A 3D-printed load sharing implant achieved union of a 9-cm femoral segmental bone defect within three months using a hybrid Masquelet induction membrane technique. A case-report.

Case: A 30-year-old male was admitted in our hospital having an open left distal femoral fracture with 9-cm segmental bone defect and a closed proximal left tibial fracture. He was treated successfully using a Hybrid (Titanium Cage and Bone Graft) Masquelet Induction Membrane Technique (MIMT). His femoral fracture united 3-months post - operatively. The left tibia was treated initially with two locking plates. Following infection, a 3-cm tibial bone gap was treated with external fixation and conventional MIMT. The tibial fracture united 12-months post- operatively. Conclusion: The Hybrid MIMT achieved a successful healing outcome in this challenging case.

Treatment and Rehabilitation Approaches for Stress Fractures in Long-Distance Runners: A Literature Review.

Stress fractures (SFs) result from repetitive mechanical stress on bones, leading to an imbalance in osseous tissue adaptation and resulting in cortical fractures. The majority of SFs occur in the lower limb due to excessive mechanical loads. Long-distance runners are highly susceptible to SFs, especially when there is a significant increase in the load or intensity of their activity. Various intrinsic and extrinsic factors contribute to the development of SFs. Common SF locations in long-distance runners include the tibial shaft, femur, metatarsal, and pelvic region. Diagnosis may be delayed due to mild symptoms and unremarkable imaging tests. However, the chronicity and recurrence of misdiagnosed SFs may lead to debilitating complete fractures that are even more challenging to treat. In this review, we present data revealed from published case reports and case series studies obtained through PubMed and Embase databases focusing on the management of SFs in long-distance runners and correlate treatment outcomes with rehabilitation and return to high-level athletic performance.

Impact of Preoperative Quality of Life and Related Factors on the Development of Surgical Site Infections Following Primary Total Joint Arthroplasty: A Prospective Case-Control Study with a Five-Year Follow-Up.

Introduction: As surgical site infections (SSIs) after joint arthroplasty contribute to increased morbidity and mortality, they require further surgical intervention, prolonged hospitalisation, and antimicrobial treatment. The aim of our study is to examine the association between preoperative quality of life (QoL) and other predictive factors on the development of SSIs after primary arthroplasty. Methods: This is a prospective study that enrolled 56 patients with hip and knee primary osteoarthritis who underwent joint replacement. Data were collected from January to March 2017, including patient demographic characteristics, comorbidities, laboratory results, and perioperative clinical data. The patients' QoL was evaluated preoperatively by applying the knee injury and osteoarthritis outcome score (KOOS) and the hip disability and osteoarthritis outcome score (HOOS) for total knee replacement (TKR) and total hip replacement (THR), respectively. A 5-year follow-up was conducted to assess the clinical status of the patients. Results: 66.1% of patients underwent TKR, with 4.9 ± 1.2 days of hospitalisation, 16% of them required autologous blood transfusion, while 33.9% of patients were treated with THR, with 5.7 ± 1 days hospitalisation and 36.8 of them required this type of transfusion. 16 patients were diagnosed with SSIs, with the older of them (>65 years old) presenting lower probability (odds ratio: 0.13, 95% CI: 0.03-0.62) requiring treatment with additional antibiotics, while revision surgery was performed in 3 of these cases, following periprosthetic joint infection (PJI). Overall preoperative QoL was not statistically associated with SSIs, but low QoL scores were associated with higher rates of SSIs and increased levels of postoperative pain (p = 0.009 < 0.05). Conclusions: The duration of each operation (>90 min), the length of hospitalisation (>4 days), and the presence of comorbidities including hypothyroidism and recurrent urinary tract infections were associated with a high risk for SSIs following arthroplasties. On the contrary, this study revealed no association between other comorbidities, including heart coronary disease, hypertension, and diabetes mellitus, with close monitoring of plasma glucose and SSIs. Moreover, the younger the patients, the more likely they were to require treatment with antibiotics. Overall, high QoL index scores were mainly accompanied by low rates of postoperative SSIs and pain.

Subchondral Bone Cyst Development in Osteoarthritis: From Pathophysiology to Bone Microarchitecture Changes and Clinical Implementations.

Osteoarthritis is a degenerative joint disease affecting middle-aged and elderly patients. It mainly involves weight-bearing joints such as the hip, knee and spine as well as the basilar joint of the thumb, causing dysfunction and painful symptoms. Often, joint arthritis is accompanied by cartilage defects, joint space narrowing, osteophytes, bone sclerosis and subchondral bone cysts (SBC). The aim of the present study was to explore the pathophysiology responsible for the development of SBCs as well as the association between SBCs and disease progress, the level of clinical symptoms and their impact on postoperative outcomes and risk of possible complications following joint replacements if left untreated. A literature review on PubMed articles was conducted to retrieve and evaluate all available evidence related to the main objective mentioned above. A few theories have been put forth to explain the formation process of SBCs. These involve MMPs secretion, angiogenesis, and enhanced bone turnover as a biological response to abnormal mechanical loads causing repeated injuries on cartilage and subchondral tissue during the development of arthritis. However, the application of novel therapeutics, celecoxib-coated microspheres, local administration of IGF-1 and activated chondrocytes following surgical debridement of SBCs hinders the expansion of SBCs and prevents the progression of osteoarthritis.

