material. Results confirm the (cyto)genetic similarity between pseudoangiomatous pleomorphic/spindle cell lipoma and spindle cell lipomas.
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http://dx.doi.org/10.21873/anticanres.11557DOI Listing
May 2017

The Scandinavian Sarcoma Group Central Register: 6,000 patients after 25 years of monitoring of referral and treatment of extremity and trunk wall soft-tissue sarcoma.

Acta Orthop 2017 Jun 7;88(3):341-347. Epub 2017 Mar 7.

u Department Cancer Epidemiology , Lund University Hospital , Lund , Sweden.

Purpose - We wanted to examine the potential of the Scandinavian Sarcoma Group (SSG) Central Register, and evaluate referral and treatment practice for soft-tissue sarcomas in the extremities and trunk wall (STS) in the Nordic countries. Background - Based on incidence rates from the literature, 8,150 (7,000-9,300) cases of STS of the extremity and trunk wall should have been diagnosed in Norway, Finland, Iceland, and Sweden from 1987 through 2011. The SSG Register has 6,027 cases registered from this period, with 5,837 having complete registration of key variables. 10 centers have been reporting to the Register. The 5 centers that consistently report treat approximately 90% of the cases in their respective regions. The remaining centers have reported all the patients who were treated during certain time periods, but not for the entire 25-year period. Results - 59% of patients were referred to a sarcoma center untouched, i.e. before any attempt at open biopsy. There was an improvement from 52% during the first 5 years to 70% during the last 5 years. 50% had wide or better margins at surgery. Wide margins are now achieved less often than 20 years ago, in parallel with an increase in the use of radiotherapy. For the centers that consistently report, 97% of surviving patients are followed for more than 4 years. Metastasis-free survival (MFS) increased from 67% to 73% during the 25-year period. Interpretation - The Register is considered to be representative of extremity and trunk wall sarcoma disease in the population of Scandinavia, treated at the reporting centers. There were no clinically significant differences in treatment results at these centers.
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http://dx.doi.org/10.1080/17453674.2017.1293441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434606PMC
June 2017

Loss of chromosome 13 material in cellular angiofibromas indicates pathogenetic similarity with spindle cell lipomas.

Diagn Pathol 2017 Feb 13;12(1):17. Epub 2017 Feb 13.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, P.O.Box 4953, Nydalen, NO-0424, Oslo, Norway.

Background: Cellular angiofibroma is a rare benign mesenchymal neoplasm with morphological and immunohistochemical similarities to spindle cell lipoma. Karyotypic information on cellular angiofibroma is restricted to one case only which showed loss of material from chromosomes 13 and 16. A few other studies using fluorescence in situ hybridization showed deletions of the RB1 and FOXO1 loci, both of which are located in chromosome band 13q14. We present here cytogenetic data on two cellular angiofibromas with an abnormal karyotype.

Methods: G-banding and fluorescence in situ hybridization (FISH) analyses were done on two cellular angiofibromas.

Results: In both tumors, a rearrangement leading to loss of chromosome 13 material was seen, together with other structural chromosome abnormalities. FISH analysis showed heterozygous deletion of the RB1 locus (13q14) in both cases.

Conclusion: Our results demonstrate loss of chromosome 13 material in cellular angiofibroma, though not as the sole cytogenetic change, confirming the (cyto)genetic similarity of these tumors with spindle cell lipomas.
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http://dx.doi.org/10.1186/s13000-017-0607-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307663PMC
February 2017

Karyotyping and analysis of GNAS locus in intramuscular myxomas.

