Joint-Sparing Resection around the Knee for Osteosarcoma: Long-Term Outcomes of Biologic Reconstruction with Vascularized Fibula Graft Combined with Massive Allograft.

(1) Background: We aim to address the following questions. What was the complication rate of vascularized fibula graft (VFG) combined with massive allograft in patients treated with joint-sparing resection around the knee for a high-grade osteosarcoma? What was the long-term survivorship of VFG free from revision and graft removal? What were the functional results as assessed by the Musculoskeletal Tumor Society (MSTS) score? (2) Methods: 39 patients treated in our unit for osteosarcoma around the knee with intercalary resection and reconstruction with VFG combined with massive allograft were included; 26 patients underwent intercalary tibial resection, while 13 underwent intercalary femoral resection. (3) Results: Mean Follow-Up was 205 months (28 to 424). Complications that required surgery were assessed in requiring surgical revision in 19 patients (49%) after a mean of 31 months (0 to 107), while VFG removal was necessary in three patients (8%). The revision-free survival of the reconstructions was 59% at 5 years and 50% at 10 to 30 years. The overall survival of the reconstructions was 95% at 5 to 15 years and 89% at 20 to 30 years. The mean MSTS score was 29.3 (23 to 30). (4) Conclusions: VFG represents an effective reconstructive option after joint-sparing intercalary resection around the knee for osteosarcoma.

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.

Garrè Sclerosing Osteomyelitis of the Clavicle: Clinical Results after Clavicular Resection.

(1) Background: Chronic non-bacterial osteomyelitis (CNO), also known as sclerosing osteomyelitis of Garrè, is a rare inflammatory bone disease with a specific clinical picture, uncertain pathogenesis, and no consensus on an effective treatment. Most frequently affecting other long bones, CNO may rarely involve the clavicle. The aim of this study was to present the results of a series of patients affected by CNO of the clavicle treated with total and partial clavicula resection. In addition, a literature review of different types of treatment of CNO was performed. (2) Methods: We retrospectively reviewed three patients with Sclerosing Osteomyelitis of Garre' of the clavicle treated with partial resection of the clavicle (one) and with total clavicular resection (two). (3) Results: Patients (two female and one male) were an average age of 35.7 years at the time of the operation. At the 4-year follow-up, the mean active ROM was: 143° forward flexion, 133° abduction, 42° external rotation with an internal rotation of two patients at the interscapular level and one patient at the lumbosacral junction. The mean ASES score was 92/100 (range 87-100). In the literature review, after screening the abstracts and full texts for eligibility, 34 studies met the inclusion criteria. Conclusions: Partial or total clavicular resection resulted an effective treatment of CNO of the clavicle. The procedure seems to be particularly indicated after the failure of more conservative treatments.

Outcomes of Long Bones Treated With Carbon-Fiber Nails for Oncologic Indications: International Multi-institutional Study.

