What Is the Revision-free Survival of Resurfaced Allograft-prosthesis Composites for Proximal Humerus Reconstruction in Children With Bone Tumors?

BACKGROUND: Reconstruction of the proximal humerus in children who undergo bone tumor resection is challenging because of patients' small bone size and possible limb length discrepancy at the end of skeletal growth due to loss of the physis. There are several options for proximal humerus reconstruction in children, such as clavicula pro humero, free vascularized fibula grafting, massive bone osteoarticular allografting, endoprostheses, and allograft-prosthesis composites, but no consensus exists on the best method for reconstruction. Resurfaced allograft-prosthesis composites could be an alternative surgical option, but little is known about the results of this surgical technique. QUESTIONS/PURPOSES: (1) What are the complications and what is the survivorship free from reconstruction failure associated with resurfaced allograft-prosthesis composites in a small, single-center case series? (2) What Musculoskeletal Tumor Society scores do patients achieve after reconstructions with resurfaced allograft-prosthesis composites? METHODS: This study was a retrospective, single-arm case analysis in a single institution. We generally considered resurfaced allograft-prosthesis composites in children with malignant bone tumors involving the metaepiphysis of the proximal humerus in whom there was no evidence of joint contamination and in whom axillary nerve preservation was possible. Between 2003 and 2021, we treated 100 children (younger than 15 years) with bone tumors of the humerus. Thirty children (30%) with diaphyseal tumors (21 children) or distal tumors (9 children) were excluded. Among the potentially eligible children, 52 were not analyzed because they were treated with other procedures such as amputation, modular prostheses, cement spacers, free vascularized fibula grafting, and massive bone osteoarticular allografts. We included 18 children (26% of the potentially eligible children) who were treated with resurfaced allograft-prosthesis composites. There were 9 boys and 9 girls, with a median age of 10 years (range 4 to 15 years) at the time of diagnosis. A long stem (≥ 6 cm) in the resurfaced allograft-prosthesis composite was used in 9 children and a short stem (< 6 cm) was used in the remaining 9. One of the 18 children had a follow-up of less than 2 years. The median follow-up of the remaining 17 children was 4.7 years (range 2 to 19 years). The children' medical records were reviewed for clinical and functional outcomes. We performed a competing risk analysis to calculate the reconstruction failure-free survival of resurfaced allograft-prosthesis composites. Reconstruction failure was defined as removal of the implant or allograft because of implant loosening or breakage and allograft fracture or resorption. We analyzed the children's postoperative complications and functional outcomes at the end of the follow-up period using the Musculoskeletal Tumor Society functional scoring system. RESULTS: The competing risk analysis revealed that reconstruction failure was 25% (95% confidence interval 7% to 40%) at 3 years, reaching a plateau. Four of 18 children underwent surgical revision with a new reconstruction. The reasons for reconstruction revision were resorption of the allograft at the proximal part (2 children) and fracture of the allograft (2 children). Reconstruction revision was performed in 3 of 9 children who underwent reconstruction with a short stem and in 1 of 9 children who underwent reconstruction with a long stem. Several children had other complications that did not result in removal of the allograft. Allograft resorption was observed in 4 of 18 children, but no additional surgical treatment was performed. Shoulder instability or subluxation was observed in 4 of 18 children, but only 1 child underwent surgery with a reverse shoulder arthroplasty without removal of the resurfaced allograft-prosthesis composite. Limited elbow motion because of plate impingement was observed in 1 child who underwent surgical cutting of the protruding distal part of the plate. Incomplete radial nerve palsy after surgery occurred in 1 child, with spontaneous resolution after 2 months. Screw loosening occurred in 2 children who underwent surgery with removal of loose screws. Two children had a nonunion at the graft-host bone junction; 1 child underwent surgery with bone grafting and refixation of the graft-host bone junction, and the other child with both nonunion and plate breakage was treated with bone grafting and refixation of the graft-host bone junction with a new plate. Among 17 children who had a follow-up longer than 2 years, the median Musculoskeletal Tumor Society functional score at the last follow-up interval was 23 of 30 (range 20 to 26); 1 child was considered to have an excellent result (functional score ≥ 26), 15 children were considered to have a good result (functional score 21 to 25), and 1 child was considered to have a fair result (functional score ≤ 20). The Musculoskeletal Tumor Society functional score did not change after excluding 4 children who underwent replacement of resurfaced allograft-prosthesis composites (24 of 30 [range 20 to 26]). The median angle of flexion of the shoulder was 40° (range 20º to 90°), and the median angle of abduction was 30° (range 20º to 90°). CONCLUSION: Resurfaced allograft-prosthesis composites showed a high risk of complications, but not all complications resulted in removal of the reconstructed allograft. We used this technique mainly for very young children with small bones and for older children who underwent axillary nerve preservation. Although its success may be limited owing to a high risk of complications, a resurfaced allograft-prosthesis composite could be an alternative surgical option in order to preserve the bone stock and achieve good functional outcomes in very young children. We recommend using a long-stem resurfaced allograft-prosthesis composite, which may reduce the risk of complications. LEVEL OF EVIDENCE: Level IV, therapeutic study.

