New therapeutic approaches in sarcoma: Immunomodulation and tumor microenvironment

High‐grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. They are usually treated with surgery combined in some cases with chemotherapy. Drugs active in osteosarcoma include adriamycin (ADM), cisplatin (CDDP), ifosfamide (IFO) and methotrexate (MTX), while ADM and IFO represent standard chemotherapy for synovial sarcomas. The survival of sarcomas has minimally improved in the past decades, and after relapse treatment options are limited. Tumors grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines, chemokines and infiltrating immune cells. T‐ lymphocyte and antigen‐presenting cells (APCs) interactions are bi‐directional and mediated by ligands such as programmed cell death ligand 1 (PD‐L1) on APCs and PD1 on lymphocytes. PD‐L1 is expressed also by several tumors. PD‐1 inhibitors such as pembrolizumab or nivolumab have been approved for many tumors and PD‐L1 expression on tumoral cells has been associated with response in some of the studies. However, few data on the prognostic and predictive role of infiltrating immune cells and PD‐1/PD‐L1 system in sarcoma are available. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4‐expressing cancer cells. CXCR4/CXCL12 signalling therefore is an attractive therapeutic target in cancer, since CXCR4 inhibition might sensitize cancer cells to conventional chemotherapy. Finally, another key element of the tumor microenvironment involves its vasculature. Tumor angiogenesis is related to suppression of T cell‐mediated tumor rejection. There are numerous examples that demonstrate a simultaneous activation of angiogenesis and immunosuppression. The overall goal of this project is to characterize the osteosarcoma and synovial sarcoma tumor microenvironment, to assess how the infiltrating immune cells can affect the prognosis of patients and to assess the activity of immune modulating (anti‐PD‐1), migration inhibitors (anti‐CXCR4) and antiangiogenetic (anti‐VEGFRs, anti‐PDGFRs) compounds in an in vitro sarcoma model

SELNET clinical practice guidelines for bone sarcoma

Bone sarcoma; Clinical guidelines; Latin-America contextSarcoma óseo; Guías clínicas; Contexto latinoamericanoSarcoma ossi; Guies clíniques; Context llatinoamericàBone sarcoma are infrequent diseases, representing < 0.2% of all adult neoplasms. A multidisciplinary management within reference centers for sarcoma, with discussion of the diagnostic and therapeutic strategies within an expert multidisciplinary tumour board, is essential for these patients, given its heterogeneity and low frequency. This approach leads to an improvement in patient’s outcome, as demonstrated in several studies. The Sarcoma European Latin-American Network (SELNET), aims to improve clinical outcome in sarcoma care, with a special focus in Latin-American countries. These Clinical Practice Guidelines (CPG) have been developed and agreed by a multidisciplinary expert group (including medical and radiation oncologist, surgical oncologist, orthopaedic surgeons, radiologist, pathologist, molecular biologist and representatives of patients advocacy groups) of the SELNET consortium, and are conceived to provide the standard approach to diagnosis, treatment and follow-up of bone sarcoma patients in the Latin-American context.The authors would like to thank the SELNET project, which has received funding from the EU Horizon 2020 research and innovation programme (grant number 825806)

Prognostic and predictive role of CXCR4, IGF-1R and Ezrin expression in localized synovial sarcoma: is chemotaxis important to tumor response?

BACKGROUND: Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. The role of adjuvant chemotherapy is debated. New prognostic and predictive factors are needed. METHODS: We reviewed patients with localized SS; SS18-SSX fusion transcript presence was confirmed by FISH and RT-PCR. Expression of CXCR4, IGF-1R and Ezrin were evaluated by immunohistochemistry. RESULTS: Tumor samples from 88 SS patients (45 female; 43 male) with median age 37 years (range 11-63) were selected. The size of the lesion was\u2009&gt;\u20095 cm in 68% of patients and 34% of cases presented biphasic histotype. All patients underwent surgery, 56% adjuvant radiotherapy (RT), 65% adjuvant chemotherapy. A positive stain for IGF-1R was detected in 55 patients, with nucleus expression in 21 patients. CXCR4 was expressed in 74 patients, nuclear pattern in 31 patients. 80 SS were positive to Ezrin, 48 had cytoplasmatic location, 32 membrane location. With a median follow-up of 6 years (1-30 years), the 5-year overall survival (OS) was 70% (95% CI 60-81). 5-year OS was 63% (95% CI 41-85%) for patients with positive IGF-1R/nuclear expression, and 73% (95% CI 61-85%; P\u2009=\u20090.05) in negative patients. 5-year OS was 47% (95% CI 27-66%) in patients with positive CXCR4/nuclear staining, and 86% (95% CI 76-96%, P = 0.0003) in negative cases. No survival difference was found according to Ezrin expression. By multivariate analysis, nuclear expression of CXCR4 and IGF-1R was confirmed independent adverse prognostic factor for SS patient survival linked to the use of chemotherapy. CONCLUSIONS: Our findings have important potential implications demonstrating that together with clinical prognostic factors such as radiotherapy and age, CXCR4 and IGF-1R negatively influences survival in patients with localized SS. We believe that further studies addressed to the effects of CXCR4 and IGF-1R inhibitors on cell viability and function are needed to plan new and more appropriate SS treatments

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study

[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. Most 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 prospectively explores the management of TGCT in tertiary sarcoma centers.[Methods] The TGCT Observational Platform Project 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, 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.[Name of registry] Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project (TOPP).[Trial registration number] NCT02948088.[Date of registration] 10 October 2016.[URL of Trial registry record] https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2.Sponsored by Daiichi Sankyo, Co., Ltd; ClinicalTrials.gov Number NCT02948088. The Department of Orthopaedics of the Leiden University Medical Center receives research funding from Daiichi Sankyo. All research funding for Memorial Sloan Kettering is supported in part by a grant from the National Institutes of Health/National Cancer Institute (#P30 CA008748).Peer reviewe

A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?

