Eicosapentaenoic acid enhances the sensitivity of osteosarcoma to cisplatin by inducing ferroptosis through the DNA-PKcs/AKT/NRF2 pathway and reducing PD-L1 expression to attenuate immune evasion.

Acquired drug resistance poses a significant challenge in osteosarcoma therapy. Therefore, it is necessary for us to discover and develop an alternative anti-cancer strategy. Previous studies have shown that eicosapentaenoic acid (EPA) significantly increases chemosensitivity in cancer cells. In this study, we discovered that EPA enhances the sensitivity of osteosarcoma to cisplatin (DDP). Interestingly, in addition to inhibiting growth and inducing apoptosis, EPA also enhances DDP-induced ferroptosis. Western blot analysis confirmed that EPA treatment significantly decreases the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), p-AKT, nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) in cells. Knockdown of DNA-PKcs by siRNA further enhances the level of ferroptosis induced by EPA. Importantly, EPA can reverse the high expression level of programmed death ligand 1 (PD-L1) induced by DDP. ELISA and western blotting analysis revealed that EPA treatment decreases the levels of IL-6 and p-STAT3, which are increased by DDP treatment. Furthermore, a co-immunoprecipitation (co-IP) assay confirmed the interaction between DNA-PKcs and PD-L1, and knockdown of DNA-PKcs further reduces the expression of PD-L1. This data provides the first evidence that EPA suppresses the DNA-PKcs/AKT/NRF2/GPX4 pathway to enhance ferroptosis, and inhibits IL-6/STAT3 and DNA-PKcs to decrease PD-L1 expression, thereby sensitizing osteosarcoma to DDP. The combination of EPA and DDP presents an encouraging and promising anti-tumor strategy.

A 3D-printed patient-specific modular implants for pelvic reconstruction of bone tumors involving the sacroiliac joint.

Background: Current reconstruction methods of the pelvic ring after extensive resection of tumors involving the sacroiliac joint have a high incidence of failure. We aimed to study the effect of 3D-printed patient-specific implant reconstruction to show that this method is stable and has a low risk of failure. Methods: Between February 2017 and November 2021, six patients with bone tumors involving the sacroiliac joint (Enneking I + IV) who received 3D-printed patient-specific implants for pelvic reconstructive surgery were retrospectively analyzed. Two female and four male patients with a mean age of 41.83 years (range 25-65 years) were included. Two were osteosarcomas, two chondrosarcomas, one malignant fibrous histiocytoma, and one giant cell tumor of bone. For each patient, preoperative osteotomy guides were designed to ensure accurate tumor resection and individualized prostheses were designed to ensure a perfect fit of the bone defect. General, oncologic, and functional outcomes, implant status, and complications were retrospectively analyzed. The Visual Analog Scale (VAS) was used to assess pain and the Musculoskeletal Tumor Society (MSTS) score was used to assess hip function. Osseointegration was assessed by CT. Results: According to the preoperative design, complete resection of the entire tumor and reconstruction with a custom 3D-printed sacroiliac joint implant was completed without perioperative severe complications or deaths. Relatively satisfactory surgical margins were achieved. The mean operative time and intraoperative blood loss were 495 min (420-600 min) and 2533.33 mL (range, 1,200-3,500 mL), respectively. The mean follow-up was 49.83 months (range, 18-75 months). At the last follow-up, all four patients were disease-free, and the two patients who developed lung metastases were alive with tumors. All patients could walk unassisted. The mean VAS was 1.33 (range, 0-2). The mean MSTS score was 25.33 (range, 24-27). CT showed complete osseointegration of the implant to the ilium and sacrum. Conclusion: The 3D-printed custom prosthesis can effectively reconstruct pelvic stability after total sacroiliac joint resection with satisfactory clinical results.

Reconstruction after hemisacrectomy with a novel 3D-printed modular hemisacrum implant in sacral giant cell tumor of the bone.

