What Are the Challenges and Complications of Sterilizing Autografts with Liquid Nitrogen for Malignant Bone Tumors? A Preliminary Report.

BACKGROUND: Reconstruction of defects after resection of malignant bone tumors with liquid nitrogen-sterilized recycled autografts is an alternative to bone allografts and endoprostheses in resource-constrained environments. Most studies reporting favorable outcomes with liquid nitrogen-sterilized autografts for bone reconstruction are geographically restricted to a few countries, and the technical challenges of routinely using liquid nitrogen intraoperatively, especially when using the pedicle freezing technique, has not been documented. QUESTIONS/PURPOSES: (1) What are the technical challenges of liquid nitrogen sterilization of bone tumors for inexperienced surgeons? (2) What are the complications associated with the procedure? METHODS: Between May 2017 and October 2019, 88 patients underwent limb salvage procedures for malignant bone tumors of the extremities at our institution. An endoprosthesis was used for reconstruction of the defect following resection in 45% (40 of 88) of these patients, mostly in adults (median age 21 years; range 9 to 68). In the remaining 55% (48 of 88) of patients undergoing biological reconstruction, liquid nitrogen-sterilized autograft was used in 90% (43 of 48), extracorporeal irradiation-sterilized autograft was used in 4% (2 of 48) and allograft was used in 6% (3 of 48). Of the 43 patients receiving liquid nitrogen-sterilized autograft, 5% (2 of 43) were excluded due to loss to follow-up and the remaining 95% (41 of 43) were included for the analysis. Liquid nitrogen-sterilized autograft was the preferred method of reconstruction at our institution during the study period, unless the patient had an indication for prosthesis reconstruction; extracorporeal irradiation-sterilized autograft was used due to resource constraints with liquid nitrogen and allograft was used when patients insisted.All surgical procedures were performed by the same team of trained orthopaedic oncology surgeons. The medical records of the included 41 patients were retrieved using an institutional database search in this retrospective study, and all were used to ascertain technical challenges associated with the operations as well as early (within 3 weeks of the index procedure) and late complications (those occurring 3 weeks or more after surgery). The technical challenges were defined as follows: the quantity of liquid nitrogen to be used; arranging, storing and handling of liquid nitrogen in the operating room, type and size of the container to be used for sterilization, the positioning of the container during pedicle freezing, level of fibular osteotomy for pedicle freezing of tibia, soft tissue protection, limb rotation during pedicle freezing, managing tourniquet time, and any other intraoperative factors with the use of liquid nitrogen for sterilizing the autograft. As our experience with the technique gradually grew, the answers to the above-mentioned factors were determined. Considering the removal of autograft as the endpoint of interest, survival of the autograft was determined by Kaplan-Meier analysis.The median (range) patient age was 14 years (2 to 49), and 54% (22 of 41) were males. Osteosarcoma was the most common diagnosis (68%, [28 of 41]) followed by Ewing's sarcoma (20%, [8 of 41]). On presentation, 27% of patients (11 of 41) had radiological evidence of pulmonary metastasis. Tumors were seen frequently around the knee (39% [16 of 41] proximal tibia and 22% [9 of 41] distal femur). Before resection 85% (35 of 41) underwent neoadjuvant chemotherapy. Sixty-six percent (27 of 41) underwent pedicle-freezing and the remaining 34% (14 of 41) underwent free-freezing of the tumor segment of the bone. The median (range) duration of surgery was 280 minutes (210 to 510). The patients were followed up for a median (range) duration of 21 months (5 to 30); two patients were lost to follow-up. RESULTS: With gradual experience using liquid nitrogen-sterilization over time at our institution, we determined that the following factors helped us in performing liquid nitrogen-sterilization more efficiently. For every operation 15 L to 20 L of unsterilized liquid nitrogen was arranged, 1 or 2 days before the procedure, and stored in industrial-grade cryocylinders in the operating complex. During the procedure, the operating surgeons wore additional plastic aprons under the surgical gowns, surgical goggles, and rubber boots. The staff managing the liquid nitrogen in the operating room wore thermal protective gloves. For most of the pedicle freezing procedures, we used a cylindrical stainless-steel container that was 30 cm in height and 15 cm in diameter, with a narrow opening. The container was kept on a separate moveable cart that was placed next to the operating table at a slightly lower level, and it was wrapped in multiple cotton rolls, plastic sheets, surgical sheets, and a crepe bandage. For pedicle freezing of the tibia, we performed the fibular osteotomy at least 5 cm away from the planned surgical margin, roughly around the axis of rotation of the limb. The soft tissue at the base of the delivered bone segment was dissected for at least 5 cm beyond the planned surgical margin of bone, and was protected with multiple layers of cotton rolls, plastic drapes, a single roll of Esmarch and crepe bandage. The tumor segment was externally rotated during pedicle freezing for all anatomic sites (proximal tibia, distal tibia, proximal humerus, and proximal femur). The tourniquet was inflated just before pedicle freezing to prevent tumor dissemination and not before the initial incision in all pedicle freezing procedures.Thirty-nine percent of patients (16 of 41) experienced complications associated with the procedures, and 15% (6 of 41) underwent revision surgery. Early complications (occurring within 3 weeks of the index procedure) were skin necrosis in four of 16 patients, intraoperative fracture in one of 16, superficial infection in one of 16, and neurapraxia in one of 16 patients. Late complications (occurring 3 weeks or more after surgery) were resorption of the recycled bone in four of 16 patients, nonunion of the osteotomy site in two of 12, delayed union of the osteotomy site in one of 16, collapse of the recycled bone in one of 16, and local recurrence in 1 of 16 patients. Kaplan-Meier survivorship free from removal of autograft at 2 years after surgery was 92% (95% confidence interval 89 to 96). CONCLUSION: Liquid nitrogen-sterilization is an alternative technique that requires some training and experience for the surgeon to become proficient in treating primary malignant bone tumors. Because it is widely available, it may be an option worth exploring in resource-constrained environments, where allografts and endoprostheses cannot be procured. The methods we developed to address the technical challenges will require more study and experience, but we believe these observations will aid others who may wish to use and evaluate liquid nitrogen sterilization of extremity bone sarcomas. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Is a Short-course of Preoperative Denosumab as Effective as Prolonged Therapy for Giant Cell Tumor of Bone?

