Michael Parry

Background and purpose: Parosteal osteosarcoma of the distal femur usually presents as a posteriorly outgrowing tumor that lies close to the popliteal neurovascular bundle, making resection with a wide margin difficult. Tumors are often lower grade meaning surgery often forms the mainstay of treatment. We aimed to evaluate resection margins on local recurrence (LR) and metastasis-free survival rates of patients undergoing surgery for parosteal osteosarcoma of the distal femur.Methods: This retrospective study evaluated patients with histologically confirmed parosteal osteosarcoma of the distal femur at a single institution between 2000 and 2022, with at least 2 years of follow-up. Patients undergoing primary amputation, those with distant metastases at diagnosis, and those with insufficient clinical information were excluded from the study. Data such as postoperative margins, tumor grade, LR, and metastasis was collected and analyzed.Results: 27 patients were included. Involved margin at resection was recorded in 4 patients: a closest margin of < 1 mm in 14 and ≥ 1 mm in 9. Local recurrence (LR) occurred in 8 patients. Compared with ≥ 1 mm margins, the risk of LR was higher for involved margins (risk difference [RD] 0.75, 95% confidence interval [CI] 0.21–0.95; relative risk [RR] 14.0, CI 0.88–222) and for < 1 mm margins (RD 0.36, CI 0.00–0.61; RR 7.33, CI 0.45–119). Metastasis-free survival showed similar trends. Compared with ≥ 1 mm margins, the risk of metastasis was higher for involved margins (RD 0.25, CI −0.11 to 0.70; RR 6.0, CI 0.29–122) and for < 1 mm margins (RD 0.36, CI 0.00–0.61; RR 7.33, CI 0.45–119). There was no significant difference between the tumor grade and rate of LR.Conclusion: A margin greater than or equal to 1 mm showed reduced LR and less metastasis in patients with parosteal osteosarcoma of the distal femur.

There has been little change to the standard treatment for osteosarcoma (OS) over the last 25 years and there is an unmet need to identify new biomarkers and novel therapeutic approaches if outcomes are to improve. Furthermore, there is limited evidence on the impact of OS treatment on patient-reported outcomes (PROs). ICONIC (Improving Outcomes through Collaboration in Osteosarcoma; NCT04132895) is a prospective observational cohort study recruiting newly diagnosed OS patients across the United Kingdom (UK) with matched longitudinal collection of clinical, biological, and PRO data. During Stage 1, which assessed the feasibility of recruitment and data collection, 102 patients were recruited at 22 sites with representation from patient groups frequently excluded in OS studies, including patients over 50 years and those with less common primary sites. The feasibility of collecting clinical and biological samples, in addition to PRO data, has been established and there is ongoing analysis of these data as part of Stage 2. ICONIC will provide a unique, prospective cohort of newly diagnosed OS patients representative of the UK patient population, with fully annotated clinical outcomes linked to molecularly characterised biospecimens, allowing for comprehensive analyses to better understand biology and develop new biomarkers and novel therapeutic approaches.

Background: Chondrosarcoma (CS) is the second most common surgically treated primary malignancy of the bone. The current study explored the effect of the margin and extraosseous tumor component in CS in the femur on local recurrence (LR), LR-free survival (LRFS), and disease-specific survival (DSS). Methods: Among 202 patients, 115 were in the proximal extremity of the femur, 4 in the corpus of the femur, and 83 in the distal extremity of femur; 105 patients had an extraosseous tumor component. Results: In the Kaplan–Meier analysis, factors significant for decreased LRFS were the extraosseous tumor component (p < 0.001), extraosseous tumor component arising from the superior aspect (p < 0.001), histological grade (p = 0.031), and narrow surgical margin < 3 mm (p < 0.001). Factors significantly affecting DSS were the histological grade (p < 0.001), extraosseous component (p < 0.001), LR (p < 0.001), metastases (p < 0.001), and surgical margin (p < 0.001). Conclusions: In CS of the femur, the presence of an extraosseous tumor component has a predictive role in LRFS, and extraosseous tumor component arising from the superior aspect was significant for decreased LRFS. Wide margins were more commonly achieved when the tumor had only an intraosseous component, and the rate of LR was significantly higher in cases with an extraosseous tumor component. When the extraosseous component arose from the superior aspect of the femur, LR occurred more frequently despite achieving adequate margins.