Background: There are a limited but increasing number of case reports and series describing the use of 3D-printed prostheses in bone tumor surgery. Methods: We describe a new approach to performing nerve-preserving hemisacrectomy in patients with sacral giant cell tumors with reconstruction using a novel 3D-printed patient-specific modular prosthesis. The series included four female and two male patients with a mean age of 34 years (range, 28-42 years). Surgical data, imaging assessments, tumor and functional status, implant status, and complications were retrospectively analyzed in six consecutive patients. Results: In all cases, the tumor was removed by sagittal hemisacrectomy, and the prosthesis was successfully implanted. The mean follow-up time was 25 months (range, 15-32 months). All patients in this report achieved successful surgical outcomes and symptomatic relief without significant complications. Clinical and radiological follow-up showed good results in all cases. The mean MSTS score was 27.2 (range, 26-28). The average VAS was 1 (range, 0-2). No structural failures or deep infections were detected in this study at the time of follow-up. All patients had good neurological function. Two cases had superficial wound complications. Bone fusion was good with a mean fusion time of 3.5 months (range, 3-5 months). Conclusion: These cases describe the successful use of custom 3D-printed prostheses for reconstruction after sagittal nerve-sparing hemisacrectomy with excellent clinical outcomes, osseointegration, and durability.

A novel three dimensional-printed biomechanically evaluated patient-specific sacral implant in spinopelvic reconstruction after total en bloc sacrectomy.

Background: Reconstruction after a total sacrectomy is a challenge due to the special anatomical and biomechanical factors. Conventional techniques of spinal-pelvic reconstruction do not reconstruct satisfactorily. We describe a novel three-dimensional-printed patient-specific sacral implant in spinopelvic reconstruction after total en bloc sacrectomy. Methods: We performed a retrospective cohort study including 12 patients with primary malignant sacral tumors, including 5 men and 7 women with a mean age of 58.25 years (range 20-66 years), undergoing total en bloc sacrectomy with 3D printed implant reconstruction from 2016 to 2021. There were 7 cases of chordoma, 3 cases of osteosarcoma, 1 case of chondrosarcoma and 1 case of undifferentiated pleomorphic sarcoma. We use CAD technology to determine surgical resection boundaries, design cutting guides, and individualized prostheses, and perform surgical simulations before surgery. The implant design was biomechanically evaluated by finite element analysis. Operative data, oncological and functional outcomes, complications, and implant osseointegration status of 12 consecutive patients were reviewed. Results: The implants were implanted successfully in 12 cases without death or severe complications during the perioperative period. Resection margins were wide in 11 patients and marginal in one patient. The average blood loss was 3875 mL (range, 2000-5,000 mL). The average surgical time was 520 min (range, 380-735 min). The mean follow-up was 38.5 months. Nine patients were alive with no evidence of disease, two patients died due to pulmonary metastases, and one patient survived with disease due to local recurrence. Overall survival was 83.33% at 24 months. The Mean VAS was 1.5 (range, 0-2). The mean MSTS score was 21 (range, 17-24). Wound complications occurred in 2 cases. A deep infection occurred in one patient and the implant was removed. No implant mechanical failure was identified. Satisfactory osseointegration was found in all patients, with a mean fusion time of 5 months (range 3-6 months). Conclusion: The 3D-printed custom sacral prosthesis has been effective in reconstructing spinal-pelvic stability after total en bloc sacrectomy with satisfactory clinical outcomes, excellent osseointegration, and excellent durability.

Primary Cooperative Application of a LARS® Tube and 3D-Printed Prosthesis for Reconstruction of the Distal Radius after en bloc Resection of Giant Cell Tumor of Bone: A Comparative Retrospective Study.

