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Purpose: A major component of cells in tenosynovial giant cell tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here, we use single-cell RNA sequencing (scRNA-seq) to investigate cellular interactions in TGCT. Experimental Design: A total of 18,788 single cells from three TGCT and two giant cell tumor of bone (GCTB) samples underwent scRNA-seq. The three TGCTs were additionally analyzed using long-read RNA sequencing. Immunofluorescence and IHC for a range of markers were used to validate and extend the scRNA-seq findings. Results: Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to nonneoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping MAB features between the giant cells in TGCT and GCTB. Conclusions: The neoplastic cells in TGCT are highly similar to nonneoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the platelet-derived growth factor receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

Introduction: There is no clear evidence regarding the benefit of restaging for distant metastases after neoadjuvant radiotherapy (RTX) in patients with soft tissue sarcoma (STS) of the extremities and trunk wall. This study aimed to determine how often restaging of the chest identified metastatic disease that altered management in these patients.Methods: We performed a single-centre retrospective study from 2010 to 2020. All patients with non-metastatic STS of the extremities and trunk wall who were treated with neoadjuvant RTX and received a staging and restaging chest CT scan or X-ray for distant metastasis were included. The outcome of interest was change in treatment strategy due to restaging after neoadjuvant RTX.Results: Within the 144 patients who were staged and treated with neoadjuvant RTX, a restaging chest CT or X-ray was performed in 134 patients (93%). A change in treatment strategy due to new findings at restaging after RTX was observed in 26 out of 134 patients (19%). In 24 patients the scheduled resection of the primary STS was cancelled at restaging (24/134, 18%), given the findings at restaging. The other two patients did receive the intended local resection, but either with palliative intent, or as a part of a previously unplanned multimodality treatment.Conclusion: In approximately one in five patients restaging results in a change in treatment strategy. This underlines the added value of routine restaging for distant metastases with chest CT or X-ray after neoadjuvant RTX in patients with STS. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Supplementary Figure from Interactions in CSF1-Driven Tenosynovial Giant Cell Tumors

Supplementary Table from Interactions in CSF1-Driven Tenosynovial Giant Cell Tumors

Purpose:A major component of cells in tenosynovial giant cell tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here, we use single-cell RNA sequencing (scRNA-seq) to investigate cellular interactions in TGCT.Experimental Design:A total of 18,788 single cells from three TGCT and two giant cell tumor of bone (GCTB) samples underwent scRNA-seq. The three TGCTs were additionally analyzed using long-read RNA sequencing. Immunofluorescence and IHC for a range of markers were used to validate and extend the scRNA-seq findings.Results:Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to nonneoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping MAB features between the giant cells in TGCT and GCTB.Conclusions:The neoplastic cells in TGCT are highly similar to nonneoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the platelet-derived growth factor receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

An appropriate reconstruction strategy after surgical resection of chest wall tumors in children is important to optimize outcomes, but there is no consensus on the ideal approach. The aim of this study was to provide an up-to-date systematic review of the literature for different reconstruction strategies for chest wall defects in patients less than 18 years old. A systematic literature search of the complete available literature was performed and results were analyzed. A total of 22 articles were included in the analysis, which described a total of 130 chest wall reconstructions. All were retrospective analyses, including eight case reports. Reconstructive options were divided into primary closure (n = 21 [16.2%]), use of nonautologous materials (n = 83 [63.8%]), autologous tissue repair (n = 2 [1.5%]), or a combination of the latter two (n = 24 [18.5%]). Quality of evidence was poor, and the results mostly heterogeneous. Reconstruction of chest wall defects can be divided into four major categories, with each category including its own advantages and disadvantages. There is a need for higher quality evidence and guidelines, to be able to report uniformly on treatment outcomes and assess the appropriate reconstruction strategy.

Introduction: This subgroup analysis of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) from the PERSARC collaborative group aimed to achieve a more personalized multimodality treatment approach for primary eUPS in elderly patients.Material and methods: A multicenter retrospective study including primary high-grade eUPS surgically treated with curative intent between 2000 and 2016. Overall survival (OS), local recurrence (LR) and distant metastasis (DM) curves were calculated by Kaplan Meier analysis. Cox proportional hazard models were used to determine the effect of radiotherapy.Results: From a total of 2511 patients with extremity soft tissue sarcoma (eSTS) of the PERSARC study collaborative; 703 patients with eUPS were included in this study. In elderly patients with eUPS 5-year OS, LR and DM were 35.4 (95%CI 29.3-42.8), 17.7 (95%CI 12.7-22.6) and 24.6 (95%CI 19.1-30.1). eUPS was significantly less treated with radiotherapy compared with other eSTS, especially in elderly patients. Patients with R1-R2 margins treated with radiotherapy had about half the risk of developing LR compared with patients treated without radiotherapy (HR = 0.454, p = 0.033).Conclusion: Elderly patients with eUPS were less often treated with radiotherapy and showed higher LR. Nowadays, given an increasing life expectancy in elderly patients, multimodality treatment should be considered. (C) 2021 The Authors. Published by Elsevier Ltd.

