Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

BACKGROUND: Reconstruction with vascularized fibula grafts (VFG) after intercalary resection of sarcoma may offer longevity by providing early graft-host union and fracture healing. The ability of the fibula to hypertrophy under mechanical stress, as well as vascularized bone in the area, may also be advantageous, given that soft tissues may be compromised because of resection, chemotherapy, or radiation therapy. VFG with a massive allograft combines the primary mechanical stability of the graft with the biological potential of the vascularized fibula; however, complications and the durability of this combined reconstruction are not well described. QUESTIONS/PURPOSES: (1) What was the proportion of complications after reconstruction with VFG, with or without allografts? (2) What was the functional result after surgical treatment as assessed by the Musculoskeletal Tumor Society (MSTS) score? (3) What was the survivorship of these grafts free from revision and graft removal? METHODS: Between 1988 and 2021, 219 patients were treated at our institution for a primary malignant or aggressive benign bone tumor of the tibia with en bloc resection. Of those, 54% (119 of 219) had proximal tibial tumors with epiphyseal involvement and were treated with either intra-articular resection and reconstruction with an osteoarticular allograft, allograft-prosthesis composite (APC), or modular prosthesis according to age, diagnosis, and preoperative or postoperative radiotherapy. Nine percent (20) of patients had distal tibial tumors that were treated with intra-articular resection and reconstruction with ankle arthrodesis using allogenic or autologous grafts, and 0.5% (1 patient) underwent total tibial resection for extensive tumoral involvement of the tibia and reconstruction with an APC. Thirty-six percent (79) of patients had a metadiaphyseal bone tumor of the tibia and were treated with intercalary joint-sparing resection. We routinely use reconstruction with VFG after intercalary tibial resection for primary malignant or aggressive benign bone tumors in patients with long life expectancy and high functional demands and in whom at least 1 cm of residual bone stock of the proximal or distal epiphysis can be preserved. By contrast, we routinely use intercalary massive allograft reconstruction in short resections or in patients with metastatic disease who do not have long life expectancy. We avoid VFG in patients with tibial bone metastasis, patients older than 70 years, or primary bone tumors in patients who may undergo postoperative radiotherapy; in these patients, we use alternative reconstructive methods such as intercalary prostheses, plate and cement, or intramedullary nailing with cement augmentation. According to the above-mentioned indications, 6% (5 of 79) of patients underwent massive allograft reconstruction because they were young and had intercalary resections shorter than 7 cm or had metastatic disease at diagnosis without long life expectancy, whereas 94% (74) of patients underwent VFG reconstruction. The median age at operation was 16 years (range 5 to 68 years). The diagnosis was high-grade osteosarcoma in 22 patients, Ewing sarcoma in 19, adamantinoma in 16, low-grade osteosarcoma in five, fibrosarcoma in three, malignant fibrous histiocytoma and Grade 2 chondrosarcoma in two, and malignant myoepitelioma, angiosarcoma of bone, malignant peripheral nerve sheath tumor of bone, squamous cell carcinoma secondary to chronic osteomyelitis, and desmoplastic fibroma in one patient each. Median follow-up was 12.3 years (range 2 to 35 years). The median tibial resection length was 15 cm (range 7 to 27 cm), and the median fibular resection length was 18 cm (range 10 to 29 cm). VFG was used with a massive allograft in 55 patients, alone in 12 patients, and combined with allogenic cortical bone struts in seven patients. We used VFG combined with a massive allograft in patients undergoing juxta-articular, joint-sparing resections that left less than 3 cm of residual epiphyseal bone, for intra-epiphyseal resections, or for long intercalary resections wherein the allograft can provide better mechanical stability. In these clinical situations, the combination of a VFG and massive allograft allows more stable fixation and better tendinous reattachment of the patellar tendon. VFG was used with cortical bone struts in distal tibia intercalary resections where the narrow diameter of the allograft did not allow concentric assembling with the fibula. Finally, VFG alone was often used after mid- or distal tibia intercalary resection in patients with critical soft tissue conditions because of previous surgery, in whom the combination with massive allograft would result in a bulkier reconstruction. We ascertained complications and MSTS scores by chart review, and survivorship free from revision and graft removal was calculated using the Kaplan-Meier estimator. In our study, however, the occurrence of death as a competing event was observed in a relatively low proportion of patients, and only occurred after the primary event of interest had already occurred. Considering the nature of our data, we did not consider death after the primary event of interest as a competing event. RESULTS: In all, 49% (36 of 74) of patients experienced complications and underwent operative treatment. There were 45 complications in 36 patients. There was one instance of footdrop secondary to common peroneal nerve palsy, four wound problems, one acute vein thrombosis of the VFG pedicle and one necrosis of the skin island, two episodes of implant-related pain, 10 nonunions, six fractures, six deep infections, nine local recurrences, one Achilles tendon retraction, one varus deformity of the proximal tibia with postoperative tibial apophysis detachment, one knee osteoarthritis, and one hypometria. The median MSTS score was 30 (range 23 to 30); the MSTS score was assessed only in patients in whom the VFG was retained at the final clinical visit, although if we had considered those who had an amputation, the overall score would be lower. Revision-free survival of the reconstructions was 58% (95% confidence interval 47% to 70%) at 5 years, 52% (95% CI 41% to 65%) at 10 and 15 years, and 49% (95% CI 38% to 63%) at 20 and 30 years. Eight patients underwent VFG removal because of complications, with an overall reconstruction survival of 91% (95% CI 84% to 98%) at 5 years and 89% (95% CI 82% to 97%) at 10 to 30 years. CONCLUSION: VFG, alone or combined with an allograft, could be considered in reconstructing a lower extremity after intercalary resections of the tibia for primary bone tumors, and it avoids the use of a large endoprosthesis. However, this procedure was associated with frequent, often severe complications during the first postoperative years and complication-free survival of 58% at 5 years. Nearly 10% of patients ultimately had an amputation. For patients whose reconstruction succeeded, the technique provides a durable reconstruction with good MSTS scores, and we believe it is useful for active patients with long life expectancy. Fractures, frequently observed in the first 5 years postoperatively, might be reduced using long-spanning plate fixation, and that appeared to be the case in our study. Nonbridging fixation can be an option in intraepiphyseal resection when a spanning plate cannot be used or in pediatric patients to enhance fibula hypertrophy and remodeling. We did not directly compare VFG with or without allografts to other reconstruction options, so the decision to use this approach should be made thoughtfully and only after considering the potential serious risks. LEVEL OF EVIDENCE: Level IV, therapeutic study.

