Muscle transcriptomic circuits linked to periarticular physiology in end-stage osteoarthritis.

The ability of individuals with end-stage osteoarthritis (OA) to functionally recover from total joint arthroplasty is highly inconsistent. The molecular mechanisms driving this heterogeneity have yet to be elucidated. Furthermore, OA disproportionately impacts females, suggesting a need for identifying female-specific therapeutic targets. We profiled the skeletal muscle transcriptome in females with end-stage OA (n = 20) undergoing total knee or hip arthroplasty using RNA-Seq. Single-gene differential expression (DE) analyses tested for DE genes between skeletal muscle overlaying the surgical (SX) joint and muscle from the contralateral (CTRL) leg. Network analyses were performed using Pathway-Level Information ExtractoR (PLIER) to summarize genes into latent variables (LVs), i.e., gene circuits, and link them to biological pathways. LV differences in SX versus CTRL muscle and across sources of muscle tissue (vastus medialis, vastus lateralis, or tensor fascia latae) were determined with ANOVA. Linear models tested for associations between LVs and muscle phenotype on the SX side (inflammation, function, and integrity). DE analysis revealed 360 DE genes (|Log2 fold-difference| ≥ 1, FDR ≤ 0.05) between the SX and CTRL limbs, many associated with inflammation and lipid metabolism. PLIER analyses revealed circuits associated with protein degradation and fibro-adipogenic cell gene expression. Muscle inflammation and function were linked to an LV associated with endothelial cell gene expression highlighting a potential regulatory role of endothelial cells within skeletal muscle. These findings may provide insight into potential therapeutic targets to improve OA rehabilitation before and/or following total joint replacement.

Evaluation of fluorescence-guided surgery agents in a murine model of soft tissue fibrosarcoma.

BACKGROUND AND OBJECTIVES: Soft tissue sarcomas (STS) are mesenchymal malignancies. Treatment mainstay is surgical resection with negative margins ± adjuvant treatment. Fluorescence-guided surgical (FGS) resection can delineate intraoperative margins; FGS has improved oncologic outcomes in other malignancies. This novel strategy may minimize resection-associated morbidity while improving local tumor control. METHODS: We evaluate the tumor-targeting specificity and utility of fluorescence-imaging agents to provide disease-specific contrast. Mice with HT1080 fibrosarcoma tumors received one of five probes: cetuximab-IRDye800CW (anti-EGFR), DC101-IRDye800CW (anti-VEGFR-2), IgG-IRDye800CW, the cathepsin-activated probe Prosense750EX, or the small molecule probe IntegriSense750. Tumors were imaged daily using open- and closed-field fluorescence imaging systems. Tumor-to-background ratios (TBR) were evaluated. On peak TBR days, probe sensitivity was evaluated. Tumors were stained and imaged microscopically. RESULTS: At peak, closed-field imaging TBR of cetuximab-IRDye800CW (16.8) was significantly greater (P < 0.0001) than Integrisense750 (7.0), Prosense750EX (5.8), and DC101-IRDye800CW (3.7). All agents successfully localized as little as 1.0 mg of tumor tissue in the post-resection bed; cetuximab-IRDye800CW generated the greatest contrast (2.5). Cetuximab-IRDye800CW revealed strong tumor affinity microscopically; tumor fluorescence intensity was significantly greater (P < 0.0004) than 0.2 mm away from tumor border. CONCLUSION: This study demonstrates cetuximab-IRDye800CW superiority. FGS has the potential to improve post-resection morbidity and mortality by improving disease detection.

NCCN Guidelines Insights: Bone Cancer, Version 2.2017.

The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.

Silver negative pressure dressing with vacuum-assisted closure of massive pelvic and extremity wounds.

