Publications by authors named "Tomohiro Fujiwara"

83 Publications

Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression.

Cancer Chemother Pharmacol 2021 Jun 10. Epub 2021 Jun 10.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.

Background: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells.

Materials And Methods: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model.

Results: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model.

Conclusion: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.
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http://dx.doi.org/10.1007/s00280-021-04310-5DOI Listing
June 2021

CSF-1/CSF-1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-Cell Infiltration in the Sarcoma Microenvironment.

Mol Cancer Ther 2021 Jun 4. Epub 2021 Jun 4.

Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center

Colony-stimulating factor 1 (CSF-1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the pro-tumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF-1 receptor (CSF-1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF-1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF-1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward a M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF-1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T cell-modulating effects that may translate into cancer immunotherapy for bone and soft tissue sarcomas.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0591DOI Listing
June 2021

Greater travel distance to specialized facilities is associated with higher survival for patients with soft-tissue sarcoma: US nationwide patterns.

PLoS One 2021 4;16(6):e0252381. Epub 2021 Jun 4.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Purpose: The survival impact of geographic access to specialized care remains unknown in patients with soft-tissue sarcomas (STS). This study aimed to clarify the association between the patient travel distance and survival outcome and investigate the factors lying behind it.

Methods: A total of 34 528 patients with STS registered in the National Cancer Data Base, diagnosed from 2004-2016, were investigated.

Results: Tumor stage correlated with travel distance: patients with metastatic disease stayed closer to home. However, the type of facility showed greatest variation: 37.0%, 51.0%, 73.5%, and 75.9% of patients with ≤10 miles, 10.1-50 miles, 50.1-100 miles, and >100 miles, respectively (P<0.001), had a sarcoma care at academic/research centers. On a multivariable analysis, reduced mortality risk was associated with longer (versus short) travel distance (>100 miles: HR = 0.877; P = 0.001) and management at academic/research (versus non-academic/research) centers (HR = 0.857; P<0.001). The greatest divergence was seen in patients traveling very long distance (>100 miles) to an academic/research center, with a 26.9% survival benefit (HR = 0.731; P<0.001), compared with those traveling short distance (≤10 miles; 95.4% living in metropolitan area) to a non-academic/research center. There was no significant correlation between travel distance and survival in patients who had care at academic/research centers, whereas a survival benefit of management at academic/research centers was observed in every group of travel distance, regardless of tumor stage.

Conclusions: This national study demonstrated that increased travel distance was associated with superior survival, attributable to a higher proportion of patients receiving sarcoma care at distant academic/research centers. These data support centralized care for STS. Overcoming referral and travel barriers may enable more patients to be treated at specialized centers and may further improve survival rates for patients with STS, even when it imposes an increased travel burden.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177553PMC
June 2021

Prevalence of Psychological Distress and Its Risk Factors in Patients with Primary Bone and Soft Tissue Tumors.

Healthcare (Basel) 2021 May 11;9(5). Epub 2021 May 11.

Department of Orthopaedic Surgery, Okayama University Hospital, Okayama 700-8558, Japan.

Psychological distress is common in patients with soft tissue and bone tumors. We first investigated its frequency and the associated risk factors in patients with pre-operative bone and soft tissue tumors. Participants included 298 patients with bone and soft tissue tumors who underwent surgery in our institution between 2015 and 2020. Psychological distress was evaluated by the Distress and Impact Thermometer (DIT) that consists of two types of questions (questions about the severity of the patient's distress (DIT-D) and its impact (DIT-I)). We used a cut-off point of 4 on the DIT-D and 3 on the DIT-I for screening patients with psychological distress. We therefore investigated: (1) the prevalence of psychological distress as assessed with DIT or distress thermometer (DT), which can be decided by DIT-D ≥ 4, (2) what are the risk factors for the prevalence of psychological distress, and (3) what is the number of patients who consulted a psychiatrist for psychological distress in patients with pre-operative bone and soft tissue tumors. With DIT and DT, we identified 64 patients (21%) and 95 patients (32%), respectively, with psychological distress. Multivariate logistic regression revealed that older age, sex (female), malignancy (malignant or intermediate tumor), a lower Barthel Index, and higher numeric rating scale were risk factors for psychological distress. Two patients (3%) consulted a psychiatrist after surgery. In conclusion, careful attention to psychological distress is needed, especially for female patients, older patients, and those with malignant soft or bone tissue tumors who have more than moderate pain.
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http://dx.doi.org/10.3390/healthcare9050566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151264PMC
May 2021

Patients with an increased time to treatment initiation have a poorer overall survival after definitive surgery for localized high-grade soft-tissue sarcoma in the extremity or trunk : report from the National Cancer Database.

Bone Joint J 2021 Jun;103-B(6):1142-1149

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Aims: Time to treatment initiation (TTI) is generally defined as the time from the histological diagnosis of malignancy to the initiation of first definitive treatment. There is no consensus on the impact of TTI on the overall survival in patients with a soft-tissue sarcoma. The purpose of this study was to determine if an increased TTI is associated with overall survival in patients with a soft-tissue sarcoma, and to identify the factors associated with a prolonged TTI.

Methods: We identified 23,786 patients from the National Cancer Database who had undergone definitive surgery between 2004 and 2015 for a localized high-grade soft-tissue sarcoma of the limbs or trunk. A Cox proportional hazards model was used to examine the relationship between a number of factors and overall survival. We calculated the incidence rate ratio (IRR) using negative binomial regression models to identify the factors that affected TTI.

Results: Patients in whom the time to treatment initiation was prolonged had poorer overall survival than those with a TTI of 0 to 30 days. These were: 31 to 60 days (hazard ratio (HR) 1.08, p = 0.011); 61 to 90 days (HR 1.11, p = 0.044); and 91 days (HR 1.22; p = 0.003). The restricted cubic spline showed that the hazard ratio increased substantially with a TTI longer than 50 days. Non-academic centres (vs academic centres; IRR ranging from 0.64 to 0.86; p < 0.001) had a shorter TTI. Those insured by Medicaid (vs private insurance; IRR 1.34), were uninsured (vs private insurance; IRR 1.17), or underwent a transition in care (IRR 1.62) had a longer TTI.