The use of vascularized fibula flap with allograft in post-oncologic microsurgical bone reconstruction of lower limbs in pediatric patients.

BACKGROUND: Post-oncologic surgical reconstruction of lower limbs in pediatrics remains a challenging topic. Microsurgical techniques allow reconstructions of large bony defects. The use of vascularized fibular flap with allograft has proven to be an ideal biologic construct. We aim to assess the success rate of this operation, including flap survival, bony union, weight-bearing ambulation, and complications in a long-term follow-up in our case series compared to the literature. PATIENTS AND METHODS: Our case-series includes 18 femoral resections (9 osteosarcomas, 8 Ewing sarcoma, and 1 desmoid tumor) and 15 tibial resections (10 osteosarcoma, 4 Ewing sarcoma, and 1 Malignant Fibrous Histiocytoma). We collected patients' demographics, type of tumor, type of resection, defect size, fibula-flap length, method of fixation, anastomosis site, follow-up data, complications, and their management. All survivals were examined by X-ray and CT-scan to evaluate the morphological changes of the vascularized fibula and follow-up. The functional evaluation was performed by the 30-point Musculoskeletal Tumor Society Rating Score (MSTS) for the lower limb (Enneking et al., Clinical Orthopaedics and Related Research 1993(286):241-246). RESULTS: The mean age of the femur resection patients' group was 11.2 years with a mean defect size of 14 cm and a mean length of the fibular flap of 18 cm; for the tibia the mean age was 12 years with a mean defect size of 14 cm and a mean length of the fibular flap of 16.6 cm. The overall survival of the reconstructions at 5 years follow-up was 17 out 18 cases for the femur and 13 out of 15 cases for the tibia. MSTS score was 28.2 for the femur and 23.7 for the tibia. The average time of union of the fibula was seen after 5 months, while allograft consolidation was observed around 19.7 months. The mean time of follow-up was 144.5 months for the femur and 139.2 months for the tibia. The complication rate observed was 7 out of 18 for the femur and 7 out of 15 for the tibia reconstructions. CONCLUSIONS: The viability of the fibula is a cornerstone in the success of reconstruction as well as the successful management of complications in intercalary defects after tumor resection in pediatrics to restore good functionality. Our results are in line with those reported in the literature in terms of overall complication rates. The high primary union of allograft, the high MSTS score obtained, and the low rate of severe complications reflect the mechanical role of this reconstructive technique over a long follow-up.

Surgical treatment for pelvic bone metastatic disease from renal cell carcinoma.