BACKGROUND: Denosumab is an inhibitor of monoclonal receptor activator of nuclear factor-ĸB ligand, approved to treat giant cell tumors of bone (GCTB). It is commonly used for unresectable tumors and for downstaging the tumor to perform less-morbid procedures. Although denosumab has been used extensively for GCTBs, there are no recommendations regarding the duration of therapy. The risk factors associated with local recurrence (LR) in patients receiving preoperative denosumab for GCTB also are unknown. QUESTIONS/PURPOSES: (1) Is short-course (three doses or fewer) preoperative denosumab treatment as effective as longer course (more than three doses) of treatment in terms of achieving a clinical, radiologic, and histologic response in patients with GCTB? (2) Is there an increased risk of LR after short-course denosumab therapy compared with long-course denosumab therapy; and after controlling for confounding variables, what factors were associated with LR after surgery for GCTB in patients receiving preoperative denosumab? METHODS: A retrospective study was performed using an institutional database of 161 skeletally mature patients with a histologic diagnosis of GCTB who received denosumab between November 2010 and July 2019 to downstage the tumor before surgery. In general, we used denosumab when we thought it would facilitate either resection or curettage (by formation of a sclerotic rim around the osteolytic lesion), when a less-morbid procedure than initially planned might be performed, and in patients with complex presentations like cortical breech and soft tissue extension, pathological fracture, thinning of more than three cortices of the extremity. From 2010 to late 2015, denosumab was administered for approximately 4 to 6 months; starting in late 2015 through 2020, the number of denosumab doses has been reduced. We divided patients into two groups: Those who received three or fewer doses of denosumab (short-course, n = 98) and those who received more than three doses of denosumab (long-course, n = 63). Comparing those in the long-course group with those in the short-course group whose procedures were performed at least 2 years ago, there were no differences in loss to follow-up before 2 years (3% [3 of 98] versus. 3% [2 of 63]). The mean patient age was 30 years (± 6.1) and the mean number of denosumab doses was 4.4 (range 1 to 14). Overall, 77% (37 of 48) of patients taking short-course denosumab and 75% (27 of 36) of patients on long-course denosumab underwent curettage, and the remaining patients with an inadequate bony shell around the tumor or destruction of articular cartilage in both groups underwent tumor resection. With the numbers available, the patients with short- and long-course denosumab were not different in terms of age, sex, MSTS score on presentation, lesion size, lesion location, Campanacci grade, presence of pathological fracture and pulmonary metastasis on presentation, and the type of surgery performed (curettage versus resection). We analyzed the change in the Musculoskeletal Tumor Society score, change in Campanacci grade, radiologic objective tumor response (defined as a partial or complete response, per the modified inverse Choi criteria), and histologic response (defined as reduction of more than 90% of osteoclast-like giant cells or a reduction of more than 50% of mesenchymal spindle-like stromal cells, along with evidence of lamellar or woven bone formation, when compared with the biopsy sample) between the two groups (short- and long-course denosumab). LR rates were compared between the two groups, and after controlling for confounding variables, factors associated with LR in all operated patients were analyzed with a Cox proportional hazards regression analysis. RESULTS: With the numbers available, there was no difference between the short- and long-course denosumab groups in terms of mean percentage improvement in MSTS score (20 [± 18.5] versus 24 [± 12.6]; p = 0.37), radiologic objective tumor response (90% [43 of 48] versus 81% [29 of 36]; p = 0.24) and histologic response (79% [38 of 48] versus 83% [30 of 36]; p = 0.81). With the numbers available, there was no difference between the short- and long-course denosumab groups in terms of Kaplan-Meier survivorship free from LR at 5 years after surgery (73% [95% confidence interval, 68 to 76] versus 64% [95% CI 59 to 68]; log-rank p = 0.50). After controlling for potential confounding variables like age, sex, Campanacci grade and MSTS score on presentation, number of denosumab doses administered before surgery, clinical, radiologic and histologic response to denosumab, and time duration between denosumab therapy and surgery, we found that tumors involving the bones of the hand and the foot (hazard ratio 7.4 [95% CI 2.0 to 27.3]; p = 0.009) and curettage (HR 6.4 [95% CI 2.8 to 23.0]; p = 0.037) were independently associated with a higher risk of LR. CONCLUSIONS: In this preliminary, single-center study, we found that a short-course of preoperative denosumab (three or fewer doses) was associated with no differences in clinical scores, histological and radiological response, or LR-free survivorship, compared with longer-course of denosumab (more than three doses). Fewer preoperative doses can reduce the complications and costs associated with more-prolonged therapy. Denosumab must be used cautiously before curettage for GCTB, and only if the benefit of joint salvage outweighs the possibility of LR. However, given the small number of patients, potentially clinically important differences might have been missed, and so our findings need to be confirmed by larger, multicenter, prospective trials. LEVEL OF EVIDENCE: Level III, therapeutic study.