Conclusion: A time to treatment initiation of more than 30 days after diagnosis was independently associated with poorer survival. The hazard ratio showed linear increase, especially if the TTI was more than 50 days. We recommend starting treatment within 30 days of diagnosis to achieve the highest likelihood of cure for localized high-grade soft-tissue sarcomas in the limbs and trunk, even when a patient needs to be referred to a specialist centre. Cite this article:  2021;103-B(6):1142-1149.
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http://dx.doi.org/10.1302/0301-620X.103B6.BJJ-2020-2087.R1DOI Listing
June 2021

Is 2 mm a wide margin in high-grade conventional chondrosarcomas of the pelvis?

Bone Joint J 2021 Jun;103-B(6):1150-1154

Oncology Department, The Royal Orthopaedic Hospital, Birmingham, UK.

Aims: Controversy exists as to what should be considered a safe resection margin to minimize local recurrence in high-grade pelvic chondrosarcomas (CS). The aim of this study is to quantify what is a safe margin of resection for high-grade CS of the pelvis.

Methods: We retrospectively identified 105 non-metastatic patients with high-grade pelvic CS of bone who underwent surgery (limb salvage/amputations) between 2000 and 2018. There were 82 (78%) male and 23 (22%) female patients with a mean age of 55 years (26 to 84). The majority of the patients underwent limb salvage surgery (n = 82; 78%) compared to 23 (22%) who had amputation. In total, 66 (64%) patients were grade 2 CS compared to 38 (36%) grade 3 CS. All patients were assessed for stage, pelvic anatomical classification, type of resection and reconstruction, margin status, local recurrence, distant recurrence, and overall survival. Surgical margins were stratified into millimetres: < 1 mm; > 1 mm but < 2 mm; and > 2 mm.

Results: The disease--specific survival (DSS) at five years was 69% (95% confidence interval (CI) 56% to 81%) and 51% (95% CI 31% to 70%) for grade 2 and 3 CS, respectively (p = 0.092). The local recurrence-free survival (LRFS) at five years was 59% (95% CI 45% to 72%) for grade 2 CS and 42% (95% CI 21% to 63%) for grade 3 CS (p = 0.318). A margin of more than 2 mm was a significant predictor of increased LRFS (p = 0.001). There was a tendency, but without statistical significance, for a > 2 mm margin to be a predictor of improved DSS. Local recurrence (LR) was a highly significant predictor of DSS, analyzed in a competing risk model (p = 0.001).

Conclusion: Obtaining wide margins in the pelvis remains challenging for high-grade pelvic CS. On the basis of our study, we conclude that it is necessary to achieve at least a 2 mm margin for optimal oncological outcomes in patients with high-grade CS of the pelvis. Cite this article:  2021;103-B(6):1150-1154.
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http://dx.doi.org/10.1302/0301-620X.103B6.BJJ-2020-1869.R1DOI Listing
June 2021

Pelvic Ewing sarcoma: Should all patients receive pre-operative radiotherapy, or should it be delivered selectively?

Eur J Surg Oncol 2021 May 18. Epub 2021 May 18.

Oncology Department, The Royal Orthopaedic Hospital, Birmingham, UK; Faculty of Health Sciences, Aston University, Birmingham, UK. Electronic address:

Background: Locally recurrent disease following surgical resection of Ewing sarcoma (ES) confers a poor prognosis. Limited evidence is available evaluating non-selective use of pre-operative radiotherapy (RT) for patients with pelvic ES and its effect on local control and survival.

Patients And Methods: 49 consecutive patients with pelvic ES were identified retrospectively from a prospectively collated database. Patients either received non-selective pre-operative RT and surgery (n = 27), or selective post-operative RT (n = 22) (surgery alone (n = 11) or surgery and post-operative RT (n = 11)).

Results: Patients who had non-selective pre-operative radiotherapy appeared to have a higher LRFS, 88.0% compared to 66.5% in the selective RT group (p = 0.096, Kaplan Meier; p = 0.028, Chi-squared). Administration of non-selective, pre-operative RT to all patients with pelvic ES elevates the LFRS to that of the good responder group (≥90% tumour necrosis and margins, p = 0.880). There was no difference in metastasis-free survival, 60.0% and 54.5% (p = 0.728) and overall survival (OS), 57.7% and 63.6% (p = 0.893). The majority of pre-operative RT patients had both good necrosis (≥90%) (p = 0.003) and widely excised tumours, 81.5% vs 59.1% (p = 0.080). Tumour volume ≥250 ml was associated with worse LRFS (p = 0.045) and post-operative complications (p = 0.017). There may be improved LRFS (p = 0.057) with pre-operative proton-beam RT compared to surgery and selective post-operative RT.

Conclusion: Pre-operative photon or proton-beam RT to all pelvic ES may improve LRFS compared to the selective delivery of post-operative RT. Radiotherapy delivered to all patients results in a greater percentage of highly necrotic tumours at surgical excision, enabling a greater proportion of patients with wide resection margins.
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http://dx.doi.org/10.1016/j.ejso.2021.05.027DOI Listing
May 2021

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma.

Cancers (Basel) 2021 Apr 11;13(8). Epub 2021 Apr 11.

Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1CD9 EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume ( = 0.003). Furthermore, serum levels of MCT1CD9 EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival ( = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1CD9 EVs and indicates the therapeutic potential of MCT1 in SS.
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http://dx.doi.org/10.3390/cancers13081823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069269PMC
April 2021

Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression.

PLoS One 2021 22;16(4):e0250643. Epub 2021 Apr 22.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250643PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061981PMC
April 2021

Role of Tumor-Associated Macrophages in Sarcomas.

Cancers (Basel) 2021 Mar 3;13(5). Epub 2021 Mar 3.

Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.
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http://dx.doi.org/10.3390/cancers13051086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961818PMC
March 2021

Anti-IL17 antibody Secukinumab therapy is associated with ossification in giant cell tumor of bone: a case report of pathologic similarities and therapeutic potential similar to Denosumab.