OBJECTIVE: Using a fibula autograft (FA) to reconstruct defects after en bloc resection of giant cell tumor of bone (GCTB) in the distal radius is classic but has high complication rates. We describe a novel reconstruction method employing the cooperative application of LARS® and a 3D-printed prosthesis (L-P) and investigate whether it improves postoperative outcomes. METHODS: From April 2015 to August 2022, 14 patients who underwent the cooperative L-P reconstruction method after en bloc resection of distal radial GCTBs and 31 patients who received FA reconstruction were enrolled as two retrospective cohorts in this comparative study. The properties of the implants and critical surgical techniques were elaborated in the L-P group. Preoperative function, intraoperative data, and postoperative clinical, functional, and radiographic outcomes of all patients were recorded and compared between the two groups. The grip strength and range of wrist motion, including extension, flexion, radial deviation, and ulnar deviation, were measured. The Mayo modified wrist and Musculoskeletal Tumor Society scores were chosen to assess wrist function and surgical functional outcomes, respectively. Kaplan-Meier curves were generated to analyze the significant differences in complication rates and implant survival between the two groups. RESULTS: In both groups, all 45 patients underwent the operation without complication with similar average osteotomy lengths and bleeding volumes, while a shorter operative duration was achieved in the L-P group (201.43 ± 22.87 min vs. 230.16 ± 51.44 min, P = 0.015). At a mean follow-up of 40.42 ± 18.43 months (range, 14-72 months), both reconstruction methods effectively ameliorated postoperative function. Patients who received L-P showed higher postoperative modified Mayo wrist scores (81.43 ± 5.49 vs. 71.13 ± 16.10, P = 0.003), Musculoskeletal Tumor Society scores (27.64 ± 1.34 vs. 25.06 ± 2.95, P = 0.004), and grip strength on the normal side (68.71% ± 8.00% vs. 57.81% ± 12.31%, P = 0.005) than the FA group. Better wrist extension (63.21° ± 8.99° vs. 45.32° ± 14.53°, P < 0.001) and flexion (45.36° ± 7.90° vs. 30.48° ± 12.07°, P < 0.001) were also observed in the L-P group. The complication rate was significantly higher in the FA group (29/31, 93.55%) than in the L-P group (1/14 7.14%, P < 0.001). The L-P group showed higher implant survival than the FA group, but the difference was not statistically significant. CONCLUSION: The cooperative application of LARS® and 3D-printed prostheses is an effective modality for reconstructing musculoskeletal defects after en bloc resection of distal radial GCTBs, which can improve functional outcomes, diminish complication rates, and promote wrist joint stability and motion.

A novel three-dimensional-printed patient-specific sacral implant for spinopelvic reconstruction in sacral giant cell tumour.

PURPOSE: Spinopelvic reconstruction after sacral tumour resection is one of the most demanding procedures in sacral tumour surgery. The aims of this study were to evaluate the feasibility of spinopelvic reconstruction with 3D-printed prostheses in sacral giant cell tumours and the clinical outcomes and complications at follow-up. METHODS: We retrospectively analyzed ten consecutive patients with giant cell tumors of the sacrum who underwent intralesional nerve-sparing resection with curative intent and custom implant reconstruction between 2016 and 2021. There were four males and six females with a mean age of 40.2 years (range, 25-62 years) at surgery. A computer-aided-design implant was prepared using 3D printing technology that was both matched to the bone defect and biomechanically evaluated. A 3D-printed surgical guide was used to replicate the resection procedure as planned. We analyzed operational outcomes, oncological outcomes, functional outcomes, complications, and prosthetic outcomes. Pain at rest was assessed according to a 10-cm VAS score. The results of functional improvement were evaluated using the MSTS-93 score at the final follow-up. RESULTS: All patients were observed for 26 to 61 months, with an average follow-up of 43.8 months. No deep infection or prosthetic structural failure occurred in this study. A total of 80% of patients had good neurological function and normal urinary, bowel, and ambulatory functions. The mean MSTS score was 24.1 (range, 22-26). The mean VAS score was 2 (range 0 to 2). Delayed wound healing occurred in three patients, and the wounds healed after debridement. One case had local recurrence and survived tumour-free after resection of the recurrent lesion. An aseptic loosening was found in a patient that did not require secondary surgery. By radiographical assessments, we found that 90% of implants were well osseointegrated at the final follow-up examination. CONCLUSIONS: The 3D-printed sacral implants might provide a promising strategy for spinopelvic reconstruction in sacral giant cell tumours undergoing intralesional nerve-sparing surgery with satisfactory clinical outcomes, osseointegration, and excellent durability.

One-Step Reconstruction with a Novel Suspended, Modular, and 3D-Printed Total Sacral Implant Resection of Sacral Giant Cell Tumor with Preservation of Bilateral S1-3 Nerve Roots via a Posterior-Only Approach.