INTRODUCTION: Pelvic bone metastases from renal cell carcinoma (RCC) are challenging due to their destructive pattern, poor response to radiotherapy and hypervascularity. The purpose of our study was to review a series of patients undergoing surgical treatment with the aim to investigate: 1) survival; 2) local disease control; and 3) complications. METHODS: A series of 16 patients was reviewed. A curettage procedure was performed on 12 patients. In eight the lesion involved the acetabulum; a cemented hip arthroplasty with cage was performed in seven; a flail hip in one. Four patients received a resection; in two cases with acetabular involvement, reconstruction was performed with a custom-made prosthesis and with an allograft and prosthesis. RESULTS: Disease-specific survival accounted for 70% at 3 years and 41% at 5 years. Only one local tumor progression after curettage occurred. Revision surgery (flail hip) was necessary for deep infection of the custom-made prosthesis. CONCLUSION: A prolonged survival in patients affected by bone metastatic disease from RCC can justify also major surgical procedures. Due to a low local progression rate after intralesional procedures, curettage, cement and a total hip arthroplasty with cage, when feasible, should be considered as an alternative to more demanding surgeries like resections and reconstructions. LEVEL OF EVIDENCE (OXFORD): Level 4.

Are Vascularized Fibula Autografts a Long-lasting Reconstruction After Intercalary Resection of the Humerus for Primary Bone Tumors?

BACKGROUND: A vascularized fibula graft (VFG) is the vascular autograft most frequently used to restore large segmental long bone defects, particularly in the upper limb. Because the use of a vascularized fibula involves an operation in an uninvolved extremity with potential morbidity, it is important to document that this type of reconstruction is successful in restoring function to the humerus. However, the long-term results of VFG after intercalary resection of the humeral diaphysis for bone tumors are still unknown. QUESTIONS/PURPOSES: (1) What was the complication rate of reconstruction? (2) What was the functional result after surgical treatment, as assessed by the Musculoskeletal Tumor Society (MSTS) score, the American Shoulder and Elbow Society (ASES) score, and Constant score? (3) What was the survivorship of these grafts free from revision and graft removal at 5, 10, and 15 years? METHODS: Between 1987 and 2021, 127 patients were treated at our institution with en bloc resection for a primary malignant or an aggressive benign bone tumor of the humerus; we excluded patients treated with extra-articular resection or amputation. Of those, 14% (18 of 127) were treated with intercalary resection of the humeral diaphysis for primary bone tumors and reconstruction with VFG, with or without a bulk allograft, and were analyzed in this retrospective study. Generally, our indications for reconstruction with VFG are intercalary resection of the humerus for primary malignant or aggressive benign bone tumors in patients with long life expectancy and high functional demands, in whom adequate bone stock of the proximal and distal epiphysis can be preserved. In 13 patients, VFG was used alone, whereas in five patients, a massive allograft was used. Our policy was to use VFG combined with a massive allograft in patients undergoing juxta-articular joint-sparing resections in which proximal osteotomy was performed close to the anatomic neck of the humerus to obtain more stable fixation and better tendinous reattachment of the rotator cuff and deltoid. All 18 patients who were treated with a VFG were available for follow-up at a minimum of 2 years (median follow-up 176 months, range 26 to 275 months), and although three have not been seen in the past 5 years and are not known to have died, they had 172, 163, and 236 months of follow-up, and were included. The median age at surgery was 25 years (range 2 to 63 years), the median humeral resection length was 15 cm (range 8 to 21 cm), and the median fibular length was 16 cm (range 12 to 23 cm). Complications and functional scores were ascertained by chart review that was performed by an individual not involved in patient care. Functional results were assessed with the MSTS score (range 0 to 30), the ASES score (range 0 to 100), and the Constant score (range 0% to 100%). Survivorship was estimated using a Kaplan-Meier survivorship estimator, which was suitable because there were few deaths in this series. RESULTS: Seven patients underwent a revision procedure (one radial nerve transient palsy because of screw impingement, four nonunions in three patients with one humeral head avascular necrosis, treatment for screw-related pain in one patient, and two VFG fractures), and one patient underwent VFG removal. Donor site complications were observed in four patients (one ankle valgus deformity and three claw toes-the first toe in two patients and the other toes in the third). At the final clinical control, at a median follow-up of 176 months (range 26 to 275 months), the median MSTS score was 30 of 30 (range 28 to 30), the median ASES score was 98.3 (range 93 to 100), and the median Constant score was 93.5% (range 79% to 100%). Revision-free survival was 71% (95% CI 53% to 96%) at 5 years and 57% (95% CI 37% to 88%) at 10 and 15 years; VFG removal-free survival was 94% (95% CI 83% to 100%) at 5, 10, and 15 years. CONCLUSION: VFG appears to be an effective reconstructive option after humeral intercalary resection for primary bone tumors. These are complex procedures and should be performed by an experienced team of surgeons who recognize that complications may occur frequently in the first years after the procedure. The frequency of mechanical complications observed in the first 5 years postoperatively may be lessened by using long spanning-plate fixation, and if successful, this reconstruction provides a long-term, durable reconstruction with excellent functional results. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Long term outcome of surgical treatment of chondroblastoma: analysis of local control and growth plate/articular cartilage related complications.

