Publications by authors named "Marco Gambarotti"

98 Publications

Giant Cell Tumor of Bone in Patients under 16 Years Old: A Single-Institution Case Series.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

Background: Giant cell tumor of bone is a locally aggressive, rarely metastasizing tumor that accounts for about 5% of bone tumors and generally occurs in patients between 20 and 45 years old. A driver mutation in the histone 3.3 (H3.3) gene has been identified in as many as 96% of giant cell tumors of bone. The immunohistochemical expression of H3F3A H3.3 G34 expression was found in 97.8% of cases. In the present study, we describe our series of cases of giant cell tumor of bone in pediatric patients <16 years old.

Methods: All cases of giant cell tumor of bone in pediatric patients <16 years old treated in our institute between 1982 and 2018 were reviewed. Immunohistochemistry and/or molecular analysis for gene mutations was performed to confirm the diagnosis. A group of aneurysmal bone cysts in patients <16 years old was used as a control group.

Results: Fifteen cases were retrieved. A pronounced female predominance (93%) was observed. A pure metaphyseal central location occurs in 2 skeletally immature patients.

Conclusions: Giant cell tumor of bone should be distinguished from its mimickers due to differences in prognosis and treatment. Immunohistochemical and molecular detection of gene mutation represents a reliable diagnostic tool.
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http://dx.doi.org/10.3390/cancers13112585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197501PMC
May 2021

Clinical, Histological, and Molecular Features of Solitary Fibrous Tumor of Bone: A Single Institution Retrospective Review.

Cancers (Basel) 2021 May 19;13(10). Epub 2021 May 19.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

Primary solitary fibrous tumor (SFT) of the bone is extremely rare, with only few cases reported in the literature. We retrieved all cases of primary SFT of the bone treated at our institution and we assessed the morphology and the immunohistochemical and molecular features to investigate the clinical outcome of primary SFT of the bone and any clinical relevance of clinical and histological criteria of aggressiveness currently adopted for the soft tissues counterpart. Morphologically, 15 cases evidenced high cellularity, cytologic atypia, and foci of necrosis and were associated with more than 4 mitotic figures/10 HPF. Immunohistochemical analysis showed an expression of CD34 and of STAT6 immunopositivity in 95% and in 100% of cases, respectively. The presence of chimeric transcripts was found in 10 out of 12 cases in which RT-PCR analysis was feasible, whereas promoter mutations analysis was feasible in 16 cases and only a C-to-T substitution in a heterozygous state was found in one DNA sample for the C228T genetic variant. variants were assessed in 12 cases: 11 (91.6%) cases showed a variation, while in one case, no alteration was found. Disease-specific survival was 64% at 5 years and 49% at 10 years. Statistical analysis showed no correlation between survival and all the clinicopathological and molecular parameters evaluated. In conclusion, at difference to SFT of soft tissues, aggressive behavior of primary SFT of the bone seems to be independent from mitotic count or any other clinicopathological and molecular features.
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http://dx.doi.org/10.3390/cancers13102470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158730PMC
May 2021

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

Histological response to neoadjuvant chemotherapy in localized Ewing sarcoma of the bone: A retrospective analysis of available scoring tools.

Eur J Surg Oncol 2021 Jul 16;47(7):1778-1783. Epub 2021 Feb 16.

Department of Pathology, Azienda Ospedaliera di Padova, Padua, Italy.

Aim: The aim is to evaluate which of the existing scoring systems of histological response to neoadjuvant chemotherapy best stratifies the clinical outcome of patients with localized Ewing sarcoma of bone.

Methods: 474 patients with diagnosis of localized Ewing sarcoma of bone were included. The median follow-up was 13.5 years.

Results: The overall survival and the disease-free survival (DFS) were 70.8% and 63.9% at 5 years. The percentage of histological response to neoadjuvant chemotherapy ranged between 5% and 100% (mean 83%). The agreement between Bologna System and the different percentual cut-offs of histological response to neoadjuvant chemotherapy was high, with kappa statistics of 0.83 for a cut-off of ≥90%; 0.86 for a cut-off of ≥95%; 0.79 for a cut-off of ≥96% and 0.61 for a cut-off of 100%. Statistically higher DFS rates for good responders compared to poor responders were found when using each given system. Model performance indicators showed that Bologna system had a lower AIC score and a higher c-statistics to predict DFS. When the patients classified as good responders using the different percentual cut-offs of histological response to neoadjuvant chemotherapy, were instead re-classified using the Bologna system, statistical differences were noted in DFS within each specific group.

Conclusions: All scoring tools to evaluate histological response to neoadjuvant chemotherapy offer good predictive value for DFS in localized Ewing's sarcoma of bone. The Bologna system better stratifies those patients with histological response to neoadjuvant chemotherapy between 90 and 99%, representing a more reliable scoring tool in this subset.
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http://dx.doi.org/10.1016/j.ejso.2021.02.009DOI Listing
July 2021

Usefulness of β-catenin expression in the differential diagnosis of osteosarcoma, osteoblastoma, and chondroblastoma.

Virchows Arch 2021 Jan 28. Epub 2021 Jan 28.

Department of Pathology, Azienda Ospedaliera di Padova, Padua, Italy.

The aim of this study is to assess the usefulness of beta-catenin immunohistochemical expression in the differential diagnosis of osteoid-producing primary tumors of bone. Seventy cases of osteoid-producing tumors of bone (24 conventional osteosarcomas, 18 osteoblastomas, 13 osteoblastoma-like osteosarcomas, 10 chondroblastomas, and 5 chondroblastoma-like osteosarcomas) diagnosed at Istituto Ortopedico Rizzoli were reviewed and evaluated for the intensity, extension, and subcellular distribution of immunohistochemical expression of beta-catenin. A majority of cases (73%, 51 cases) exhibited cytoplasmic and/or membranous positivity in varied degrees of intensity and proportion of positive cells, in the absence of nuclear staining. Fifteen cases (21%) were completely negative, including two osteoblastomas, five chondroblastomas, three conventional osteosarcomas, four osteoblastoma-like osteosarcomas, and one chondroblastoma-like osteosarcoma. A minority of cases (6%) including three osteoblastoma-like osteosarcomas and one osteoblastoma showed focal nuclear beta-catenin positivity with or without concomitant cytoplasmic staining. In the current series, beta-catenin showed not to be useful in the differential diagnosis of osteoid-producing primary bone tumors.
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http://dx.doi.org/10.1007/s00428-020-03004-2DOI Listing
January 2021

Malignancy in giant cell tumor of bone: analysis of an open-label phase 2 study of denosumab.

