Whole Blood Titanium Concentration after Limb Salvage Surgery with Three-Dimensional-Printed Ti6Al4V Implants

Background@#Three-dimensional (3D)-printed customized implants can be fabricated and utilized for all bones with massive bone defects. The main safety issues with 3D-printed implants made of Ti6Al4V alloy are related to the release of metal debris and residual powder. In this study, we investigated the perioperative titanium concentrations in whole blood and peri-implant fluid samples of patients who underwent limb salvage surgery with a 3D-printed Ti6Al4V implant. @*Methods@#Nineteen patients who underwent limb salvage surgery with 3D-printed Ti6Al4V implants were divided into two groups:the serial samples group and the follow-up group. To observe metal distribution and clearance in the body, serial samples of blood and peri-implant fluid from the surgical drain were prospectively collected for five patients in the serial samples group. For the remaining 14 patients who were followed up for more than a year, blood samples were collected only once. @*Results@#In the serial samples group, the mean baseline titanium concentration was 0.78 μg/L (range, 0.1–2.2 μg/L): 3 patients showed peak concentration before the third postoperative month, while 2 patients still showed an increasing pattern at this point.Total titanium mass in the surgical drain showed a wash-out phenomenon in a week, with a significant uniform decrease (p = 0.04).In 14 patients in the follow-up group, the mean titanium concentration in the whole blood was 10.8 μg/L (range, 0.3–36.6 μg/L). For the 14 patients with a long-term follow-up, the aluminum and vanadium concentrations were all negligible. @*Conclusions@#Whole blood titanium concentrations were higher after surgery using 3D-printed implants than after that using conventional orthopedic implants, but markedly lower than in patients with implant failure. None of the patients developed serious clinical adverse effects during follow-up.

Vincristine, Irinotecan, and Temozolomide as a Salvage Regimen for Relapsed or Refractory Sarcoma in Children and Young Adults / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#No standard salvage regimen is available for relapsed or refractory sarcoma. We investigated the efficacy and toxicity of the vincristine, irinotecan, and temozolomide combination (VIT) for relapsed or refractory sarcomas of variable histology in children and young adults. @*Materials and Methods@#We retrospectively reviewed data from the relapsed or refractory sarcoma patients who were treated with VIT. The VIT protocol was given every 3 weeks as follows: vincristine, 1.5 mg/m2 intravenously on day 1, irinotecan, 50 mg/m2/day intravenously on days 1-5, and temozolomide, 100 mg/m2/day orally on days 1-5. @*Results@#A total of 26 patients (12 males) with various sarcoma histology were included in the study. Most common diagnosis was rhabdomyosarcoma (n=8) followed by osteosarcoma (n=7). Median age at the start of VIT was 18.5 years (range, 2.0 to 39.9). VIT was delivered as 2nd to 7th line of treatment, with 4th line most common (9/26, 34.6%). Median number of VIT courses given was 3 (range, 1 to 18). Of the 25 evaluable patients, there was two partial response (PR) and 11 stable disease (SD) with an overall control rate (complete remission+PR+SD) of 52%. PR was seen in one (50%) of the two evaluable patients with Ewing sarcoma and one (14.3%) of the seven patients with osteosarcoma. Overall survival and progression-free survival rates were 79.3% and 33.9% at 1 year, and 45.5% and 25.4% at 2 years, respectively. There was no treatment-related mortality. @*Conclusion@#The VIT regimen was effective and relatively safe in our cohort of sarcoma patients.