BACKGROUND: Chondroblastoma (CBL) is a rare benign chondroid producing bone tumor that typically occurs in epiphysis or apophysis of growing children and young adults. Intralesional curettage is the treatment of choice, while resection is required in selected cases, even though the use of minimally invasive ablation techniques has been advocated. Authors reviewed a series of 75 CBLs with the aim of assess risk factors for local recurrence, the growth plate related complications after epiphyseal curettage and the risk of arthritis of the adjacent joint after epiphyseal curettage. METHODS: We retrospectively review 69 CBLs treated with intralesional curettage and 6 treated with resection from March 1995 to February 2020. The median age was 18.8 years (7 to 42, median 16). The site was proximal humerus in 18 cases, proximal tibia in 17, distal femur in 16, talus in 6, femur's head in 4, calcaneus in 3, acromion in 3, trochanteric region in 2, distal tibia in 2, patella in 2, supracetabular region in 1 and distal humerus in 1 patient. RESULTS: Mean follow-up was 124.2 months (24 to 322, median 116). Among patients treated with curettage, 7.3% of local recurrence was observed and 12 (17.4%) patients developed osteoarthritis of the adjacent joint. Five patients (7.3%) presented limb length discrepancy of the operated limb ranging from 0.5 to 2 cm. Recurrence free survival rate was 94.2% at 5 and 91.6% at 10 years. A mean Musculoskeletal Tumor Society (MSTS) of 29.3 points (20 to 30, median 30) was observed. CONCLUSION: More than 90% of CBLs were successfully treated with aggressive curettage but segmental resection is required in selected cases. In a relatively small proportion of cases long term complications can occur due to growth plate damage or osteoarthritis. TRIAL REGISTRATION: Retrospectively registered.

Do's and Don'ts in Primary Aneurysmal Bone Cysts of the Proximal Femur in Children and Adolescents: Retrospective Multicenter EPOS Study of 79 Patients.

BACKGROUND: Aneurysmal bone cysts (ABC) are rare benign cystic bone tumors, generally diagnosed in children and adolescents. Proximal femoral ABCs may require specific treatment strategies because of an increased pathologic fracture risk. As few reports are published on ABCs, specifically for this localization, consensus regarding optimal treatment is lacking. We present a large retrospective study on the treatment of pediatric proximal femoral ABCs. METHODS: All eligible pediatric patients with proximal femoral ABC were included, from 11 tertiary referral centers for musculo-skeletal oncology (2000-2021). Patient demographics, diagnostics, treatments, and complications were evaluated. Index procedures were categorized as percutaneous/open procedures and osteosynthesis alone. Primary outcomes were: time until full weight-bearing and failure-free survival. Failure was defined as open procedure after primary surgery, >3 percutaneous procedures, recurrence, and/or fracture. Risk factors for failure were evaluated. RESULTS: Seventy-nine patients with ABC were included [mean age, 10.2 (±SD4.0) y, n=56 male]. The median follow-up was 5.1 years (interquartile ranges=2.5 to 8.8).Index procedure was percutaneous procedure (n=22), open procedure (n=35), or osteosynthesis alone (n=22). The median time until full weight-bearing was 13 weeks [95% confidence interval (CI)=7.9-18.1] for open procedures, 9 weeks (95% CI=1.4-16.6) for percutaneous, and 6 weeks (95% CI=4.3-7.7) for osteosynthesis alone ( P =0.1). Failure rates were 41%, 43%, and 36%, respectively. Overall, 2 and 5-year failure-free survival was 69.6% (95% CI=59.2-80.0) and 54.5% (95% CI=41.6-67.4), respectively. Risk factors associated with failure were age younger than 10 years [hazard ratios (HR)=2.9, 95% CI=1.4-5.8], cyst volume >55 cm 3 (HR=1.7, 95% CI=0.8-2.5), and fracture at diagnosis (HR=1.4, 95% CI=0.7-3.3). CONCLUSIONS: As both open and percutaneous procedures along with osteosynthesis alone seem viable treatment options in this weight-bearing location, optimal treatment for proximal femoral ABCs remains unclear. The aim of the treatment was to achieve local cyst control while minimizing complications and ensuring that children can continue their normal activities as soon as possible. A personalized balance should be maintained between undertreatment, with potentially higher risks of pathologic fractures, prolonged periods of partial weight-bearing, or recurrences, versus overtreatment with large surgical procedures, and associated risks. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Salvage of limb salvage in oncological reconstructions of the lower limb with megaprosthesis: how much to push the boundaries?