BMC Cancer 2021 Jan 22;21(1):89. Epub 2021 Jan 22.

Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University, 40136, Bologna, Italy.

Background: Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor. GCTB can rarely undergo malignant transformation. This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab.

Methods: This analysis was conducted on patients with pathologically confirmed GCTB and measurable active disease treated with denosumab 120 mg subcutaneously once every 4 weeks, with loading doses on study days 8 and 15, as part of a phase 2, open-label, multicenter study. We identified potential cases of malignancy related to GCTB through an independent multidisciplinary review or medical history, associated imaging or histopathologic reports, and disease course. The findings were summarized and no statistical analysis was performed.

Results: Twenty of five hundred twenty-six patients (3.8%) who received at least one dose of denosumab were misdiagnosed with GCTB that was later discovered to be malignancies: five primary malignant GCTB, five secondary malignant GCTB, four sarcomatous transformations, and six patients with other malignancies (giant cell-rich osteosarcoma, undifferentiated pleomorphic sarcoma, spindle cell sarcoma, osteogenic sarcoma, phosphaturic mesenchymal tumor of mixed connective tissue type, and fibrosarcoma/malignant fibrous histiocytoma). Many malignancies were present before denosumab was initiated (8 definitive cases, 7 likely cases), excluding potential involvement of denosumab in these cases. Signs associated with potential misdiagnoses of GCTB included poor mineralization with denosumab treatment, rapid relapse in pain, or a failure of the typical dramatic improvement in pain normally observed with denosumab.

Conclusions: Although rare, GCTB can undergo malignant transformation, and rates in this study were consistent with previous reports. Signs of poor mineralization or lack of response to denosumab treatment may warrant close monitoring.

Trial Registration: clinicaltrials.gov , ( NCT00680992 ). Registered May 20, 2008.
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http://dx.doi.org/10.1186/s12885-020-07739-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824947PMC
January 2021

Primary sclerosing epithelioid fibrosarcoma of the spine: a single-institution experience.

Histopathology 2021 Jun 14;78(7):976-986. Epub 2021 Apr 14.

Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Aims: To present our experience on spinal sclerosing epithelioid fibrosarcoma (SEF) and review the existing literature pertaining to SEF of the spine.

Methods And Results: Six cases of spinal SEF were reviewed, and a literature search of all primary SEFs of the spine was performed. All tumours occurred in adults (median age, 41 years) and were located all along the spine, the lumbar vertebrae being the most commonly involved. All patients presented with pain that they had experienced for months. The mean tumour size at diagnosis was 52 mm. Five tumours showed a spectrum of microscopic features consistent with pure SEF, and one showed a hybrid morphology with areas of low-grade fibromyxoid sarcoma. All were diffusely and strongly positive for mucin 4. Two cases were initially misdiagnosed as epithelioid haemangioendothelioma and aggressive chondroblastoma. Fluorescence in-situ hybridisation showed rearrangements of either FUS or EWSR1 in four cases. Reverse transcription polymerase chain reaction showed the presence of FUS-CREB3L1 and EWSR1-CREB3L1 fusion transcripts in two cases and one case, respectively. Of five patients with follow-up data available, two developed one or more local recurrences and three patients had metastatic disease. Distant metastases were mainly to other osseous locations, followed by lungs and lymph nodes. At last follow-up, three patients had died of disease and one was alive with multiple metastases.

Conclusions: SEF is an aggressive sarcoma that can involve the spine. It is important to recognise the spine as the primary location of SEF, in order to avoid misdiagnosis as more common primary spinal neoplasms, which can impact on therapeutic approaches.
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http://dx.doi.org/10.1111/his.14332DOI Listing
June 2021

Primary malignant ossifying fibromyxoid tumour of the bone. A clinicopathologic and molecular report of two cases.

Pathologica 2020 Dec 3;112(4):184-190. Epub 2020 Nov 3.

Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy.

Objective: To report the exceptional occurrence of ossifying fibromyxoid tumour (OFMT) as a primary bone lesion. OFMT is a rare soft tissue tumour of uncertain differentiation and variable malignant potential, that occurs in adults with a slight male predominance. It is typically located in the subcutis or in the skeletal muscles of the extremities, followed by trunk or head and neck.

Methods: Two cases of OFMT proven to arise from bone are presented. The first is a 65-year old female with a history of rib "osteosarcoma", presenting with an inferior lobe left lung mass. The second is a man with a lytic lesion of the 5th cervical vertebra that recurred shortly after resection. Following H&E and immunohistochemical examination, tumour samples were analysed by NGS and by break-apart FISH to detect rearrangement of the and genes.

Results: gene-rearrangement was identified by FISH on both the primary and the metastatic lesion of first patient. NGS identified a (intron1) and (exon 10) fusion transcript later confirmed by positive rearrangement on FISH in the second case.

Conclusions: The demonstration of gene rearrangements represents a fundamental ancillary diagnostic test when presented with challenging examples of OFMT.
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http://dx.doi.org/10.32074/1591-951X-207DOI Listing
December 2020

Chondroblastoma's Lung Metastases Treated with Denosumab in Pediatric Patient.

Cancer Res Treat 2021 Jan 6;53(1):279-282. Epub 2020 Aug 6.

Chemotherapy Division, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.

Chondroblastoma is a rare benign chondrogenic tumor that occurs in skeletally immature patients between ages 10 and 20 years old. In literature are reported few cases of lung metastases, mainly occurred after surgery or local recurrences. There is no evidence on the pathogenesis of lung metastasis, as well as pulmonary disease course. Few treatments for metastases with aggressive behavior were based on chemotherapy regimen employed in other sarcoma with no results or not satisfying ones. Denosumab is approved for treatment of giant cell tumors and it is under investigation for other giant cell-rich bone tumors. Here, we report a case of a 16-year-old male chondroblastoma of the left humerus with bilateral lung metastases at presentation and progressing during follow-up, treated with denosumab for almost 2 years. We confirm that denosumab treatment can be effective in controlling chondroblastoma metastasis and it has been a safe procedure in an adolescent patient.
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http://dx.doi.org/10.4143/crt.2020.384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812007PMC
January 2021

Vertebroplasty shows no antitumoral effect on vertebral metastasis: a case-based study on anatomopathological examinations.