A reduction in tumor volume exceeding 65% predicts a good histological response to neoadjuvant chemotherapy in patients with Ewing sarcoma.

OBJECTIVE: No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. MATERIALS AND METHODS: We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. RESULTS: Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. CONCLUSION: We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy.

Malawer type I/V proximal humerus reconstruction after tumor resection: a systematic review.

BACKGROUND: Several reconstruction methods exist for Malawer type I/V proximal humerus reconstruction after bone tumor resection; however, no consensus has been reached regarding the preferred methods. METHODS: We conducted a literature search on various types of proximal humerus oncologic reconstruction methods. We collected data on postoperative functional outcomes assessed based on Musculoskeletal Tumor Society (MSTS) scores, 5-year reconstruction survival rates, and complications. We calculated each reconstruction's weighted mean based on the sample size and standard errors. Complications were categorized based on the Henderson classification. Based on these integrated data, our primary objective is to propose an optimal strategy for proximal humerus reconstruction after bone tumor resection. RESULTS: We examined various reconstruction techniques, including modular prosthesis (752 patients in 21 articles), osteoarticular allograft (142 patients in 6 articles), allograft prosthesis composites (APCs) (236 patients in 12 articles), reverse shoulder total arthroplasty (141 patients in 10 articles), composite reverse shoulder total arthroplasty (33 patients in 4 articles), claviculo-pro-humero (CPH) technique (51 patients in 6 articles), and cement spacer (207 patients in 4 articles). Weighted mean MSTS scores were: modular prosthesis (73.8%), osteoarticular allograft (74.4%), APCs (79.2%), reverse shoulder total arthroplasty (77.0%), composite reverse shoulder total arthroplasty (76.1%), CPH technique (75.1%), and cement spacer (69.1%). Weighted 5-year reconstruction survival rates were modular prosthesis (85.4%), osteoarticular allograft (67.6%), APCs (85.2%), reverse shoulder total arthroplasty (84.1%), and cement spacer (88.0%). Reconstruction survival data was unavailable for composite reverse shoulder total arthroplasty and CPH technique. Major complications included shoulder joint instability: modular prosthesis (26.2%), osteoarticular allograft (41.5%), APCs (33.9%), reverse shoulder total arthroplasty (17%), composite reverse shoulder total arthroplasty (6.1%), CPH technique (2.0%), and cement spacer (8.7%). Aseptic loosening of the prosthesis occurred: modular prosthesis (3.9%) and reverse shoulder total arthroplasty (5.7%). Allograft fracture was observed in 54.9% of patients with osteoarticular allograft. CONCLUSION: The complication profiles differed among reconstruction methods. Weighted mean MSTS scores exceeded 70% in all methods except cement spacer, and the 5-year reconstruction survival rate surpassed 80% for all methods except osteoarticular allograft. Proximal humerus reconstruction after bone tumor resection should consider potential complications and patients' individual factors.

Angio-Based Fractional Flow Reserve, Functional Pattern of Coronary Artery Disease, and Prediction of Percutaneous Coronary Intervention Result: a Proof-of-Concept Study.