Pleomorphic Liposarcoma Revisited.

Pleomorphic liposarcoma (PLPS) is the rarest and more aggressive subtype of liposarcomas, accounting for 10% of all liposarcomas. The diagnosis should be considered after the detection of multivacuolated pleomorphic lipoblasts in biopsy specimens. Wide-margin resection is the treatment of choice. Complementary treatment options, such as radiation therapy and chemotherapy, are debatable in terms of their contribution to curing patients with PLPS. This article reviews the clinical, histopathological, and molecular characteristics of PLPS and discusses the latest trends in the management, therapeutic strategies, and novel investigations of the subject. [Orthopedics. 2023;46(2):e72-e80.].

Intramedullary Nailing of Concurrent Bilateral Tibial Stress Fractures Followed by Unilateral Tension Plating for a Nonunion in a Vitamin D-Deficient Elite Football Player.

Stress fractures consist of a type of bone fracture that occurs due to repetitive mechanical stress instead of acute forceful injuries that cause common fractures. They are quite common among athletes at all competition levels and in army recruits who are expected to undergo extremely demanding exercises. While stress fractures can occur in any long bone, they are usually associated with the most common weight-bearing sites of lower extremities such as phalanges, metatarsals, tarsal bones, the tibia, and fibula. In this study, we report the surgical management of a 23-year-old African football player who sustained concurrent bilateral anterior cortex tibial midshaft fractures. His initial symptom was persistent subacute pain in both tibias. The initial conservative treatment was not successful and the patient was surgically treated with bilateral tibial intramedullary nails. However, the right tibia subsequently developed nonunion. Both intramedullary nails were removed and a tension plate was applied with an autologous iliac crest graft on the right tibia. Further blood test analysis revealed a significant vitamin D deficiency. The purpose of this article is to report different outcomes of the same primary surgical treatment for concurrent bilateral tibia stress fracture syndrome in an elite athlete due to vitamin D deficiency. To our knowledge, this is the first study that highlights the necessity of revising one of the intramedullary nailed concurrent tibia stress fractures with a tension plate and autologous graft to treat the established nonunion in an elite football player.

Doxycycline inhibits the progression of metastases in early-stage osteosarcoma by downregulating the expression of MMPs, VEGF and ezrin at primary sites.

INTRODUCTION: Osteosarcoma (OS) is the most common primary osseous malignant tumour, with high propensity to metastasise in lungs. Pulmonary micro-metastases are present in up to 80% of patients at initial diagnosis and they are associated with significantly worse prognosis. Doxycycline (Dox) is a synthetic tetracycline that has been shown to have anti-cancer properties in vitro and in vivo, and inhibit angiogenesis - effects that may prove beneficial for several types of cancer. The aim of the present work was to study how Dox affects OS cell growth in vitro and in vivo and OS-driven pulmonary metastasis in vivo. METHODS: In vitro, the effect of Dox was measured in MG-63 and 143B human OS cell viability, apoptosis, invasion and migration. In vivo, highly metastatic 143B cells were orthotopically implanted into the tibia of SCID mice. The tumour growth and pulmonary metastases between Dox treated and untreated, non-amputated and early amputated xenografts were examined. RESULTS: In vitro, Dox decreased viability, inhibited invasion, migration, and induced the apoptosis of OS cells. In vivo, Dox significantly enhanced tumour necrosis at primary OS sites, similarly to its in vitro effect, and downregulated the expression of Ki67, MMP2, MMP9, VEGFA and ezrin. It also decreased circulating VEGFA and MMP9 protein levels, in line with the decreased metastatic burden in Dox-treated mice (non-amputated and early-amputated). CONCLUSIONS: Reprofiling of Dox can prevent the evolvement of pulmonary micro-metastases to clinically detectable macro-metastases and suppress the lethal progress of OS by inhibiting the expression of MMPs, VEGFA and ezrin at primary sites.

Sonication of revised hip and knee prostheses detects occult infections, improves clinical outcomes and prevents re - revisions. A case series study.