Eur Spine J 2020 12 4;29(12):3157-3162. Epub 2020 Aug 4.

Department of Oncologic and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Purpose: Percutaneous vertebroplasty (VTP) is a well-known surgical technique used for pain management and vertebral consolidation in the treatment of osteolytic metastases of the spine. While this indication is proven and commonly accepted, an antitumoral effect of polymethylmethacrylate (PMMA) has been proposed but not yet demonstrated. The aim of our study is to evaluate the evidences of antitumoral effect on anatomopathological examination. We present a small series of pathology findings after VTP for spine metastases that support the lack of antitumoral effect of PMMA.

Methods: We have retrospectively analyzed three cases of patients treated for en bloc excision of recurrent spine metastases previously submitted elsewhere to VTP on the same levels. We discuss our results with the literature reporting of an antitumoral effect of VTP.

Results: In our series, after anatomopathological examination, a cement-induced tumor necrosis was never found. Conversely, a foreign-body reaction around the cement was found, inside vital tumor. These results are consistent with an immune reaction to a foreign body without evidences of an antitumoral effect of PMMA.

Conclusion: The antitumoral effect of PMMA should not be taken into account as an indication for VTP in spinal metastases. It is important not to misuse VTP as a therapy aiming at tumor control. Other therapies such as radiotherapy, radiosurgery and open surgery are available for that purpose.
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http://dx.doi.org/10.1007/s00586-020-06555-9DOI Listing
December 2020

Lipoblastoma-like tumor of the spermatic cord: case report and review of the literature.

Virchows Arch 2021 May 2;478(5):1013-1017. Epub 2020 Jul 2.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy.

Lipoblastoma-like tumor is a very rare mesenchymal tumor believed to be restricted to female patients and only recently reported in the spermatic cord of a male patient. We describe herein an additional case of lipoblastoma-like tumor occurring in the spermatic cord, describing its histopathological, immunohistochemical, and molecular features.
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http://dx.doi.org/10.1007/s00428-020-02883-9DOI Listing
May 2021

Synovial chondrosarcoma: a single-institution experience with molecular investigations and review of the literature.

Histopathology 2020 Sep 28;77(3):391-401. Epub 2020 Jul 28.

Department of Pathology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.

Aims: To evaluate the available diagnostic histological criteria for synovial chondrosarcoma and to screen for the presence of IDH1/IDH2 mutations in a series of cases of this malignant cartilaginous neoplasm.

Methods And Results: Ten cases of synovial chondrosarcoma diagnosed at our institute were reviewed. At presentation, all tumours occurred in adults (median age, 62 years). The most common location was the knee joint (five cases), and the size at diagnosis ranged from 30 mm to 170 mm. Eight patients had secondary synovial chondrosarcomas associated with pre-existing/recurrent or concomitant synovial chondromatosis. Five patients had local recurrences and three had lung metastases. All patients with intralesional excisions developed local recurrences, whereas those who underwent wide resections did not. At last follow-up (mean, 91 months), available for nine patients, seven patients were alive and disease-free, one patient had died of disease, and one was alive with paravertebral metastases. Frequent histological features observed included loss of clustering of chondrocytes (nine cases), the presence of variable amounts of myxoid matrix (eight cases), peripheral hypercellularity (eight cases), tumour necrosis (six cases), and spindling of chondrocytes (four cases). Of the seven cases for which it was possible to evaluate bone permeation, six showed infiltration of bone marrow. All seven cases screened for mutations of exon 4 of IDH1 and IDH2 were found to be wild-type.

Conclusions: Histological criteria in correlation with clinical and radiological features allow the recognition of synovial chondrosarcoma. IDH1/IDH2 mutations were not present in synovial chondrosarcoma. Adequate surgical margins are important for disease control.
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http://dx.doi.org/10.1111/his.14170DOI Listing
September 2020

How Does the Skeletal Oncology Research Group Algorithm's Prediction of 5-year Survival in Patients with Chondrosarcoma Perform on International Validation?

Clin Orthop Relat Res 2020 Oct;478(10):2300-2308

M. E. R. Bongers, A. V. Karhade, O. Q. Groot, J. H. Schwab, Department of Orthopaedic Surgery, Division of Orthopaedic Oncology, Massachusetts General Hospital - Harvard Medical School, Boston, MA, USA.

Background: The Skeletal Oncology Research Group (SORG) machine learning algorithm for predicting survival in patients with chondrosarcoma was developed using data from the Surveillance, Epidemiology, and End Results (SEER) registry. This algorithm was externally validated on a dataset of patients from the United States in an earlier study, where it demonstrated generally good performance but overestimated 5-year survival. In addition, this algorithm has not yet been validated in patients outside the United States; doing so would be important because external validation is necessary as algorithm performance may be misleading when applied in different populations.

Questions/purposes: Does the SORG algorithm retain validity in patients who underwent surgery for primary chondrosarcoma outside the United States, specifically in Italy?