PURPOSE: Wire-based coronary physiology pullback performed before percutaneous coronary intervention (PCI) discriminates coronary artery disease (CAD) distribution and extent, and is able to predict functional PCI result. No research investigated if quantitative flow ratio (QFR)-based physiology assessment is able to provide similar information. METHODS: In 111 patients (120 vessels) treated with PCI, QFR was measured both before and after PCI. Pre-PCI QFR trace was used to discriminate functional patterns of CAD (focal, serial lesions, diffuse disease, combination). Functional CAD patterns were identified analyzing changes in the QFR virtual pullback trace (qualitative method) or after computation of the QFR virtual pullback index (QVPindex) (quantitative method). QVPindex calculation was based on the maximal QFR drop over 20 mm and the length of epicardial coronary segment with QFR most relevant drop. Then, the ability of the different functional patterns of CAD to predict post-PCI QFR value was tested. RESULTS: By qualitative method, 51 (43%), 20 (17%), 15 (12%), and 34 (28%) vessels were classified as focal, serial focal lesions, diffuse disease, and combination, respectively. QVPindex values >0.71 and ≤0.51 predicted focal and diffuse patterns, respectively. Suboptimal PCI result (post-PCI QFR value ≤0.89) was present in 22 (18%) vessels. Its occurrence differed across functional patterns of CAD (focal 8% vs. serial lesions 15% vs. diffuse disease 33% vs. combination 29%, p=0.03). Similarly, QVPindex was correlated with post-PCI QFR value (r=0.62, 95% CI 0.50-0.72). CONCLUSION: Our results suggest that functional patterns of CAD based on pre-PCI QFR trace can predict the functional outcome after PCI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , number NCT02811796. Date of registration: June 23, 2016.

Circulating Biomarkers of Endothelial Dysfunction and Inflammation in Predicting Clinical Outcomes in Diabetic Patients with Critical Limb Ischemia.

Critical limb ischemia (CLI) is a severe manifestation of peripheral artery disease characterized by ischemic pain, which is frequently associated with diabetes and non-healing lesions to inferior limbs. The clinical management of diabetic patients with CLI typically includes percutaneous transluminal angioplasty (PTA) to restore limb circulation and surgical treatment of diabetic foot ulcers (DFU). However, even after successful treatment, CLI patients are prone to post-procedure complications, which may lead to unplanned revascularization or foot surgery. Unfortunately, the factors predicting adverse events in treated CLI patients are only partially known. This study aimed to identify potential biomarkers that predict the disease course in diabetic patients with CLI. For this purpose, we measured the circulating levels of a panel of 23 molecules related to inflammation, endothelial dysfunction, platelet activation, and thrombophilia in 92 patients with CLI and DFU requiring PTA and foot surgery. We investigated whether these putative biomarkers were associated with the following clinical endpoints: (1) healing of the treated DFUs; (2) need for new revascularization of the limb; (3) appearance of new lesions or relapses after successful healing. We found that sICAM-1 and endothelin-1 are inversely associated with DFU healing and that PAI-1 and endothelin-1 are associated with the need for new revascularization. Moreover, we found that the levels of thrombomodulin and sCD40L are associated with new lesions or recurrence, and we show that the levels of these biomarkers could be used in a decision tree to assign patients to clusters with different risks of developing new lesions or recurrences.

Intercalary reconstruction of the distal femur with or without physeal preservation: results and impact on limb growth.

PURPOSE: Allograft reconstruction with or without vascularized fibula can be a valuable solution to treat childhood intercalary tumours of the distal femur. We aimed to assess the oncological status, complication rate and survival of distal femur intercalary reconstruction after trans-metaphyseal (TMR) and trans-epiphyseal resection (TER). We also evaluated the impact of distal temporary graft fixation on skeletal growth after TMR. METHODS: We retrospectively reviewed 23 skeletally immature patients affected by distal femur osteosarcoma (18) and Ewing sarcoma (5). Mean patients age was 10.3 years. In 11 cases, TMR was performed with physis preservation and temporary distal graft fixation. In 9 patients, TER was performed with growth plate sacrifice. The last 3 cases were treated with TMR and sliding plate fixation. RESULTS: Mean follow-up was 8.4 years. No deaths occurred, but 3 patients presented lung metastasis and 2 cases presented local recurrence in soft tissues. 10 implant-related complications occurred, all surgically treated. At skeletal maturity, mean femoral dysmetria was 2.3 cm after TMR and temporary epiphysiodesis, and 3.1 cm after TER. In TMR group, a strong trend towards physeal recovery was observed after epiphyseal screws removal (p = 0.061), but valgus deformity in distal femur was more frequent (p = 0.049). MSTS score was good or excellent in all patients, with no statistically significant difference between TMR and TER. CONCLUSIONS: Intercalary graft reconstruction after TMR and TER allows good local disease control and excellent functional results with long-term follow-up. Temporary distal fixation might reduce the final limb discrepancy after TMR, but valgus deformity could develop. LEVEL OF EVIDENCE: Level IV.

Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.

What Is the Survival of the Telescope Allograft Technique to Augment a Short Proximal Femur Segment in Children After Resection and Distal Femur Endoprosthesis Reconstruction for a Bone Sarcoma?

BACKGROUND: Large, malignant bone tumors and revision limb salvage procedures often result in the resection of extensive lengths of the involved bone segment, leaving a residual segment of bone that may be too short to support a standard intramedullary stem for endoprosthetic reconstruction. Telescope allografting, in which an allograft is used to augment the remaining bone segment by telescoping it into the residual bone segment, was described for situations in which residual bone stock is insufficient after tumor resection or prosthetic revision. Apart from one study that first described the procedure [15], there are no other studies reporting the outcome of this telescopic concept for restoring bone stock. QUESTIONS/PURPOSES: For patients younger than 18 years who underwent the telescopic allograft technique to augment a short segment of the proximal femur after resection of bone sarcomas who also underwent endoprosthesis reconstruction of the distal femur, we asked: (1) What is the survivorship free from removal of the telescopic allograft and the endoprosthetic stem at 7 years after surgery? (2) What proportion of these reconstructions will heal to the host bone without delayed union or nonunion? (3) What is the functional outcome based on the Musculoskeletal Tumor Society (MSTS) score? METHODS: We retrospectively studied our institutional database and identified 127 patients younger than 18 years who underwent surgery for a primary malignant bone tumor of the distal femur between December 2008 and October 2018. After excluding 16 patients undergoing amputation and rotationplasty and 57 patients undergoing recycled autograft/allograft reconstruction, 54 patients who underwent primary or revision distal femur endoprosthesis reconstruction were identified. Among these patients, we considered 15 patients who underwent telescopic allograft augmentation of the femur for analysis. One patient was lost to follow-up before 2 years but was not known to have died, leaving 14 for analysis at a median (range) 49 months (24 to 136 months) of follow-up. The indications for telescopic allograft augmentation of the femur in our institution were a proximal femur length of less than 120 mm after resection or resection of more than two-thirds of the total length of the femur. Ten of 14 patients underwent telescopic allograft augmentation as a revision procedure (distal femur resorption in five patients, endoprosthesis stem loosening in three patients, implant fracture in one patient, and infection in one patient), and the remaining four patients underwent telescopic allograft augmentation as a primary limb salvage procedure for large malignant bone tumors of the distal femur. The histologic diagnosis in all patients was osteosarcoma. At the time of telescopic allograft augmentation and reconstruction, the median age of the patients was 14 years (7 to 18 years). The size and the type of bone allograft to be used (femoral shaft or proximal femur) was planned before surgery, with consideration of the extent of resection, level of osteotomy, diameter of the host bone at the osteotomy site, and approximate diameter of the endoprosthesis stem to be used. The segment of the cylindrical allograft used for telescoping was thoroughly washed, prepared, and impacted onto the native femur to achieve telescoping and overlap. Serial digital radiographs were performed once a month for the first 6 months after the procedure, every 2 months until 1 year, and then every 6 months thereafter. Two surgeons in the department (at least one of which was involved in the surgery) retrieved and reviewed clinical notes and radiographs to determine the status of the telescopic allograft and endoprosthesis stem. We defined delayed union as radiological union at the osteotomy site more than 6 months after the procedure without additional surgery; we defined nonunion as no radiological evidence of callus formation at the osteotomy site 9 months after the procedure, necessitating additional surgery. The reviewers did not disagree about the definition of healing time. None of the patients missed radiographic follow-up. Kaplan-Meier survivorship free from removal of telescopic allograft and the endoprosthesis stem at 7 years after surgery was estimated. Patient function was assessed using the 1993 version of the MSTS [9], as determined by chart review of the institutional database performed by one of the surgeons from the department. RESULTS: The survivorship free from removal of the telescopic allograft and endoprosthesis stem at 7 years after surgery was 80% (95% confidence interval 22% to 96%). The allograft united with the host bone in 100% (14 of 14) of the patients. Though 21% (3 of 14) had delayed union, no nonunions were seen. The median (range) MSTS score at the final follow-up interval was 27 (22 to 30). CONCLUSION: Although this is a small group of patients, we believe that allograft segments help augment short bone stock of the proximal femur after long-segment resections, and the telescopic technique seems to be associated with a low proportion of nonunion or delayed union, which is one of the most common complications of allografts. Maintaining an adequate length of the proximal femur is important in preserving the hip, and this technique may be especially useful for young individuals who may undergo repeated revision procedures. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Does the Addition of a Vascularized Fibula Improve the Results of a Massive Bone Allograft Alone for Intercalary Femur Reconstruction of Malignant Bone Tumors in Children?