Background: The optimal surgical treatment for patients presenting with (impending and complete) pathological proximal femoral fractures is predicated on prognosis. Guidelines recommend a preoperative biopsy to exclude sarcomas, however no evidence confirms a benefit. Objective: This study aimed to describe the diagnostic accuracy, morbidity and sarcoma incidence of biopsy results in these patients. Material and Methods: All patients (n = 153) presenting with pathological proximal femoral fractures between 2000 and 2019 were retrospectively evaluated. Patients after inadvertent surgery (n = 25) were excluded. Descriptive statistics were used to evaluate the accuracy and morbidity of diagnostic biopsies. Results: Of 112/128 patients who underwent biopsy, nine (8%) biopsies were unreliable either due to being inconclusive (n = 5) or because the diagnosis changed after resection (n = 4). Of impending fractures, 32% fractured following needle core biopsy. Median time from diagnosis to surgery was 30 days (interquartile range 21–46). The overall biopsy positive predictive value (PPV) to differentiate between sarcoma and non-sarcoma was 1.00 (95% confidence interval [CI] 0.88–1.00). In patients with a previous malignancy (n = 24), biopsy (n = 23) identified the diagnosis in 83% (PPV 0.91, 95% CI 0.71–0.99), of whom five (24%) patients had a new diagnosis. In patients without a history of cancer (n = 61), final diagnosis included carcinomas (n = 24, 39.3%), sarcomas (n = 24, 39.3%), or hematological malignancies (n = 13, 21.3%). Biopsy (n = 58) correctly identified the diagnosis in 66% of patients (PPV 0.80, 95% CI 0.67–0.90). Conclusion: This study confirms the importance of a preoperative biopsy in solitary pathological proximal femoral fractures due to the risk of sarcoma in patients with and without a history of cancer. However, biopsy delays the time to definite surgery, results can be inconclusive or false, and it risks completion of impending fractures.

Chondrosarcoma (CS) is the second most common primary malignant bone tumour and, in the absence of reliable chemotherapy and radiotherapy, is effectively a surgical disease. Overall disease specific survival (DSS) is affected by tumour grade, whilst resection margin contributes to local recurrence free survival (LRFS). The aim of this study was to investigate factors that affect the local and systemic prognoses for conventional central CSs arising from the proximal humerus. A multi-centre, retrospective study from three international collaborative sarcoma centres identified 110 patients between 1995 and 2020 undergoing treatment for a conventional central CS of the proximal humerus; 58 patients (53%) had a grade 1 tumour, 36 (33%) had a grade 2 tumour, and 16 patients (13%) had a grade 3 CS. The mean age of patients was 50 years (range 10–85). The incidence of local recurrence (LR) was 9/110 (8.2%), and the disease specific mortality was 6/110 (5.5%). The grade was a statistically significant factor for LRFS (p < 0.001). None of the grade 1 tumours developed LR. The DSS was affected by the grade (p < 0.001) but not by the LR (p = 0.4). Only one patient with a grade 2 tumour died from the disease. The proximal humeral grade 1 CS behaved as a benign tumour, having no cases of LR nor death due to disease. Grade 2 CSs of the proximal humerus behaved in a more indolent way when compared with comparable grade tumours elsewhere in the appendicular skeleton, being locally aggressive with a higher LR rate than grade 1 CSs but still having very low mortality and a high rate of DSS. The LR in grade 2 CSs did not affect the DSS; therefore, surgical management in proximal humeral grade 2 CSs should have a greater emphasis on preserving function whilst maintaining an adequate margin for resection. The proximal humeral grade 3 CS was, as elsewhere in the skeleton, an aggressive, high-grade tumour. Therefore, surgical management should include en bloc resection with clear margins to avoid LR.

