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Recurrent loss of chromosome 22 and SMARCB1 deletion in extra-axial chordoma: A clinicopathological and molecular analysis

Wen, Xiaoyun; Cimera, Robert; Aryeequaye, Ruth; Abhinta, Mohanty; Athanasian, Edward; Healey, John; Fabbri, Nicola; Boland, Patrick; Zhang, Yanming; Hameed, Meera
Extra-axial chordoma is a rare neoplasm of extra-axial skeleton and soft tissue that shares identical histomorphologic and immunophenotypic features with midline chordoma. While genetic changes in conventional chordoma have been well-studied, the genomic alterations of extra-axial chordoma have not been reported. It is well known that conventional chordoma is a tumor with predominantly non-random copy number alterations and low mutational burden. Herein we describe the clinicopathologic and genomic characteristics of six cases of extra-axial chordoma, with genome-wide high-resolution single nucleotide polymorphism array, fluorescence in situ hybridization and targeted next-generation sequencing (NGS) analysis. The patients presented at a mean age of 33 years (range: 21-54) with a female to male ratio of 5:1. Four cases were histologically conventional type, presented with bone lesions and three of them had local recurrence. Two cases were poorly differentiated chordomas, presented with intra-articular soft tissue masses and both developed distant metastases. All cases showed brachyury positivity and the two poorly differentiated chordomas showed in addition loss of INI-1 expression by immunohistochemical analysis. Three of four extra-axial conventional chordomas showed simple genome with loss of chromosome 22 or a heterozygous deletion of SMARCB1. Both poorly differentiated chordomas demonstrated a complex hyperdiploid genomic profile with gain of multiple chromosomes and homozygous deletion of SMARCB1. Our findings show that heterozygous deletion of SMARCB1 or the loss of chromosome 22 is a consistent abnormality in extra-axial chordoma and transformation to poorly differentiated chordoma is characterized by homozygous loss of SMARCB1 associated with genomic complexity and instability such as hyperdiploidy.
PMID: 34392582
ISSN: 1098-2264
CID: 5293742

Computer-Assisted Surgical Navigation for Primary and Metastatic Bone Malignancy of the Pelvis: Current Evidence and Future Directions

Christ, Alexander B; Hansen, Derek G; Healey, John H; Fabbri, Nicola
Computer-assisted navigation and robotic surgery have gained popularity in the treatment of pelvic bone malignancies, given the complexity of the bony pelvis, the proximity of numerous vital structures, and the historical challenges of pelvic bone tumor surgery. Initial interest was on enhancing the accuracy in sarcoma resection by improving the quality of surgical margins and decreasing the incidence of local recurrences. Several studies have shown an association between intraoperative navigation and increased incidence of negative margin bone resection, but long-term outcomes of navigation in pelvic bone tumor resection have yet to be established. Historically, mechanical stabilization of pelvic bone metastases has been limited to Harrington-type total hip arthroplasty for disabling periacetabular disease, but more recently, computer-assisted surgery has been employed for minimally invasive percutaneous fixation and stabilization; although still in its incipient stages, this procedure is potentially appealing for treating patients with bone metastases to the pelvis. The authors review the literature on navigation for the treatment of primary and metastatic tumors of the pelvic bone and discuss the best practices and limitations of these techniques.
PMID: 34539276
ISSN: 1556-3316
CID: 5293762

Life or limb: an international qualitative study on decision making in sarcoma surgery during the COVID-19 pandemic

Bunzli, Samantha; O'Brien, Penny; Aston, Will; Ayerza, Miguel A; Chan, Lester; Cherix, Stephane; de Las Heras, Jorge; Donati, Davide; Eyesan, Uwale; Fabbri, Nicola; Ghert, Michelle; Hilton, Thomas; Idowu, Oluwaseyi Kayode; Imanishi, Jungo; Puri, Ajay; Rose, Peter; Sabah, Dundar; Turcotte, Robert; Weber, Kristy; Dowsey, Michelle M; Choong, Peter F M
OBJECTIVES:The COVID-19 pandemic is unprecedented as a global crisis over the last century. How do specialist surgeons make decisions about patient care in these unprecedent times? DESIGN:Between April and May 2020, we conducted an international qualitative study. Sarcoma surgeons from diverse global settings participated in 60 min interviews exploring surgical decision making during COVID-19. Interview data were analysed using an inductive thematic analysis approach. SETTING:Participants represented public and private hospitals in 14 countries, in different phases of the first wave of the pandemic: Australia, Argentina, Canada, India, Italy, Japan, Nigeria, Singapore, Spain, South Africa, Switzerland, Turkey, UK and USA. PARTICIPANTS:From 22 invited sarcoma surgeons, 18 surgeons participated. Participants had an average of 19 years experience as a sarcoma surgeon. RESULTS:). CONCLUSIONS:In the context of rapidly changing standards of justice and beneficence in patient care, traditional decision-making frameworks may no longer apply. Based on the experiences of surgeons in this study, we describe a framework of least-worst decision making. This framework gives rise to actionable strategies that can support decision making in sarcoma and other specialised fields of surgery, both during the current crisis and beyond.
PMID: 34475158
ISSN: 2044-6055
CID: 5293752