BACKGROUND: Intramedullary nail fixation is commonly used for prophylactic stabilization of impending and fixation of complete pathological fractures of the long bones. However, metallic artifacts complicate imaging evaluation for bone healing or tumor progression and postoperative radiation planning. Carbon-fiber implants have gained popularity as an alternative, given their radiolucency and superior axial bending. This study evaluates incidences of mechanical and nonmechanical complications. METHODS: Adult patients (age 18 years and older) treated with carbon-fiber nails for impending/complete pathological long bone fractures secondary to metastases from 2013 to 2020 were analyzed for incidences and risk factors of mechanical and nonmechanical complications. Mechanical complications included aseptic screw loosening and structural failures of host bone and carbon-fiber implants. Deep infection and tumor progression were considered nonmechanical. Other complications/adverse events were also reported. RESULTS: A total of 239 patients were included; 47% were male, and 53% were female, with a median age of 68 (IQR, 59 to 75) years. Most common secondary metastases were related to breast cancer (19%), lung cancer (19%), multiple myeloma (18%), and sarcoma (13%). In total, 17 of 30 patients with metastatic sarcoma received palliative intramedullary nail fixation for impending/complete pathological fractures, and 13 of 30 received prophylactic nail stabilization of bone radiated preoperatively to manage juxta-osseous soft-tissue sarcomas, where partial resection of the periosteum or bone was necessary for negative margin resection. 33 (14%) patients had complications. Mechanical failures included 4 (1.7%) structural host bone failures, 7 (2.9%) implant structural failures, and 1 (0.4%) aseptic loosening of distal locking screws. Nonmechanical failures included 8 (3.3%) peri-implant infections and 15 (6.3%) tumor progressions with implant contamination. The 90-day and 1-year mortalities were 28% (61/239) and 53% (53/102), respectively. The literature reported comparable failure and mortality rates with conventional titanium treatment. CONCLUSIONS: Carbon-fiber implants might be an alternative for treating impending and sustained pathological fractures secondary to metastatic bone disease. The seemingly comparable complication profile warrants further cohort studies comparing carbon-fiber and titanium nail complications.

Survival and Results after Resection and Reconstruction with Megaprosthesis at the Hip in Octogenarians.

Few data are available about results after procedures of resection and megaprosthesis at the hip in very elderly patients. The aim of our study was to ascertain survival and complications in patients aged 80 or older undergoing these major orthopedic procedures. A consecutive series of 27 procedures in 26 patients aged 80-93 years was evaluated. In total, 15 procedures were performed due to oncological diseases, 6 were performed following joint arthroplasty failures or periprosthetic fractures, and 6 were performed after trauma or trauma sequelae. Survival of the patients ranged from 0 to 122 months. Overall survival was 56% at 3 years, 24% at 5 years, and 16% at 8 years. An early postoperative death during the first 3 months occurred in five patients (18.5%). The only preoperative parameter negatively affecting survival was preoperative hemoglobin lower than 11 g/dL. Local complications were similar to reported rates in all-age patients' series. In our experience, resection and megaprosthetic reconstruction can also be a valid choice in very elderly patients, with 56% of patients living more than two years from surgery and 24% more than five. Nevertheless, early postoperative deaths are frequent. A multidisciplinary evaluation of frailty of the patient must be accomplished, and patients and relatives must be informed about the risks of the procedure.

Silver-Coated Distal Femur Megaprosthesis in Chronic Infections with Severe Bone Loss: A Multicentre Case Series.

Periprosthetic joint infections (PJI) and fracture-related infections (FRI) of the distal femur (DF) may result in massive bone defects. Treatment options include articulated silver-coated (SC) megaprosthesis (MP) in the context of a two-stage protocol. However, there is limited evidence in the literature on this topic. A retrospective review of the prospectively maintained databases of three Institutions was performed. Forty-five patients were included. The mean follow-up time was 43 ± 17.1 months. Eight (17.8%) patients had a recurrent infection. The estimated recurrence-free survival rate was 91.1% (93.5% PJI vs. 85.7% FRI) 2 years following MP implantation, and 75.7% (83.2% PJI vs. 64.3% FRI; p = 0.253) after 5 years. No statistically relevant difference was found according to the initial diagnosis (PJI vs. FRI). Among possible risk factors, only resection length was found to significantly worsen the outcomes in terms of infection control (p = 0.031). A total of eight complications not related to infection were found after reimplantation, but only five of them required further surgery. Above-the-knee amputation was performed in two cases (4.4%), both for reinfection. Articulated DF SC MP in a two-stage protocol is a safe and effective treatment for chronic knee infection with severe bone loss.

Tumor size and surgical margins are important prognostic factors of synovial sarcoma - A retrospective study.

