Primary Ewing sarcoma/peripheral primitive neuroectodermal tumors in the cranial bone and mobile spine: what is the difference?

Background Primary Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumors (pPNETs) are aggressive bone tumors that rarely occur in the axial skeleton, including the cranial bone and mobile spine. The purpose of this study was to investigate whether there were any differences in patient characteristics, treatment strategies, and outcomes between patients with ES/pPNETs of the cranial bone and those with ES/pPNETs of the mobile spine. Methods A retrospective study was performed on 33 patients with ES/pPNETs who had been surgically treated and pathologically confirmed at our institution between 2010 and 2020. Patient characteristics were compared using Fisher exact tests or independent t tests. Survival rates were estimated via Kaplan–Meier survival analysis and compared using log-rank tests. Results Thirteen patients had ES/pPNETs of the cranial bone (39.4%), while 20 patients had ES/pPNETs of the mobile spine (60.6%). Patients with ES/pPNETs of the cranial bone had a younger mean age (14.8 vs 22.6 years; p = 0.047) and longer mean disease duration (2.5 vs 1.9 months; p = 0.008) compared with those of patients with ES/pPNETs of the mobile spine. Kaplan–Meier analysis showed that gross total resection (GTR) and radiotherapy resulted in a longer median survival time. The overall survival rates and progression-free survival rates of patients with ES/pPNETs of the cranial bone versus those of the mobile spine were not significantly different (p = 0.386 and p = 0.368, respectively). Conclusions Patients with ES/pPNETs of the cranial bone were younger compared to patients with ES/pPNETs of the mobile spine. There was no significant difference in the prognosis of patients with ES/pPNETs of the cranial bone versus those of the mobile spine. Taken together, our findings suggest that GTR and radiotherapy offer the best prognosis for improved long-term survival.

DDRE-45. HIGH-THROUGHPUT SCREENING OF EPIGENETIC COMPOUNDS FOR THE TREATMENT OF CHORDOMA IDENTIFIES POTENTIAL NOVEL THERAPEUTICS

BACKGROUND Chordoma is a rare malignant tumor with few treatment options. While surgical resection is deemed the most effective treatment, the 5-year overall survival rate is 61% and 5-year recurrence free survival rate is approximately 50%. To date, no FDA approved pharmacotherapies exist for the treatment of chordoma, and adjuvant therapy remains highly debated. This necessitates the need for further research to provide clinicians with more options to treat this patient population. METHODS In this study, we conducted a high-throughput 139-compound epigenetic inhibitor screen against 12 chordoma patient-derived cell lines; 4 were resected at our institution and 8 were graciously donated by the Chordoma Foundation. RESULTS 8 tumors were located in the sacrum, 3 were located in the mobile spine, and 1 tumor was located in the clivus. 5 tumors were primary, 5 were recurrent, and 2 were metastatic. 6 tumors came from female patients and 6 tumors came from male patients. The top three most effect compounds across the cohort were the G9a inhibitor UNC0631 (cell viability = 64.5% +/-25.1SD; p=1.53x10-9), the KDM inhibitor JIB-04 (cell viability = 68.4% +/-27.2SD; p=9.81x10-8), and the G9a inhibitor BIX01294 (cell viability = 68.6% +/-27.9SD; p=1.27x10-7). No single compound significantly reduced viability in every tumor in the cohort, although the HDAC inhibitor HC Toxin significantly reduced viability in 9 tumors (cell viability = 69.7% +/-16.6SD; p=2.6x10-12). The most effective compound for sacral tumors was UNC0631 (viability = 68.6% +/-22.1SD; p=4x10-7), UNC0631 was also the most effective for spinal tumors (viability = 54.4% +/-32.1SD; p=2.72x10-3), and notably, no significant compounds were identified for the single clival tumor. CONCLUSIONS Based on our drug screen results, epigenetic inhibition, particularly methyltransferase inhibition, may be a promising therapeutic avenue for the treatment of chordomas.