Oncotarget 2017 Mar;8(13):22086-22094

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Intramuscular myxoma is a benign soft tissue tumor about which very limited genetic information exists. We studied 68 intramuscular myxomas by means of chromosome banding analysis finding abnormal karyotypes in 21 of them. The most clearly nonrandom involvement was of chromosome 8 which was found gained in seven tumors (+8 was the sole change in five myxomas) and structurally rearranged in another two. Since mutation of the gene GNAS (20q13) has been implicated in the pathogenesis of both solitary and hereditary multiple myxomas, we assessed the transcription and mutation status of this gene in five tumors from which we had suitable RNA. All five intramuscular myxomas expressed biallelic transcripts. The mutated GNAS allele found in one tumor was also biallelically transcribed. In none of the five myxomas were maternally expressed transcripts detected. Collectively, the data suggest that intramuscular myxomas have acquired genetic abnormalities that often include chromosome 8 changes but may also involve alterations of GNAS. To what extent these aberrations are pathogenetically important, remains uncertain.
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http://dx.doi.org/10.18632/oncotarget.14986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400648PMC
March 2017

Use of liquid biopsies to monitor disease progression in a sarcoma patient: a case report.

BMC Cancer 2017 01 6;17(1):29. Epub 2017 Jan 6.

Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Background: Many patients experience local recurrence or metastases after receiving potentially curative treatment, and early detection of these events is important for disease control. Recent technological advances make it possible to use blood plasma containing circulating cell-free tumour DNA (ctDNA) as a liquid biopsy. In this case report we show how serial liquid biopsies can be used to monitor the disease course and detect disease recurrence in a sarcoma patient.

Case Presentation: A 55-year-old male presented with a rapidly growing, painful palpable mass in the left groin region, and a biopsy revealed a high-grade malignant spindle cell sarcoma. No metastases were detected on radiologic imaging scans. Using targeted resequencing with a custom 900 cancer gene panel, eight somatic mutations among them KRAS and NF1, were identified in the primary tumour. Targeted resequencing of plasma cell-free DNA (ctDNA) collected before and after surgery and at disease progression confirmed the presence of six of eight mutations at all three time points. The ctDNA level, estimated from the somatic allele frequencies of these six mutations, was high in plasma taken at the time of surgery, at levels similar to the primary tumour. Detection of low levels of ctDNA three days after surgery indicated persistent microscopic disease. Repeated radiologic imaging six weeks postoperatively showed widespread metastatic disease in the lungs, skeleton and the pelvic region. At this time point there was a dramatic increase in the ctDNA level, reflecting the disease progression of the patient. The patient had an unusually aggressive cancer, and succumbed to the disease 13 weeks after surgery.

Conclusions: This case report demonstrated that targeted resequencing of ctDNA from longitudinal collected plasma can be used to monitor disease progression in a soft tissue sarcoma patient, including manifestation of metastatic disease. The ctDNA represented the genomic profile of the tumour, supporting clinical use of liquid biopsies to identify tumour-specific mutations as well as recurrent disease.
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http://dx.doi.org/10.1186/s12885-016-2992-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5219677PMC
January 2017

Multimodal treatment of craniofacial osteosarcoma with high-grade histology. A single-center experience over 35 years.

Neurosurg Rev 2017 Jul 17;40(3):449-460. Epub 2016 Nov 17.

Department of Neurosurgery, Oslo University Hospital - Rikshospitalet, 4950 Nydalen, Oslo, 0424, Norway.

High-grade craniofacial osteosarcoma (CFOS) is an aggressive malignancy with a poor prognosis. Our goals were to evaluate treatment outcomes in those treated at a single referral institution over 35 years and to compare our results to the available literature. A retrospective analysis of all 42 patients treated between 1980 and 2015 at Oslo University Hospital, Norway, identified in a prospectively collected database, was conducted. Mean follow-up was 79.6 months. Overall survival at 2 and 5 years was 70.5 and 44.7%, respectively. The corresponding disease-specific survival rates were 73.0 and 49.8%. Treatment was surgery only in eight cases. Additional therapy was administered in 34 patients: chemotherapy in nine, radiotherapy in seven, and a combination of these in 18 cases. Stratified analysis by resection margins demonstrated significantly better survival at 2 and 5 years after radical surgical treatment. Neoadjuvant chemotherapy and subsequent adequate surgery resulted in better survival than surgery alone. Half of the patients either had a primary or familial cancer predisposition. This is the largest single-center study conducted on high-grade CFOS to date. Our experience indicates that neoadjuvant chemotherapy with complete surgical resection significantly improved survival, compared to surgery alone.
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http://dx.doi.org/10.1007/s10143-016-0802-zDOI Listing
July 2017