BMC Musculoskelet Disord 2021 Apr 1;22(1):320. Epub 2021 Apr 1.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA.

Background: Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage.

Case Presentation: One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB.

Conclusions: Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease.
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http://dx.doi.org/10.1186/s12891-021-04182-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015053PMC
April 2021

Postradiation Fractures after Combined Modality Treatment in Extremity Soft Tissue Sarcomas.

Sarcoma 2021 15;2021:8877567. Epub 2021 Mar 15.

Department of Surgery, Orthopedic Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.

Soft tissue sarcoma (STS) of the extremities is typically treated with limb-sparing surgery and radiation therapy; with this treatment approach, high local control rates can be achieved. However, postradiation bone fractures, fractures occurring in the prior radiation field with minimal or no trauma, are a serious late complication that occurs in 2-22% of patients who receive surgery and radiation for STS. Multiple risk factors for sustaining a postradiation fracture exist, including high radiation dose, female sex, periosteal stripping, older age, femur location, and chemotherapy administration. The treatment of these pathological fractures can be difficult, with complications including delayed union, nonunion, and infection posing particular challenges. Here, we review the mechanisms, risk factors, and treatment challenges associated with postradiation fractures in STS patients.
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http://dx.doi.org/10.1155/2021/8877567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984930PMC
March 2021

Limb-salvage reconstruction following resection of pelvic bone sarcomas involving the acetabulum.

Bone Joint J 2021 Apr;103-B(4):795-803

The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.

Aims: Limb salvage for pelvic sarcomas involving the acetabulum is a major surgical challenge. There remains no consensus about what is the optimum type of reconstruction after resection of the tumour. The aim of this study was to evaluate the surgical outcomes in these patients according to the methods of periacetabular reconstruction.

Methods: The study involved a consecutive series of 122 patients with a periacetabular bone sarcoma who underwent limb-salvage surgery involving a custom-made prosthesis in 65 (53%), an ice-cream cone prosthesis in 21 (17%), an extracorporeal irradiated autograft in 18 (15%), and nonskeletal reconstruction in 18 (15%).

Results: The rates of major complications necessitating further surgery were 62%, 24%, 56%, and 17% for custom-made prostheses, ice-cream cone prostheses, irradiated autografts and nonskeletal reconstructions, respectively (p = 0.001). The ten-year cumulative incidence of failure of the reconstruction was 19%, 9%, 33%, and 0%, respectively. The major cause of failure was deep infection (11%), followed by local recurrence (6%). The mean functional Musculoskeletal Tumour Society (MSTS) scores were 59%, 74%, 64%, and 72%, respectively. The scores were significantly lower in patients with major complications than in those without complications (mean 52% (SD 20%) vs 74% (SD 19%); p < 0.001). For periacetabular resections involving the ilium, the mean score was the highest with custom-made prostheses (82% (SD 10%)) in patients without any major complication; however, nonskeletal reconstruction resulted in the highest mean scores (78% (SD 12%)) in patients who had major complications. For periacetabular resections not involving the ilium, significantly higher mean scores were obtained with ice-cream cone prostheses (79% (SD 17%); p = 0.031).

Conclusion: Functional outcome following periacetabular reconstruction is closely associated with the occurrence of complications requiring further surgery. For tumours treated with periacetabular and iliac resection, skeletal reconstruction may result in the best outcomes in the absence of complications, whereas nonskeletal reconstruction is a reasonable option if the risk of complications is high. For tumours requiring periacetabular resection without the ilium, reconstruction using an ice-cream cone prosthesis supported by antibiotic-laden cement is a reliable option. Cite this article:  2021;103-B(4):795-803.
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http://dx.doi.org/10.1302/0301-620X.103B4.BJJ-2020-0665.R1DOI Listing
April 2021

Pelvic reconstruction using an ice-cream cone prosthesis: correlation between the inserted length of the coned stem and surgical outcome.

Int J Clin Oncol 2021 Jun 15;26(6):1139-1146. Epub 2021 Mar 15.

Department of Oncology, The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.

Background: Acetabular reconstruction using an ice-cream cone prosthesis has been a reliable reconstruction option following pelvic tumour resection. However, it remains unknown which factor determines the success of this procedure. We aimed to determine risk factors for complications and functional loss in acetabular reconstruction using an ice-cream cone prosthesis.

Patients And Methods: Fifty-four patients with malignant bone tumours who underwent acetabular reconstruction using an ice-cream cone prosthesis between 2004 and 2016 were studied. The bone-stem ratio was calculated as the ratio of the inserted length into the bone per the entire stem length.

Results: A total of 26 (48%) patients had at least one complication and 11 patients (20%) required surgical interventions. The complication rates were 71% and 40% with a bone-stem ratio ≤ 50% and > 50%, respectively (p = 0.026), and the bone-stem ratio significantly stratified the risk of complications (≤ 50%: OR, 4.67 versus > 50%; p = 0.048). The mean MSTS score at the final follow-up was 60% (range 23-97%): the scores were significantly lower in patients with complications/leg-length discrepancy (52%) than in those without (79%; p = 0.002). The mean score with a bone-stem ratio ≤ 50% was significantly lower than the score with a ratio > 50%, especially in patients who underwent non-navigated reconstructions (33% versus 64%; p = 0.001).

Conclusion: The inserted length of the coned stem into residual bone was predictive of complications and functional outcome. Surgical indication for this procedure should be considered with the size of the remaining ilium to stabilise the prosthesis with a coned stem longer than half length.
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http://dx.doi.org/10.1007/s10147-021-01882-3DOI Listing
June 2021

The role of imaging in computer assisted tumor surgery of the sacrum and pelvis.

Curr Med Imaging 2021 Mar 2. Epub 2021 Mar 2.

IRCCS Policlinico di Sant'Orsola, Bologna. Italy.

The use of a navigation system allows precise resection of a tumor and accurate reconstruction of the resultant defect thereby sparing important anatomical structures and preserving function. It is an "image-based" system where the imaging (computed tomography and magnetic resonance imaging) is required to supply the software with data. The fusion of the preoperative imaging provides pre-operative information about local anatomy and extent of the tumor, so that it allows an accurate preoperative planning. Accurate pre-operative imaging is mandatory in order to minimize CATS errors, thus performing accurate tumor resections.
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http://dx.doi.org/10.2174/1573405617666210303105735DOI Listing
March 2021

Impact of NICE guidelines on the survival of patients with soft-tissue sarcomas.