INTRODUCTION: Megaprosthesis represent the most commonly used limb salvage method after musculoskeletal tumor resections. Nevertheless, they are burdened by high complication rate, requiring several surgical revisions and eventually limb amputation. The aims of this study were to evaluate the effect of rescuing the limb with subsequent revisions on complication rates (a), incidence of amputations (b), and whether complications reduce functional outcome after the first surgical revision (c). MATERIALS AND METHODS: We retrospectively reviewed 444 lower limb megaprosthesis implanted for primary musculoskeletal tumors or metastatic lesions, from February 2000 to November 2017. 59 patients received at least one revision megaprosthesis surgery. MSTS score was used to assess final functional results. Complication-revision-amputation free survival rates were calculated both at 5 and 10 years of follow-up. RESULTS: Complication free survival, revision free survival and amputation free survival at 10 years were 47% and 53%, 61% and 67%, 90% and 86% among all 444 patients and the group of 59 revised patients, respectively. The incidence of further complications after the first complication was 26% in the group treated with no subsequent revision surgeries and 51% in the group with at least one revision surgery. We found a trend of inverse linear relationship between the number of complications needing subsequent revision surgeries and the final MSTS. CONCLUSION: The number of further revision surgeries after limb salvage with megaprosthesis increases the incidence of complications. Repeated surgical revisions, in particular after infection, increase the amputation rate. The most frequent causes of failure were structural failures and infections. MSTS score was superior for patients undergoing limb salvage than amputees. However, MSTS progressively decreased with multiple revisions becoming inferior to the functional score of an amputated patient.

An improved NMR approach for metabolomics of intact serum samples.

NMR metabolomics has inherent capabilities for studying biofluids, such as reproducibility, minimal sample preparation, non-destructiveness, and molecular structure elucidation; however, reliable quantitation of metabolites is still a challenge because of the complex matrix of the samples. The serum is one of the most common samples in clinical studies but possibly the most difficult for NMR analysis because of the high content of proteins, which hampers the detection and quantification of metabolites. Different processes for protein removal, such as ultrafiltration and precipitation, have been proposed, but require sample manipulation, increase time and cost, and possibly lead to loss of information in the metabolic profile. Alternative methods that rely on filtering protein signals by NMR pulse sequencing are commonly used, but standardisation of acquisition parameters and spectra calibration is far from being reached. The present technical note is a critical assessment of the sparsely suggested calibrants, pulse sequences and acquisition parameters toward an optimised combination of the three for accurate and reproducible quantification of metabolites in intact serum.

Growth arrest-specific 5 lncRNA as a valuable biomarker of chemoresistance in osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumour in children and teenagers, and it is characterised by drug resistance and high metastatic potential. Increasing studies have highlighted the critical roles of long noncoding RNAs (lncRNAs) as oncogenes or tumour suppressors as well as new biomarkers and therapeutic targets in osteosarcoma. The growth arrest-specific 5 (GAS5) lncRNA can function as a tumour suppressor in several cancers. The present study aimed to validate GAS5 and other chemoresistance-associated lncRNAs as biomarkers in a cohort of primary osteosarcoma samples, to obtain predictive information on resistance or sensitivity to treatment. The GAS5 and a panel of lncRNAs related to chemoresistance [SNGH1, FOXD2-AS1, deleted in lymphocytic leukemia (DLEU2) and LINC00963] were evaluated in a cohort of osteosarcoma patients enrolled at the Careggi University Hospital. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections and the expression levels of the lncRNAs were quantified by qPCR. A bioinformatic analysis on deposited RNA-seq data was performed to validate the qPCR results. Clustering analysis shows that GAS5 could be linked to the expression of isoforms 02 and 04 of the lncRNA DLEU2, whereas the DLEU2 isoform 08 is linked to the lncRNA LINC00963. We found that GAS5 is significantly increased in patients with a good prognosis and is expressed differently between chemosensitive and chemoresistant osteosarcoma patients. However, the results obtained are not concordant with the in-silico analysis performed on the TARGET osteosarcoma dataset. In the future, we would enlarge the case series, including different disease settings.

Cemented vs uncemented megaprostheses in proximal femur metastases: a multicentric comparative study.