BACKGROUND: Massive soft tissue loss involving the pelvis and extremities from trauma, infections, and tumors remains a challenging and debilitating problem. Although vacuum-assisted closure (VAC) technology is effective in the management of soft tissue loss, the adjunct of a silver dressing in the setting of massive wounds has not been as well tested. QUESTIONS/PURPOSES: Does a silver negative pressure dressing used in conjunction with a wound VAC decrease (1) the length of acute hospital stay and overall length of treatment; (2) the number of surgical débridements the patients underwent as part of their care; and (3) the likelihood of wound closure without soft tissue transposition? METHODS: We evaluated 42 patients with massive (> 200 cm(2)) pelvic and extremity wounds from trauma, infection, or tumor who were treated with the wound VAC with or without a silver negative pressure dressing between January 2003 and January 2010; the first 26 patients were treated with the wound VAC alone, and in the final 16 consecutively treated patients, the silver dressing was added to the regimen. We reviewed medical records to determine length of treatment as well as the number and type of surgical interventions these patients underwent. We compared the group treated with the wound VAC alone with those patients treated with the wound VAC and silver negative pressure dressing. RESULTS: Hospital stay averaged 19 days in the VAC only group and 7.5 days in the VAC with silver dressing group (p < 0.041), length of overall treatment averaged 33 days in the VAC only group and 14.3 days in the VAC with silver dressing group (p < 0.022), number of operative débridements averaged 7.9 in the VAC alone group and 4.1 in the VAC with silver dressing group (p < 0.001), and success of wound closure without soft tissue transposition was 16 of 26 patients in the VAC alone group and three of 16 patients in the VAC with silver dressing group (p < 0.033). CONCLUSIONS: Based on the reduced length of care and the number of surgical procedures these patients with massive wounds of the pelvis and extremities underwent, we now use the silver negative pressure dressing in combination with the wound VAC as part of routine care of such patients. These results may be used as hypothesis-generating data for future randomized studies. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Bone cancer.

Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma.

Intravenous tranexamic acid decreases intraoperative transfusion requirements and does not increase incidence of symptomatic venous thromboembolic events in musculoskeletal sarcoma surgery.

BACKGROUND AND OBJECTIVES: Tranexamic acid (TXA) is poorly studied in patients with bone and musculoskeletal sarcoma due to perceived increased risk of venous thromboembolism (VTE). This study aims to assess the safety and efficacy of intravenous (IV) TXA for patients undergoing surgical resection of primary bone or soft-tissue sarcoma. METHODS: A retrospective, single center review of adult patients with pelvic or extremity sarcoma who underwent surgical resections between January 2005 and March 2020 was performed. Patients between 2005 and 2012 were included as a historical comparison prior to the routine use of IV TXA for all sarcoma resections at our institution. RESULTS: Thirty-nine non-TXA and 59 TXA resections were identified. Two non-TXA patients experienced symptomatic pulmonary embolism compared to zero VTEs amongst TXA patients. IV TXA administered at any dose significantly reduced the probability of intraoperative transfusion (p = 0.003) and the median units of blood transfused at the time of any perioperative transfusion (p = 0.007). Intraoperative times were significantly shorter for TXA patients (128 vs 190 min; p = 0.004). A subset of patients who underwent wide resection with endoprosthetic reconstruction and received TXA similarly showed decreased requirement for intraoperative transfusion (p = 0.014) and decreased procedure times (p = 0.009). CONCLUSIONS: During sarcoma resection, at least 1 g of IV TXA can safely decrease the need for any intraoperative transfusion and the median number of PRBCs transfused by 2 units when any perioperative transfusion is given.

Perioperative assessment of muscle inflammation susceptibility in patients with end-stage osteoarthritis.