BACKGROUND: Massive bone allograft with or without a vascularized fibula is a potentially useful approach for femoral intercalary reconstruction after resection of bone sarcomas in children. However, inadequate data exist regarding whether it is preferable to use a massive bone allograft alone or a massive bone allograft combined with a vascularized free fibula for intercalary reconstructions of the femur after intercalary femur resections in children. Because the addition of a vascularized fibula adds to the time and complexity of the procedure, understanding more about whether it reduces complications and improves the function of patients who undergo these resections and reconstructions would be valuable for patients and treating physicians. QUESTIONS/PURPOSES: In an analysis of children with bone sarcomas of the femur who underwent an intercalary resection and reconstruction with massive bone allograft with or without a vascularized free fibula, we asked: (1) What was the difference in the surgical time of these two different surgical techniques? (2) What are the complications and number of reoperations associated with each procedure? (3) What were the Musculoskeletal Tumor Society scores after these reconstructions? (4) What was the survival rate of these two different reconstructions? METHODS: Between 1994 and 2016, we treated 285 patients younger than 16 years with a diagnosis of osteosarcoma or Ewing sarcoma of the femur. In all, 179 underwent resection and reconstruction of the distal femur and 36 patients underwent resection and reconstruction of the proximal femur. Additionally, in 70 patients with diaphyseal tumors, we performed total femur reconstruction in four patients, amputation in five, and a rotationplasty in one. The remaining 60 patients with diaphyseal tumors underwent intercalary resection and reconstruction with massive bone allograft with or without vascularized free fibula. The decision to use a massive bone allograft with or without a vascularized free fibula was probably influenced by tumor size, with the indication to use the vascularized free fibula in longer reconstructions. Twenty-seven patients underwent a femur reconstruction with massive bone allograft and vascularized free fibula, and 33 patients received massive bone allograft alone. In the group with massive bone allograft and vascularized fibula, two patients were excluded because they did not have the minimum data for the analysis. In the group with massive bone allograft alone, 12 patients were excluded: one patient was lost to follow-up before 2 years, five patients died before 2 years of follow-up, and six patients did not have the minimum data for the analysis. We analyzed the remaining 46 children with sarcoma of the femur treated with intercalary resection and biological reconstruction. Twenty-five patients underwent femur reconstruction with a massive bone allograft and vascularized free fibula, and 21 patients had reconstruction with a massive bone allograft alone. In the group of children treated with massive bone allograft and vascularized free fibula, there were 17 boys and eight girls, with a mean ± SD age of 11 ± 3 years. The diagnosis was osteosarcoma in 14 patients and Ewing sarcoma in 11. The mean length of resection was 18 ± 5 cm. The mean follow-up was 117 ± 61 months. In the group of children treated with massive bone allograft alone, there were 13 boys and eight girls, with a mean ± SD age of 12 ± 2 years. The diagnosis was osteosarcoma in 17 patients and Ewing sarcoma in four. The mean length of resection was 15 ± 4 cm. The mean follow-up was 130 ± 56 months. Some patients finished clinical and radiological checks as the follow-up exceeded 10 years. In the group with massive bone allograft and vascularized free fibula, four patients had a follow-up of 10, 12, 13, and 18 years, respectively, while in the group with massive bone allograft alone, five patients had a follow-up of 10 years, one patient had a follow-up of 11 years, and another had 13 years of follow-up. In general, there were no important differences between the groups in terms of age (mean difference 0.88 [95% CI -0.6 to 2.3]; p = 0.26), gender (p = 0.66), diagnosis (p = 0.11), and follow up (mean difference 12.9 [95% CI-22.7 to 48.62]; p = 0.46). There was a difference between groups regarding the length of the resection, which was greater in patients treated with a massive bone allograft and vascularized free fibula (18 ± 5 cm) than in those treated with a massive bone allograft alone (15 ± 4 cm) (mean difference -3.09 [95% CI -5.7 to -0.4]; p = 0.02). Complications related to the procedure like infection, neurovascular compromise, and graft-related complication, such as fracture and nonunion of massive bone allograft or vascularized free fibula and implant breakage, were analyzed by chart review of these patients by an orthopaedic surgeon with experience in musculoskeletal oncology. Survival of the reconstructions that had no graft or implant replacement was the endpoint. The Kaplan-Meier test was performed for a survival analysis of the reconstruction. A p value less than 0.05 was considered significant. RESULTS: The surgery was longer in patients treated with a massive bone allograft and vascularized free fibula than in patients treated with a massive bone allograft alone (10 ± 0.09 and 4 ± 0.77 hours, respectively; mean difference -6.8 [95% CI -7.1 to -6.4]; p = 0.001). Twelve of 25 patients treated with massive bone allograft and vascularized free fibula had one or more complication: allograft fracture (seven), nonunion (four), and infection (four). Twelve of 21 patients treated with massive bone allograft alone had the following complications: allograft fracture (five), nonunion (six), and infection (one). The mean functional results were 26 ± 4 in patients with a massive bone allograft and vascularized free fibula and 27 ± 2 in patients with a massive bone allograft alone (mean difference 0.75 [95% CI -10.6 to 2.57]; p = 0.39). With the numbers we had, we could not detect a difference in survival of the reconstruction between patients with a massive bone allograft and free vascularized fibula and those with a massive bone allograft alone (84% [95% CI 75% to 93%] and 87% [95% CI 80% to 94%], respectively; p = 0.89). CONCLUSION: We found no difference in the survival of reconstructions between patients treated with a massive bone allograft and vascularized free fibula and patients who underwent reconstruction with a massive bone allograft alone. Based on this experience, our belief is that we should reconstruct these femoral intercalary defects with an allograft alone and use a vascularized fibula to salvage the allograft only if a fracture or nonunion occurs. This approach would have resulted in about half of the patients we treated not undergoing the more invasive, difficult, and risky vascularized procedure.Level of Evidence Level III, therapeutic study.