BACKGROUND: Hip megaprostheses are a long known reconstructive method in the treatment of proximal femur metastases. The use of cemented or uncemented stems is still matter of debate. The aim of this study to compare cemented and uncemented megaprostheses on functional outcomes and complications, in order to establish the role of cementation. METHODS: We retrospectively analysed 51 metastatic patients with proximal femur metastases treated with endoprosthetic reconstruction by megaprostheses, 25 with cementless stems and 26 with cemented ones with different megaprosthetic implants. The primary endpoint was MSTS score, and the secondary endpoint was to state the incidence of surgical and clinical complications in the two groups. An un-paired T test was used to compare anthropometric, anamnestic data, and MSTS. Chi-square test was performed for evaluation of complication in the two group. Multiple linear regression was used to match the functional outcomes and complications' incidence in the population study. Logistic regression was performed to analyse the odds ratio of different parameters and their role in the incidence of complications. RESULTS: The mean follow-up was 50.1 months (+ 12.5). In thirty case right side was involved. No statistical differences were noticed between Group A and B regard the age, gender, active fracture/impending fracture. Comparing the MSTS results within the two groups at last follow-up, the score cemented group was higher than cementless one (17.9 + 7.8 vs 24.2 + 5.3; statistical significance p = 0.001). Regarding surgical complications a logistic regression was performed to analyse the odds ratio of age, cementation and length of resection; cementation confirm and odds ratio of 11 times in the incidence of surgical complications. CONCLUSIONS: Cementation seems to be more liable to complications onset, while improves functional score in metastatic patients compared to uncemented megaprostheses. More studies have to be conducted in order to create a protocol and establish criteria to use cemented or uncemented stems in a frail population like metastatic patients.

Surgical treatment scenario for osteoblastoma of the pelvis: Long-term follow-up results.

BACKGROUND: The aim of this study was to evaluate the results of different treatments for pelvic Osteoblastoma (OB). METHODS: We retrospectively evaluated 34 patients affected by primary pelvic OB from 3 oncologic referral centers. Patients with a minimum follow-up of 24 months were included. Local recurrence (LR) rate and complications were recorded. RESULTS: The primary treatment was radio-frequency ablation (RFA) in 4 patients (11.8%), curettage (ILC) in 21 (61.7%) and resection (EBR) in 9 (26.5%). Mean follow-up was 8.9 years (SD ± 6.6). Local recurrence free survival (LRFS) rate after primary surgery was 79.4% at 3 and 5 years. In details, LRFS rate at 3 and 5 years was 50.0% in RFA, 81.0% in ILC and 88.9% in EBR. Post-operative complications occurred in 6/34 patients (17.7%), in particular after EBR. CONCLUSIONS: RFA is the least invasive technique to treat OB but with high LR rate. Thus, it should be reserved to very small lesions. ILC is a suitable treatment for stage II OB. For stage III OB, EBR is the treatment of choice, despite an increased risk of complications. For selected stage III OB (relatively small, periacetabular area) ILC might be considered.

Radiosensitizing Effect of Trabectedin on Human Soft Tissue Sarcoma Cells.

Trabectedin is used for the treatment of advanced soft tissue sarcomas (STSs). In this study, we evaluated if trabectedin could enhance the efficacy of irradiation (IR) by increasing the intrinsic cell radiosensitivity and modulating tumor micro-environment in fibrosarcoma (HS 93.T), leiomyosarcoma (HS5.T), liposarcoma (SW872), and rhabdomyosarcoma (RD) cell lines. A significant reduction in cell surviving fraction (SF) following trabectedin + IR compared to IR alone was observed in liposarcoma and leiomyosarcoma (enhancement ratio at 50%, ER50: 1.45 and 2.35, respectively), whereas an additive effect was shown in rhabdomyosarcoma and fibrosarcoma. Invasive cells' fraction significantly decreased following trabectedin ± IR compared to IR alone. Differences in cell cycle distribution were observed in leiomyosarcoma and rhabdomyosarcoma treated with trabectedin + IR. In all STS lines, trabectedin + IR resulted in a significantly higher number of γ-H2AX (histone H2AX) foci 30 min compared to the control, trabectedin, or IR alone. Expression of ATM, RAD50, Ang-2, VEGF, and PD-L1 was not significantly altered following trabectedin + IR. In conclusion, trabectedin radiosensitizes STS cells by affecting SF (particularly in leiomyosarcoma and liposarcoma), invasiveness, cell cycle distribution, and γ-H2AX foci formation. Conversely, no synergistic effect was observed on DNA damage repair, neoangiogenesis, and immune system.

Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma.

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

The use of a non-biological, bridging, antiprotrusio cage in complex revision hip arthroplasty and periacetabular reconstructive oncologic surgery. Is still today a valid option?: A mid/long-term survival and complications' analysis.

