Single-Center Experience with Ifosfamide Monotherapy as Second-Line Treatment of Recurrent/Metastatic Osteosarcoma.

BACKGROUND: The effectiveness of second-line palliative chemotherapy in patients with recurrent/metastatic osteosarcoma is not well defined. Several small studies (6-19 patients) have reported on ifosfamide as second-line treatment. In this study we report our single-center experience with second-line ifosfamide monotherapy in patients treated for recurrent/metastatic osteosarcoma. METHODS: A chart review was conducted of all patients with osteosarcoma treated with ifosfamide from 1978 until 2017. Until 1997 a 5 g/m2 regimen was used, and from 1997 onwards a 9 g/m2 regimen was used. Overall survival (OS) from start of ifosfamide was the primary endpoint. Progression-free survival (PFS) from start of treatment was also studied. To assess difference in survival between groups the log rank test was applied. To investigate the effect of ifosfamide dose and World Health Organization performance status (PS) a Cox proportional hazard regression model was estimated. RESULTS: Sixty-two patients were selected with recurrent/metastatic osteosarcoma treated with second-line ifosfamide monotherapy (dose of 5 g/m2 , n = 26; 9 g/m2 , n = 36). OS was significantly better in univariate analysis for 9 g/m2 compared with 5 g/m2 (10.9 months [95% confidence interval (CI), 9.3-12.6] vs. 6.7 months [95% CI, 5.9-7.6], respectively) and for PS (median OS PS 0, 13.0 months [95% CI, 2.3-23.8]; PS 1, 8.2 months [95% CI, 5.4-11.1]; PS ≥2, 6.2 months [95% CI, 2.2-10.3]; and unknown PS, 5.4 months [95% CI, 2.2-8.5]). In multivariate analysis only PS showed a significant difference. No difference in PFS was found between 5 and 9 g/m2 ifosfamide treatment or PS. CONCLUSION: This study suggests that ifosfamide is an effective second-line treatment for patients with recurrent/metastatic osteosarcoma. IMPLICATIONS FOR PRACTICE: Ifosfamide monotherapy is commonly used as second-line treatment in osteosarcoma, although large series to support this are lacking. This retrospective study reports overall and progression-free survival for regimens with 5 g/m2 and with 9 g/m2 . This study was unable to show a significant difference in survival between 5 and 9 g/m2 but showed an important impact of World Health Organization performance status on overall survival. This study sets a standard and reference for comparison with the multiple phase II studies under development.

Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT.

PURPOSE: To quantify Na18F-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of Na18F-PET/CT uptake parameters in HB and FD. Relating Na18F uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). METHODS: In a prospective cohort study (n = 20), Na18F-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. RESULTS: Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7 g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R2 = 0.571, p = 0.004) and procollagen type 1 N-terminal propeptide (R2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R2 = 0.596, p = 0.007 and R2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R2 = 0.535, p = 0.045), work-related BPI scores to higher SBS (R2 = 0.518, p = 0.024), higher TLF (R2 = 0.478, p = 0.036), and higher levels of FGF-23 (R2 = 0.567, p = 0.034). CONCLUSIONS: Individualized Na18F-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with Na18F-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on Na18F-PET/CT was higher in baseline patients using bisphosphonates. This makes Na18F-PET/CT a promising tool to quantitatively measure treatment efficacy in FD.

Which Factors Are Associated with Local Control and Survival of Patients with Localized Pelvic Ewing's Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99 Trial.