Bone Joint J 2021 Mar;103-B(3):569-577

Department of Oncology, The Royal Orthopaedic Hospital, Birmingham, UK.

Aims: Urgent referral to a specialist centre for patients with a soft-tissue sarcoma (STS) has been recommended by the National Institute for Health and Care Excellence (NICE) in the UK since 2006. However, the impact of this recommendation on the prognosis for these patients remains unclear. We aimed to determine the impact of the NICE guidelines on the disease-specific survival (DSS) of patients with an STS.

Methods: A total of 2,427 patients with an STS referred to a supraregional centre in the ten-year periods before (n = 1,386) and after (n = 1,041) the issue of the NICE guidelines were evaluated.

Results: The mean size of the tumour was significantly smaller at the time of diagnosis (10.3 cm (SD 6.5) vs 9.1 cm (SD 6.2); p < 0.001) and the number of patients who had undergone an inadvertent excision significantly decreased (28% (n = 389) vs 20% (n = 204); p < 0.001) following the introduction of the NICE guidelines. The five-year DSS was 63% in the pre-NICE and 71% in post-NICE groups (p < 0.001). The improved survival was more significant for those with a high-grade tumour (pre-NICE, 48%; post-NICE, 68%; p < 0.001). In those with a high-grade tumour, the mean size of the tumour (11.6 cm (SD 6.2) vs 9.6 cm (SD 5.8); p < 0.001) and the number of patients with metastasis at the time of diagnosis (15% (n = 124 vs 10% (n = 80); p = 0.007) significantly decreased in the post-NICE group.

Conclusion: An improvement in survival was seen after the introduction of the NICE guidelines, especially in patients with a high-grade STS. More patients were referred at an earlier stage, indicating a clearer pathway after the issue of national policy for the management of STSs in the UK. Cite this article:  2021;103-B(3):569-577.
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http://dx.doi.org/10.1302/0301-620X.103B3.BJJ-2020-0743.R1DOI Listing
March 2021

Immunotherapy for sarcomas.

Jpn J Clin Oncol 2021 Apr;51(4):523-537

Department of Orthopedic Surgery, Okayama University Hospital, Okayama City, Okayama, Japan.

Sarcomas are a heterogeneous group of malignancies of mesenchymal origin; their molecular and genomic mechanisms differ with regard to histology. These characteristics lead to the presentation of varied immunological profiles based on the tumor microenvironment. Various immunotherapies are considered for the treatment of sarcoma. These treatments are performed either in isolation or in combination with other methods such as cytotoxic chemotherapy or the use of molecular target agents. Among these, two recently emerging immunotherapies include T-cell receptor gene therapy and immune checkpoint inhibitor therapy, which are expected to be effective for many types of sarcoma. A sarcoma with a disease-specific translocation and a limited number of mutations, such as synovial sarcoma, expresses high levels of self-antigens, like the New York esophageal squamous cell carcinoma 1, which has been targeted in T-cell receptor gene therapy. On the other hand, sarcomas with a greater number of mutations, such as undifferentiated pleomorphic sarcomas, myxofibrosarcoma and dedifferentiated liposarcomas, can be good candidates for immune checkpoint inhibitors. Among immune checkpoint inhibitor therapies, programmed cell death-1 blockade (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte-associated antigen 4 blockade (ipilimumab) have been investigated most often in sarcoma. Although the sole use of immune checkpoint inhibitors provides limited efficacy, combined immunotherapy with immune checkpoint inhibitors or molecular target agents, especially antiangiogenic agents, has shown moderate results against some types of sarcoma, such as the alveolar soft part sarcoma. Several clinical trials utilizing immunotherapy, including T-cell receptor gene therapy and immune checkpoint inhibitors, in sarcomas are under progress. By clarifying the tumor microenvironment and biomarker-predictive capacity of immunotherapy in sarcomas, better clinical trials can be designed; this could lead to improved outcomes for immunotherapy in sarcoma.
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http://dx.doi.org/10.1093/jjco/hyab005DOI Listing
April 2021

Compliant Compression Reconstruction of the Proximal Femur Is Durable Despite Minimal Bone Formation in the Compression Segment.

Clin Orthop Relat Res 2021 07;479(7):1577-1585

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, affiliated with Weill Medical College of Cornell University, New York, NY, USA.

Background: Compliant compression fixation was developed to promote permanent bone-prosthesis osteointegration while preserving bone stock in patients needing endoprosthetic reconstructions. This has demonstrated durability in the distal femur, with reliable cortical hypertrophy adjacent to the implant. However, the extent of bone formation and prosthetic survivorship of proximal femoral replacements with compliant compression fixation has not been established.

Questions/purposes: (1) How much bone formation occurs across the compression segment in patients treated with a proximal femoral replacement implant using compliant compression fixation? (2) What were the Musculoskeletal Tumor Society (MSTS) scores at minimum 24-month follow-up of patients who received this reconstruction? (3) What is the implant survivorship free from implant removal or revision for any reason at final follow-up?

Methods: From 2006 to 2018, we performed 213 proximal femoral replacements in patients with oncologic conditions of the proximal femur where the trochanters could not be preserved. Of these, 6% (12 of 213) were performed with an implant that used compliant compression fixation. We used this device in primary oncologic reconstructions in patients younger than 65 years of age without metastases who had nonirradiated bone with the requisite ≥ 2.5 mm of cortical thickness in the hope that it would provide more durable fixation and bone stock preservation than conventional reconstructions. All patients were followed for longer than 2 years except one who died in that interval. Median (range) follow-up was 6 years (2 to 10 years). Seven patients received diagnosis-specific chemotherapy in a consistent manner based on Children's Oncology Group chemotherapy protocols. Using the NIH-developed ImageJ open-access software, we measured the area of bone under compression on 3-, 6-, 9-, 12-, 18-, and 24-month radiographs and the length of the traction bar potential-compression distance, reconciling independent measures from two investigators using the identical method as published for the distal femur with compression fixation. The duration of prosthesis retention was evaluated using a competing risk analysis for the 11 surviving patients.