INTRODUCTION: Burch-Schneider-like antiprotrusio cages (B-SlAC) still remain helpful implants to bridge severe periacetabular bone losses. The purpose of this study was to evaluate outcomes and estimate both cages' failures and complication risks in a series of B-SlAC implanted in revision of failed total hip arthroplasties (THA) or after resection of periacetabular primary or secondary bone malignancies. Risk factors enhancing the chance of dislocations and infections were checked. MATERIALS AND METHODS: We evaluated 73 patients who received a B-SlAC from January 2008 to January 2018. Group A, 40 oncological cases (22 primary tumors; 18 metastases); Group B, 33 failed THAs. We compared both Kaplan-Meier estimates of risk of failure and complication with the cumulative incidence function, taking account the competing risk of death. Cox proportional hazards model was utilized to identify possible predictors of instability and infection. Harris hip score HHS was used to record clinical outcomes. RESULTS: Medium follow-up was 80 months (24-137). Average final HHS was 61 (28-92), with no differences within the two groups (p > 0.05). The probabilities of failure and complications were 57% and 26%, respectively, lower in the oncologic group than in the rTHA group (p =0 .176; risk 0.43) (p = 0.52; risk 0.74). Extended ileo-femoral approach and proximal femur replacement (p =0.02, risk ratio = 3.2; p = 0.04, rr = 2.1) were two significant independent predictors for dislocations, while belonging to group B (p = 0.04, rr = 2.6) was predictable for infections. CONCLUSION: Burch-Schneider-like antiprotrusio cages are a classical non-biological acetabular reconstruction method that surgeons should bear in mind when facing gross periacetabular bone losses, independently of their cause. However, dislocation and infection rates are high. Whenever possible, we suggest preserving the proximal femur in revision THA, and to use a less-invasive postero-lateral approach to reduce dislocation rates in non-oncologic cases.

Extraskeletal Myxoid Chondrosarcoma with Molecularly Confirmed Diagnosis: A Multicenter Retrospective Study Within the Italian Sarcoma Group.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain origin, marked by specific chromosomal translocations involving the NR4A3 gene, and usually characterized by an indolent course. Surgery (with or without radiotherapy) is the treatment of choice in localized disease. The treatment for advanced disease remains uncertain. In order to better evaluate prognostic factors and outcome, a retrospective pooled analysis of patients with EMC treated at three Italian Sarcoma Group (ISG) referral centers was carried out. METHODS: All patients with localized EMC surgically treated from 1989 to 2016 were identified. Diagnosis was centrally reviewed according to WHO 2013. Only patients with NR4A3 rearrangement were included. RESULTS: Sixty-seven patients were identified: 13 (20%) female, 54 (80%) male. Median age was 56 years (range 18-84). Numbers and type of translocation were: 50 (80%) NR4A3-EWS, 10 (16%) NR4A3-TAF15, 1 (2%) NR4A3-TCF12, and 1 (2%) NR4A3-TFG. Median follow-up was 55 months (range 2-312). Five- and ten-year overall survival rates were 94% (86-100 95%CI) and 84% (69-98 95%CI). Thirty-five (52%) patients relapsed: 9 had local recurrence (LR) and 26 had distant metastasis (5 with concomitant LR). The 5- and 10-year disease-free survival rates (DFS) were 51% (38-65 95%CI) and 20% (7-33 95%CI). Size of the primary tumor was significantly related to distant metastasis-free survival (DMFS) (p = 0.004). Patients carrying the NR4A3-EWS translocation had a trend in favor of better DFS (p = 0.08) and DMFS (p = 0.09) compared with the patients with NR4A3-TAF15. CONCLUSIONS: Prolonged survival can be expected in patients with EMC, in spite of a high rate of recurrence. Size is significantly associated with distant relapse. The type of NR4A3 translocation could influence outcome.

Extra-abdominal desmoid tumor fibromatosis: a multicenter EMSOS study.

BACKGROUND: Extra-abdominal desmoid tumor fibromatosis (DTF) is a rare, locally aggressive soft tissue tumour. The best treatment modality for this patient cohort is still object of debate. QUESTIONS/PURPOSE: This paper aimed to (1) to compare the outcomes of DTF after different treatment modalities, (2) to assess prognostic factors for recurrence following surgical excision, and (3) to assess prognostic factors for progression during observation. METHODS: This was a retrospective multicenter study under the patronage of the European Musculoskeletal Oncology Society (EMSOS). All seven centres involved were tertiary referral centres for soft tissue tumours. Baseline demographic data was collected for all patients as well as data on the diagnosis, tumour characteristics, clinical features, treatment modalities and whether they had any predisposing factors for DTF. RESULTS: Three hundred eighty-eight patients (240 female, 140 male) with a mean age of 37.6 (±18.8 SD, range: 3-85) were included in the study. Two hundred fifty-seven patients (66%) underwent surgical excision of ADF, 70 patients (18%) were observed without therapy, the residual patients had different conservative treatments. There were no significant differences in terms of tumour recurrence or progression between the different treatment groups. After surgical excision, younger age, recurrent disease and larger tumour size were risk factors for recurrence, while tumours around the shoulder girdle and painful lesions were at risk of progression in the observational group. CONCLUSION: Local recurrence rate after surgery was similar to progression rates under observation. Hence, observation in DTF seems to be justified, considering surgery in case of dimensional progression in 2 consecutive controls (3 and 6 months) and in painful lesions, with particular attention to lesions around the shoulder girdle.