BACKGROUND: Local treatment of pelvic Ewing's sarcoma may be challenging, and intergroup studies have focused on improving systemic treatments rather than prospectively evaluating aspects of local tumor control. The Euro-EWING99 trial provided a substantial number of patients with localized pelvic tumors treated with the same chemotherapy protocol. Because local control included surgical resection, radiation therapy, or a combination of both, we wanted to investigate local control and survival with respect to the local modality in this study cohort. QUESTIONS/PURPOSES: (1) Do patients with localized sacral tumors have a lower risk of local recurrence and higher survival compared with patients with localized tumors of the innominate bones? (2) Is the local treatment modality associated with local control and survival in patients with sacral and nonsacral tumors? (3) Which local tumor- and treatment-related factors, such as response to neoadjuvant chemotherapy, institution where the biopsy was performed, and surgical complications, are associated with local recurrence and patient survival in nonsacral tumors? (4) Which factors, such as persistent extraosseous tumor growth after chemotherapy or extent of bony resection, are independently associated with overall survival in patients with bone tumors undergoing surgical treatment? METHODS: Between 1998 and 2009, 1411 patients with previously untreated, histologically confirmed Ewing's sarcoma were registered in the German Society for Pediatric Oncology and Hematology Ewing's sarcoma database and treated in the Euro-EWING99 trial. In all, 24% (339 of 1411) of these patients presented with a pelvic primary sarcoma, 47% (159 of 339) of which had macroscopic metastases at diagnosis and were excluded from this analysis. The data from the remaining 180 patients were reviewed retrospectively, based on follow-up data as of July 2016. The median (range) follow-up was 54 months (5 to 191) for all patients and 84 months (11 to 191) for surviving patients. The study endpoints were overall survival, local recurrence and event-free survival probability, which were calculated with the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HRs) with their respective 95% CIs were estimated in a multivariate Cox regression model. RESULTS: Sacral tumors were associated with a reduced probability of local recurrence (12% [95% CI 1 to 22] versus 28% [95% CI 20 to 36] at 5 years, p = 0.032), a higher event-free survival probability (66% [95% CI 51 to 81] versus 50% [95% CI 41 to 58] at 5 years, p = 0.026) and a higher overall survival probability (72% [95% CI 57 to 87] versus 56% [95% CI 47 to 64] at 5 years, p = 0.025) compared with nonsacral tumors. With the numbers available, we found no differences between patients with sacral tumors who underwent definitive radiotherapy and those who underwent combined surgery and radiotherapy in terms of local recurrence (17% [95% CI 0 to 34] versus 0% [95% CI 0 to 20] at 5 years, p = 0.125) and overall survival probability (73% [95% CI 52 to 94] versus 78% [95% CI 56 to 99] at 5 years, p = 0.764). In nonsacral tumors, combined local treatment was associated with a lower local recurrence probability (14% [95% CI 5 to 23] versus 33% [95% CI 19 to 47] at 5 years, p = 0.015) and a higher overall survival probability (72% [95% CI 61 to 83] versus 47% [95% CI 33 to 62] at 5 years, p = 0.024) compared with surgery alone. Even in a subgroup of patients with wide surgical margins and a good histologic response to induction treatment, the combined local treatment was associated with a higher overall survival probability (87% [95% CI 74 to 100] versus 51% [95% CI 33 to 69] at 5 years, p = 0.009), compared with surgery alone.A poor histologic response to induction chemotherapy in nonsacral tumors (39% [95% CI 19 to 59] versus 64% [95% CI 52 to 76] at 5 years, p = 0.014) and the development of surgical complications after tumor resection (35% [95% CI 11 to 59] versus 68% [95% CI 58 to 78] at 5 years, p = 0.004) were associated with a lower overall survival probability in nonsacral tumors, while a tumor biopsy performed at the same institution where the tumor resection was performed was associated with lower local recurrence probability (14% [95% CI 4 to 24] versus 32% [95% CI 16 to 48] at 5 years, p = 0.035), respectively.In patients with bone tumors who underwent surgical treatment, we found that after controlling for tumor localization in the pelvis, tumor volume, and surgical margin status, patients who did not undergo complete (defined as a Type I/II resection for iliac bone tumors, a Type II/III resection for pubic bone and ischium tumors and a Type I/II/III resection for tumors involving the acetabulum, according to the Enneking classification) removal of the affected bone (HR 5.04 [95% CI 2.07 to 12.24]; p < 0.001), patients with a poor histologic response to induction chemotherapy (HR 3.72 [95% CI 1.51 to 9.21]; p = 0.004), and patients who did not receive additional radiotherapy (HR 4.34 [95% CI 1.71 to 11.05]; p = 0.002) had a higher risk of death. The analysis suggested that the same might be the case in patients with a persistent extraosseous tumor extension after induction chemotherapy (HR 4.61 [95% CI 1.03 to 20.67]; p = 0.046), although the wide CIs pointing at a possible sparse-data bias precluded any definitive conclusions. CONCLUSION: Patients with sacral Ewing's sarcoma appear to have a lower probability for local recurrence and a higher overall survival probability compared with patients with tumors of the innominate bones. Our results seem to support a recent recommendation of the Scandinavian Sarcoma Group to locally treat most sacral Ewing's sarcomas with definitive radiotherapy. Combined surgical resection and radiotherapy appear to be associated with a higher overall survival probability in nonsacral tumors compared with surgery alone, even in patients with a wide resection and a good histologic response to neoadjuvant chemotherapy. Complete removal of the involved bone, as defined above, in patients with nonsacral tumors may be associated with a decreased likelihood of local recurrence and improved overall survival. Persistent extraosseous tumor growth after induction treatment in patients with nonsacral bone tumors undergoing surgical treatment might be an important indicator of poorer overall survival probability, but the possibility of sparse-data bias in our cohort means that this factor should first be validated in future studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

Can Navigation Improve the Ability to Achieve Tumor-free Margins in Pelvic and Sacral Primary Bone Sarcoma Resections? A Historically Controlled Study.