Incidence Patterns and Outcomes of Ewing Sarcoma in South Korea (1999-2017): A Retrospective Analysis Using Korea Central Cancer Registry Data / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Due to low incidence, epidemiologic data of Ewing sarcoma in the Asian population are scarce. We aimed to examine the incidence pattern and outcome of patients with Ewing sarcoma in the Republic of Korea. @*Materials and Methods@#Data of patients with Ewing sarcoma diagnosed between 1999 and 2017 were obtained from the Korea Central Cancer Registry (KCCR). Incidence, clinical characteristics, and survival rates were analyzed and compared between different age groups. @*Results@#There were 788 cases (459 males, 329 females), with a median age at diagnosis of 20 years. The age-standardized rate of Ewing sarcoma was 1.01. The number of cases and incidence rates in each age group were as follows: children, 1.6; adolescents and young adults (AYA), 0.93; adults, 0.44; and elderly, 0.53. There were more male cases in children and the AYA group (p < 0.001). Extraskeletal tumors (p < 0.001), primary sites other than extremity (p=0.007), and presence of metastasis at diagnosis (p=0.031) were more frequent in the adults and elderly group. With a median survival time of 78 months, the 5-year overall survival (OS) rate of the entire cohort was 52%. Children fared best (5-year OS, 75%), and the 5-year OS of AYA patients (51%) approximated the OS of the entire cohort. A two-fold difference of 5-year OS was observed between adults and elderly patients (42% vs. 19%). On univariate and multivariate analyses, age ≥ 15 years and presence of metastasis were adverse prognostic factors. @*Conclusion@#This was the first epidemiologic study of Ewing sarcoma using the KCCR data. With a similar incidence to other Asian countries, the survival rate was slightly lower than that of Euro-American cases. Collaborative clinical studies are necessary to improve the outcome of Ewing sarcoma in low-incidence populations.

Three Dimensional Printing Technique and Its Application to Bone Tumor Surgery / 대한정형외과학회잡지

Orthopaedics is an area where 3-dimensional (3D) printing technology is most likely to be utilized because it has been used to treat a range of diseases of the whole body. For arthritis, spinal diseases, trauma, deformities, and tumors, 3D printing can be used in the form of anatomical models, surgical guides, metal implants, bio-ceramic body reconstruction, and orthosis. In particular, in orthopaedic oncology, patients have a wide variety of tumor locations, but limited options for the limb salvage surgery have resulted in many complications. Currently, 3D printing personalized implants can be fabricated easily in a short time, and it is anticipated that all bone tumors in various surgical sites will be reconstructed properly. An improvement of 3D printing technology in the healthcare field requires close cooperation with many professionals in the design, printing, and validation processes. The government, which has determined that it can promote the development of 3D printing-related industries in other fields by leading the use of 3D printing in the medical field, is also actively supporting with an emphasis on promotion rather than regulation. In this review, the experience of using 3D printing technology for bone tumor surgery was shared, expecting orthopaedic surgeons to lead 3D printing in the medical field.

Diagnoses and Approaches of Soft Tissue Tumors for Orthopaedic Non-Oncologists / 대한정형외과학회잡지

Soft tissue tumors are classified into benign and malignant on the basis of the patient's age, medical history, physical examination, pathological and radiologic examination. We have to caution against misdiagnosis of malignant tumor which can delay the treatment time. Lipoma, schwannoma, hemangioma, and ganglion cysts are common benign tumors, usually of small size and are often located in the superficial layer. Although it may be suspected as a benign tumor, performing contrast-enhanced magnetic resonance maging is preferably advantageous. Liposarcoma and undifferentiated pleomorphic sarcoma, the most common malignant soft tissue tumors, usually occur after middle age; rhabdomyosarcoma is usually presented in children and synovial sarcoma often occurs at a younger age. The magnetic resonance (MR) signal intensity of lipoma shows uniformity with subcutaneous fat, sarcoma should be suspected if it has a contrast-enhanced and non-fat-suppressed part. The MR signals of ganglion cysts show homogeneous and same signal intensity with joint fluid and urine, while the liquid containing sarcoma, like synovial sarcoma, is characterized by heterogeneous signal intensity and contrast enhancement. If surgery is performed, an incision should be made in the longitudinal direction of the limb and the excised tumor should be sent for pathology analysis. When the macroscopic finding of the tumor during surgery is different from the expected diagnosis, the operation should cease with biopsy only or the small superficial tumor can be excised widely if possible. The transfer should be considered unless you can be sure of a benign tumor in hands and feet of children. When diagnosed as malignant tumors, patients should be provided with sufficient information that can lead them to a musculoskeletal tumor specialist.