Methods: A total of 737 patients were treated for chondrosarcoma between January 2000 and October 2014 at the Italian tertiary care center which was used for international validation. We excluded patients whose first surgical procedure was performed elsewhere (n = 25), patients who underwent nonsurgical treatment (n = 27), patients with a chondrosarcoma of the soft tissue or skull (n = 60), and patients with peripheral, periosteal, or mesenchymal chondrosarcoma (n = 161). Thus, 464 patients were ultimately included in this external validation study, as the earlier performed SEER study was used as the training set. Therefore, this study-unlike most of this type-does not have a training and validation set. Although the earlier study overestimated 5-year survival, we did not modify the algorithm in this report, as this is the first international validation and the prior performance in the single-institution validation study from the United States may have been driven by a small sample or non-generalizable patterns related to its single-center setting. Variables needed for the SORG algorithm were manually collected from electronic medical records. These included sex, age, histologic subtype, tumor grade, tumor size, tumor extension, and tumor location. By inputting these variables into the algorithm, we calculated the predicted probabilities of survival for each patient. The performance of the SORG algorithm was assessed in this study through discrimination (the ability of a model to distinguish between a binary outcome), calibration (the agreement of observed and predicted outcomes), overall performance (the accuracy of predictions), and decision curve analysis (establishment on the ability of a model to make a decision better than without using the model). For discrimination, the c-statistic (commonly known as the area under the receiver operating characteristic curve for binary classification) was calculated; this ranged from 0.5 (no better than chance) to 1.0 (excellent discrimination). The agreement between predicted and observed outcomes was visualized with a calibration plot, and the calibration slope and intercept were calculated. Perfect calibration results in a slope of 1 and an intercept of 0. For overall performance, the Brier score and the null-model Brier score were calculated. The Brier score ranges from 0 (perfect prediction) to 1 (poorest prediction). Appropriate interpretation of the Brier score requires comparison with the null-model Brier score. The null-model Brier score is the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for every patient. A decision curve analysis was performed to compare the potential net benefit of the algorithm versus other means of decision support, such as treating all or none of the patients. There were several differences between this study and the earlier SEER study, and such differences are important because they help us to determine the performance of the algorithm in a group different from the initial study population. In this study from Italy, 5-year survival was different from the earlier SEER study (71% [319 of 450 patients] versus 76% [1131 of 1487 patients]; p = 0.03). There were more patients with dedifferentiated chondrosarcoma than in the earlier SEER study (25% [118 of 464 patients] versus 8.5% [131 of 1544 patients]; p < 0.001). In addition, in this study patients were older, tumor size was larger, and there were higher proportions of high-grade tumors than the earlier SEER study (age: 56 years [interquartile range {IQR} 42 to 67] versus 52 years [IQR 40 to 64]; p = 0.007; tumor size: 80 mm [IQR 50 to 120] versus 70 mm [IQR 42 to 105]; p < 0.001; tumor grade: 22% [104 of 464 had Grade 1], 42% [196 of 464 had Grade 2], and 35% [164 of 464 had Grade 3] versus 41% [592 of 1456 had Grade 1], 40% [588 of 1456 had Grade 2], and 19% [276 of 1456 had Grade 3]; p ≤ 0.001).

Results: Validation of the SORG algorithm in a primarily Italian population achieved a c-statistic of 0.86 (95% confidence interval 0.82 to 0.89), suggesting good-to-excellent discrimination. The calibration plot showed good agreement between the predicted probability and observed survival in the probability thresholds of 0.8 to 1.0. With predicted survival probabilities lower than 0.8, however, the SORG algorithm underestimated the observed proportion of patients with 5-year survival, reflected in the overall calibration intercept of 0.82 (95% CI 0.67 to 0.98) and calibration slope of 0.68 (95% CI 0.42 to 0.95). The Brier score for 5-year survival was 0.15, compared with a null-model Brier of 0.21. The algorithm showed a favorable decision curve analysis in the validation cohort.

Conclusions: The SORG algorithm to predict 5-year survival for patients with chondrosarcoma held good discriminative ability and overall performance on international external validation; however, it underestimated 5-year survival for patients with predicted probabilities from 0 to 0.8 because the calibration plot was not perfectly aligned for the observed outcomes, which resulted in a maximum underestimation of 20%. The differences may reflect the baseline differences noted between the two study populations. The overall performance of the algorithm supports the utility of the algorithm and validation presented here. The freely available digital application for the algorithm is available here: https://sorg-apps.shinyapps.io/extremitymetssurvival/.

Level Of Evidence: Level III, prognostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491905PMC
October 2020

The natural history of epithelioid sarcoma. A retrospective multicentre case-series within the Italian Sarcoma Group.

Eur J Surg Oncol 2020 07 8;46(7):1320-1326. Epub 2020 Apr 8.

Sarcoma Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Introduction: This case-series is aimed to describe the natural history of epithelioid sarcoma (ES) and to provide insights into the differential clinical behaviour of its two variants ("classic-type" and "proximal-type"). The value of a subtype-adapted grading system based on pathological features is explored.

Methods: Data from consecutive, primary, localised, INI1-deleted ES operated at three Italian sarcoma reference centres (1995-2015) were included. Centralised pathological review was performed. Classic-type ES was broken down into "high-grade" and "low-grade", according to number of mitoses, evidence of necrosis and nuclear atypia. Five- and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were estimated.

Results: Fifty-two patients were included. 5- and 10-year OS estimates were 70% and 47% in the whole series, 57% and 37% in patients with proximal-type ES, 77% and 54% in patients with classic-type ES (P = 0.02). In classic-type ES, 5- and 10-year OS was higher for low-grade (95% and 72%, respectively) than high-grade tumours (P = 0.002). 5- and 10-year CCI estimates for LR were 21% and 33% in the whole series. 5- and 10-year CCI estimates for DM were 35% and 39% in the whole series, both 28% in classic-type ES, 47% and 59% in proximal-type ES (P = 0.03).

Conclusions: Suffering from a proximal- or a classic-type is the stronger predictor of outcome in patients with localised ES, with proximal-type ES patients having lower survival due to a higher tendency toward metastatic spreading. However, the "high-grade" classic-type ES was associated with outcomes close to proximal-type ES.
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http://dx.doi.org/10.1016/j.ejso.2020.03.215DOI Listing
July 2020

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors.

Cells 2020 04 14;9(4). Epub 2020 Apr 14.

IRCCS Istituto Ortopedico Rizzoli, Laboratory of Experimental Oncology, via di Barbiano 1/10, 40136 Bologna, Italy.

Osteosarcoma, Ewing sarcoma and chondrosarcoma are rare diseases but the most common primary tumors of bone. The genes directly involved in the sarcomagenesis, tumor progression and treatment responsiveness are not completely defined for these tumors, and the powerful discovery of genetic analysis is highly warranted in the view of improving the therapy and cure of patients. The review summarizes recent advances concerning the molecular and genetic background of these three neoplasms and, of their most common variants, highlights the putative therapeutic targets and the clinical trials that are presently active, and notes the fundamental issues that remain unanswered. In the era of personalized medicine, the rarity of sarcomas may not be the major obstacle, provided that each patient is studied extensively according to a road map that combines emerging genomic and functional approaches toward the selection of novel therapeutic strategies.
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http://dx.doi.org/10.3390/cells9040968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227002PMC
April 2020

Primary Vascular Tumors of Bone: A Monoinstitutional Morphologic and Molecular Analysis of 427 Cases With Emphasis on Epithelioid Variants.