Many individuals with end-stage osteoarthritis (OA) undergo elective total hip/knee arthroplasty (THA/TKA) to relieve pain, improve mobility and quality of life. However, ∼30% suffer long-term mobility impairment following surgery. This may be in part due to muscle inflammation susceptibility (MuIS+), an overt proinflammatory pathology localized to skeletal muscle surrounding the diseased joint, present in some patients with TKA/THA. We interrogated the hypothesis that MuIS+ status results in a perturbed perioperative gene expression profile and decreases skeletal muscle integrity in patients with end-stage OA. Samples were leveraged from the two-site, randomized, controlled trial R01HD084124, NCT02628795. Participants were dichotomized based on surgical (SX) muscle gene expression of TNFRSF1A (TNF-αR). MuIS+/- samples were probed for gene expression and fibrosis. Paired and independent two-tailed t tests were used to determine differences between contralateral (CTRL) and surgical (SX) limbs and between-subject comparisons, respectively. Significance was declared at P < 0.05. Seventy participants (26M/44F; mean age 62.41 ± 8.86 yr; mean body mass index 31.10 ± 4.91 kg/m2) undergoing THA/TKA were clustered as MuIS+ (n = 24) or MuIS- (n = 46). Lower skeletal muscle integrity (greater fibrosis) exists on the SX versus CTRL limb (P < 0.001). Furthermore, MuIS+ versus MuIS- muscle exhibited higher proinflammatory (IL-6R and TNF-α) and catabolic (TRIM63) gene expression (P < 0.001, P = 0.004, and 0.024 respectively), with a trend for greater fibrosis (P = 0.087). Patients with MuIS+ exhibit more inflammation and catabolic gene expression in skeletal muscle of the SX limb, accompanied by decreased skeletal muscle integrity (Trend). This highlights the impact of MuIS+ status emphasizing the potential value of perioperative MuIS assessment to inform optimal postsurgical care.NEW & NOTEWORTHY This study assessed the skeletal muscle molecular characteristics associated with end-stage osteoarthritis and refined an important phenotype, in some patients, termed muscle inflammation susceptibility (MuIS+) that may be an important consideration following surgery. Furthermore, we provide evidence of differential inflammatory and catabolic gene expression between the contralateral and surgical limbs along with differences between the skeletal muscle surrounding the diseased hip versus knee joints.

Unplanned surgical excision of extremity soft tissue sarcomas: patient profile and referral patterns.

Unplanned surgical excision of sarcomas remains a major treatment dilemma in the control of local disease. The purpose of this study is to develop a patient profile to identify patients at high risk for an unplanned excision. The study group consisted of 54 patients following an unplanned excision of a soft tissue sarcoma. The characteristics that were identified as high risk included the following: 20- to 40-year age range,>5 cm, trauma, and deep to fascia. It was common for the interpretation of imaging studies not to mention the possibility of sarcoma in the differential diagnosis. Patient referral was most commonly from general surgeons without specialty training in oncology. Orthopaedic surgeons should not rely solely on the radiologist's interpretation because they often lack clinical information necessary to direct them toward the diagnosis of sarcoma. This is particularly important in patients who are at high risk for unplanned excision as identified in this study. Unplanned excisions by nononcologic surgeons remain a problem; however, it appears that it is more prevalent in the general surgical community than in orthopaedics. This may be as a result of studies addressing this issue in orthopaedic journals, with emphasis of these articles at teaching institutions.

Stabilization of pathologic long bone fractures with the Fixion expandable nail.

The Fixion intramedullary nail technology is safe and effective in the treatment of pathologic bone fractures.

Intracranial metastasis from synovial sarcoma.

Synovial sarcomas comprise between 5% to 10% of all soft tissue sarcomas in adults. It has a predilection for young adults and is one of the more frequently misdiagnosed soft tissue sarcomas. It is not unusual for synovial sarcoma to present initially after a traumatic event. It most commonly occurs in close proximity to a large joint. The most common site for metastasis is the lung, followed by lymph node involvement. Synovial sarcoma rarely metastasizes to the skeleton and when it occurs, it most commonly involves the long bones. Cranial metastasis is rare and has only been described in 2 previously reported cases. Reports of other sarcomas having intracranial metastasis include rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, Ewing's sarcoma, and clear cell sarcoma from the kidney. The synchronous or metachronous development of >or=2 primary soft tissue sarcomas has been reported. These are primary soft tissue sarcomas occurring at multiple soft tissue sites without pulmonary or lymphatic involvement. It is often difficult to distinguish between the synchronous or metachronous appearance of a second primary and soft tissue sarcoma metastasis. This article presents a case of a 17-year-old adolescent boy who presented with simultaneous enlarging masses involving the skull and thigh. Open biopsies confirmed synovial sarcoma in both regions. Staging studies, including computed tomography (CT) of his chest, abdomen/pelvis and bone scan were otherwise negative for metastasis.

The outcome of composite bone graft substitute used to treat cavitary bone defects.