Distal femoral replacement - Cemented or cementless? Current concepts and review of the literature

Christ, Alexander B; Hornicek, Francis J; Fabbri, Nicola
Distal femoral endoprosthetic replacement has been successfully used to reconstruct distal femoral defects after tumor resection for over four decades. Despite continued advances, aseptic loosening continues to be the most common failure mode after infection. Debate still exists about a variety of design features and the optimal fixation method remains controversial. To date, no large-scale study or meta-analysis has demonstrated the superiority of one fixation technique over another. While the classic dichotomy of cemented versus cementless stems is well-known, the contemporary surgeon needs to fully understand the optimal clinical setting for each type of fixation technique and additional strategies to maximize implant stability. In clinical practice, the choice of fixation must be tailored to the individual patient. The surgeon must consider whether the operation is being performed for primary sarcoma or metastatic carcinoma, the presence of distant metastases, age, comorbidities, and whether radiotherapy has been previously given or will be required at the site of fixation. The best strategy for each patient optimizes tumor control and appropriately weighs risks of fixation failure versus the expected patient survival. This review will explore cemented and uncemented distal femoral replacement and highlight modern concepts to optimize each technique.
PMID: 34040980
ISSN: 0976-5662
CID: 5293732

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

Christ, Alexander B; Fujiwara, Tomohiro; Fabbri, Nicola; Healey, John H
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.
PMID: 33595932
ISSN: 1528-1132
CID: 5293712

Femoral Fracture in Primary Soft Tissue Sarcoma Treated with Intensity-Modulated Radiation Therapy with and Without Dose Constraints

Casey, Dana L; Berry, Sean L; Crago, Aimee; Fabbri, Nicola; Singer, Samuel; Alektiar, Kaled M
BACKGROUND:We previously reported that the cumulative risk of femoral fracture in patients treated with intensity-modulated radiation therapy (IMRT) for thigh and groin soft tissue sarcoma (STS) is low. In the current study, we sought to evaluate the effect of radiation dose constraints on the rate of femoral fracture in a more contemporary cohort. METHODS:All patients treated with IMRT for STS of the thigh or groin from 2004 to 2016 were included (n = 145). Beginning in 2011, radiation dose was constrained to a mean dose of < 37 Gy, volume of bone receiving ≥ 40 Gy (V40Gy) < 64%, and maximum dose < 59 Gy to limit the dose to the femur. RESULTS:Sixty-one patients were treated before dose constraints were implemented, and 84 patients were treated after. Median follow-up for patients treated before and after constraints were implemented was 6.1 and 5.7 years, respectively, and the two groups were demographically and clinically similar. On univariate analysis, the 5-year cumulative incidence of femoral fracture among patients treated with and without dose constraints was 1.8% (95% confidence interval [CI] 0.3-12.2%) versus 7.4% (95% CI 3.1-17.6%) [p = 0.11, p = non-significant, respectively]. On multivariable analysis, only age  ≥ 60 years was significantly associated with increased risk of fracture. CONCLUSIONS:The risk of femoral fracture after IMRT for STS of the thigh/groin is low, and with the implementation of radiation dose constraints, the risk is < 2%. Although longer follow-up is needed, our results support the utilization of extremity sarcoma IMRT-specific dose constraints for fracture prevention.
PMID: 33073343
ISSN: 1534-4681
CID: 5293682

Poorly differentiated chordoma with whole-genome doubling evolving from a SMARCB1-deficient conventional chordoma: A case report [Case Report]