Am J Surg Pathol 2020 09;44(9):1192-1203

Department of Pathology.

Recent molecular discoveries have refined vascular bone tumor classification. To investigate the clinical relevance of these refinements, we reviewed all cases of primary vascular bone tumors treated at our Institute. On the basis of morphology, cases were assessed immunohistochemically and molecularly. A total of 427 cases of primary vascular tumor of bone with available follow-up and histologic material were retrieved and reclassified according to the most recent diagnostic criteria as follows: 289 hemangiomas, 38 epithelioid hemangiomas, 21 epithelioid hemangioendotheliomas, 2 retiform hemangioendotheliomas, 1 intraosseous papillary intralymphatic angioendothelioma, 24 pseudomyogenic hemangioendotheliomas, and 52 angiosarcomas (of these, 45 were epithelioid angiosarcomas and 7 spindle cell secondary angiosarcoma). Both epithelioid and classic hemangiomas behave as benign tumors with excellent prognosis. The distinction between cellular and conventional type of epithelioid hemangioma was not associated with a different clinical course. Conversely, epithelioid hemangioendothelioma exhibited a more aggressive clinical behavior than hemangioma, with higher rates of multifocality and distant spread. Immunohistochemical positivity for CAMTA1 or TFE3 did not have a prognostic implication. In epithelioid hemangioendothelioma, the presence of morphologic malignant features was associated with reduced disease-free (P=0.064) and overall survival (P=0.055). Pseudomyogenic hemangioendothelioma featured local aggressiveness in 5/24 patients exhibiting a clinical behavior closer to epithelioid hemangioma than epithelioid hemangioendothelioma. Last, 32/45 patients with epithelioid angiosarcoma died of disease with a median survival time of 10 months from diagnosis. In conclusion, the integration of morphologic, immunohistochemical, and molecular features allows a better stratification of primary vascular tumors of bone with significant prognostic and therapeutic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001487DOI Listing
September 2020

Inflammation and infiltration: can the radiologist draw a line? MRI versus CT to accurately assess medullary involvement in parosteal osteosarcoma.

Int J Biol Markers 2020 Feb;35(1_suppl):31-36

Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Cancer causes inflammation as it progresses through healthy tissue. The differentiation of tumoral growth from the surrounding inflammatory change is paramount in planning surgeries seeking to preserve function. This retrospective study aims at illustrating how a careful use of imaging (computed tomography (CT)/magnetic resonance imaging (MRI)) can help to draw the line between infiltration and inflammation. Out of 72 cases of parosteal osteosarcoma in our institution we selected 22 which had pretreatment imaging, and out of those, 14 that had both MRI and CT. Using Fisher's exact test, we evaluated the performance of each technique on accurately diagnosing medullary tumor infiltration, using histological analysis as a gold standard. All cases (14/14) demonstrated medullary abnormality on MRI, but only 6/14 (42.9%) demonstrated abnormality on CT. The 8/14 cases with MRI abnormality but no CT abnormality (57.1%) showed inflammation with no tumoral cells present on histological analysis. In the cases where the two examinations showed medullary abnormality (6/14) histology demonstrated tumoral infiltration. MRI demonstrated high sensitivity and negative predictive value, but low specificity and low positive predictive value and accuracy (P=1). CT demonstrated high sensitivity, specificity, high positive and negative predictive values and accuracy (P = 0.000333). MRI is highly sensitive for the detection of medullary abnormality but lacks specificity for tumor invasion. Correlation with CT is recommended in all cases of positive MR to add specificity for tumors. The adequate use of the two imaging methods allows to differentiate between inflammatory change and tumoral infiltration in POS, relevant for surgical planning.
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http://dx.doi.org/10.1177/1724600819900516DOI Listing
February 2020

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity.

J Exp Clin Cancer Res 2019 Dec 26;38(1):503. Epub 2019 Dec 26.

Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, via di Barbiano 1/10, 40136, Bologna, Italy.

Background: The treatment of metastatic osteosarcoma (OS) remains a challenge for oncologists, and novel therapeutic strategies are urgently needed. An understanding of the pathways that regulate OS dissemination is required for the design of novel treatment approaches. We recently identified Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as a crucial driver of OS cell migration. In this study, we explored the impact of ROCK2 disruption on the metastatic capabilities of OS cells and analyzed its functional relationship with Yes-associated protein-1 (YAP), the main transcriptional mediator of mechanotransduction signaling.

Methods: The effects of ROCK2 depletion on metastasis were studied in NOD Scid gamma (NSG) mice injected with U-2OS cells in which ROCK2 expression had been stably silenced. Functional studies were performed in vitro in human U-2OS cells and in three novel cell lines derived from patient-derived xenografts (PDXs) by using standard methods to evaluate malignancy parameters and signaling transduction. The nuclear immunostaining of YAP and the evaluation of its downstream targets Cysteine Rich Angiogenic Inducer 6, Connective Tissue Growth Factor and Cyclin D1 by quantitative PCR were performed to analyze YAP activity. The effect of the expression and activity of ROCK2 and YAP on tumor progression was analyzed in 175 OS primary tumors.

Results: The silencing of ROCK2 markedly reduced tumor growth and completely abolished the metastatic ability of U-2OS cells. The depletion of ROCK2, either by pharmacological inhibition or silencing, induced a dose- and time-dependent reduction in the nuclear expression and transcriptional activity of YAP. The nuclear expression of YAP was observed in 80/175 (46%) tumor samples and was significantly correlated with worse patient prognosis and a higher likelihood of metastasis and death. The use of verteporfin, a molecule that specifically inhibits the TEAD-YAP association, remarkably impaired the growth and migration of OS cells in vitro. Moreover to inhibiting YAP activity, our findings indicate that verteporfin also affects the ROCK2 protein and its functions.

Conclusions: We describe the functional connection between ROCK2 and YAP in the regulation of OS cell migration and metastasis formation. These data provide support for the use of verteporfin as a possible therapeutic option to prevent OS cell dissemination.
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http://dx.doi.org/10.1186/s13046-019-1506-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933701PMC
December 2019

Identification of a novel fusion transcript EWSR1-VEZF1 by anchored multiplex PCR in malignant peripheral nerve sheath tumor.

