Current questions in bone sarcomas

Purpose of review Osteosarcoma and Ewing sarcoma, the most common primary bone tumours in young people, are curable in most patients. However, these tumours remain a significant challenge due to the complexity and intensity of treatment and its long-term morbidity and the significant proportion of patients in whom treatment is unsuccessful. This review addresses questions about current management and emerging therapeutic targets for patients with osteosarcoma, Ewing sarcoma and chondrosarcoma, the commonest bone sarcoma but more common in older patients. Recent findings The largest collaborative international study in osteosarcoma, EURAMOS-1 determined that treatment of patients with resectable disease should not be altered on basis of pathological response to neoadjuvant chemotherapy. In view of little improvement in outcome being evident in recent years, novel therapeutic approaches are required. Putative targets and clinical trials of novel agents are discussed, including emerging targets such as poly (ADP-ribose) polymerase inhibition and isocitrate dehydrogenase inhibition in Ewing sarcoma and chondrosarcoma, respectively. Newer radiotherapy techniques including proton beam and particle ion therapy may be important for local tumour control in selected patients. Summary Collaborative studies are essential to answer current questions and investigate novel therapies in these malignancies to improve outcome and quality of life for patients

The diagnosis of pulmonary metastases on chest computed tomography in primary bone sarcoma and musculoskeletal soft tissue sarcoma

The lungs are the commonest site of metastasis for primary high-grade bone and soft tissue sarcoma, but current guidelines on the management of pulmonary nodules do not specifically cater for this group of patients. The current article reviews the literature from the past 20 years that has reported the CT features of pulmonary metastases in the setting of known primary bone and soft tissue sarcoma, with emphasis on osteosarcoma, chondrosarcoma, and trunk and extremity soft tissue sarcoma, the aim being to aid radiologists who report chest CT of musculoskeletal sarcoma patients in deciding which lesions should be considered metastatic, which lesions are indeterminate and require follow-up, and which lesions are of no concern

Is It Time to Call Time on Bone Marrow Biopsy for Staging Ewing Sarcoma (ES)?

Primary malignant bone sarcomas are rare and Ewing sarcoma (ES), along with osteosarcoma, predominates in teenagers and young adults. The well-established multimodality treatment incorporates systemic chemotherapy with local control in the form of surgery, with or without radiation. The presence and extent of metastases at diagnosis remains the most important prognostic factor in determining patient outcome; patients with skeletal metastases or bone marrow infiltration having a significantly worse outcome than those with lung metastases alone. There is, however, no accepted staging algorithm for ES. Large cooperative groups and national guidelines continue to advocate bone marrow biopsy (BMB) for staging but functional imaging techniques, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with computerised tomography (CT) have been increasingly used for staging cancers and whole-body magnetic resonance imaging (WB-MRI) for staging skeletal metastases. This review outlines the current literature, from which we conclude that BMB is no longer required for the staging of ES as it does not influence the standard of care management. BMB may, however, provide prognostic information and insights into the biology of ES in selected patients on prospective clinical trials

Is [F-18]-fluorodeoxy-D-glucose positron emission tomography of value in the management of patients with craniofacial bone sarcomas undergoing neo-adjuvant treatment?

We evaluated the role of 18FDG PET/CT used to assess response to preoperative chemotherapy in patients with primary craniofacial bone sarcomas