Curcio, Christian; Cimera, Robert; Aryeequaye, Ruth; Rao, Mamta; Fabbri, Nicola; Zhang, Yanming; Hameed, Meera
Evolution of poorly differentiated chordoma from conventional chordoma has not been previously reported. We encountered a case of a poorly differentiated chordoma with evidence of whole-genome doubling arising from a SMARCB1-deficient conventional chordoma. The tumor presented as a destructive sacral mass in a 43-year-old man and was comprised of a highly cellular poorly differentiated chordoma with small, morphologically distinct nodules of conventional chordoma accounting for <5% of the total tumor volume. Immunohistochemistry (IHC) revealed both components were strongly reactive for brachyury and lacked normal staining for INI1. Single nucleotide polymorphism (SNP) array analysis identified multiple genomic imbalances in the conventional component, including deletions of 1p, 3p, and 22q (involving SMARCB1) and loss of chromosomes 5 and 15, while the poorly differentiated component exhibited the same aberrations at a more profound level with additional loss of chromosome 4, low level focal deletion of 17p (involving TP53), and tetraploidy. Homozygous deletion of SMARCB1 was present in both components. Fluorescence in situ hybridization (FISH) analysis confirmed the relevant deletions in both components as well as genome doubling in the poorly differentiated tumor. This case suggests that SMARCB1 loss is an early event in rare conventional chordomas that could potentially evolve into poorly differentiated chordoma through additional genomic aberrations such as genome doubling. Further studies with additional patients will be needed to determine if genome doubling is a consistent pathway for evolution of poorly differentiated chordoma.
PMID: 32920865
ISSN: 1098-2264
CID: 5293672

Postradiation Fractures after Combined Modality Treatment in Extremity Soft Tissue Sarcomas

Bartelstein, Meredith K; Yerramilli, Divya; Christ, Alexander B; Kenan, Shachar; Ogura, Koichi; Fujiwara, Tomohiro; Fabbri, Nicola; Healey, John H
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.
PMID: 33790687
ISSN: 1357-714x
CID: 5293722

Minimally Invasive Fixation of Pelvic Metastases by CT-Assisted Surgical Navigation

Hansen, Derek G; Fabbri, Nicola
The treatment of patients with painful metastases and pathologic fracture of the pelvis is challenging and based on multidisciplinary approach. Although radiation and disease-specific systemic therapy are the mainstay of treatment, the goal of surgery is to maintain functional independence. Harrington-type total hip arthroplasty has proven invaluable to address periacetabular cancer. However, data on how to best treat patients with disabling pain due to metastases outside the periacetabular region or involving the entire hemipelvis are scant, heterogeneous, and hardly comparable. Minimally invasive strategies in this setting are appealing and conceivably preferable to open surgery because of lower risk of complications and expedited recovery.
PMID: 33438930
ISSN: 0065-6895
CID: 5293702

Impact of Magnetic Resonance Imaging (MRI) Findings on Management of Symptomatic Patients Following Radiofrequency Ablation (RFA) of Osteoid Osteoma (OO)

Maybody, Majid; Soliman, Mohamed M; Hwang, Sinchun; Gonzalez-Aguirre, Adrian; Martin, Ernesto G Santos; Kaye, Elena; Hsu, Meier; Moskowitz, Chaya; Healey, John H; Fabbri, Nicola
OBJECT/OBJECTIVE:To assess the impact of MRI findings on management of symptomatic patients following RFA of OO. MATERIALS & METHODS/METHODS:Retrospective review of 43 patients with RFA for OO between June 2010 and June 2017 was performed. Patient, nidus and ablation data were reviewed. Pre- and 6-8 weeks post-procedural MRI (n=32) were compared for coverage of nidus by ablation zone, bone marrow edema, nidus hyperintensity and other findings. Baseline pain levels and analgesic use were compared with post-procedural follow-up visit at 6-8 weeks. Three groups of clinical and MRI outcomes of complete (CR), partial (PR) and no response (NR) were defined. A weighted-kappa statistic was used to assess for agreement. RESULTS:Clinical responses were CR in 34/43 (79.1%, 95%CI: 64.0-90.0%), PR in 8/43 (18.6%) and NR in 1/43 (2.3%) patients. All 19/32 patients with MRI CR experienced clinical CR. One patient with MRI NR had clinical NR. All 7/32 patients with clinical PR had MRI PR. All 4/43 complications were in MRI PR or NR groups. Substantial agreement was observed between MRI and clinical outcomes (kappa:0.69, 95%CI:0.45-0.95). MRI helped determine etiologies in all symptomatic patients and their management (n=8). CONCLUSIONS:MRI is recommended for symptomatic patients after ablation.
PMID: 33235978
ISSN: 2523-8973
CID: 5293692