Since Ewing sarcoma (ES) is a stem cell-like cancer1, improved outcome for some patients will be realised when treatments to eradicate ES stem-like cells (ES-CSCs) are evaluated in clinical trials. Therefore, we have identified small molecules that kill ES-CSCs, and examined their efficacy alone and in combination with chemotherapy. ES patient-derived cultures and paired ES-CSCs established from treatment-naïve tumors were investigated1. The effect of 1293 small molecules (5µM, 48h) on ES-CSC cell number was examined using high content imaging (Operetta). The effect of the most active small molecules was examined in combination with chemotherapies used to treat ES using high content imaging and CalcuSyn (Biosoft). ES-CSCs were more resistant to chemotherapy than paired patient derived cells (p<0.05)1. In the drug screen, 6% (75/1293) of small molecules were more effective at killing ES-CSCs than doxorubicin. Eight percent (6/75) of the most effective small molecules targeted the Ras/MAPK pathway, including inhibitors of aurora kinases (n=3) and RAS GTPases (n=3). The efficacy of aurora kinase inhibitors, CCT137690 and CD532, was confirmed in 6 ES-CSCs. Patient-derived cells were more sensitive to aurora kinase inhibitors than ES-CSCs (p<0.0001). In combination with chemotherapy, CCT137690 and CD532 synergistically killed patient-derived ES cells (Table 1). We have identified small molecules that kill patient-derived ES-CSCs and confirmed they have synergistic activity with classic chemotherapies, supporting our hypothesis that ES-CSC targeted drugs in combination with existing chemotherapies is a promising therapeutic strategy. 1 Roundhill et al. 2021. Cellular Oncology, 44(5):1065-1085 Table 1. Summary of synergy between the aurora kinase inhibitors and chemotherapeutic agents in 4 patient-derived cell cultures (ES1 - ES4). Patient derived cells were treated with increasing concentrations of chemotherapies and small molecules (0.25x, 0.5x, 2x, 4x the EC50). Concentration range of doxorubicin=0.08-6.7µM, vincristine=0.01-1.5µM, etoposide=0.01-33µM, actinomycin-D=0.02-10µM, carboplatin=8.4-135µM, 4-hyperoxyifosfamide=2.6-152µM, CCT137690=0.07-14µM, CD532=0.05-14µM. Where data is available, concentrations did not exceed the maximum achievable concentration in plasma (Liston and Davis. 2017. Clinical Cancer Research, 15(14):3489-3498). Synergy = combination index <0.9. ES1 ES2 ES3 ES4 CCT137690 (EC50, uM) 3 3.6 0.3 0.4 CD532 (EC50, uM) 1.8 3.5 0.2 1.1 Doxorubicin + CCT137690 Synergy Synergy Synergy Synergy Doxorubicin + CD532 Synergy Synergy Vincristine + CCT137690 Synergy Vincristine + CD532 Synergy Synergy Etoposide + CCT137690 Synergy Synergy Etoposide + CD532 Synergy Synergy Actinomycin-D + CCT137690 Synergy Synergy Actinomycin-D + CD532 Synergy Synergy Synergy Carboplatin + CCT137690 Synergy Synergy Carboplatin + CD532 Synergy Synergy 4-Hyperoxyifosfamide + CCT137690 Synergy Synergy 4-Hyperoxyifosfamide + CD532 Synergy Citation Format: Elizabeth A. Roundhill, Lee Jeys, Michael Parry, Kenneth S. Rankin, Richard Foster, Jacquelyn Bond, Susan Burchill. Enhancing the efficacy of conventional chemotherapy with novel targeted small molecules to kill Ewing sarcoma cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1847.