Introduction: Periprosthetic joint infection (PJI) is a devastating complication occurring in 1-2% of primary and up to 10% of revised total hip and knee arthroplasties (THA and TKA) impairing patient's quality of life. Occult infections are underdiagnosed, sub-treated and sub-clinically experienced by patients. This study aimed to correlate patients' clinical outcomes with early antibiotic treatment based on use or non-use of a sonication technique on explanted prostheses. Methods: 33 patients with revised THA or TKA were retrospectively evaluated. Clinical outcomes were assessed via Oxford hip or knee scores, and correlated with administration or not of antibiotic treatment based on sonication results. Results: According to laboratory findings the patients were divided in the following three groups: 1. Septic loosening (conventional cultures and/or sonication positive), 2. Aseptic loosening (conventional cultures and sonication negative) and 3. Occult loosening (conventional cultures negative, sonication not performed). The average Oxford score was poor (27.9/60) for the septic, excellent (43.8/60) for the aseptic and intermediate (37.7/60) for the occult group. Additionally, conventional cultures were negative, but sonication-positive, in 6 individuals with patient-related risk factors (male gender, BMI > 30 kg/m2, diabetes, hypertension, steroids and rheumatoid arthritis). Conclusions: Sonication represents a valuable diagnostic technique to guide administration of effective antibiotic treatment for patients, especially for detection of persistent post-revision occult infections. We recommend the systematic investigation of revised prostheses with a sonication technique, but especially in cases with risk factors for infection who it is suspected may have occult loosening.

Therapeutic Efficacy and Safety of Osteoinductive Factors and Cellular Therapies for Long Bone Fractures and Non-Unions: A Meta-Analysis and Systematic Review.

BACKGROUND: Long bone fractures display significant non-union rates, but the exact biological mechanisms implicated in this devastating complication remain unclear. The combination of osteogenetic and angiogenetic factors at the fracture site is an essential prerequisite for successful bone regeneration. The aim of this study is to investigate the results of the clinical implantation of growth factors for intraoperative enhancement of osteogenesis for the treatment of long bone fractures and non-unions. METHODS: A systematic literature review search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed and Web of Science databases from the date of inception of each database through to 10 January 2022. Specific inclusion and exclusion criteria were applied in order to identify relevant studies reporting on the treatment of upper and lower limb long bone non-unions treated with osteoinductive or cellular factors. RESULTS: Overall, 18 studies met the inclusion criteria and examined the effectiveness of the application of Bone Morphogenetic Proteins-2 and -7 (BMPs), platelet rich plasma (PRP) and mesenchymal stem cells (MSCs). Despite the existence of limitations in the studies analysed (containing mixed groups of open and close fractures, different types of fractures, variability of treatment protocols, different selection criteria and follow-up periods amongst others), their overall effectiveness was found significantly increased in patients who received them compared with the controls (I2 = 60%, 95% CI = 1.59 [0.99-2.54], Z =1.93, p = 0.05). CONCLUSION: Administration of BMP-2 and -7, PRP and MSCs were considered effective and safe methods in fracture treatment, increasing bone consolidation, reducing time to repair and being linked to satisfactory postoperative functional scores.

The EPH/Ephrin System in Bone and Soft Tissue Sarcomas' Pathogenesis and Therapy: New Advancements and a Literature Review.

Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell-cell and cell-substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas.

Ray Resection as a Personalized Surgical Technique for Progressive Hand Macrodactyly in a 60-Year-Old Patient: A Case Report and Literature Review.

Hand macrodactyly is a very scarce deformity. It was first described over 200 years ago and was characterized as "local gigantism" of one or multiple digits. Benign bone overgrowth, massive increase of soft tissue volume, and nerve involvement are associated with hand macrodactyly have been consistently reported in the literature. Often, macrodactyly affects one or more digits and is further classified as static or progressive, depending on the growth pattern, and as sporadic or syndromic, according to its genetic predisposition. Surgical treatment for hand macrodactyly remains a complex issue even for expert hand surgeons. In most of the cases, macrodactyly is diagnosed during early childhood and can be appropriately managed with minimal and well affordable surgical approaches that stabilize its fast progression. However, adults with progressive hand macrodactyly develop advanced deformities leading to severe functional deterioration and aesthetic hand dysmorphia. The purpose of this report is to document the management and surgical approach of the oldest published case, a 60-year-old adult patient with neglected progressive hand macrodactyly despite previous surgical attempts for disease stabilization. A personalized preoperative planning was created, which included ray resection involving the fourth metacarpal and fourthfinger along with extensive debulking of the overgrown fatty soft tissue and carpal tunnel release. At six months' follow-up, the patient reported an excellent aesthetic and functional outcome.