BACKGROUND: Anatomic and surgical complexity make pelvic and sacral bone sarcoma resections challenging. Positive surgical margins are more likely to occur in patients with pelvic and sacral bone sarcomas than in those with extremity sarcomas and are associated with an increased likelihood of local recurrence. Intraoperative navigation techniques have been proposed to improve surgical accuracy in achieving negative margins, but available evidence is limited to experimental (laboratory) studies and small patient series. Only one small historically controlled study is available. Because we have experience with both approaches, we wanted to assess whether navigation improves our ability to achieve negative resection margins. QUESTIONS/PURPOSES: Are navigated resections for pelvic and sacral primary bone sarcomas better able to achieve adequate surgical margins than nonnavigated resections? METHODS: Thirty-six patients with pelvic or sacral sarcomas treated with intraoperative navigation were retrospectively compared with 34 patients undergoing resections without navigation. All patients underwent resections between 2000 and 2017 with the intention to achieve a wide margin. Patients in the navigation group underwent surgery between 2008 and 2017; during this period, all resections of pelvic and sacral primary bone sarcomas with the intention to achieve a wide margin were navigation-assisted by either CT fluoroscopy or intraoperative CT. Patients in the control group underwent surgery before 2008 (when navigation was unavailable at our institution), to avoid selection bias. We did not attempt to match patients to controls. Nonnavigated resections were performed by two senior orthopaedic surgeons (with 10 years and > 25 years of experience). Navigated resections were performed by a senior orthopaedic surgeon with much experience in surgical navigation. The primary outcome was the bone and soft-tissue surgical margin achieved, classified by a modified Enneking system. Wide margins (≥ 2 mm) and wide-contaminated margins, in which the tumor or its pseudocapsule was exposed intraoperatively but further tissue was removed to achieve wide margins, were considered adequate; marginal (0-2 mm) and intralesional margins were considered inadequate. RESULTS: Adequate bone margins were achieved in more patients in the navigated group than in the nonnavigation group (29 of 36 patients [81%] versus 17 of 34 [50%]; odds ratio, 4.14 [95% CI, 1.43-12.01]; p = 0.007). With the numbers available, we found no difference in our ability to achieve adequate soft-tissue margins between the navigation and nonnavigation group (18 of 36 patients [50%] versus 18 of 34 [54%]; odds ratio, 0.89 [95% CI, 0.35-2.27]; p = 0.995). CONCLUSIONS: Intraoperative guidance techniques improved our ability to achieve negative bony margins when performing surgical resections in patients with pelvic and sacral primary bone sarcomas. Achieving adequate soft-tissue margins remains a challenge, and these margins do not appear to be influenced by navigation. Larger studies are needed to confirm our results, and longer followup of these patients is needed to determine if the use of navigation will improve survival or the risk of local recurrence. LEVEL OF EVIDENCE: Level III, therapeutic study.

Pathologic fractures of the distal femur: Current concepts and treatment options.

Pathologic fractures of the distal femur caused by bone metastases are not as common as those in the proximal femur but provide great difficulty to adequately treat. This systematic review shows that insufficient literature exists to draw clinically relevant conclusions for essential questions, such as "what factors indicate an endoprosthetic reconstruction for distal femur pathologic fractures?" Due to paucity of literature in the systematic review, a current concepts review (including treatment flowchart), based on instructional reviews and experience, was also performed.

What Factors Are Associated With Implant Breakage and Revision After Intramedullary Nailing for Femoral Metastases?