Distinct Clinical Characteristics of Unplanned Excision in Synovial Sarcoma

BACKGROUND: We aimed to describe the clinical characteristics and outcomes of unplanned excisions of synovial sarcomas. METHODS: In total, 90 patients with synovial sarcomas in the extremities were retrospectively reviewed. Patients were divided into unplanned excision (n = 38) and planned excision (n = 52) groups. The average follow-up period was 6 years. The clinicopathological characteristics and oncologic outcomes were compared. RESULTS: The unplanned excision group showed longer duration of symptoms before diagnosis (p = 0.023), smaller lesion dimensions (p = 0.001), superficial location (p = 0.049), and predilection in the upper extremities (p = 0.037). Synovial sarcomas were most commonly misdiagnosed as neurogenic tumors (56%) in the upper extremities or as cystic masses (47%) in the lower extremities. Oncological outcomes, including disease-specific survival, metastasis-free survival, or local recurrence were not significantly different between the 2 groups (p = 0.159, p = 0.444, and p = 0.335, respectively). Repeated unplanned excision (p = 0.012) and delayed re-excision (p = 0.038) were significant risk factors for local recurrence in the unplanned excision group. CONCLUSIONS: Synovial sarcomas treated with unplanned excision had distinct characteristics. These findings are important for developing diagnostic and therapeutic strategies for synovial sarcoma.

Limb Salvage Surgery Using Whole Knee Joint Allograft Reconstruction in Osteosarcoma / 대한정형외과학회잡지

Limb salvage should be considered after complete remission in young and physically active patients with osteosarcoma. Herein we described a patient who was treated with whole knee allograft reconstruction for the clinical implications of biological reconstruction which can avoid the problems with several consecutive sessions of mega-prosthesis revision. The mid-term result of this whole knee joint allograft reconstruction showed that it provided optimal joint congruence with durable joint stability, well balanced mechanical axis without joint space narrowing, and satisfactory gait pattern.

Low Grade Chondrosarcoma Presenting as Progressive Valgus Limb Deformity in a Growing Period / 대한골관절종양학회지

A femoral bone tumor causing a valgus deformity by affecting the growth plate was found. Long intramedullary diaphyseal tumor was separated by septum at the metapysis. Low grade chondrosarcoma was confirmed diagnosed by pathologists. Progressive limb deformity can be a sign of bone tumor in growing period.

Intercalary Allograft Reconstruction after Malignant Tumor Resection around the Knee / 대한정형외과학회잡지

PURPOSE: We aimed to assess the treatment outcomes and factors affecting bone union of intercalary allograft reconstruction after primary malignant bone tumor resection around the knee. MATERIALS AND METHODS: Twenty-one patients who underwent intercalary allograft reconstruction after resection of a malignant tumor of femur or tibia were retrospectively reviewed. The average follow-up period was 46.4 months. Location of the tumor was as follows: femur in 12 cases and tibia in 9. Osteosarcoma was the most common tumor (12 cases). Intercalary allograft was internally fixed with an intramedullary (IM) nail in 3 cases, with a plate in 12 cases and with an IM nail combined with a plate in 6 cases. The survival of the grafts and functional outcomes were evaluated. Factors affecting bone union and complications were assessed. RESULTS: All allografts survived without removal. The average Musculoskeletal Tumor Society functional score was 27. The mean length of the allograft was 16.7 cm and bony union took 10.9 months, in average. Nonunion occurred in 6 cases: at the diaphyseal side in 3, and the remaining 3 at the metaphyseal side. The graft length was shorter than average in all the diaphyseal side nonunion cases and longer than average in all the metaphyseal side nonunion cases. All cases of nonunion obtained bone union after additional operations (autologous bone graft alone: 1, bone graft with hardware change: 5). CONCLUSION: Survival and functional outcomes of intercalary allograft were satisfactory. Long allograft showed a tendency of fracture or nonunion at the metaphyseal side. Nonunion could be managed with additional operation without allograft removal.

Soft Tissue Reconstruction of the Foot Using the Distally Based Island Pedicle Flap after Resection of Malignant Melanoma

BACKGROUND: We report on our experience with using a distally based island flap for soft tissue reconstruction of the foot in limb salvage surgery for malignant melanoma patients. METHODS: A distally based sural flap was used for 10 cases for the hindfoot reconstruction, and a lateral supramalleolar flap was used for 3 cases for the lateral arch reconstruction of the mid- and forefoot after wide excision of malignant melanomas. RESULTS: The length of the flap varied from 7.5 cm to 12 cm (mean, 9.6 cm) and the width varied from 6.5 cm to 12 cm (mean, 8.8 cm). Superficial necrosis developed in four flaps, but this was successfully treated by debridement and suture or a skin graft. All thirteen flaps survived completely and they provided good contour, stable and durable coverage for normal weight bearing. CONCLUSIONS: The distally based sural flap is considered to be useful for reconstructing the hindfoot, and the lateral supramalleolar flap is good for reconstructing the lateral archs of the mid- and forefoot after resection of malignant melanoma of the foot.