Current Aspects on the Pathophysiology of Bone Metabolic Defects during Progression of Scoliosis in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1), which is the most common phacomatoses, is an autosomal dominant disorder characterized by clinical presentations in various tissues and organs, such as the skin, eyes and nervous and skeletal systems. The musculoskeletal implications of NF1 include a variety of deformities, including scoliosis, kyphoscoliosis, spondylolistheses, congenital bony bowing, pseudarthrosis and bone dysplasia. Scoliosis is the most common skeletal problem, affecting 10-30% of NF1 patients. Although the pathophysiology of spinal deformities has not been elucidated yet, defects in bone metabolism have been implicated in the progression of scoliotic curves. Measurements of Bone Mineral Density (BMD) in the lumbar spine by using dual energy absorptiometry (DXA) and quantitative computer tomography (QCT) have demonstrated a marked reduction in Z-score and osteoporosis. Additionally, serum bone metabolic markers, such as vitamin D, calcium, phosphorus, osteocalcin and alkaline phosphatase, have been found to be abnormal. Intraoperative and histological vertebral analysis confirmed that alterations of the trabecular microarchitecture are associated with inadequate bone turnover, indicating generalized bone metabolic defects. At the molecular level, loss of function of neurofibromin dysregulates Ras and Transforming Growth factor-ß1 (TGF-ß1) signaling and leads to altered osteoclastic proliferation, osteoblastic activity and collagen production. Correlation between clinical characteristics and molecular pathways may provide targets for novel therapeutic approaches in NF1.

Liquid Biopsy: A New Translational Diagnostic and Monitoring Tool for Musculoskeletal Tumors.

Soft tissue and bone sarcomas represent a group of aggressive neoplasms often accompanied by dismal patient prognosis, especially when distant metastases are present. Moreover, effective treatment can pose a challenge, as recurrences are frequent and almost half of patients present with advanced disease. Researchers have unveiled the molecular abnormalities implicated in sarcomas' carcinogenesis, paving the way for novel treatment strategies based on each individual tumor's characteristics. Therefore, the development of new techniques aiding in early disease detection and tumor molecular profiling is imperative. Liquid biopsy refers to the sampling and analysis of patients' fluids, such as blood, to identify tumor biomarkers, through a variety of methods, including qRT-PCR, qPCR, droplet digital PCR, magnetic microbeads and digital PCR. Assessment of circulating tumor cells (CTCs), circulating free DNA (ctDNA), micro RNAs (miRs), long non-coding RNAs (lncRNAs), exosomes and exosome-associated proteins can yield a plethora of information on tumor molecular signature, histologic type and disease stage. In addition, the minimal invasiveness of the procedure renders possible its wide application in the clinical setting, and, therefore, the early detection of the presence of tumors. In this review of the literature, we gathered information on biomarkers assessed through liquid biopsy in soft tissue and bone sarcoma patients and we present the information they can yield for each individual tumor type.

The anti-neoplastic effect of doxycycline in osteosarcoma as a metalloproteinase (MMP) inhibitor: a systematic review.

BACKGROUND: Osteosarcoma is a very aggressive primary bone tumour, affecting mainly young populations. Most cases diagnosed have distant macro- and micro-metastases at the time of diagnosis. Surgical resection with neoadjuvant and adjuvant therapies improves the overall and disease-free survival of patients. Doxycycline, a synthetic tetracycline, has been found to act either as an antibiotic drug or as a chemotherapeutic agent. Its anti-neoplastic role has been found to be significant, in vitro and in vivo laboratory trials, in various types of cancer, such as prostate, intestinal, central neural system cancers and osteosarcoma. Inhibition of metalloproteinases (MMPs) in different stages of tumour expansion is the most well-understood mechanism. MMPs are secreted molecules from various normal cells, such as fibroblasts, leucocytes and vascular smooth muscles, as well as from cells with high proliferative potential, such as tumour cells. In osteosarcoma, MMPs have been found to be overexpressed. MMPs help osteosarcoma cells survive, grow and produce metastases in distant sites, mainly in the lungs. Doxycycline blocks extracellular matrix and basic membrane degradation by suppressing MMP function. As a consequence, osteosarcoma cells lose their ability to invade and metastasize. Additionally, doxycycline eliminates the secretion of vascular endothelial growth factor (VEGF) and deprives the supply of circulating nutrients by its anti-angiogenesis action. The aim of this review is to evaluate doxycycline's action against osteosarcoma cells as an MMP-inhibitor and interpret its usage as a chemotherapeutic agent. METHODS: We checked PubMed and Google Scholar for recently published data, on the tumour-supportive role of MMPs and VEGF in osteosarcoma cells. We further studied published experimental trials on the role of doxycycline as a tumour-suppressive agent via MMPs and VEGF inhibition. RESULTS: MMPs and VEGF have been found to play a fundamental role in osteosarcoma cells survival and high aggressiveness by in vitro, in vivo and clinical trials. Nevertheless, doxycycline has proved its tumour-suppressive effect by in vivo experimental trials in various cancers but not yet in osteosarcoma. CONCLUSION: Doxycycline remains a promising chemotherapeutic agent against osteosarcoma via MMP inhibition, showing the need for further in vivo and clinical trials to be carried out in the future.