BACKGROUND: Actual and impending pathologic fractures of the femur are commonly treated with intramedullary nails because they provide immediate stabilization with a minimally invasive procedure and enable direct weightbearing. However, complications and revision surgery are prevalent, and despite common use, there is limited evidence identifying those factors that are associated with complications. QUESTIONS/PURPOSES: Among patients treated with intramedullary nailing for femoral metastases, we asked the following questions: (1) What is the cumulative incidence of local complications? (2) What is the cumulative incidence of implant breakage and what factors are associated with implant breakage? (3) What is the cumulative incidence of revision surgery and what factors are associated with revision surgery? METHODS: Between January 2000 and December 2015, 245 patients in five centers were treated with intramedullary nails for actual and impending pathologic fractures of the femur caused by bone metastases. During that period, the general indications for intramedullary nailing of femoral metastases were impending fractures of the trochanter region and shaft and actual fractures of the trochanter region if sufficient bone stock remained; nails were used for lesions of the femoral shaft if they were large or if multiple lesions were present. Of those treated with intramedullary nails, 51% (117) were actual fractures and 49% (111) were impending fractures. A total of 60% (128) of this group were women; the mean age was 65 years (range, 29-93 years). After radiologic followup (at 4-8 weeks) with the orthopaedic surgeon, because of the palliative nature of these treatments, subsequent in-person followup was performed by the primary care provider on an as-needed basis (that is, as desired by the patient, without any scheduled visits with the orthopaedic surgeon) throughout each patient's remaining lifetime. However, there was close collaboration between the primary care providers and the orthopaedic team such that orthopaedic complications would be reported. A total of 67% (142 of 212) of the patients died before 1 year, and followup ranged from 0.1 to 175 months (mean, 14.4 months). Competing risk models were used to estimate the cumulative incidence of local complications (including persisting pain, tumor progression, and implant breakage), implant breakage separately, and revision surgery (defined as any reoperation involving the implant other than débridement with implant retention for infection). A cause-specific multivariate Cox regression model was used to estimate the association of factors (fracture type/preoperative radiotherapy and fracture type/use of cement) with implant breakage and revision, respectively. RESULTS: Local complications occurred in 12% (28 of 228) of the patients and 6-month cumulative incidence was 8% (95% confidence interval [CI], 4.7-11.9). Implant breakage occurred in 8% (18 of 228) of the patients and 6-month cumulative incidence was 4% (95% CI, 1.4-6.5). Independent factors associated with increased risk of implant breakage were an actual (as opposed to impending) fracture (cause-specific hazard ratio [HR_cs], 3.61; 95% CI, 1.23-10.53, p = 0.019) and previous radiotherapy (HR_cs, 2.97; 95% CI, 1.13-7.82, p = 0.027). Revisions occurred in 5% (12 of 228) of the patients and 6-month cumulative incidence was 2.2% (95% CI, 0.3-4.1). The presence of an actual fracture was independently associated with a higher risk of revision (HR_cs, 4.17; 95% CI, 0.08-0.82, p = 0.022), and use of cement was independently associated with a lower risk of revision (HR_cs, 0.25; 95% CI, 1.20-14.53, p = 0.025). CONCLUSIONS: The cumulative incidence of local complications, implant breakage, and revisions is low, mostly as a result of the short survival of patients. Based on these results, surgeons should consider use of cement in patients with intramedullary nails with actual fractures and closer followup of patients after actual fractures and preoperative radiotherapy. Future, prospective studies should further analyze the effects of adjuvant therapies and surgery-related factors on the risk of implant breakage and revisions. LEVEL OF EVIDENCE: Level III, therapeutic study.

Functional outcome after surgery in patients with bone sarcoma around the knee; results from a long-term prospective study.

BACKGROUND AND OBJECTIVES: In a previous conducted study functional outcome of young patients with bone sarcoma located around the knee was longitudinally evaluated during the first 2 years postoperatively. Functional outcome improved significantly over the first 2 years. The purpose of this descriptive study was to evaluate the functional outcome of these patients at long-term follow-up of 7 years. METHODS: Functional outcome was assessed with the TESS, MSTS, Baecke questionnaire, and three functional performance tests: time up and down stairs (TUDS), various walking activities (VWA), and the 6-min walking test (6MWT). Linear Mixed Model has been employed for the repeated measurements. RESULTS: Twenty patients of the original study (n = 44) participated in the current study. Fifteen limb-salvage and five ablative surgery patients, median follow-up 7.4 years (6.8-8.0) (CI 95%), mean age 22.3 years (18.2-31.6). Between 2 and 7 years after surgery, 8 limb-salvage patients (53%) encountered surgery related complications. Questionnaires and functional performance tests showed no significant difference in functional outcome between 2 years and 7 years after surgery (P < 0.05). CONCLUSIONS: Between 2 years and follow-up at average 7 years after surgery no further improvements were noticed at young patients with a bone sarcoma located around the knee.