Results: Bone hypertrophy in the compression segment was scant. At the final analysis, cortical bone formation was a median (range) of 4 (-7 to 14) above baseline. The median (range) MSTS score was 27 (19 to 30). One implant failed after trauma, and the patient underwent revision of the implant.

Conclusion: Despite scant bone formation across the compression segment and drastically less formation than reported for distal femoral replacements, compliant compression fixation of the proximal femur demonstrated good survivorship in patients 65 years or younger with localized sarcoma and nonirradiated, adequate bone stock in this small, retrospective series. Patients achieved good functional outcomes at final follow-up. The potential benefit of this reconstruction method should be weighed against the initial period of limited weightbearing and the life expectancy of the patient.

Level Of Evidence: Level IV, cohort study.
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http://dx.doi.org/10.1097/CORR.0000000000001663DOI Listing
July 2021

Interlocking reconstruction-mode stem-sideplates preserve at-risk hips with short residual proximal femora.

Bone Joint J 2021 Feb;103-B(2):398-404

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Aims: We have evaluated the survivorship, outcomes, and failures of an interlocking, reconstruction-mode stem-sideplate implant used to preserve the native hip joint and achieve proximal fixation when there is little residual femur during large endoprosthetic reconstruction of the distal femur.

Methods: A total of 14 patients underwent primary or revision reconstruction of a large femoral defect with a short remaining proximal femur using an interlocking, reconstruction-mode stem-sideplate for fixation after oncological distal femoral and diaphyseal resections. The implant was attached to a standard endoprosthetic reconstruction system. The implant was attached to a standard endoprosthetic reconstruction system. None of the femoral revisions were amenable to standard cemented or uncemented stem fixation. Patient and disease characteristics, surgical history, final ambulatory status and Musculoskeletal Tumor Society (MSTS) score were recorded. The percentage of proximal femur remaining was calculated from follow-up radiographs.

Results: All 14 at-risk native hip joints were preserved at a mean final follow-up of 6.0 years (SD 3.7), despite a short residual femur, often after proximal osteotomies through the lesser trochanter. Overall, 13 of 14 stems had long-term successful fixation. Eight patients required no reoperation. Three patients required reoperation due to implant-related issues, and three patients required reoperation for wound healing problems or infection. There were no dislocations or fractures. At final follow-up the mean MSTS score was 24.9 (SD 4.1). Nine patients required no ambulation aids, and only one had a Trendelenburg gait.

Conclusion: This interlocking, reconstruction-mode stem-sideplate reliably preserves native hip joint anatomy and function after large femoral resection with a short remaining proximal femur, both in the primary and revision setting. This is particularly important for preventing or delaying total femoral arthroplasty in young patients after oncological reconstruction. Hip abductor strength and function could be maintained by this method, and the risk of dislocation eliminated. The success of this technique in this modest series should be verified in a larger collaborative study and will be of interest to revision surgeons and oncologists. Cite this article: 2021;103-B(2):398-404.
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http://dx.doi.org/10.1302/0301-620X.103B2.BJJ-2020-0654.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926295PMC
February 2021

The critical difference in the DASH (Disabilities of the Arm, Shoulder, and Hand) outcome measure after essential upper extremity tumor surgery.

J Shoulder Elbow Surg 2021 Jan 20. Epub 2021 Jan 20.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: The DASH (Disabilities of the Arm, Shoulder, and Hand) is a scored questionnaire that is widely used to evaluate the health-related quality of life of patients with upper limb musculoskeletal disorders. However, numerical changes in the measure scores lack clinical significance without meaningful threshold change values of outcome measures that are diagnostically specific. The minimal clinically important difference (MCID) is useful for the interpretation of scores by defining the smallest change that a patient would perceive. However, the MCIDs of the scores in orthopedic oncology patients has not been reported. We aimed to determine the MCIDs of the measure in orthopedic oncology patients.

Methods: Data from our health-related quality of life database from 1999 to 2005 were retrospectively reviewed after institutional review board approval. Seventy-eight patients who underwent surgery and completed 2 surveys during postoperative follow-up were evaluated. Two different methods were used to estimate the MCIDs: distribution-based and anchor-based approaches (the latter used receiver operating characteristic analysis).

Results: Using distribution-based methods, the MCIDs of the DASH questionnaire were 7.4 and 8.3 by half standard deviation and the 90% interval of minimal detectable change, respectively. By anchor-based method (receiver operating characteristic analysis), the MCID was 8.3.

Conclusion: The MCID values calculated by each method validates that the results for upper extremity oncology patients were similar to those reported in other orthopedic conditions. These results identify the threshold for meaningful improvements in DASH scores in orthopedic oncology patients and establish the reference to evaluate health-related quality of life and the outcomes of upper extremity oncology surgery. These data should be further refined for disease- and reconstruction-specific analyses.
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http://dx.doi.org/10.1016/j.jse.2020.11.027DOI Listing
January 2021

The role of surgical margin quality in myxofibrosarcoma and undifferentiated pleomorphic sarcoma.

Eur J Surg Oncol 2020 Nov 29. Epub 2020 Nov 29.

Department of Orthopaedic Oncology, The Royal Orthopaedic Hospital, Birmingham, UK.

Objectives: The effect of margin quality as a barrier against infiltration of soft-tissue sarcomas (STSs) has been unclear. We aimed to investigate the effect of margin quantity and quality on local control for myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS).

Methods: 278 patients with a localised MFS and UPS were studied. Margin quality was categorized into five types; type 1, pseudocapsule/reactive zone; type 2, fat/fibrofatty tissue; type 3, muscle; type 4, fascia; type 5, periosteum.