Pathol Res Pract 2020 Jan 22;216(1):152760. Epub 2019 Nov 22.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

The aim of the study is to describe a novel genetic finding examining the molecular and pathological features of a case of malignant peripheral nerve sheath tumor occurring in the thigh of a 17-year-old male. Fusion gene detection using a next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) was used to identify the novel fusion of EWSR1-VEZF1 from the frozen tumor sample. EWSR1-VEZF1 fusion is a novel molecular gene rearrangement involving exon 8 of the EWSR1 gene and exon 2 of the VEZF1 gene. Data were validated with gene sequencing and fluorescent in situ hybridization (FISH) analysis. This case report describes a novel rearrangement involving EWSR1 on chromosome 22 and VEZF1 on chromosome 17. The result obtained demonstrates the value of the next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) both in diagnosis and patient care and might become a helpful diagnostic tool for this tumor type.
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http://dx.doi.org/10.1016/j.prp.2019.152760DOI Listing
January 2020

Can Osteoblastoma Evolve to Malignancy? A Challenge in the Decision-Making Process of a Benign Spine Tumor.

World Neurosurg 2020 Apr 4;136:150-156. Epub 2019 Dec 4.

Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Background: Osteoblastoma is a rare benign aggressive tumor, with one third occurring in the spine. Conversion of osteoblastoma to osteosarcoma is uncommon, and histologically proven conversion has been rarely reported.

Case Description: Cases of 2 patients with rare occurrences of spinal osteoblastomas recurring and transforming into osteosarcomas are presented. Initial presentation, treatment, imaging, and histology findings are described. The outcomes of the patients following surgical intervention for histologically diagnosed osteoblastoma with subsequent transformation to osteosarcoma and relative management are described. A literature review of osteoblastoma converting to osteosarcoma also is provided.

Conclusions: The rare occurrence of osteoblastoma converting to osteosarcoma imparts several lessons, including performing Enneking appropriate surgery for benign aggressive tumors (Enneking stage 3) and always performing a biopsy, particularly at the time of recurrence if imaging is not pathognomonic for a benign primary spine tumor.
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http://dx.doi.org/10.1016/j.wneu.2019.11.148DOI Listing
April 2020

Ewing sarcoma and Ewing-like tumors.

Virchows Arch 2020 Jan 4;476(1):109-119. Epub 2019 Dec 4.

Department of Pathology, Azienda Ospedaliera Universitaria di Padova, Padova, Italy.

Ewing sarcoma (ES) and Ewing-like sarcomas are highly aggressive round cell mesenchymal neoplasms, most often occurring in children and young adults. The identification of novel molecular alterations has greatly contributed to a profound reappraisal of classification, to the extent that the category of undifferentiated round cell sarcoma has significantly shrunk. In fact, in addition to Ewing sarcoma, we currently recognize three main categories: round cell sarcomas with EWSR1 gene fusion with non-ETS family members, CIC-rearranged sarcomas, and BCOR-rearranged sarcomas. Interestingly, despite significant morphologic overlap, most of these entities tend to exhibit morphologic features predictive of the underlying molecular alteration. Ewing sarcoma is the prototype of round cell sarcoma whereas in CIC sarcomas, focal pleomorphism and epithelioid morphology can predominate. BCOR sarcomas often exhibit a spindled neoplastic cell population. NFATC2 sarcoma may exhibit remarkable epithelioid features, and PATZ1 sarcomas often feature a sclerotic background. The differential diagnosis for these tumors is rather broad, and among round cell sarcomas includes alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, poorly differentiated round cell synovial sarcoma, small cell osteosarcoma, and mesenchymal chondrosarcoma. A combination of morphologic, immunohistochemical, and molecular findings allows accurate classification in most cases. A granular diagnostic approach to Ewing sarcoma and Ewing-like sarcomas is justified by significant differences in terms of both response to chemotherapy and overall survival. As all these entities are in part defined by specific fusion genes, a molecular diagnostic approach based on NGS technology should be considered. In consideration of the extreme rarity of many of these tumor entities, referral to expert rare cancer centers or to rare cancer networks represents the best strategy in order to minimize diagnostic inaccuracy, and allow proper patient management.
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http://dx.doi.org/10.1007/s00428-019-02720-8DOI Listing
January 2020

Expression of the double-stranded RNA-dependent kinase PKR influences osteosarcoma attachment independent growth, migration, and invasion.

J Cell Physiol 2020 02 25;235(2):1103-1119. Epub 2019 Jun 25.

Istituto di Genetica Molecolare-Luigi Luca Cavalli Sforza, UOS Bologna, Consiglio Nazionale Delle Ricerche (IGM-CNR), Bologna, Italy.

Osteosarcoma (OS) is a rare, insidious tumor of mesenchymal origin that most often affects children, adolescents, and young adults. While the primary tumor can be controlled with chemotherapy and surgery, it is the lung metastases that are eventually fatal. Multiple studies into the initial drivers of OS development have been undertaken, but few of these have examined innate immune/inflammatory signaling. A central figure in inflammatory signaling is the innate immune/stress-activated kinase double-stranded RNA-dependent protein kinase (PKR). To characterize the role of PKR in OS, U2OS, and SaOS-2 osteosarcoma cell lines were stably transfected with wild-type or dominant-negative (DN) PKR. Overexpression of PKR enhanced colony formation in soft agar (U2OS and SaOS-2), enhanced cellular migration (U2OS), and invasive migration (SaOS-2). In contrast, overexpression of DN-PKR inhibited attachment-independent growth, migration and/or invasion. These data demonstrate a role for inflammatory signaling in OS formation and migration/invasion and suggest the status of PKR expression/activation may have prognostic value.
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http://dx.doi.org/10.1002/jcp.29024DOI Listing
February 2020

Parosteal osteosarcoma: a monocentric retrospective analysis of 195 patients.

Hum Pathol 2019 09 23;91:11-18. Epub 2019 May 23.