Objective: The aim of the study is to assess the effect of perioperative chemo-therapy (CTX) in patients with grade II-III extremity soft tissue sarcoma (eSTS) on overall survival (OS) and evaluate whether the PERSARC prediction tool could identify patients with eSTS more likely to benefit from CTX.Methods: Patients (18-70 years) with primary high-grade eSTS surgically treated with cura-tive intent were included in the retrospective cohort study. The effect of any perioperative CTX and anthracycline + ifosfamide (AI)-based CTX on OS was investigated in three PERSARC-risk groups (high/intermediate/low). The PERSARC-risk groups were defined by the 33% and 66% quantile of the predicted 5-year OS of the study population equal to a 5-year OS of 65.8% and 79.8%, respectively. The effect of CTX on OS was investigated with weighted Kaplan-Meier curves and multivariable Cox models with an interaction between risk group and CTX.Results: This study included 5683 patients. The weighted Kaplan-Meier curves did not demonstrate a beneficial effect of any CTX and AI-based CTX on OS in the overall population. However, in the high PERSARC-risk group the 5-year OS of AI-based CTX was significantly better than no CTX (69.8% vs 59.0%, respectively, p Z 0.004) (HR 0.66, 95% CI 0.53-0.83).Conclusions: This study demonstrated a beneficial effect of AI-based CTX on OS in a selected group of high-risk patients with an absolute survival benefit of 11% as stratified by the PERSARC prediction tool. However, no beneficial effect of CTX on OS was found in the overall population of patients with primary high-grade eSTS younger than 70 years.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

AIM: Follow-up strategies for high-grade bone sarcomas have been optimized to facilitate early detection of local recurrence and distant metastasis. The ideology is that early detection enables early treatment presuming better survival. However, the clinical value for each individual patient remains questionable. This study aims to evaluate oncological events after initial treatment in order to assess current follow-up strategies for high-grade bone sarcomas in the Netherlands.PATIENTS AND METHODS: A retrospective cohort study was conducted based on a national registry. All cases were retrieved from the Netherlands Cancer Registry. Our study consisted of 393 patients treated between 2007 and 2011 with complete follow-up data. Baseline characteristics were analysed for all entities. Local recurrence and distant metastasis was analysed along with overall survival for high-grade chondrosarcoma, high-grade osteosarcoma, Ewing sarcoma and chordoma.RESULTS: Median follow-up was 8,3 years for high-grade chondrosarcoma, 4,9 for high-grade osteosarcoma, 3,8 for Ewing sarcoma and 7,5 for chordoma. Median time to local recurrence and distant metastasis was 1,2 years for high-grade osteosarcoma and 1,5 years for Ewing sarcoma. For high-grade osteosarcoma with localized disease at presentation, 0.09 new distant metastatic events per patient per year were seen after five years of follow-up with 11,1 patients needed to follow-up for any event. Five-year overall survival was 60,0% for high-grade chondrosarcoma, 50,0% for high-grade osteosarcoma, 45,3% for Ewing sarcoma and 71,4% for chordoma.CONCLUSIONS: This nationwide study shows a plateau in local recurrences and distant metastatic events after four years of treatment for patients with high-grade osteosarcoma and Ewing sarcoma. Due to a lack of reliable evidence however, we were not able to provide additional guidance on follow-up intervals and duration. Collaborative research with larger groups is needed in order to provide a solid scientific recommendation for follow-up in the heterogenous patient population with bone sarcoma.

Compared with other soft tissue sarcomas, myxoid liposarcoma (MLS) occurs in younger patients, has a propensity for intermuscular locations and is highly radiosensitive. With pre-operative radiotherapy, intermuscular MLS demonstrates substantial volume reduction and can be easily separated from surrounding tissues during resection. However, it is unclear whether marginal excision of MLS is oncologically safe. This study aimed to assess the association between margins and survival in irradiated, intermuscular MLS.The study identified 198 patients from seven sarcoma centres with a first presentation of localized, extremity, intermuscular MLS that received pre-operative radiotherapy and was diagnosed between 1990 and 2017. Patient and treatment characteristics, radiological and histological responses to neoadjuvant treatment and clinical surveillance were recorded.Margins were microscopically positive in 11% (n = 22),1.0 mm in 15% (n = 29) and ≥1.0 mm in 72% (n = 143). There was no association between margin status and local recurrence-free, metastasis-free or overall survival. This finding held true even in patients at higher risk of worse overall survival based on multivariable analysis (% round cell≥5%, percentage ellipsoid tumour volume change ≤ -60.1%).Irradiated, extremity, intermuscular myxoid liposarcoma can safely undergo marginal resection without compromising oncologic control.