Background: Synovial Sarcoma (SS) is a rare soft tissue sarcoma. Mean time to get a SS diagnosis from the onset of symptoms is 10 years, furthermore, SS is associated with late metastasis. Surgery is the main treatment option, whose quality deeply affects SS outcomes, and it can be associated to preoperative or post-operative radiotherapy. Chemotherapy is considered very effective in Children, while in adults its efficacy is still under debate. The aim of this study was to investigate the oncologic results in SS treatment and to identify the risk factors for local and systemic control of the disease. Methods: From 1994 to 2018, 211 patients affected by SS were treated in 3 Referral Centres of Orthopaedic Oncology. One hundred seventy-seven patients were included in the study, the median follow-up length was 96 months (5-374). Results: Overall Survival on the Kaplan Meier Analyses was 80%, 70% and 56% at 5, 10 and 20 years. In multivariate analyses, OS correlated with tumour size and negative surgical margins. Chemotherapy use wasn't associated with better survival although patients who underwent CT had bigger and more aggressive tumours. Conclusions: Our findings suggests that surgery with negative margins is the most important factor in Synovial Sarcoma. Adjuvant treatments as chemotherapy and radiation therapy didn't change the disease's course.

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.

A 54-Year-Old Man Who Developed a Femoral Pathologic Fracture from a Giant Popliteal Artery Pseudoaneurysm 7 Years After Ligation and Bypass of a Popliteal Artery Aneurysm: A Case Report and Literature Review.

BACKGROUND This case report describes a giant pseudoaneurysm that grew in size during the years following surgical treatment of a popliteal artery aneurysm, eventually causing a femoral fracture. Bone fractures secondary to vascular injuries are rarely described in the literature. CASE REPORT A 54-year-old man underwent surgical ligation and bypass for left popliteal artery aneurysm. Seven years later, he suffered a left distal femur pathologic fracture surrounded by a giant soft-tissue mass. The patient came to us with a diagnostic hypothesis of angiosarcoma from another hospital at imaging evaluation. After computed tomography angiography (CTA) and angio-magnetic resonance imaging (MRI), we made a diagnosis of femoral pathologic fracture caused by a giant pseudoaneurysm of a treated popliteal artery aneurysm refilled by an aberrant anterior tibial artery (IIA2, Kim classification). We performed excision of the mass and open reduction and internal fixation, with anatomic plate, of the fracture. Fracture healing and good functional outcome were observed at follow-up. CONCLUSIONS A possible complication of surgical treatment of popliteal artery aneurysms is refilling of the excluded aneurysm due to collateral blood flow or, such as in the present case, aberrant vessels. Therefore, the knowledge of anatomical variants of the vessels is important in surgery. Follow-up evaluation after surgery is advisable and a growing mass should be further investigated with an angio-CT scan. In case of a non-pulsating soft-tissue mass causing pathologic bone fracture, a biopsy is mandatory to exclude malignancy.

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.

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.

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.

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.

Management of Squamous Cell Carcinoma in Chronic Osteomyelitis: Our Experience, Review of the Literature and Role of MRI in Differential Diagnosis.

BACKGROUND: The authors describe a series of patients with chronic osteomyelitis associated with squamous cell carcinoma, whilst analyzing its incidence in chronic osteomyelitis, surgical options for treatment and focusing on the role of MRI in differential diagnosis. METHODS: The authors reviewed 73 cases of chronic osteomyelitis (CO) treated in their department between 1995 and 2019. Six of these patients (8.2%) had a malignant degeneration in squamous cell carcinoma (SCC). All cases with malignancy were evaluated with preoperative gadolinium-enhanced MRI. RESULTS: In this series, the authors observed an incidence rate of 8.2% (6 cases out of 73); all patients were male with a mean age of 63.5 years. The mean time between the occurrence of chronic osteomyelitis and the diagnosis of squamous cell carcinoma was 36 years (range: 21-66). The treatment consisted of amputation in five patients and limb salvage with vascularized fibula autograft in one case. CONCLUSIONS: MRI played a key role in the differential diagnosis between infected and tumoral tissue, and was found to be crucial during follow-up. Amputation is the treatment of choice in extended tumoral involvement of bone and soft tissue.