Department of Pathology, IRCCS Rizzoli Orthopedic Institute, Bologna, Italy. Electronic address:

Parosteal osteosarcoma is a low-grade malignant bone tumor that can undergo dedifferentiation. The aim of this study was to analyze clinicopathologic features associated with clinical outcome in a large cohort of patients. Patients consecutively treated for parosteal osteosarcoma at Rizzoli Orthopedic Institute from 1900 to 2018 were reviewed and analyzed. Clincopathologic data of 195 patients with parosteal osteosarcoma were analyzed. Age at diagnosis ranged from 9 to 75 years (median 31). Median follow-up time was 150 months (range, 3-720). The most common tumor locations were femur (61.5%), humerus (15.9%) and tibia (12.8%). Wide surgical margins were achieved in 125 (64.1%) patients. Medullary involvement was present in 69 (35.4%) cases. Dedifferentiation occurred in 48 (24.6%) patients. Forty-five patients developed recurrence (23.1%; median time to recurrence of 36 months). At last follow-up, 155 (79.5%) patients were alive and without evidence of disease, 8 (4.1%) were alive with active disease, 23 (11.8%) died from disease, and 9 (4.6%) from unrelated causes. Patients with dedifferentiated parosteal osteosarcoma had worse 5-year (65% versus 96%) and 10-year survival (60% versus 96%) when compared to conventional tumors (P < .001). Wide surgical margins had positive impact on both disease-free (P < .001) and overall survival (P = .036). Medullary involvement, age at presentation and tumor size had no impact on survival. Dedifferentiation is the most important factor that negatively impacts clinical outcome. Surgical aim is to ensure radical removal with wide surgical margins to improve disease-free survival.
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http://dx.doi.org/10.1016/j.humpath.2019.05.009DOI Listing
September 2019

Denosumab in the treatment of giant cell tumor of the spine. Preliminary report, review of the literature and protocol proposal.

Eur Spine J 2020 02 16;29(2):257-271. Epub 2019 May 16.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Background: The interest on the role of Denosumab in the treatment strategy of giant cell tumor of the spine is growing. En bloc resection is considered the Enneking appropriate treatment, but morbidity and functional loss are sometimes unacceptable. Denosumab could play a role as a stand-alone treatment, but also as preoperative treatment or as postoperative after intralesional surgery.

Materials And Methods: A cohort of 10 out of 12 cases of spinal GCT consecutively treated with Denosumab are analyzed and discussed compared to the cases reported in the literature. A staging of the radiological effect of the treatment is proposed.

Results: The stand-alone and postoperative treatments are still running (12 to 88 months). One therapy was stopped after 15 months, once a satisfactory local effect was achieved, but the treatment had to be restarted 2 months later due to the recurrence of the erosive images. The new treatment was successful. At 1-year follow-up after the gross total excision followed by postoperative Denosumab treatment, no evidence of local recurrence was found. The preoperative treatment duration ranged from 3 to 24 months. No local recurrence followed the en bloc resections.

Conclusions: Denosumab alone is effective in relieving pain, increasing the ossification and sometimes reducing the tumor volume. It can be considered an excellent solution in spine GCTs whose surgical treatment cannot be Enneking appropriate or is associated with unacceptable morbidity or loss of functions. It is still impossible to state when to safely stop the treatment. Denosumab also plays a role as preoperative protocol. These slides can be retrieved under Electronic Supplementary Material.
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http://dx.doi.org/10.1007/s00586-019-05997-0DOI Listing
February 2020

Prognostic significance of human telomerase reverse transcriptase promoter region mutations C228T and C250T for overall survival in spinal chordomas.

Neuro Oncol 2019 08;21(8):1005-1015

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Spinal chordomas, a subtype of primary spinal column malignancies (PSCM), are rare tumors with poor prognosis, and we have limited understanding of the molecular drivers of neoplasia.

Methods: Study design was a retrospective review of prospectively collected data with cross-sectional survival. Archived paraffin embedded pathologic specimens were collected for 133 patients from 6 centers within Europe and North America between 1987 and 2012. Tumor DNA was extracted and the human telomerase reverse transcriptase (hTERT) promoter was sequenced. The hTERT mutational status was correlated with overall survival (OS) and time to first local recurrence.

Results: Ninety-two chordomas, 26 chondrosarcomas, 7 osteosarcomas, 3 Ewing's sarcomas, and 5 other malignant spinal tumors were analyzed. Median OS following surgery was 5.8 years (95% CI: 4.6 to 6.9) and median time to first local recurrence was 3.9 years (95% CI: 2.5 to 6.7). Eight chordomas, 2 chondrosarcomas, 1 Ewing's sarcoma, and 1 other malignant spinal tumor harbored either a C228T or C250T mutation in the hTERT promoter. In the overall cohort, all patients with hTERT mutation were alive at 10 years postoperative with a median OS of 5.1 years (95% CI: 4.5 to 6.6) (P = 0.03). hTERT promoter mutation was observed in 8.7% of spinal chordomas, and 100% of chordoma patients harboring the mutation were alive at 10 years postoperative compared with 67% patients without the mutation (P = 0.05).

Conclusions: We report for the first time that hTERT promoter mutations C228T and C250T are present in approximately 8.7% of spinal chordomas. The presence of hTERT mutations conferred a survival benefit and could potentially be a valuable positive prognostic molecular marker in spinal chordomas.
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http://dx.doi.org/10.1093/neuonc/noz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682209PMC
August 2019

Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution.

Pediatr Blood Cancer 2019 06 5;66(6):e27653. Epub 2019 Feb 5.

Chemotherapy Section, IRCCS-Rizzoli Orthopaedic Institute, Bologna, Italy.

Background: Ewing sarcoma (ES) is the second most common bone tumor in adolescents and children. Staging workup for ES includes imaging and bone marrow biopsy (BMB). The effective role of BMB is now under discussion.

Procedure: A monoinstitutional retrospective analysis reviewed clinical charts, imaging, and histology of patients with diagnosis of ES treated at the Rizzoli Institute between 1998 and 2017.

Results: The cohort included 504 cases of ES of bone; 137 (27%) had metastases at diagnosis, while the remaining 367 had localized disease. Twelve patients had a positive BMB (2.4%). Eleven had distant metastases detected at initial workup staging with imaging assessment: six patients presented with bone metastases, five with both bone and lung metastases. Only one patient with ES of the foot (second metatarsus) was found to have bone marrow involvement with negative imaging evaluation (0.3%).