What Are the Long-term Results of MUTARS® Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia?

BACKGROUND: Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce. QUESTIONS/PURPOSES: (1) What proportion of patients experience a mechanical complication with the MUTARS® modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? METHODS: Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS® knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0-9.7). Mean age at surgery was 36 years (range, 13-82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 [6%]). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) (hazard ratio [HR], 1.72; 95% CI, 0.55-5.38; p = 0.354). Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 [5%]) than uncoated uncemented implants (11 of 36 [31%]) (HR, 0.23; 95% CI, 0.05-1.06; p = 0.060). Structural complications occurred in 15 reconstructions (15 of 110 [14%]). Infections occurred in 14 reconstructions (14 of 110 [13%]). Ten patients had a local recurrence (10 of 101 [10%]). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% (95% CI, 9.6-24.2), 20.7% (95% CI, 12.5-28.8%), and 37.9% (95% CI, 16.1-59.7), respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 [89%]) had a MUTARS® in situ. CONCLUSIONS: Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS® modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation. LEVEL OF EVIDENCE: Level IV, therapeutic study.

LUMiC® Endoprosthetic Reconstruction After Periacetabular Tumor Resection: Short-term Results.

BACKGROUND: Reconstruction of periacetabular defects after pelvic tumor resection ranks among the most challenging procedures in orthopaedic oncology, and reconstructive techniques are generally associated with dissatisfying mechanical and nonmechanical complication rates. In an attempt to reduce the risk of dislocation, aseptic loosening, and infection, we introduced the LUMiC® prosthesis (implantcast, Buxtehude, Germany) in 2008. The LUMiC® prosthesis is a modular device, built of a separate stem (hydroxyapatite-coated uncemented or cemented) and acetabular cup. The stem and cup are available in different sizes (the latter of which is also available with silver coating for infection prevention) and are equipped with sawteeth at the junction to allow for rotational adjustment of cup position after implantation of the stem. Whether this implant indeed is durable at short-term followup has not been evaluated. QUESTIONS/PURPOSES: (1) What proportion of patients experience mechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (2) What proportion of patients experience nonmechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (3) What is the cumulative incidence of implant failure at 2 and 5 years and what are the mechanisms of reconstruction failure? (4) What is the functional outcome as assessed by Musculoskeletal Tumor Society (MSTS) score at final followup? METHODS: We performed a retrospective chart review of every patient in whom a LUMiC® prosthesis was used to reconstruct a periacetabular defect after internal hemipelvectomy for a pelvic tumor from July 2008 to June 2014 in eight centers of orthopaedic oncology with a minimum followup of 24 months. Forty-seven patients (26 men [55%]) with a mean age of 50 years (range, 12-78 years) were included. At review, 32 patients (68%) were alive. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 3.9 years (95% confidence interval [CI], 3.4-4.3). During the period under study, our general indications for using this implant were reconstruction of periacetabular defects after pelvic tumor resections in which the medial ilium adjacent to the sacroiliac joint was preserved; alternative treatments included hip transposition and saddle or custom-made prostheses in some of the contributing centers; these were generally used when the medial ilium was involved in the tumorous process or if the LUMiC® was not yet available in the specific country at that time. Conventional chondrosarcoma was the predominant diagnosis (n = 22 [47%]); five patients (11%) had osseous metastases of a distant carcinoma and three (6%) had multiple myeloma. Uncemented fixation (n = 43 [91%]) was preferred. Dual-mobility cups (n = 24 [51%]) were mainly used in case of a higher presumed risk of dislocation in the early period of our study; later, dual-mobility cups became the standard for the majority of the reconstructions. Silver-coated acetabular cups were used in 29 reconstructions (62%); because only the largest cup size was available with silver coating, its use depended on the cup size that was chosen. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Six patients (13%) had a single dislocation; four (9%) had recurrent dislocations. The risk of dislocation was lower in reconstructions with a dual-mobility cup (one of 24 [4%]) than in those without (nine of 23 [39%]) (hazard ratio, 0.11; 95% CI, 0.01-0.89; p = 0.038). Three patients (6%; one with a preceding structural allograft reconstruction, one with poor initial fixation as a result of an intraoperative fracture, and one with a cemented stem) had loosening and underwent revision. Infections occurred in 13 reconstructions (28%). Median duration of surgery was 6.5 hours (range, 4.0-13.6 hours) for patients with an infection and 5.3 hours (range, 2.8-9.9 hours) for those without (p = 0.060); blood loss was 2.3 L (range, 0.8-8.2 L) for patients with an infection and 1.5 L (range, 0.4-3.8 L) for those without (p = 0.039). The cumulative incidences of implant failure at 2 and 5 years were 2.1% (95% CI, 0-6.3) and 17.3% (95% CI, 0.7-33.9) for mechanical reasons and 6.4% (95% CI, 0-13.4) and 9.2% (95% CI, 0.5-17.9) for infection, respectively. Reasons for reconstruction failure were instability (n = 1 [2%]), loosening (n = 3 [6%]), and infection (n = 4 [9%]). Mean MSTS functional outcome score at followup was 70% (range, 33%-93%). CONCLUSIONS: At short-term followup, the LUMiC® prosthesis demonstrated a low frequency of mechanical complications and failure when used to reconstruct the acetabulum in patients who underwent major pelvic tumor resections, and we believe this is a useful reconstruction for periacetabular resections for tumor or failed prior reconstructions. Still, infection and dislocation are relatively common after these complex reconstructions. Dual-mobility articulation in our experience is associated with a lower risk of dislocation. Future, larger studies will need to further control for factors such as dual-mobility articulation and silver coating. We will continue to follow our patients over the longer term to ascertain the role of this implant in this setting. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Higher incidence rates than previously known in tenosynovial giant cell tumors.