Background/Objective: To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.// Methods: A systematic review of trials registered on trial registries between 01/01/2017–14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022.// Results: Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H1/H0 hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors.// Conclusion: Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies

Denosumab in patients with aneurysmal bone systs: A case series with preliminary results

Abstract PURPOSE:: Aneurysmal bone cyst (ABC) is a rare skeletal tumor usually treated with surgery/embolization. We hypothesized that owing to similarities with giant cell tumor of bone (GCTB), denosumab was active also in ABC. METHODS:: In this observational study, a retrospective analysis of ABC patients treated with denosumab was performed. Patients underwent radiologic disease assessment every 3 months. Symptoms and adverse events were noted. RESULTS:: Nine patients were identified (6 male, 3 female), with a median age of 17 years (range 14-42 years). Primary sites were 6 spine-pelvis, 1 ulna, 1 tibia, and 1 humerus. Patients were followed for a median time of 23 months (range 3-55 months). Patients received a median of 8 denosumab administrations (range 3-61). All symptomatic patients had pain relief and 1 had paresthesia improvement. Signs of denosumab activity were observed after 3 to 6 months of administration: bone formation by computed tomography scan was demonstrated in all patients and magnetic resonance imaging gadolinium contrast media decrease was observed in 7/9 patients. Adverse events were negligible. At last follow-up, all patients were progression-free: 5 still on denosumab treatment, 2 off denosumab were disease-free 11 and 17 months after surgery, and the last 2 patients reported no progression 12 and 24 months after denosumab interruption and no surgery. CONCLUSIONS:: Denosumab has substantial activity in ABCs, with favorable toxicity profile. We strongly support the use of surgery and/or embolization for the treatment of ABC, but denosumab could have a role as a therapeutic option in patients with uncontrollable, locally destructive, or recurrent disease

Peripheral Inflammatory Indexes Neutrophil/Lymphocyte Ratio (NLR) and Red Cell Distribution Width (RDW) as Prognostic Biomarkers in Advanced Solitary Fibrous Tumour (SFT) Treated with Pazopanib

Simple Summary Pazopanib treatment in advanced solitary fibrous tumour patients, assessed in the prospective GEIS-32 phase II clinical trial, has shown longer progression-free survival and overall survival versus chemotherapy treatment in control patients. In recent years, the interest in the prognostic and predictive value of different peripheral inflammatory indexes, such as neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and red cell distribution width, has been increased in sarcomas, showing significant results in different soft tissue sarcomas. However, they have not been previously analysed in solitary fibrous tumour (SFT) patients. These indexes were retrospectively analysed in the typical- and malignant-SFT cohorts treated with pazopanib of the GEIS-32 trial to evaluate their predictive or prognostic value. Pazopanib was assessed prospectively in the GEIS-32 phase II study (NCT02066285) on advanced solitary fibrous tumour (SFT), resulting in a longer progression-free survival (PFS) and overall survival (OS) compared with historical controls treated with chemotherapy. A retrospective analysis of peripheral inflammatory indexes in patients enrolled into GEIS-32 was performed to evaluate their prognostic and predictive value. Patients received pazopanib 800 mg/day as the first antiangiogenic line. The impacts of baseline neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and red cell distribution width (RDW) on PFS, OS, and Choi response were evaluated by univariate and multivariate analysis. Metastasis-free interval (MFI), mitotic count, and ECOG were also included as potential prognostic factors. Sixty-seven SFT patients, enrolled in this study, showed a median age of 63 years and a female/male distribution of 57/43. The median follow-up from treatment initiation was 16.8 months. High baseline NLR, PLR, and standardised RDW were significantly associated with worse PFS and OS. NLR, RDW, MFI, and mitotic count were independent variables for PFS, while RDW and ECOG were independent for OS. Further, NLR and mitotic count were independent factors for Choi response. High baseline NLR and RDW values were independent prognostic biomarkers for worse outcome in advanced SFT patients treated with pazopanib

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study

SIMPLE SUMMARY: The lung is the most frequent site of metastasis in Ewing sarcoma, the second most common bone cancer affecting children, adolescents and young adults. The five-year overall survival of patients with isolated lung metastasis is approximately 50% after multimodal treatments including chemotherapy, surgery and radiotherapy. This retrospective study aimed to investigate the feasibility and the predictors of survival in 68 Ewing sarcoma patients with lung metastases who received high-dose chemotherapy with busulfan and melphalan, followed by reduced dose whole-lung irradiation, as part of two prospective and consecutive treatment protocols. This combined treatment strategy is feasible and might contribute to the disease control in lung metastatic Ewing sarcoma with responsive disease. Furthermore, the results of this study provide support to explore the treatment stratification for lung metastatic Ewing sarcoma based on the histological response of the primary tumor. ABSTRACT: Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. Results: After WLI, grade 1–2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1–79.3), 61.2% (48.4–71.7) and 70.5% (56.3–80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor

Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial)

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09697-9