DDRE-43. SCREENING OF FDA-APPROVED COMPOUNDS FOR THE TREATMENT OF CHORDOMA, WITH IN VIVO VALIDATION USING THREE DIFFERENT XENOGRAFT MODELS, IDENTIFIES BRIGATINIB AS A POTENTIAL TREATMENT

BACKGROUND Chordoma is a rare malignant tumor with poor surgical control and no existing pharmacotherapies. Therefore, these tumors require additional research into novel therapeutics for their treatment. METHODS In this study we created a high-throughput drug screen and culture system to evaluate the efficacy of existing FDA-approved compounds in 10 chordoma cell lines and primary tumors. The cell lines were graciously donated by the Chordoma Foundation. Primary tumors were collected from our operating room. In vivo validation using three separate chordoma xenograft models was also performed through the Chordoma Foundation. One model was a primary clival pediatric tumor, the second was a metastatic sacral tumor, and the third model was a recurrent skull base tumor. RESULTS Using a 127 FDA-approved compound library, we screened 6 donated chordoma cell lines and 4 tumors resected from our institution. 5 of the chordomas were primary, 3 were recurrent, and 2 were metastatic. 6 chordoma were located in the sacrum, three were located in the mobile spine, and one was located in the clivus. Five tumors came from female patients and five came from male patients. After a single 72-hour 1um dose of brigatinib, the average tumor viability in our drug screen was reduced to 81.5% +/-9.5SD (p=1.61x10-13). In the in vivo studies, brigatinib achieved a full response in the metastatic sacral chordoma xenograft model (TGI=100%, p< 0.0001), a partial response in the recurrent skull base xenograft model (TGI=54%, p=0.3048), and no response in the primary clival pediatric xenograft model (TGI = 0%, p >0.9). CONCLUSIONS Brigatinib may be a viable treatment option for recurrent and metastatic chordomas.

Obeid-Coronal Malalignment Classification Is Age Related and Independently Associated to Personal Reported Outcome Measurement Scores in the Nonfused Spine

Objective: To evaluate Obeid-coronal malalignment (O-CM) modifiers according to age, sagittal alignment, and patient-reported outcome measures (PROMs), in the mobile spine.Methods: Retrospective review of a prospective multicenter adult spinal deformity (ASD) database with 1,243 (402 nonoperative, 841 operative) patients with no prior fusion surgery. Patients were included if they were aged over 18 years and were affected by spinal deformity defined by one of: Cobb angle ≥ 20°, pelvic tilt ≥ 25°, sagittal vertical axis ≥ 5 cm, thoracic kyphosis ≥ 60°. Patients were classified according to the O-CM classification and compared to coronally aligned patients. Multivariate analysis was performed on the relationship between PROMs and age, global tilt (GT) and coronal malalignment (CM).Results: Four hundred forty-three patients had CM of more than 2 cm compared to 800 who did not. The distribution of these modifiers was correlated to age. After multivariate analysis, using age and GT as confounding factors, we found that before the age of 50 years, 2A1 patients had worse sex life and greater satisfaction than patients without CM. After 50 years of age, patients with CM (1A1, 1A2) had worse self-image and those with 2A2, 2B had worse self-image, satisfaction, and 36-item Short Form Health Survey physical function. Self-image was the consistent determinant of patients opting for surgery for all ages.Conclusion: CM distribution according to O-CM modifiers is age dependent. A clear correlation between the coronal malalignment and PROMs exists when using the O-CM classification and in the mobile spine, this typically affects self-image and satisfaction. Thus, CM classified according to O-CM modifiers is correlated to PROMs and should be considered in ASD.

Giant cell tumors of the mobile spine with invasion of adjacent vertebrae: an unusual imaging finding

Background Giant cell tumors of the mobile spine invasion of the adjacent vertebrae are an ignored imaging finding. Methods Nine patients with giant cell tumors of the mobile spine with invasion of the adjacent vertebrae confirmed by pathology were enrolled. Eight patients had pure giant cell tumors (GCTs), while one patient also had an aneurysmal bone cyst. All patients underwent conventional computed tomography, three-dimensional reconstruction, and conventional magnetic resonance imaging, while seven patients also underwent post-contrast magnetic resonance imaging. Results All patients showed GCTs of the mobile spine that arose from the vertebral body and extended to the vertebral arch. The tumors showed soft-tissue attenuation with no evidence of a mineralized matrix. Pathological fracture was seen in five patients. The margin of the original tumor showed partial sclerosis in four patients and involved an adjacent vertebral body with a sclerotic rim in two patients. The tumors showed a homogeneous and similar signal intensity to the normal spinal cord on T1WI (T1-weighted image) in five patients. The cystic area of the tumors was hyperintense on T2WI in the remaining four patients, while one patient showed hemorrhage that was hyperintense on T1WI. The solid components of the GCTs show marked enhancement in all cases, while the cystic area of the tumors was observed without enhancement on contrast-enhanced images in four patients. Bone destruction of the adjacent vertebral body showed a homogeneous signal on T1WI and T2WI and marked enhancement on contrast-enhanced images. Conclusions Giant cell tumors of the mobile spine with invasion into adjacent vertebrae are an unusual imaging finding. Radiologists should be familiar with this imaging characteristic.