Background and purpose - Tenosynovial giant cell tumors (TGCT) are rare, benign tumors, arising in synovial lining of joints, tendon sheaths, or bursae. 2 types are distinguished: localized, either digits or extremity, and diffuse lesions. Current TGCT incidence is based on 1 single US-county study in 1980, with an incidence of 9 and 2 per million person-years in localized (including digits) and diffuse TGCT, respectively. We aim to determine nationwide and worldwide incidence rates (IR) in TGCT affecting digits, localized-extremity TGCT and diffuse-type TGCT. Material and methods - Over a 5-year period, the Dutch Pathology Registry (PALGA) identified 4,503 pathology reports on TGCT. Reports affecting digits were solely used for IR calculations. Reports affecting extremities were clinically evaluated. Dutch IRs were converted to world population IRs. Results - 2,815 (68%) digits, 933 (23%) localized-extremity and 390 (9%) diffuse-type TGCT were identified. Dutch IR in digits, localized-extremity, and diffuse-type TGCT was 34, 11 and 5 per million person-years, respectively. All 3 groups showed a female predilection and highest number of new cases in age category 40-59 years. The knee joint was most often affected: localized-extremity (46%) and diffuse-type (64%) TGCT, mostly treated with open resection: localized (65%) and diffuse (49%). Reoperation rate due to local recurrence for localized-extremity was 9%, and diffuse TGCT 23%. Interpretation - This first nationwide study and detailed analyses of IRs in TGCT estimated a worldwide IR in digits, localized-extremity and diffuse TGCT of 29, 10, and 4 per million person-years, respectively. Recurrence rate in diffuse type is 2.6 times higher, compared with localized extremity. TGCT is still considered a rare disease; however, it is more common than previously understood.

The clinical approach toward giant cell tumor of bone.

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.

New vertebral fractures after percutaneous vertebroplasty for painful osteoporotic vertebral compression fractures: a clustered analysis and the relevance of intradiskal cement leakage.

