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LAY SUMMARY Combat-related extremity amputations are common injuries during armed conflict. In recent years, improvised explosive devices have been responsible for massive trauma, including major amputations. Many war amputees have functional limitations that affect quality of life. Surgeons can now insert a metal implant directly in the residual bone to provide a stable anchor for an extremity prosthesis. This procedure improves the ability to walk but carries a high risk of infection. Veterans with serious functional limitations due to problems with socket fixation may consider this treatment option a?er consulting with a specialized team.

Differential Expression in Isogenic Lines

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR–Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1+ osteoblast-like progenitor population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction.Significance:This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.See related commentary by Licht, p. 1794.This article is highlighted in the In This Issue feature, p. 1775

Supplementary Figures

Supplementary Information

Appendix A. Calculation of Structural Rigidity

Purpose: Pathologic fractures could be prevented if reliable methods of fracture risk assessment were available. A multicenter prospective study was conducted to identify significant predictors of physicians' treatment plan for skeletal metastasis based on clinical fracture risk assessments and the proposed CT-based Rigidity Analysis (CTRA).Experimental Design: Orthopedic oncologists selected a treatment plan for 124 patients with 149 metastatic lesions based on the Mirels method. Then, CTRA was performed, and the results were provided to the physicians, who were asked to reassess their treatment plan. The pre- and post-CTRA treatment plans were compared to identify cases in which the treatment plan was changed based on the CTRA report. Patients were followed for a 4-month period to establish the incidence of pathologic fractures.Results: Pain, lesion type, and lesion size were significant predictors of the pre-CTRA plan. After providing the CTRA results, physicians changed their plan for 36 patients. CTRA results, pain, and primary source of metastasis were significant predictors of the post-CTRA plan. Follow-up of patients who did not undergo fixation resulted in 7 fractures; CTRA predicted these fractures with 100% sensitivity and 90% specificity, whereas the Mirels method was 71% sensitive and 50% specific.Conclusions: Lesion type and size and pain level influenced the physicians' plans for the management of metastatic lesions. Physicians' treatment plans and fracture risk predictions were significantly influenced by the availability of CTRA results. Due to its high sensitivity and specificity, CTRA could potentially be used as a screening method for pathologic fractures. Clin Cancer Res; 21(11); 2514–9. ©2015 AACR.

Histology has not been accepted as a valid predictor of the biological behavior of extra-meningeal solitary fibrous tumors (SFTs). Based on the lack of a histologic grading system, a risk stratification model is accepted by the WHO to predict the risk of metastasis; however, the model shows some limitations to predict the aggressive behavior of a low-risk/benign-appearing tumor. We conducted a retrospective study based on medical records of 51 primary extra-meningeal SFT patients treated surgically with a median follow-up of 60 months. Tumor size (p = 0.001), mitotic activity (p = 0.003), and cellular variants (p = 0.001) were statistically associated with the development of distant metastases. In cox regression analysis for metastasis outcome, a one-centimeter increment in tumor size enhanced the expected metastasis hazard by 21% during the follow-up time (HR = 1.21, CI 95% (1.08–1.35)), and each increase in the number of mitotic figures escalated the expected hazard of metastasis by 20% (HR = 1.2, CI 95% (1.06–1.34)). Recurrent SFTs presented with higher mitotic activity and increased the likelihood of distant metastasis (p = 0.003, HR = 12.68, CI 95% (2.31–69.5)). All SFTs with focal dedifferentiation developed metastases during follow-up. Our findings also revealed that assembling risk models based on a diagnostic biopsy underestimated the probability of developing metastasis in extra-meningeal SFTs.

Case: We describe a case of 72-year-old male with dedifferentiated chondrosarcoma with osteosarcomatous and epithelioid (squamous) dedifferentiation. As first described in the literature by Dahlin and Beabout, a well-differentiated benign chondral lesion abruptly juxtaposed to a high-grade non-cartilaginous component is the classical definition of a chondrosarcoma [1]. The non-cartilaginous component is typically an osteosarcoma, fibrosarcoma or malignant fibrous histiocytoma with rare instances of leiomyosarcoma, giant cell tumor and rhabdomyosarcoma [2]. Conclusion: We report our rare instance of squamous dedifferentiation of a dedifferentiated chondrosarcoma along with other five cases that have been reported so far in the literature

Angiosarcoma is an uncommon malignant vascular tumor that can occur anywhere on the body, with a predilection for the skin or soft tissues of the scalp and face. By whole exome sequencing, we identified recurrent somatic mutations in PTPRB, which encodes an endothelial-specific phosphatase that negatively regulates angiogenesis, in three secondary angiosarcoma tumors (3/10). In addition, four tumors harbored missense variants in the KDR gene, including three germline substitutions. Neither the PTPRB nor the KDR alterations were found in the 5 primary tumors studied. Copy number analysis derived from the exome and methylation data revealed frequent MYC amplification in the majority of secondary angiosarcoma tumors (9/10). Altogether, our data provide a comprehensive overview of genetic and epigenetic landscapes of angiosarcoma, and demonstrate that aberrant angiogenesis associated with PTPRB and KDR mutations may contribute to the pathogenesis of angiosarcoma. Citation Format: Tenzin Gayden, Brendan C. Dickson, Hamid Nikbakht, Pierre-Olivier Fiset, Nicolas De Jay, Javad Nadaf, David L. Burk, Albert Berghuis, Rebecca Gladdy, Jay Wunder, Robert Turcotte, Jacek Majewski, Nada Jabado. Whole exome sequencing identifies frequent mutations of PTPRB and KDR in secondary angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 756.