Results: The 5-year cumulative LR incidence was 22% and 13% in patients with positive and 0.1-9.9 mm margins, respectively, but decreased to 3% with ≥10.0 mm margins (p = 0.009); the cumulative LR incidence was significantly lower in patients with ≥10.0 mm margins than those with positive margins (p = 0.033) but was not significantly different in those with 0.1-9.9 mm margins (p = 0.183). In patients with 0.1-9.9 mm margins, the cumulative LR incidence was affected by margin quality; type 4 and 5 provided an LR risk less than 5% (p < 0.001), which was similar to those with margins ≥10.0 mm. Combining these two factors together, the LR risk in patients with positive or 0.1-9.9 mm margins without fascia/periosteum was approximately 11 × higher than patients with 0.1-9.9 mm margins with fascia/periosteum or margins ≥10.0 mm (p = 0.002).

Conclusions: A resection margin of 0.1-9.9 mm with fascia or periosteum provided a similar LR risk profile to ≥10 mm margins with any margin quality, which provided the lowest LR risk. The quality of fascial or periosteal tissue margins may be equivalent to a margin quantity of 10 mm as a barrier to LR.
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http://dx.doi.org/10.1016/j.ejso.2020.11.144DOI Listing
November 2020

Radiographic and clinical assessment of unidirectional porous hydroxyapatite to treat benign bone tumors.

Sci Rep 2020 12 9;10(1):21578. Epub 2020 Dec 9.

Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558, Japan.

Unidirectional porous hydroxyapatite (UDPHAp) was developed as an excellent scaffold with unidirectional pores oriented in the horizontal direction with interpore connections. The purpose of this study was to assess radiographic changes and clinical outcomes and complications following UDPHAp implantation to treat benign bone tumors. We retrospectively analyzed 44 patients treated with intralesional resection and UDPHAp implantation for benign bone tumors between 2010 and 2015. Clinical and radiographic findings were evaluated postoperatively at regular follow-up visits. The mean follow-up was 49 months. Radiographic changes were classified into five stages based on bone formation in the implanted UDPHAp according to Tamai's classification. All patients showed excellent bone formation inside and around implanted UDPHAp. Absorption of UDPHAp and bone marrow cavity remodeling was identified in 20 patients at a mean of 17 months postoperatively, and was significantly more common in young patients. Preoperative cortical thinning was completely regenerated in 26 of 31 patients on average 10 months after surgery. There were no cases of delayed wound healing, postoperative infection, or allergic reaction related to implanted UDPHAp. UDPHAp is a useful bone-filling substitute for treating benign bone tumor, and the use of this material has a low complication rate.
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http://dx.doi.org/10.1038/s41598-020-78409-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725991PMC
December 2020

Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma.

Bone Joint J 2020 Dec;102-B(12):1752-1759

Department of Oncology, Royal Orthopaedic Hospital, Birmingham, UK.

Aims: Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma.

Methods: The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot.

Results: In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit.

Conclusion: Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: 2020;102-B(12):1752-1759.
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http://dx.doi.org/10.1302/0301-620X.102B12.BJJ-2020-0810.R1DOI Listing
December 2020

Low-grade soft-tissue sarcomas: What is an adequate margin for local disease control?

Surg Oncol 2020 Dec 26;35:303-308. Epub 2020 Aug 26.

Oncology Service, The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.

Background: Whilst the resection margin is an established factor predictive of local control of soft-tissue sarcomas (STSs), the adequacy of margin width for low-grade STSs has been rarely described. We aimed to investigate the margin adequacy and its prognostic relevance in low-grade STSs.

Methods: 109 patients who underwent surgical treatment for a low-grade STS were studied. The prognostic value of margin status was evaluated according to the R-, R+1-classification, and width in millimetres.

Results: The 10-year local recurrence (LR) rates were 6%, 27%, 54% in R0, R1, and R2, respectively (p < 0.001), according to the R-classification. The R+1-classification resulted in a decreased LR rate in R1, but no major differences in LR rates in R0 and R2; 7%, 14%, 54% in R0, R1, and R2, respectively (p < 0.001). When classified by metric distance, 10-year LR rates were 0%, 8%, and 38% by ≥ 2.0 mm, 0.1-1.9 mm, and 0 mm margins, respectively (p < 0.001). Patients with close margins (0.1-1.9 mm) who received adjuvant radiotherapy had a trend toward lower LR risk than those without radiotherapy (10-year, 4% vs. 12%; p = 0.406). The 5 and 10-year disease-specific mortality was 9% and 13%, respectively; margin width was not associated with disease-specific mortality but LR was a poor prognostic factor for survival (p = 0.003).

Conclusion: Whilst negative margin provided local control over 90%, excellent local control was achieved with microscopic margins ≥2 mm. The role of margins is more important than radiotherapy in local control. Margins do not determine survival, but LR is associated with a poor prognosis.
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http://dx.doi.org/10.1016/j.suronc.2020.08.022DOI Listing
December 2020

How Are Indeterminate Pulmonary Nodules at Diagnosis Associated with Survival in Patients with High-Grade Osteosarcoma?

Clin Orthop Relat Res 2021 02;479(2):298-308

K. M. Tsoi, M. Lowe, Y. Tsuda, J. R. Lex, T. Fujiwara, J. Gregory, J. Stevenson, S. E. Evans, L. M. Jeys, Oncology Department, Royal Orthopaedic Hospital, Birmingham, UK.

Background: Pulmonary metastases are a poor prognostic factor in patients with osteosarcoma; however, the clinical significance of subcentimeter lung nodules and whether they represent a tumor is not fully known. Because the clinician is faced with decisions regarding biopsy, resection, or observation of lung nodules and the potential impact they have on decisions about resection of the primary tumor, this remains an area of uncertainty in patient treatment. Surgical management of the primary tumor is tailored to prognosis, and it is unclear how aggressively patients with indeterminate pulmonary nodules (IPNs), defined as nodules smaller than 1 cm at presentation, should be treated. There is a clear need to better understand the clinical importance of these nodules.

Questions/purposes: (1) What percentage of patients with high-grade osteosarcoma and spindle cell sarcoma of bone have IPNs at diagnosis? (2) Are IPNs at diagnosis associated with worse metastasis-free and overall survival? (3) Are there any clinical or radiologic factors associated with worse overall survival in patients with IPN?