Conclusions: On the basis of our data, we suggest reconsidering the effective role of BMB in initial staging workup for patients with ES with no signs of metastases by modern imaging techniques. In metastatic disease, the assessment of the bone marrow status may remain useful to identify a group of patients at very high risk who could benefit from different treatment strategies.
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http://dx.doi.org/10.1002/pbc.27653DOI Listing
June 2019

Unlocking bone for proteomic analysis and FISH.

Lab Invest 2019 05 18;99(5):708-721. Epub 2019 Jan 18.

Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.

Bone tissue is critically lagging behind soft tissues and biofluids in our effort to advance precision medicine. The main challenges have been accessibility and the requirement for deleterious decalcification processes that impact the fidelity of diagnostic histomorphology and hinder downstream analyses such as fluorescence in-situ hybridization (FISH). We have developed an alternative fixation chemistry that simultaneously fixes and decalcifies bone tissue. We compared tissue morphology, immunohistochemistry (IHC), cell signal phosphoprotein analysis, and FISH in 50 patient matched primary bone cancer cases that were either formalin fixed and decalcified, or theralin fixed with and without decalcification. Use of theralin improved tissue histomorphology, whereas overall IHC was comparable to formalin fixed, decalcified samples. Theralin-fixed samples showed a significant increase in protein and DNA extractability, supporting technologies such as laser-capture microdissection and reverse phase protein microarrays. Formalin-fixed bone samples suffered from a fixation artifact where protein quantification of β-actin directly correlated with fixation time. Theralin-fixed samples were not affected by this artifact. Moreover, theralin fixation enabled standard FISH staining in bone cancer samples, whereas no FISH staining was observed in formalin-fixed samples. We conclude that the use of theralin fixation unlocks the molecular archive within bone tissue allowing bone to enter the standard tissue analysis pipeline. This will have significant implications for bone cancer patients, in whom personalized medicine has yet to be implemented.
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http://dx.doi.org/10.1038/s41374-018-0168-7DOI Listing
May 2019

Coexistence of secondary chondrosarcoma and lung carcinoma metastasis in the humerus of a patient with Ollier's disease: A case report.

Acta Orthop Traumatol Turc 2019 Jan 3;53(1):68-73. Epub 2018 Dec 3.

Department of Pathology, Istituto Ortopedico Rizzoli, Bologna, Italy.

Tumor-to-tumor metastasis in the same bone is an extremely rare condition. Limited number of case reports exists for coincidence of benign and malign neoplasms but none for malignant to malignant metastasis. Occurrence of several individual malignancies in the same patient may eventually cause such coexistences. We report an Ollier's disease patient with malignant transformation to chondrosarcoma complicated by a pathologic fracture and eventually whose pathological examination revealed that the lesion was not only the chondrosarcoma but an accompanying metastasis from existing lung adenocarcinoma. This report includes clinical, radiological, histological diagnostic challenges in an unexpected lesion and a review of literature.
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http://dx.doi.org/10.1016/j.aott.2018.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424710PMC
January 2019

miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene.

Int J Oncol 2019 Jan 6;54(1):361-369. Epub 2018 Nov 6.

Laboratory of Experimental Oncology, IRCCS, Rizzoli Orthopedic Institute, I‑40136 Bologna, Italy.

Synovial sarcoma (SS) is a rare tumour, with dismal survival when metastasis occurs. SS contains a characteristic translocation (X;18)(p11;q11) and the fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. Novel prognostic and predictive factors are required. The C‑X‑C motif chemokine ligand 12 (CXCL12)/C‑X‑C chemokine receptor 4 (CXCR4) axis is involved in tumour development and metastatic spread in many types of cancer and previous data have demonstrated a pivotal role of CXCR4 in SS cell migration and invasion. Bioinformatics and biological data indicated CXCR4 is a possible candidate target of miR‑494.3p, known to be involved in tumour progression. In this study, we analysed the expression of miR‑494.3p and its potential target, CXCR4, in a series of SS specimens. A significantly lower miR‑494.3p expression was found in the tumour compared to normal tissue associated with higher levels of CXCR4 both at the gene and protein level. The role of CXCR4 as a potential target of miR‑494.3p was assessed in two SS cell lines (SW982 and SYO‑I). Transfection with miR‑494.3p expression plasmid led to a marked decrease in CXCR4 gene and protein expression, concomitant with a transitory decrease in cell proliferation and migration. The SYO‑I cells also responded with an increased apoptotic fraction. The data of this study also demonstrate that the downregulation of miR‑494.3p in SS surgical specimens, concomitant with an increased expression of its potential target, CXCR4, was more evident in the metastatic subset. In vitro experiments confirmed that miR‑494.3p functioned as a tumour suppressor through the involvement of CXCR4 and ongoing studies are directed to better clarify its role in SS therapeutic strategies.
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http://dx.doi.org/10.3892/ijo.2018.4627DOI Listing
January 2019

Osteoblastoma-like osteosarcoma: high-grade or low-grade osteosarcoma?

Histopathology 2019 Feb 4;74(3):494-503. Epub 2018 Nov 4.

Department of Pathology, IRCCS Rizzoli Orthopaedic Institute, Bologna, Italy.

Aims: Osteoblastoma-like osteosarcoma is a rare variant of osteosarcoma (1% of all osteosarcomas), histologically similar to osteoblastoma. In the current World Health Organisation (WHO) classification, osteoblastoma-like osteosarcoma is classified within the group of conventional (high-grade) osteosarcomas. However, several published cases have been actually regarded as low-grade malignant tumours. As strict morphological criteria to distinguish between low- and high-grade lesions are not available, we reviewed our series of osteoblastoma-like osteosarcomas in the attempt to identify clinical and morphological features predictive of aggressiveness.

Methods And Results: We retrieved 15 cases of osteoblastoma-like osteosarcoma from the files of the Istituto Ortopedico Rizzoli. Patients received various treatments. Five patients developed metastasis and five patients developed local recurrences (all after incomplete surgery). Eleven patients were alive without disease, while four patients died of their disease. Statistical analysis revealed a statistically significant (P = 0.048) lower disease-free survival in patients with areas of conventional (high-grade) osteosarcoma.

Conclusions: With the important limitation of a small cohort of patients, the presence of areas of conventional (high-grade) osteosarcoma is the only parameter to predict the aggressiveness of osteoblastoma-like osteosarcoma.
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http://dx.doi.org/10.1111/his.13746DOI Listing
February 2019