Low-heat Treated Intercalary Autograft Reconstruction in Limb Salvage of Primary Malignant Bone Tumor / 대한정형외과학회잡지

PURPOSE: This study evaluated the effectiveness of a low-heat treated intercalary autograft reconstruction in primary malignant bone tumors mainly involving the diaphysis. MATERIALS AND METHODS: Twenty patients who had primary malignant bone tumors underwent a low-heat treated intercalary autograft reconstruction between May 1987 and May 2004. The mean age was 24 years, and the mean follow up was 59.8 months. Osteosynthesis between host bone and low-heat treated autograft was carried out using plates and screws (n=7), rigid IM nails (n=6), plates and flexible IM nails or K-wires (n=4), and rigid IM nail and plate (n=3). Intramedullary cement augmentation was performed in 10 patients but the primary bone graft on the host-graft junction was not performed. RESULTS: The mean segmental excised bone length was 152 mm. One patient died from acute cardiac arrest unrelated to the tumor but there was no local recurrence and metastasis. Host graft union was achieved in 18 patients after a mean of 8.5 months after surgery. Complications were observed in 7 patients (35%), including 3 fractures, 2 nonunions, and 2 infections. The mean functional outcome was 82% (24.6). CONCLUSION: A low-heat treated intercalary autograft is a simple, economic and best fitting reconstruction system with a low rate of ultimate failure in carefully selected patients. However, a long term study will be needed to evaluate the graft incorporation and possibility of bone resorption.

Reconstruction with Replantation of the Resected Bone after Low Heat Treatment for Malignant Pelvic Bone Tumors / 대한정형외과학회잡지

PURPOSE: This study evaluated the oncological and functional results of a surgical treatment for malignant pelvic bone tumors using a low-heat-treated autologous bone graft. MATERIALS AND METHODS: Eleven patients with malignant pelvic bone tumors who were followed-up for more than one year were enrolled in this study. There were six males and five females. The mean age was forty-one years and the mean follow-up period was thirty months. Nine patients had primary bone tumors and two patients had metastatic tumors with various histological origins. A surgical resection was carried out according to the anatomic location (Type I/II 3 cases, Type II 2 cases, Type II/III 6 cases). The surgical methods used were a wide resection, a low-heat-treated autologous bone graft, total hip arthroplasty and rigid internal fixation. The ISOLS score was used to determine the oncological outcome. RESULTS: The mean ISOLS score was 61.2% at the final follow-up. The index of pain and emotional acceptance showed high scores, but functional ability, support, walking ability and gait showed relatively low scores. Bone union was achieved at a mean post-operative 6 months. The post-operative complications were one case of a local recurrence, two cases of infection and one case of a dislocation of the total hip arthroplasty. CONCLUSION: A wide resection and reconstruction with a low-heat-treated autologous bone graft in malignant pelvic bone tumors were satisfactory oncologically as well as functionally in the brief period. However, a longer follow-up and an examination of more cases will be needed.

Prosthetic Survival and Functional Evaluation in Prosthetic Reconstruction of Malignant Bone Tumors of the Proximal Tibia / 대한정형외과학회잡지

PURPOSE: This study retrospectively analyzed the prosthetic survival and functional results after a prosthetic reconstruction for malignant bone tumors of the proximal tibia. MATERIALS AND METHODS: Thirty-five patients (32 osteosarcomas and 3 chondrosarcomas) were followed up for an average 72 months (24-167 months). A gastrocnemius flap was transferred in 12 patients and cement fixation of the stem was performed in 10. More than 40% of the bone length was resected in 12 patients. RESULTS: Three patients had died of the disease at the time of the final follow-up. There were one local recurrence and five distant metastases. The major complications were infection (5), aseptic loosening (5) and periprosthetic fractures (1). Gastrocnemius flap affected the incidence of a deep infection in the proximal tibia (17.4% vs. 8.3%) but there were no statistical correlation. A resection of >40% of the involved tibia increased the incidence of aseptic loosening (p=0.002). The rate of prosthetic survival was 72% at 5 years and 58% at 10 years. The functional score at the final follow-up was 81% (43-93%). CONCLUSION: A prosthetic reconstruction in the proximal tibia showed acceptable oncologic and functional outcomes in patients at an intermediate term follow-up. Infection and loosening were the main factors threatening the survival of the prosthesis.