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.

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.

The Performances of Conventional Titanium and Silver-Coated Megaprostheses in Non-oncological and Post-oncological Patients: An Analysis of Infection Failures in 142 Patients.

Background: Megaprostheses are one of the preferred choices of reconstruction after tumor resection. Periprosthetic joint infections are one of the most serious complications of joint prostheses surgeries. In this study, our aim was to analyze the efficacy of silver-coated megaprostheses in reducing the risk of prosthesis-related infection. Methods: One hundred forty-two patients who had undergone implantation of a mega-endoprosthesis for non-neoplastic or post-neoplastic conditions were included in this retrospective study. The end-point of the survival analysis was the prosthesis failure due to infection. Results: Thirty-eight patients had undergone implantation of a silver-coated megaprosthesis and 104 patients a megaprosthesis without silver coating. The survival analysis showed an overall infection-free survival rate of 82.3% at five years and 61.9% at 10 years. Silver-coated prostheses had an HR of 0.72 (95% CI: 0.26-2.05; P=0.54). Conclusion: Implantation of a silver-coated mega-prosthesis in non-oncological patients did not significantly reduce the risk of prosthesis-related infection.

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities.

Undifferentiated round cell sarcomas (URCS) of soft tissue and bone and tumours of uncertain differentiation (TUD) are commonly ascribed to a subset of neoplasms with low frequency of NTRK gene fusions. However, more recently NTRK-rearranged round and spindle cell tumours have been noted in case reports and in limited or heterogeneous cohorts. The aim of our study was to investigate the presence of NTRK gene fusions in a large retrospective cohort of paediatric URCS and TUD after a systematic review of the diagnosis, according to the recently updated WHO classification scheme. One-hundred and five patients with diagnosis of URCS or TUD, involving the bone or soft tissue, were retrospectively evaluated. After the case selection and the histopathological review of the case cohort, pan-Trk immunohistochemistry (IHC) testing was performed on formalin-fixed paraffin-embedded (FFPE) tissues. Tumour RNA was extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation, using a 10-gene NGS fusion panel, sequenced on an Illumina MiSeq. The NGS-positive cases were further confirmed by real-time PCR. On immunohistochemical screening, 12/105 (11.4%) cases were positive using the pan-Trk antibody, showing three different staining patterns with the cytoplasmic distribution being most common. Molecular analysis using NGS and confirmed by the real-rime PCR detected two positive cases for the ETV6-NTRK3 fusion. The histological pattern of the two positive cases, together with the demonstration of the NTRK rearrangement, leaded to re-classify these previously not otherwise specified sarcomas with uncertain differentiation into the emerging category of NTRK-rearranged neoplasms. In addition, we found the two NTRK fused neoplasms showing a clinical indolent course, in contrast with literature.

Pharmacogenomics of soft tissue sarcomas: New horizons to understand efficacy and toxicity.

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unfortunately limited to a small subset of patients. Much of the inter-individual variability in treatment efficacy and risk of toxicities is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. Therefore, the detection of pharmacogenomics (PGx) biomarkers that might predict drug response and toxicity can be useful to explain the genetic basis for the differences in treatment efficacy and toxicity among STS patients. PGx markers are frequently located in transporters, drug-metabolizing enzyme genes, drug targets, or HLA alleles. Along this line, genetic variability harbouring in the germline genome of the patients can influence systemic pharmacokinetics and pharmacodynamics of the treatments, acting as predictive biomarkers for drug-induced toxicity and treatment efficacy. By linking drug activity to the functional complexity of cancer genomes, also systematic pharmacogenomic profiling in cancer cell lines and primary STS samples represents area of active investigation that could eventually lead to enhanced efficacy and offer a powerful biomarker discovery platform to optimize current treatments and improve the knowledge about the individual's drug response in STS patients into the clinical practice.