Minimally invasive aortic valve surgery in obese patients: Can the bigger afford the smaller?

BACKGROUND: Ministernotomy and right minithoracotomy are well-known minimally invasive approaches for aortic valve replacement (AVR); however, controversial opinions exist for their utilization in obese patients. The aim of this study is to check a potential positive role of minimally invasive surgery in this population. METHODS: From January 2010 to November 2019, 613 obese patients (defined by a body mass index ≥30) underwent isolated AVR at our institution. Surgical approach included standard median sternotomy (176 patients), partial upper sternotomy (271 patients), or right anterior minithoracotomy (166 patients). Intra- and postoperative data were retrospectively collected. RESULTS: Patients treated with minimally invasive approaches had shorter cardiopulmonary bypass time (p = .012) and aortic cross-clamp time (p = .022), mainly due to the higher utilization of sutureless valve implantation. They also presented advantages in terms of reduced postoperative ventilation time (p = .010), incidence of wound infection (p = .009), need of inotropic support (p = .004), and blood transfusion (p = .001). The univariable logistic regression showed the traditional full sternotomy approach as compared with ministernotomy (p = .026), active smoking (p = .009), peripheral vascular disease (p = .003), ejection fraction (p = .026), as well Logistic European system for cardiac operative risk evaluation (EuroSCORE; p = .015) as factors associated with hospital mortality. The multivariable logistic regression adjusted for the logistic EuroSCORE revealed that surgical approaches do not influence hospital mortality. CONCLUSIONS: Obese patients with severe aortic valve pathology can be treated with minimally invasive approaches offering a less biological insult and reduced postoperative complications, but without impact on hospital mortality.

Resurfaced allograft-prosthetic composite for distal femur reconstruction in children with bone tumor.