Analysis of RECK (a novel MMP inhibitor) Expression and its Roles as a Biomarker and Evaluation of RECK as a Potential Therapeutic Agent for Osteosarcoma / 대한정형외과연구학회지

PURPOSE: The purpose of this study is to analyze the mechanism of RECK gene (a novel MMP inhibitor) in human osteosarcoma and evaluation of RECK as a prognostic factor and therapeutic target. MATERIALS AND METHODS: Osteosarcoma cell lines were established from tumor samples of 23 patients who had been treated from March 2003 to April 2004 and 4 standard cell lines (HOS, MG-63, SaOS-2, U-2OS). We isolated the RNA from 27 cell lines and evaluated the expression level of RECK gene using quantitative real time-PCR method. MMP-2 and MMP-9 expression were evaluated by gelatin zymography. Five cell lines were selected which had a statistical significance between RECK gene up-regulation and MMP expression (p=0.01). Then 5 cell lines and 3 standard cell lines were transfected by RECK gene. We compared RECK gene expression with MMP down-regulation between transfected cell lines and non-transfected cell lines. Invasion of transfected cell lines were evaluated by invasion assay using matrigel. RESULTS: RECK genes were expressed in all cell lines and 1 cell line showed especially high expression. In zymography, pro-MMP-2 was expressed in almost cell lines whereas pro-MMP-9 was rarely expressed. RECK gene expressions were increasingly high and MMP expressions were low in transfected cell lines via zymography. Transfected HOS cells decreased invasiveness in matrigel invasion assay and showed small number of migrated cells. It had a statistical significance (p<0.01). CONCLUSION: It is expected that down-regulation of MMP by RECK gene expression can be used as a biologic marker. It can be a new therapeutic strategies and valuable prognostic factors in treating osteosarcoma.

Integrin alphavbeta3, alpha5beta1 Effects on Cell Proliferation and Migration in Human Osteosarcoma / 대한정형외과연구학회지

BACKGROUND: We investigate the influence of cell surface adhesion receptor integrin alphavbeta3, alpha5beta1 contributes to proliferation and migration of tumor cell in osteosarcoma for carves out a new treatment model by regulation of integrin roles in human osteosarcoma. MATERIALS AND METHODS: We performed proliferation assay, total 11 cell lines including 7 osteosarcoma cell lines established from patients and 4 osteosarcoma standard cell lines. Murine monoclonal anti-alpha5beta1 and anti-alphavbeta3 (Chemicon International Inc. Temecula, CA) were used for growth inhibition assays. We also performed cell motility assay by using the Boyden chamber to evaluate the effect of integrin mediated cell migration. We used the HOS standard osteosarcoma cell lines and each separates contained serum free media with mouse IgG1 negative control antibody, anti-alpha5beta1 antibody and anti-alphavbeta3 antibody. RESULTS: Proliferation of cells decreased significantly in 10 out of 11 cell lines when blocking with alphavbeta3 or alpha5beta1 respectively. Blocking with anti-alphavbeta3 antibody decreased significantly tumor cell proliferation in 10 cell lines. Among the 10 cell lines, 7 cell lines showed significantly more decrease of proliferation with anti-alphavbeta3 antibody than with anti-alpha5beta1antibody. Blocking with anti-alpha5beta1 antibody decreased significantly tumor cell proliferation in 10 cell lines. Among the 10 cell lines, 3 cell lines showed significantly more decrease of proliferation with anti-alpha5beta1 antibody than with anti-alphavbeta3 antibody. Including statistically not significant 2 cell lines the growth inhibition of osteosarcoma cell lines was more obvious (10 out of 11) in blocking with anti-alphavbeta3 antibody. The migration of cells was significantly decreased when blocked with anti-alpha5beta1 antibody and anti-alphavbeta3 antibody. CONCLUSION: Under the based on the integrin alphavbeta3, alpha5 beta1 are central role on proliferation and migration of osteosarcoma cells, we could be more approach to new therapeutic endeavors with antibody to integrin alphavbeta3, alpha5beta1 molecular target of osteosarcoma.