Methods: Between 2008 and 2016, 484 patients with a first presentation of osteosarcoma or spindle cell sarcoma of bone were retrospectively identified from an institutional database. Patients with the following were excluded: treatment at another institution (6%, 27 of 484), death related to complications of neoadjuvant chemotherapy (1%, 3 of 484), Grade 1 or 2 on final pathology (4%, 21 of 484) and lack of staging chest CT available for review (0.4%, 2 of 484). All patients with abnormalities on their staging chest CT underwent imaging re-review by a senior radiology consultant and were divided into three groups for comparison: no metastases (70%, 302 of 431), IPN (16%, 68 of 431), and metastases (14%, 61 of 431) at the time of diagnosis. A random subset of CT scans was reviewed by a senior radiology registrar and there was very good agreement between the two reviewers (κ = 0.88). Demographic and oncologic variables as well as treatment details and clinical course were gleaned from a longitudinally maintained institutional database. The three groups did not differ with regard to age, gender, subtype, presence of pathological fracture, tumor site, or chemotherapy-induced necrosis. They differed according to local control strategy and tumor size, with a larger proportion of patients in the metastases group presenting with larger tumor size and undergoing nonoperative treatment. There was no differential loss to follow-up among the three groups. Two percent (6 of 302) of patients with no metastases, no patients with IPN, and 2% (1 of 61) of patients with metastases were lost to follow-up at 1 year postdiagnosis but were not known to have died. Individual treatment decisions were determined as part of a multidisciplinary conference, but in general, patients without obvious metastases received (neo)adjuvant chemotherapy and surgical resection for local control. Patients in the no metastases and IPN groups did not differ in local control strategy. For patients in the IPN group, staging CT images were inspected for IPN characteristics including number, distribution, size, location, presence of mineralization, and shape. Subsequent chest CT images were examined by the same radiologist to reevaluate known nodules for interval change in size and to identify the presence of new nodules. A random subset of chest CT scans were re-reviewed by a senior radiology resident (κ = 0.62). The association of demographic and oncologic variables with metastasis-free and overall survival was first explored using the Kaplan-Meier method (log-rank test) in univariable analyses. All variables that were statistically significant (p < 0.05) in univariable analyses were entered into Cox regression multivariable analyses.

Results: Following re-review of staging chest CTs, IPNs were found in 16% (68 of 431) of patients, while an additional 14% (61 of 431) of patients had lung metastases (parenchymal nodules 10 mm or larger). After controlling for potential confounding variables like local control strategy, tumor size, and chemotherapy-induced necrosis, we found that the presence of an IPN was associated with worse overall survival and a higher incidence of metastases (hazard ratio 1.9 [95% CI 1.3 to 2.8]; p = 0.001 and HR 3.6 [95% CI 2.5 to 5.2]; p < 0.001, respectively). Two-year overall survival for patients with no metastases, IPN, or metastases was 83% [95% CI 78 to 87], 65% [95% CI 52 to 75] and 45% [95% CI 32 to 57], respectively (p = 0.001). In 74% (50 of 68) of patients with IPNs, it became apparent that they were true metastatic lesions at a median of 5.3 months. Eighty-six percent (43 of 50) of these patients had disease progression by 2 years after diagnosis. In multivariable analysis, local control strategy and tumor subtype correlated with overall survival for patients with IPNs. Patients who were treated nonoperatively and who had a secondary sarcoma had worse outcomes (HR 3.6 [95% CI 1.5 to 8.3]; p = 0.003 and HR 3.4 [95% CI 1.1 to 10.0]; p = 0.03). The presence of nodule mineralization was associated with improved overall survival in the univariable analysis (87% [95% CI 39 to 98] versus 57% [95% CI 43 to 69]; p = 0.008), however, because we could not control for other factors in a multivariable analysis, the relationship between mineralization and survival could not be determined. We were unable to detect an association between any other nodule radiologic features and survival.

Conclusion: The findings show that the presence of IPNs at diagnosis is associated with poorer survival of affected patients compared with those with normal staging chest CTs. IPNs noted at presentation in patients with high-grade osteosarcoma and spindle cell sarcoma of bone should be discussed with the patient and be considered when making treatment decisions. Further work is required to elucidate how the nodules should be managed.

Level Of Evidence: Level III, prognostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899536PMC
February 2021

Chondrosarcoma of bone in children and adolescents.

J Child Orthop 2020 Aug;14(4):330-334

Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.

Purpose: Chondrosarcomas typically present in adults during the fifth to seventh decades and are rare in young patients. The biological behaviour and oncological outcomes may be different in children and adolescents.

Methods: We retrospectively evaluated the outcomes of all patients with chondrosarcoma of bone who were younger than 18 years of age at the time of diagnosis and were treated at our centre between 1995 and 2018.

Results: The 15 consecutive patients studied included nine male and six female cases, with a mean age at diagnosis of 13 years (7 to 17). The median follow-up was 117 months (30 to 277). The tumours were primary and secondary in ten and five patients, respectively. The tumours were central in 13 and surface in two patients. The tumour locations were the humerus in five, digits in five, femur in three, radius in one and pelvis in one patient. The histological grades were grade I in seven, grade II in seven and grade III in one patient. The surgical treatments were limb salvage in ten patients and ray amputation in five patients. The surgical margins were wide in eight, marginal in two and intralesional in five patients. All the patients were alive and continuously free of disease at the time of the last follow-up. No patient developed metastases or local recurrence.

Conclusion: Chondrosarcoma of bone in children and adolescent patients has a very good prognosis and is less aggressive compared with published outcomes in older patients.

Level Of Evidence: IV.
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http://dx.doi.org/10.1302/1863-2548.14.200046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453173PMC
August 2020

Navigation-assisted pelvic resections and reconstructions for periacetabular chondrosarcomas.

Eur J Surg Oncol 2021 02 3;47(2):416-423. Epub 2020 Jul 3.

Oncology Service, The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, United Kingdom.

Objectives: Survival in patients with chondrosarcomas has not improved over 40 years. Although emerging evidence has documented the efficacy of navigation-assisted surgery, the prognostic significance in chondrosarcomas remains unknown. We aimed to assess the clinical benefit of navigation-assisted surgery for pelvic chondrosarcomas involving the peri-acetabulum.