Evaluation of Local Recurrence in Giant-Cell Tumor of Bone Treated by Neoadjuvant Denosumab.

BACKGROUND: Giant-cell tumor of bone (GCTB) is a locally aggressive primary benign tumor presenting as an expansile osteolytic lesion affecting the epiphysis of long bones. Denosumab halts the osteolysis by giant cells thereby downstaging the tumor, helping in performing less morbid procedures to remove the tumor. Our aim was to report the incidence of local recurrence (LR) in patients operated following neoadjuvant denosumab, to investigate factors associated with LR following extended curettage for GCTB, and to compare the postoperative functional and oncological outcome of patients operated with and without neoadjuvant denosumab. METHODS: A total of 123 patients with a mean age of 29.6 years undergoing extended curettage for GCTB were retrospectively divided into group 1 receiving neoadjuvant denosumab and group 2 operated without denosumab. The mean follow-up period was 35 months. The perioperative characteristics and outcome were compared between the two groups and the factors for LR of GCTB were analyzed. RESULTS: The incidence of LR among patients operated after neoadjuvant denosumab therapy was 42.8% and was significantly high compared to that in patients without denosumab (p < 0.001). On multivariate logistic regression analysis, use of denosumab as a neoadjuvant was the only factor independently associated with LR following surgery (p = 0.002). Patients treated with denosumab had a lower LR-free survival rate (log-rank, p = 0.018). CONCLUSIONS: Denosumab was independently associated with increased LR following surgery for GCTB. Denosumab has to be used cautiously in patients in whom the burden of downstaging the disease outweighs the possible chance of LR.

Massive FungatingEwing's Sarcoma of Scapula Treated by Limb Salvage Surgery: A Case Report.

INTRODUCTION: Ewing's sarcoma (ES) is a malignant tumor of the bone and soft tissue arising from the neuroectodermal cells. It commonly arises from the extremities of children and young adults and very rarely from flat bones like the scapula. Locally advanced disease with prior history of surgery and poor response to neoadjuvant chemotherapy in a bedridden patient is usually treated by forequarter amputation, considering the anatomical complexity of the shoulder girdle. CASE REPORT: A young adult diagnosed and previously operated for ES of the left scapula, presented to us with a massive fun gating mass over the left upper back, excruciating pain and inability to use the left upper limb. Limb salvage surgery was performed, followed by adjuvant radiotherapy, chemotherapy, and autologous stem-cell transplantation. The patient is disease free with a functional limb on 3 years of follow-up. CONCLUSION: ES of scapula is very rare. With meticulous surgery and multidisciplinary treatment approach, limb salvage can be achieved even in such advanced cases, thereby prolonging survival and providing better quality of life.

Robotic Surgery Assisted Staged En-Bloc Sacrectomy for Sacral Chordoma: A Case Report.

CASE: Two male patients aged 37 years and 39 years, diagnosed with sacral chordoma, underwent robotic-assisted preparatory adhesiolysis from the anterior aspect of the tumor, followed by posterior en-bloc partial sacrectomy. The average total operative time was 360 minutes (anterior docking + anterior console + posterior excision), and mean blood loss was 930 mL. Both patients were mobilized early, had no postoperative complications, and were free of local recurrence at 18 month of follow-up. CONCLUSIONS: Robotic-assisted surgery is a novel, valid, safe, and minimally invasive technique which drastically reduces the associated surgical complications of single-staged posterior sacrectomy, resulting in excellent functional and oncological outcome.