Shalini Singh1, Isabella Mak1, Patricia Power1, Melissa Cunnigham2, Robert Turcotte3, Michelle Ghert11Departments of Surgery, 2Biology, McMaster University, Hamilton, Ontario; 3Department of Orthopaedic Surgery, McGill University Medical Centre, Montreal, Quebec, CanadaAbstract: The neoplastic stem-like stromal cell of giant cell tumor of bone (GCT) survives for multiple passages in primary culture with a stable phenotype, and exhibits multipotent characteristics. The pathophysiology of this tumor has been studied through the primary culture of these cells. However, successful gene transfer of these cells has not been reported to date. In this short report, we describe the development of the first reported technique that results in efficient gene transfection in primary stem-like cells of GCT.Keywords: gene, transfection, primary cells, TWIST, giant cell tumor

Introduction Les troubles mentaux courants (TMC) sont une des causes majeures d’invalidité au travail dans le monde. Plusieurs études démontrent que plus la durée de l’arrêt de travail est longue, plus minces sont les chances que la personne avec un TMC retourne au travail. Il est donc important que l’arrêt de travail soit d’une durée adéquate pour permettre à l’individu un rétablissement durable tout en diminuant les risques de rechute. Les médecins traitants ont un rôle important à jouer dans le cadre de la reprise professionnelle des personnes avec un TMC.Objectif Cet article a comme principal objectif de présenter des vignettes cliniques supportées par la littérature relativement à la gestion par les médecins traitants de la reprise professionnelle de leurs patients avec un TMC.Méthodologie Issues d’expériences cliniques, 3 vignettes cliniques illustrant plusieurs dilemmes que des médecins traitants peuvent rencontrer lors de la reprise professionnelle de leurs patients avec un TMC sont présentées. Les dilemmes sont soutenus par des articles publiés entre 2000 à 2020, provenant des bases de données Medline et PsycInfo.Résultats et discussion Les 3 vignettes portent sur les dilemmes relatifs aux thèmes suivants : 1) l’évaluation du potentiel thérapeutique des arrêts de travail ; 2) le rôle d’expert octroyé aux médecins traitants et au processus d’évaluation de la capacité à travailler ; 3) les aspects administratifs liés à cette évaluation ; 4) la relation thérapeutique médecin-patient. La littérature nous indique que ce sont des dilemmes récurrents chez les médecins traitants dans le contexte de la gestion de la reprise professionnelle à la suite d’un TMC.Conclusion La gestion des arrêts maladie chez les travailleurs avec un TMC par les médecins traitants comporte plusieurs dilemmes. Ces dilemmes mettent en lumière, entre autres, l’importance pour les médecins traitants de travailler en collaboration avec les autres acteurs et d’obtenir leur soutien et collaboration. Ces observations nous amènent à conduire une revue plus systématique de l’expérience des médecins traitants et de leurs besoins., Introduction Common mental disorders (CMD) are one of the leading causes of workplace disability worldwide. Many studies show that the longer a person is on sick leave, the less likely they are returning to work. It is therefore important that the duration of a work absence be an adequate duration to allow the individual to make a lasting recovery while reducing the risk of relapse. Clinicians have an important role to play in the professional recovery of people with CMD.Purpose The main objective of this article is to present clinical cases supported by the literature related to the management of return to work by clinicians treating their patients with CMD.Methods Based on clinical observations, three clinical cases illustrating several dilemmas that clinicians may encounter when managing return to work of their patients with a CMD are presented. These dilemmas are supported by articles published between 2000 and 2020 from the Medline and PsycInfo databases.Results and discussion Three clinical cases address dilemmas related to the following themes: 1) the assessment of the therapeutic potential of work absence, 2) the expert role given to clinicians and the process of assessing work disability, 3) the administrative aspects related to this assessment and 4) the impact of this assessment on therapeutic alliance between the clinician and his/her patient with CMD. The literature tells us that these are recurring dilemmas for clinicians when managing the return to work of their patients with CMD.Conclusions There are several dilemmas in the management of sick leave among workers with CMD by clinicians. These dilemmas highlight, among other things, the importance for clinicians to work collaboratively with other stakeholders and to obtain their support and collaboration. These observations lead us to conduct a more systematic review of the experience of clinicians and their needs.