Methods: We studied 50 patients who underwent limb-sparing surgery for periacetabular chondrosarcomas performed with navigation (n = 13) without it (n = 37) at a referral musculoskeletal oncology centre between 2000 and 2015.

Results: The intralesional resection rates in the navigated and non-navigated groups were 8% (n = 1) and 19% (n = 7), respectively; all bone resection margins were clear in the navigated group. The 5-year cumulative incidence of local recurrence was 23% and 56% in the navigated and non-navigated groups, respectively (p = 0.035). There were no intra-operative complications related to use of navigation. There was a trend toward better functional outcomes in the navigated group (mean MSTS score, 67%) than the non-navigated group (mean MSTS score, 60%; p = 0.412). At a mean follow-up of 63 months, the 5-year disease-specific survival was 76% and 53% in the navigated and non-navigated group, respectively (p = 0.085), whilst the 5-year progression-free survival was 62% and 28% in the navigated and non-navigated group, respectively (p = 0.032).

Conclusion: This study confirmed improved local control and progression-free survival with the use of computer navigation in patients with limb-salvage surgery for periacetabular chondrosarcomas, although the advancement in other treatment modalities is required for improvement of disease-specific survival.
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http://dx.doi.org/10.1016/j.ejso.2020.05.025DOI Listing
February 2021

The role of radiotherapy in the treatment of superficial soft-tissue sarcomas.

Bone Joint J 2020 Aug;102-B(8):1088-1094

The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.

Aims: The existing clinical guidelines do not describe a clear indication for adjuvant radiotherapy (RT) in the treatment of superficial soft tissue sarcomas (STSs). We aimed to determine the efficacy of adjuvant RT for superficial STSs.

Methods: We retrospectively studied 304 patients with superficial STS of the limbs and trunk who underwent surgical resection at a tertiary sarcoma centre. The efficacy of RT was investigated according to the tumour size and grade: group 1, ≤ 5 cm, low grade; group 2, ≤ 5cm, high grade; group 3, > 5 cm, low grade; group 4, > 5 cm, high grade.

Results: The five- and ten-year local recurrence-free survival (LRFS) for all patients was 88% and 81%, respectively. While the efficacy of adjuvant RT was not proven in local control of all patients (five-year LRFS; RT+, 90% versus RT-, 83%; p = 0.074), the LRFS was significantly improved by adjuvant RT in group 2 (five-year LRFS; RT+, 96% versus RT-, 82%; p = 0.019), and group 4 (five-year LRFS; RT+, 87% versus RT-, 73%; p = 0.027). In groups 2 and 4, adjuvant RT significantly reduced the LR risk if the resection margin was clear but less than 5 mm; the LR rate was 7% with adjuvant RT compared with 26% with surgery alone (p = 0.003). There was no statistical relationship with the use of adjuvant RT and survival in every group.

Conclusion: Adjuvant RT reduces the risk of local recurrence in patients with superficial high-grade STS regardless of tumour size, especially when resection margin is less than 5 mm. Cite this article: 2020;102-B(8):1088-1094.
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http://dx.doi.org/10.1302/0301-620X.102B8.BJJ-2020-0043.R1DOI Listing
August 2020

Myxofibrosarcoma: Clinical and Prognostic Value of MRI Features.

Curr Med Imaging 2021 ;17(2):217-224

Orthopaedic Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Myxofibrosarcoma is one of the most common soft tissue sarcomas in the elderly. It is characterized by an extremely high rate of local recurrence, higher than other soft tissue tumors, and a relatively low risk of distant metastases.Magnetic resonance imaging (MRI) is the imaging modality of choice for the assessment of myxofibrosarcoma, which plays a key role in the preoperative setting of these patients. MRI features associated with the high risk of local recurrence are: high myxoid matrix content (water-like appearance of the lesions), high grade of contrast enhancement and presence of an infiltrative pattern ("tail sign"). On the other hand, MRI features associated with worse sarcoma specific survival are: large size of the lesion, deep location, high grade of contrast enhancement. Recognizing the above-mentioned imaging features of myxofibrosarcoma may be helpful in stratifying the risk for local recurrence and disease-specific survival. Moreover, the surgical planning should be adjusted according to the MRI features.
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http://dx.doi.org/10.2174/1573405616999200729152135DOI Listing
January 2021

The adequacy of resection margin for non-infiltrative soft-tissue sarcomas.

Eur J Surg Oncol 2021 02 18;47(2):429-435. Epub 2020 Jun 18.

Oncology Service, The Royal Orthopaedic Hospital, Birmingham, UK.

Objectives: There remains no consensus on what constitutes an adequate margin of resection for non-infiltrative soft-tissue sarcomas (STSs). We aimed to investigate the role of resection margins in millimetres for non-infiltrative STSs.

Methods: 502 patients who underwent surgical resection for a localized, non-infiltrative, high-grade STSs were studied. The prognostic significance of margin width was analysed and compared with the conventional R- and R+1-classification of surgical margins.

Results: The overall local recurrence (LR) rate was 13%; 9% and 27% with negative and positive margins, respectively (p < 0.001). In patients with negative margins, the LR rates were greater than 10% in patients with margins ≤5.0 mm but reduced to less than 4% with margins >5.0 mm. When classified by the R- (or R+1)-classification, the 5-year cumulative LR incidence was 8%, 23% (16%), and 31% for R0, R1, and R2, respectively, which did not stratify the LR risk with negative margins. On the other hand, an accurate risk stratification was possible by metric distance; the 5-year cumulative incidence of LR was 29%, 10%, and 1% with 0 mm, 0.1-5.0 mm, and >5.0 mm, respectively (p < 0.001). This classification also stratified the LR risk in patients with or without adjuvant radiotherapy.

Conclusion: While a negative margin is essential to optimize local control in patients with non-infiltrative STSs, surgical margin width greater than 5 mm minimises the risk of local failure regardless of the use of adjuvant radiotherapy.
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http://dx.doi.org/10.1016/j.ejso.2020.06.020DOI Listing
February 2021