Analysis of a Preliminary microRNA Expression Signature in a Human Telangiectatic Osteogenic Sarcoma Cancer Cell Line.

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior.

Antibacterial hydrogel coating in joint mega-prosthesis: results of a comparative series.

PURPOSE: Joint mega-prosthesis after bone tumors, severe trauma or infection is associated with high rates of post-surgical septic complications. A fast-resorbable antibacterial hydrogel coating (DAC®, Defensive Antibacterial Coating) has previously been shown to be able to significantly reduce surgical site infection in various clinical settings. Aim of the present study was to evaluate the safety and efficacy of the DAC hydrogel coating to prevent early periprosthetic joint infection after joint mega-prosthesis. METHODS: In this three-centers, case-control study, 43 patients, treated with an antibacterial hydrogel coated mega-prosthesis for oncological (N = 39) or non-oncological conditions (N = 4), were retrospectively compared with 43 matched controls, treated with mega-implants without the coating. Clinical, laboratory and radiographic examinations were performed to evaluate the occurrence of post-surgical infection, complications and adverse events. RESULTS: At a mean follow-up of 2 years, no evidence of infection or adverse events were observed in the DAC-treated group, compared to six cases of post-surgical infection in the control group. CONCLUSION: This matched case-control study shows that a fast-resorbable, antibiotic-loaded coating can be safely used to protect joint mega-prosthesis, providing a reduction of early surgical site infections with no side effects. Larger prospective trials with longer follow-ups are warranted to confirm this report. TRIAL REGISTRATION: RS1229/19 (Regina Elena National Cancer Institute Experimental Registry Number).

Ewing family tumors of the appendicular skeleton: a retrospective analysis of prognostic factors.

PURPOSE: Authors retrospectively analyzed possible prognostic factors in a series of patients affected by Ewing sarcoma of extremities (eEWS) and treated over a 20-year period at a single institution. METHODS: Between 1997 and 2017, 88 bone eEWS were treated at our institution. Staging, age, gender, tumoral volume, local treatment, surgical margins, post-ChT necrosis were investigated for prognostic correlation with overall survival (OS) and event-free survival (EFS). Median follow-up was 74 months (1-236). RESULTS: Staging of disease correlated with OS (81% vs 59%, p = 0.01) and not with EFS (68% vs 57%, p = 0.28) in localized vs metastatic eEWS at presentation. Age ≥ 14 years (p = 0.002) and volume ≥ 100 cm3 (p = 0.04) were significant negative prognostic factors. No difference was found in local treatment: OS was 76% vs 63% (p = 0.33), while EFS was 68% vs 49% (p = 0.06) after surgery alone or surgery + radiotherapy, respectively. Regarding surgical margins, OS was 76% vs 38% (p = 0.14), and EFS was 65% vs 33% (p = 0.14) in adequate vs not adequate, respectively. OS was 86% and 68% in good and poor responders, respectively (p = 0.13). CONCLUSION: In eEWS, metastatic disease at presentation, age > 14 years and tumoral volume > 100 cm3 are negative prognostic factors. Intensified adjuvant ChT can improve prognosis in poor responders and metastatic patients.

Expandable distal femur megaprosthesis: A European Musculoskeletal Oncology Society study on 299 cases.

BACKGROUND AND OBJECTIVES: Expandable distal femur prostheses have become more popular over the last decades, but scientific data is limited. METHODS: A retrospective study was performed, including cases treated between 1986 and 2019 in 15 European referral centers for bone sarcomas. RESULTS: A total of 299 cases were included. Average follow-up was 80 months (range, 8-287 months). Mean patient age was 10 years. Most (80%) of the implants were noninvasive growers and a fixed hinge knee was used more often (64%) than a rotating hinge. Most prosthetic designs showed good (>80%) implant survival at 10 years, but repeat surgery was required for 63% of the patients. The most frequent reason for revision procedure was the completion of lengthening potential. Noninvasive expandable implants showed less risk of infection compared to invasive growers (11.8% vs 22.9% at 10 years). No difference in aseptic loosening was found between cemented and uncemented stems. CONCLUSIONS: This study shows the increasing popularity of expandable distal femur prostheses, with overall good results for function and implant survival. However, repeat surgery is frequently required, especially in patients under the age of 10 years old. Infection is less frequent in noninvasive growers compared to implants that require invasive lengthening procedures.