PURPOSE: To perform clustered analysis of fracture-free probabilities of intact nontreated vertebrae after percutaneous vertebroplasty (PVP) in painful long-standing osteoporotic vertebral compression fractures (OVCFs) to determine risk factors for new vertebral fractures and estimate fracture-free probabilities of multiple intact nontreated vertebrae given their patient- and vertebra-specific covariate status. MATERIALS AND METHODS: Informed consent and institutional review board approval were obtained. A total of 115 patients who underwent PVP for 216 painful long-standing OVCFs were prospectively followed up to detect new OVCFs during the 1st postoperative year. A total of 1031 intact vertebrae were available for clustered analysis of fracture-free probabilities by using a Cox proportional hazard frailty model. A clustered analysis takes clustering or correlation of fracture-free survival probabilities of individual intact vertebrae within one patient into account to improve estimates of fracture-free probabilities and risk factors. Relevant patient- and vertebra-specific covariates were included. Volumetric analysis of intradiskal cement leakage was performed by using a receiver operating characteristic curve (ROC). RESULTS: Three- and 12-month vertebral fracture-free probability was 97.0% and 94.5%, respectively. Strong patient-level risk factors included low bone mineral density (hazard ratio [HR], 0.53 per unit increase), high spinal deformity index (HR, 2.23 per five units increase), and low fracture age (HR, 0.52 per 2 months increase). Strong vertebra-specific risk factors were thoracolumbar localization (HR, 2.33), vicinity to the treated level (adjacent level HR, 3.53), and presence of intradiskal cement leakage (HR, 8.21). Fracture-free probabilities of individual vertebrae were clustered within a patient (ie, not independent) (P = .009). The predicted 1-year fracture-free probability of an individual vertebra could be as high as 99.8% or as low as 19.9% based on absence or presence of risk factors, respectively. Larger intradiskal cement leakage volumes were associated with a higher likelihood of occurrence of new adjacent OVCFs (area under the ROC curve, 0.70). CONCLUSION: New vertebral fractures after PVP were clustered within patients and depended heavily on the presence or absence of both patient- and vertebra-specific risk factors. Intradiskal cement leakage was a pronounced augmentation-related risk factor, for which a volumetric association was found.

A multidisciplinary approach to giant cell tumors of tendon sheath and synovium--a critical appraisal of literature and treatment proposal.

Giant cell tumors deriving from synovium are classified into a localized (GCT of tendon sheath; GCT-TS) and diffuse form (diffuse-type GCT, Dt-GCT). We propose a multidisciplinary management based upon a systematic review and authors' opinion. Open excision for GCT-TS and open synovectomy (plus excision) for Dt-GCT is advised to reduce the relatively high recurrence risk. External beam radiotherapy should be considered in severe cases, as Dt-GCT commonly extends extra-articular.

Long-term clinical outcome of patients with soft tissue sarcomas treated with limb-sparing surgery and postoperative radiotherapy.

BACKGROUND: To evaluate long-term local control, survival, radiation side effects and functional outcome after limb-sparing surgery followed by postoperative radiotherapy (RT) for soft tissue sarcoma (STS). MATERIAL AND METHODS: Between 1995 and 2010, 118 patients with STS of an extremity were treated with limb-sparing surgery and postoperative RT. Follow-up was complete for all patients. Acute and late radiation related toxicities were scored using CTCAE v4.0. RESULTS: Median follow-up was 93 months. RT dose was 60 Gy in 92.4% of the patients; 5.1% received 66 Gy; 2.5% 50-56 Gy. Actuarial local recurrence rates at five and 10 years were 9% and 12%. Five- and 10-year overall survival rates were 69% and 51%. Acute radiation toxicities occurred in 91% of the patients; 19% were grade 3, 2% grade 4. Late radiation toxicities were reported in 71% of the patients: 50% grade 1, 18% grade 2, and 3% grade 3. Limb and joint function after treatment were good, 19% having mild limitation of motion, 1.5% moderate, and 2.5% severe limitations. CONCLUSION: Limb-sparing surgery with 60 Gy postoperative radiotherapy for patients with STS provides excellent local control and high survival rates with acceptable toxicity and functional outcomes.

Giant cell tumor with pathologic fracture: should we curette or resect?

BACKGROUND: Approximately one in five patients with giant cell tumor of bone presents with a pathologic fracture. However, recurrence rates after resection or curettage differ substantially in the literature and it is unclear when curettage is reasonable after fracture. QUESTIONS/PURPOSES: We therefore determined: (1) local recurrence rates after curettage with adjuvants or en bloc resection; (2) complication rates after both surgical techniques and whether fracture healing occurred after curettage with adjuvants; and (3) function after both treatment modalities for giant cell tumor of bone with a pathologic fracture. METHODS: We retrospectively reviewed 48 patients with fracture from among 422 patients treated between 1981 and 2009. The primary treatment was resection in 25 and curettage with adjuvants in 23 patients. Minimum followup was 27 months (mean, 101 months; range, 27-293 months). RESULTS: Recurrence rate was higher after curettage with adjuvants when compared with resection (30% versus 0%). Recurrence risk appears higher with soft tissue extension. The complication rate was lower after curettage with adjuvants when compared with resection (4% versus 16%) and included aseptic loosening of prosthesis, allograft failure, and pseudoarthrosis. Tumor and fracture characteristics did not increase complication risk. Fracture healing occurred in 24 of 25 patients. Mean Musculoskeletal Tumor Society score was higher after curettage with adjuvants (mean, 28; range, 23-30; n = 18) when compared with resection (mean, 25; range, 13-30; n = 25). CONCLUSIONS: Our observations suggest curettage with adjuvants is a reasonable option for giant cell tumor of bone with pathologic fractures. Resection should be considered with soft tissue extension, fracture through a local recurrence, or when structural integrity cannot be regained after reconstruction. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Surgical technique: Tibia cortical strut autograft interposition arthrodesis after distal radius resection.