Local tissue and serum metal ions have been shown to be elevated in some metal-on-metal and metal-on-polyethylene joint replacements. Local elevations have been linked to adverse local tissue reactions in some patients, and systemic elevation has been less commonly implicated cardiac and neurologic issues. Using a prospective study design, we aimed to identify the changes in serum metal ion levels after hip or knee megaprosthesis reconstruction. Furthermore, we will evaluate the occurrence of adverse effects and complications, possibly linked to metal ion elevation.Fourteen consecutive patients receiving a Modular Universal Tumor Revision System megaprosthesis were enrolled. Blood samples were collected preoperatively and postoperatively to determine the serum ion concentrations of aluminum, chromium, cobalt, and silver. To evaluate the safety of the megaprostheses and the subsequently possible related (elevated) serum metal ion concentrations, all adverse effects and complications were registered until last outpatient clinic visit at the time of this study.Compared to the preoperative median serum concentrations, the postoperative median serum concentrations of chromium, silver, and cobalt increased 11-fold, 62-fold, and 64-fold, respectively. The median serum concentration of aluminum increased with 16%. Elevations were primarily noted in patients with knee prostheses. Eight patients had no adverse effects or complications during the period between preoperative and postoperative blood sampling. One adverse effect directly related to the serum metal ion concentrations, namely argyria, was observed.This study documents significantly elevated concentrations of the metal ions, but only one adverse effect directly related to the metal ion concentrations was observed. Future studies are needed to further assess the impact of elevated metal ion levels after megaprostheses, specifically knee implants, which are metal-on-metal.

TPS11590 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths. TGCT is caused by upregulation of the colony-stimulating factor 1 (CSF1) gene, resulting in aberrant CSF1 expression and the recruitment of CSF1 receptor (R)-dependent inflammatory cells. Resection is the primary treatment, but nonsurgical treatment options are necessary for patients with symptomatic TGCT not amenable to surgical resection. Vimseltinib is an oral switch control TKI specifically designed to selectively and potently inhibit CSF1R. In a Phase 1/2 study in patients with TGCT, vimseltinib showed encouraging antitumor activity with an overall objective response rate (ORR) of 42% in the cohort receiving 30 mg twice weekly (recommended phase 2 dose; Gelderblom et al, ESMO 2021 Poster). Vimseltinib was also well tolerated, and the majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grades 1–2. Among these common TEAEs, the only Grade 3–4 event in the Phase 2, twice-weekly, 30-mg cohort was increased blood creatine phosphokinase (CPK); however, this elevated CPK was not associated with any symptoms (Gelderblom et al, ESMO 2021 Poster). Phase 1/2 efficacy and safety data support further development of vimseltinib; here, we describe the ongoing Phase 3 study for patients with TGCT not amenable to surgical resection. Methods: MOTION (NCT05059262) is a Phase 3, randomized, placebo-controlled, double-blind study that aims to evaluate the efficacy and safety of vimseltinib for the treatment of TGCT not amenable to surgical resection. Participants must be at least 18 years of age and have histologically confirmed and symptomatic TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. Prior CSF1R therapy is not permitted (previous imatinib and nilotinib is allowed). In Part 1 of the study, eligible participants will be randomized 2:1 to receive either vimseltinib 30 mg twice a week or matched placebo for 24 weeks. The primary outcome measure is ORR assessed by central read using Response Evaluation Criteria in Solid Tumors version 1.1 at 25 weeks. Secondary outcome measures include ORR per tumor volume score, range of motion, and patient-reported outcomes. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib in Part 2, a long-term treatment phase in which participants will receive open-label vimseltinib. This international study plans to randomize 120 participants and is currently enrolling. Clinical trial information: NCT05059262.

Background: Tenosynovial giant cell tumor (TGCT) is a rare locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. The majority of findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study explores prospectively the real-world management of TGCT.Methods: The TGCT Observational Platform Project (TOPP) registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, and 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%), and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases.

The authors respond to the observations and remarks of Cavanna et al. concerning the clinical guidance paper on giant cell tumor of bone (GCTB) in the era of denosumab and update the paper with respect to the European Medicines Agency's recent positive opinion recommending denosumab for the treatment of adults and skeletally mature adolescents with GCTB that is unresectable or for which surgical resection is likely to result in severe morbidity