OBJECTIVE: To investigate the efficacy and safety of spinopelvic reconstruction based on a novel suspended, modular, and 3D-printed total sacral implant after total piecemeal resection of a sacral giant cell tumor (SGCT) with the preservation of bilateral S1-3 nerve roots via a posterior-only approach. METHODS: Five patients who had undergone total piecemeal resection of SGCT involving upper sacral segments (S1 and S2 ) and the midline with the preservation of bilateral S1-3 nerve roots via a posterior-only approach between September 2017 and July 2018 were retrospectively reviewed. A novel suspended, modular, and 3D-printed total sacral implant had been used for reconstruction. This series included two female and three male patients, with a mean age of 42.2 years (range, 31-53 years). Surgical time, blood loss, complications, preoperative and postoperative neurological function, instrumentation failure, and local control were presented and analyzed. RESULTS: All patients underwent the operation without death or serious complications. The implant was installed on the defect, connecting the ilium and lumbar vertebrae, and fixed with a screw-rod system up to the level of L3-4 or L4-5 . The mean operative time was 502 min (range, 360-640 min) and the mean operative blood loss 4400 mL (range, 3000-7000 mL). The mean follow-up was 15 months. After the operation, pain was significantly relieved, and the patients resumed walking as early as 2 weeks later. The patients showed no neurogenic bladder dysfunction and no fecal incontinence or gait disturbance. Wound healing was poor in one patient. Patients recovered well without evidence of local recurrence. No implant failures or related clinical symptoms were detected during follow up. Satisfactory bone ingrowth and osseointegration at the bone-implant junctions was found in follow-up CT. CONCLUSION: Although technically challenging, it is feasible and safe to use a suspended, modular, and 3D-printed implant for reconstruction after total piecemeal resection with the preservation of bilateral S1-3 nerve roots in patients with SGCT. We believe that this implant can be applied to sacral reconstruction in a wide variety of diseases.

Successful treatment of a primary thoracic dumb-bell yolk sac tumor presenting with severe spinal cord compression: Case report.

RATIONALE: Primary thoracic dumb-bell yolk sac tumor (YST) with both epidural and extraspinal extension is a rare disease with no standard curative managements yet. The objective of this study is to report a primary thoracic dumb-bell YST presenting with severe spinal cord compression successfully treated with posterior-only approach operation, followed by chemotherapy. The management of these unique cases has not been fully documented. PATIENT CONCERNS: A 26-mounth-old, previously healthy girl presented with progressive numbness and weakness of the lower extremities. Neurological examination revealed paralysis of both lower extremities, sensory disturbance below T-8 and bladder-bowel dysfunction. DIAGNOSIS: CT and MRI of spine showed a dumb-bell mass lesion with both epidural and extraspinal extension through enlarged intervertebral foramina and marked spinal cord compression at T7-T9. The AFP level was 13738 ng/ml. Preoperative puncture and Postoperative pathology confirmed the diagnosis of YST. INTERVENTIONS: By needle biopsy, we identified the pathological diagnosis is YST. Subsequently, the patient was treated with one-stage posterior-only approach operation, followed by 9 courses of chemotherapy based on cisplatin, bleomycin, etoposide. OUTCOMES: The patient has a complete neurologic recovery and remains recurrence free as of more than 2 years after the completion of operation. There were no other complications associated with the operation during the follow-up period. LESSONS: YST should be considered in the range of children with thoracic dumb-bell tumor presenting with spinal cord compression. Needle biopsy is valuable for preoperative diagnosis and design of the treatment strategy. If there is no evidence of CSF spread, metastasis or multiple diseases, it is effective to remove tumors as thoroughly as possible immediately, avoid further nerve injury and conduct enough chemotherapy. This case suggests that this treatment strategy is an effective option for primary YST with both epidural and extraspinal extension and severe spinal cord compression.

Total En Bloc Spondylectomy for the Fifth Lumbar Solitary Metastasis by a Posterior-Only Approach.

BACKGROUND: Relatively few cases of total en bloc spondylectomy (TES) for the L5 tumors have been reported. TES in the lower lumbar region is usually performed through a combined anterior and posterior approach. TES for L5 tumors by a posterior-only approach is technically challenging. CASE DESCRIPTION: A 62-year-old woman with persistent pain in her lumbosacral area and lower extremities and numbness of her lateral left lower extremity for 2 months came to our department. She had undergone radical mastectomy 4 years earlier. X-ray and magnetic resonance imaging (MRI) showed that the tumor had destroyed the vertebral body of L5. No other lesions were revealed by emission computed tomography (ECT) or positron emission tomography/computed tomography (PET/CT). With a diagnosis of breast cancer and a solitary metastasis to L5, the patient was treated with posterior-only TES of the L5 tumor and reconstruction. The whole procedure took 10 hours, and her intraoperative blood loss was 9000 mL. The lumbar and leg pain of the patient disappeared postoperatively without serious complications. She started walking 4 weeks after surgery and resumed her daily life. New multiple metastases developed 6 months after surgery, with no sign of local recurrence. Despite active treatment, she died 18 months after surgery. CONCLUSION: TES of the L5 tumor can be achieved by a posterior-only approach, with good results and limited complications.