Follow-up practices for high-grade extremity Osteosarcoma

BACKGROUND: The optimal conduct of follow-up (FU) of patients with osteosarcoma is uncertain. In the absence of any formal validation of optimal timing and method of surveillance, guidance is provided by oncology societies' recommendations. FU is designed to detect either local recurrence or metastatic disease at a time when early treatment is still possible and might be effective. METHODS: We performed a retrospective analysis of 101 patients with high-grade extremity osteosarcoma in a single centre. Chest x-ray (CXR) was used as routine surveillance method; however patients with initial lung metastases or previous suspicious findings had computed tomography (CT) scans. RESULTS: With a median FU time of 30.7 months 34 patients relapsed. Relapse-free survival after 5 years was 61% (CI 52%; 73%), late relapses occurred in only two patients between 2 and 5 years of FU. Twenty-five of the 34 relapses were detected at routine FU appointments. All 8 local recurrences were noted clinically. Twenty-two patients had metastases confined to the lungs, either detected on CXR or CT. Thirty-two percent of patients with lung metastases only were salvaged successfully. CONCLUSIONS: Routine FU in high-grade osteosarcoma results in clinical detection of local relapse, and detection of lung metastases by CXR at a time when metastatectomy is possible. The optimal time interval for FU appointments is not known, however we recommend more frequent surveillance visits during the two years after treatment. We hypothesize that routine CT scans are not required and propose CXR for detection of lung metastases

Durable response to serial tyrosine kinase inhibitors (TKIs) in an adolescent with metastatic TFG-ROS1 fusion positive Inflammatory Myofibroblastic Tumor (IMT)

Here, we present the case of an adolescent with a rare metastatic Inflammatory myofibroblastic tumor (IMT) harboring a TFG-ROS1 fusion initially detected on tumor progression and retrospectively identified in the primary tumor after targeted RNA sequencing. The patient benefitted from sequential TKIs over a 5-year period with response to the third generation ALK/ROS inhibitor, lorlatinib leading to resection of the primary tumor. Detailed molecular analysis can identify targetable oncogenic kinase fusions that alters management in patients with unresectable disease and should be considered in all patients

Current approaches to management of bone sarcoma in adolescent and young adult patients

Bone tumors are a group of histologically diverse diseases that occur across all ages. Two of the commonest, osteosarcoma (OS) and Ewing sarcoma (ES), are regarded as characteristic adolescent and young adult (AYA) cancers with an incidence peak in AYAs. They are curable for some but associated with unacceptably high rates of treatment failure and morbidity. The introduction of effective new therapeutics for bone sarcomas is slow, and to date, complex biology has been insufficiently characterized to allow more rapid therapeutic exploitation. This review focuses on current standards of care, recent advances that have or may soon change that standard of care and challenges to the expert clinical research community that we suggest must be met

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) “humanized” mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg “humanized” mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary components as tickborne disease vaccines

Continuous 14 Day Infusional Ifosfamide for Management of Soft-Tissue and Bone Sarcoma: A Single Centre Retrospective Cohort Analysis

Ifosfamide is used to treat soft-tissue sarcoma (STS) and bone sarcoma (BS), with improved efficacy at doses above 9 g/m2/cycle. To mitigate treatment-associated toxicity with higher doses, continuous infusional ifosfamide is increasingly used. However, clinical outcome data remain limited. Single-centre retrospective analysis of patients treated with four-weekly infusional ifosfamide (14 g/m^{2}/14 days) between August 2012 and February 2019 was conducted. Radiological response, progression-free survival (PFS), overall survival (OS) and toxicity were evaluated. Eighty patients were treated-46 with STS and 34 with BS. Patients received a median of three cycles of infusional ifosfamide (1-24). Overall disease control rate (DCR) in STS was 50% (23 of 46 patients), with a median PFS of 3.8 months, and median OS of 13.0 months. In synovial sarcoma (SS), DCR was 80% (12/15), median PFS 8.1 months and median OS 20.9 months. Overall DCR in BS (34 patients) was 30%, with a median PFS of 2.5 months and median OS of 6.2 months. Five patients (6%) stopped treatment due to toxicity alone within the first two cycles. A further 10 patients stopped treatment due to toxicity during later treatment cycles (12%) and 18 patients (23%) required dose modification. Forty-five patients (56%) experienced grade (G) 3/4 haematological toxicity, with 12 episodes of febrile neutropenia and one treatment-related death. Twenty-seven patients (34%) experienced G3/4 non-haematological toxicity, most commonly nausea and vomiting (10, 13%). In summary, infusional ifosfamide has efficacy in STS, most notable in SS. Benefit appears limited in BS. Treatment is associated with toxicity that requires specialist supportive care