INTRODUCTION: Reconstruction of the distal femur in children following resection of bone sarcoma is challenging. The main problem in children is the small size of bone and a possible limb-length discrepancy at the end of skeletal growth secondary to the loss of the physes. We reported the results of a new surgical technique for distal femur reconstruction after bone tumor resection in children. MATERIAL AND METHODS: We analyzed 5 patients with distal femoral sarcomas who underwent intra-articular resection and reconstruction with resurfaced allograft-prosthetic composite at a mean follow-up of 70 months. There were 2 males and 3 females, with a mean age of 10 years (range 8-12) at the time of the diagnosis. All patients were affected by high-grade osteosarcoma. The patients' medical records were reviewed for clinical and functional outcomes as well as post-operative complications. The functional evaluation of the patients was done at the end of the follow-up using Musculoskeletal Tumor Society scoring system. The minimal follow-up was 24 months. RESULTS: At the last follow-up, 4 patients were continuously disease-free. We excluded one patient who died of disease secondary to lung metastases 16 months after the surgery. Complications occurred in 2 of 4 patients at 17 months and 24 months, respectively. One patient developed deep infection who required the removal of the original reconstruction and, once the infection was treated, the patient underwent reconstruction with an expandable prosthesis. An allograft fracture occurred in another of the 4 patients at 24 months after the first surgery, thus the original reconstruction was removed and the patient underwent reconstruction with modular prosthesis. In the two patients who retained the original reconstruction at the time of their latest follow-up, the mean implant survival time was 70 months. These patients had an excellent MSTS score (29.5 points) and walked without support or limitations with an active knee range of motion of > 90° and complete active extension of the knee. No degenerative changes of the articular surface of the proximal tibia and the patella were observed at the time of the last follow-up. Growth of the physis of the proximal tibia was observed in all the patients during follow-up and no angular deformity of the joint was observed. The limb discrepancy was 4 cm and 2 cm, respectively. CONCLUSIONS: Resurfaced allograft-prosthetic composite may represent an alternative surgical technique for distal femur reconstruction in children with bone sarcomas. Although its success is limited by high risk of complications, resurfaced allograft-prosthetic composite seems to be a viable option to preserve the bone stock and the physis of the proximal tibia in selected young patients, minimizing a potential limb-length discrepancy at the end of the skeletal growth.

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.

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease.

Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery.

BACKGROUND: Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. METHODS: To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases. RESULTS: A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E-AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression. CONCLUSIONS: These findings indicate that aneuploidy-related and leukemia-specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.

Stanmore noninvasive extendible endoprosthesis in the treatment of bone sarcoma in the preadolescent.

AIMS: The aim of this study is to assess outcomes of patients ≤12 years who undergo Stanmore noninvasive extendible endoprosthetic replacement of the distal femur (DF NIEPR). PATIENTS AND METHODS: A total of 101 children (mean age 9.6 years) were included. All complications which required further surgery were recorded. Clinical and functional outcomes were evaluated with Musculoskeletal Tumor Society (MSTS) scores at a mean follow-up of 64 months (range 6-174). RESULTS: Thirty-one (30.7%) patients died at a mean of 33 months. Forty had prosthesis removed after a mean of 43 months (range, 7-103). Attaining of the full lengthening potential before skeletal maturity was the most frequent reason for revision surgery, particularly in those with smaller lengthening potential (P = 0.039). Implant survival rate for other causes was 61.7% at 5 years and 45.0% at 10 years. At final follow-up mean MSTS score was 26 (range, 13-29). Twenty-two (21.5%) patients had a final limb-length discrepancy (LLD) > 2 cm. CONCLUSIONS: DF NIEPR produces a good functional outcome, with the prevention of major LLD at skeletal maturity in the majority of the cases. We suggest patient selection criteria to account for the stage of the disease due to the high cost of the NIEPR, and high percentage requiring revision, and a 60% mortality rate in those patients presenting with distant disease burden.

Innovative Biomaterials for Bone Regrowth.

The regenerative medicine, a new discipline that merges biological sciences and the fundamental of engineering to develop biological substitutes, has greatly benefited from recent advances in the material engineering and the role of stem cells in tissue regeneration. Regenerative medicine strategies, involving the combination of biomaterials/scaffolds, cells, and bioactive agents, have been of great interest especially for the repair of damaged bone and bone regrowth. In the last few years, the life expectancy of our population has progressively increased. Aging has highlighted the need for intervention on human bone with biocompatible materials that show high performance for the regeneration of the bone, efficiently and in a short time. In this review, the different aspects of tissue engineering applied to bone engineering were taken into consideration. The first part of this review introduces the bone cellular biology/molecular genetics. Data on biomaterials, stem cells, and specific growth factors for the bone regrowth are reported in this review.

Microsurgical reconstruction with vascularized fibula and massive bone allograft for bone tumors.