BACKGROUND: Distal radius reconstruction after en bloc tumor resection remains a surgical challenge. Although several surgical techniques, either reconstructing the wrist or achieving a stable arthrodesis, have been described, it is unclear to what degree these restore function. DESCRIPTION OF TECHNIQUE: We describe an updated technique making use of a tibia cortical strut autograft (TCSA) to perform a functional arthrodesis from the remaining radius to the first carpal row. This, in theory, could lead to less donor site morbidity while resulting in a stable but functional and pain-free arthrodesis of the wrist. METHODS: Between 1987 and 2010 we reconstructed the wrists of 17 patients using a TCSA arthrodesis (six primary and three revisions), seven with an osteoarticular allograft, three using an ulnar translocation, and one with a fibula autograft. Median age at diagnosis was 24 years (range, 9-58 years) and minimum followup was 2.7 years (median, 13.8 years; range, 2.7-24.5 years). Patients were evaluated using radiographs and clinical examination. We used Musculoskeletal Tumor Society (MSTS), Disabilities of the Arm, Shoulder, and Hand (DASH), and SF-36 questionnaires to assess function and quality of life. RESULTS: All TCSA reconstructions fused; one patient had a second surgery to expedite union with the carpal row. After osteoarticular allograft, five patients were revised (three to a TCSA) for nonunion, fracture, or joint collapse. ROM and grip strength were comparable in both AO and TCSA, all above 60% of the contralateral side. Median MSTS and DASH scores were 73% and 6, respectively, and did not differ between the groups. The SF-36 scores showed less pain after TCSA; otherwise, all patients presented with comparable function. CONCLUSIONS: TCSA wrist arthrodesis resulted in a functional and painless wrist reconstruction with a relatively low complication and donor site morbidity rate and comparable functional results as other techniques. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone.

BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce. METHODS: We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential. RESULTS: We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5-8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type. CONCLUSIONS: Based on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies.

Percutaneous vertebroplasty in very severe osteoporotic vertebral compression fractures: feasible and beneficial.

PURPOSE: To assess clinical outcome and technical feasibility of percutaneous vertebroplasty (PVP) in 34 patients with 37 osteoporotic vertebral compression fractures (OVCFs) with vertebral body collapse to less than one-third of the original height, termed very severe osteoporotic vertebral compression fractures (vsOVCFs). MATERIALS AND METHODS: A prospective follow-up study was conducted using a 0-10 pain intensity numerical rating scale and the Short Form-36 General Health Survey (SF-36) quality-of-life questionnaire, completed before PVP and 7 days (pain only), 1 month, 3 months, and 12 months after PVP. Cement leakage was analyzed on postoperative computed tomography (CT) scanning. The presence of new fractures was assessed at 6 weeks and 52 weeks and when suspected clinically. RESULTS: Decrease in average and worst back pain was 2.5 points and 3.0 points after 7 days, and 2.5 points and 2.9 points after 12 months. The physical and mental SF-36 summary scores were significantly increased. Incidence of cement leakage in vsOVCFs was 91.9%, which was substantially higher compared with non-vsOVCFs (n = 40) treated in the same patients (64.1%; odds ratio [OR] 6.4, 95% confidence interval [CI] 1.7-24.5, P = .004). Mean leakage volume per treated vertebra was more than twice as high (0.80 mL vs 0.32 mL; P < .001). Seventeen new OVCFs in 11 patients (32.4%) were identified. Only one (2.9%) minor complication occurred, confirming the feasibility of PVP in vsOVCFs. CONCLUSIONS: Patients with painful vsOVCFs can be treated with, and benefit from, PVP. Although technically more demanding and with a higher procedural risk (ie, more frequent necessity of placement of a second needle, higher leakage incidence, and greater leakage volumes), PVP is technically feasible and should not be withheld from these patients.