INTRODUCTION: Combining massive bone allograft and vascularized fibula in intercalary reconstruction following resection of bone tumors represents a complex reconstructive procedure that requires specialists in microvascular surgery as well as orthopedic surgery. The purpose of our study was to examine the outcomes using this surgical technique in patients with bone tumors in terms of oncologic results, complications related to surgery, Musculoskeletal Tumor Society (MSTS) scores and duration of surgery. MATERIALS AND METHODS: We analyzed 81 patients with femoral or tibial sarcomas who underwent intercalary resection and microsurgical reconstruction with massive bone allograft and vascularized fibula. There were 56 boys and 25 girls with a mean age of 13.4 years at the time of surgery. The patients' medical records were reviewed for clinical and functional outcomes as well as postoperative complications. The study group was comprised of 33 patients who underwent reconstruction of the femur with massive bone allograft and free vascularized fibula and 48 patients who underwent reconstruction of the tibia with massive bone allograft and free or pedicle vascularized fibula. The mean length of resection was 15.9 cm (8-31 cm). The functional evaluation of the patients was done at the end of the follow-up using MSTS score for the lower limb. All patients had at least a 2-year follow-up. RESULTS: The overall limb salvage rate was 94%, although many patients required re-operation after the procedure. Complications occurred in 24 patients, 18 of which underwent additional surgical procedures. They included fractures of the massive bone allograft-vascularized fibula construct with or without implant failure (19) and deep infection (5). After surgical or conservative treatment, all the fractures successfully healed. The overall MSTS functional score was good to excellent in 91% of patients. CONCLUSIONS: The combination of massive bone allograft and vascularized fibula seems to be a reasonable option for reconstruction of diaphyseal defects following intercalary resection of bone tumors. Although there was a high rate of complications and therefore re-operations, the biology of vascularized fibula was able to save the reconstruction in most of the cases that had complications.

Serum IgG antibodies from healthy subjects up to 100 years old react to JC polyomavirus.

JC polyomavirus (JCPyV) was identified in 1971 in the brain tissue of a patient (J.C.) affected by the progressive multifocal leukoencephalopathy (PML). JCPyV encodes for the oncoproteins large T antigen (Tag) and small t-antigen (tag). These oncoproteins are responsible of the cell transformation and tumorigenesis in experimental animals. JCPyV is ubiquitous in human populations. After the primary infection, which is usually asymptomatic, JCPyV remains lifelong in the host in a latent phase. Its reactivation may occur in heathy subjects and immunocompromised patients. Upon reactivation, JCPyV could reach (i) the CNS inducing the PML, (ii) the kidney of transplant patients causing the organ rejection. Association between JCPyV, which is a small DNA tumor virus, and gliomas and colorectal carcinomas has been published. In the present investigation, we report on a new indirect ELISA with two specific synthetic peptides mimicking JCPyV VP1 immunogenic epitopes to detect specific serum IgG antibodies against JCPyV. Serum samples of healthy subjects (n = 355) ranging 2-100 years old, were analyzed by this new indirect ELISA. The linear peptides VP1 K and VP1 N resemble the natural JCPyV VP1 capsidic epitopes constituting a docking site for serum antibodies. Data from this innovative immunologic assay indicate that the overall prevalence of JCPyV-VP1 antibodies in healthy subjects is at 39%. The innovative indirect ELISA with JCPyV VP1 mimotopes seems to be a useful method to detect specific IgG antibodies against this virus, without cross-reactivity with the closely related SV40 and BKPyV polyomaviruses.

Human adipose stem cells induced to osteogenic differentiation by an innovative collagen/hydroxylapatite hybrid scaffold.

Novel biomaterials are of paramount importance for bone regrowth. In this study, we investigated human adipose stem cells (hASCs) for osteogenic, osteoconductivity, and osteoinductivity effects of an innovative collagen/hydroxylapatite hybrid scaffold. In hASCs that were grown on this scaffold, osteogenic genes were analyzed for their expression profiles, together with adhesion and extracellular matrix genes. In hASC integrins, basement membrane constituents and collagens were up-regulated, together with cell proliferation. In addition, expression of osteopontin and activated focal adhesion kinase was studied at the protein level. Our in vitro data indicate that hASCs, together with hybrid biomaterial, is an important model of study to investigate in vitro bone induction.-Mazzoni, E., D'Agostino, A., Manfrini, M., Maniero, S., Puozzo, A., Bassi, E., Marsico, S., Fortini, C., Trevisiol, L., Patergnani, S., Tognon, M. Human adipose stem cells induced to osteogenic differentiation by an innovative collagen/hydroxylapatite hybrid scaffold.

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.