Although autogenous bone graft remains the gold standard graft material, it is associated with an unacceptably high incidence of morbidity. Furthermore, operative time, blood loss, and length of hospitalization are often increased. In order for a graft substitute to replicate the optimal bone healing properties of autogenous graft, 3 essential elements must be present: scaffolding for osteoconduction, growth factors for osteoinduction, and progenitor cells for osteogenesis. A composite graft that combines a synthetic scaffold with osteoprogenitor cells from bone marrow aspirate (BMA) may potentially deliver the advantages of autogenous bone grafts without the procurement morbidity. Sixty consecutive patients with cavitary bone defects were treated with a composite of b-tricalcium phosphate (beta-TCP), Vitoss (Orthovita, Malvern, Pennsylvania), and BMA. The cavitary defects were measured on orthogonal views by experienced musculoskeletal radiologists. Radiographically, resorption and trabeculation increased steadily with time. This differential was slightly more noticeable in large defects with a central trabeculation occurring in advance of the peripheral region. The majority of patients progressed to unrestricted activities by 6 weeks and had returned to their usual activities by 12 weeks. No significant difference in graft incorporation rate was noted based on age, size of defect, or use of adjuvant local treatment. The use of a composite graft (ultraporous beta-TCP+BMA) in the treatment of cavitary lesions appears to be safe and effective.

Massive prepatellar bursitis in cerebral palsy.

This case report describes a 36-year-old African American male with cerebral palsy and bilateral slowly enlarging knee masses. He has 90 degrees fixed flexion knee contractures bilaterally. Although he has poor communication skills, he does not have discomfort while ambulating. He has developed massive bilateral prepatellar bursitis from chronic and repetitive injury to the region bearing his body weight while ambulating. As the result of a protective response, the bursa provides a cushion for the underlying bone prominences of the tibial tubercle and patella. This compensatory mechanism has allowed the patient to have functional, painless household ambulation.

Synovial sarcoma: clinicopathologic features, treatment, and prognosis.

Synovial sarcoma is a characteristic subtype of soft tissue sarcomas with a predilection for young people. There may be a long delay in diagnosis or misdiagnosis, because of its insidious growth, varied presentation on imaging studies and associated joint pain, which can be confused with trauma. Diagnosis requires a tissue sample in the form of a needle or open biopsy. The needle biopsy may not be representative of the tumor, particular if it is biphasic, and it may be necessary to proceed to open biopsy. Ideally, the biopsy should be performed by the surgeon who will be performing the definitive surgical resection. Although treatment is predicated on surgery, adjuvant radiation and/or chemotherapy may be beneficial, particularly in high risk patients. Significant prognostic factors include: size > 5 cm, deep-seated location, adequacy of surgical margins, and history of recurrence. In the future, multi-institutional prospectively randomized, controlled studies will be needed to better define the role of adjuvant chemotherapy. Currently, outcome may be optimized by early suspicion and detection with referral to an orthopedic oncology specialist prior to the biopsy.

Assessing the reading level of online sarcoma patient education materials.

Cancer patients rely on patient education materials (PEMs) to gather information regarding their disease. Patients who are better informed about their illness have better health outcomes. The National Institutes of Health (NIH) recommends that PEMs be written at a sixth- to seventh-grade reading level. The purpose of this study was to evaluate the readability of online PEMs of bone and soft-tissue sarcomas and related conditions. We identified relevant online PEMs from the following websites: American Academy of Orthopaedic Surgeons, academic training centers, sarcoma specialists, Google search hits, Bonetumor.org, Sarcoma Alliance, Sarcoma Foundation of America, and Medscape. We used 10 different readability instruments to evaluate the reading level of each website's PEMs. In assessing 72 websites and 774 articles, we found that none of the websites had a mean readability score at or below 7 (seventh grade). Collectively, all websites had a mean readability score of 11.4, and the range of scores was grade level 8.9 to 15.5. None of the PEMs in this study of bone and soft-tissue sarcomas and related conditions met the NIH recommendation for PEM reading levels. Concerted efforts to improve the reading level of orthopedic oncologic PEMs are necessary.

Advances in radionuclide therapeutics in orthopaedics.

Radiopharmaceuticals not only are used for diagnostic purposes but also increasingly in the treatment of many orthopaedic-related disorders. With the development of specific bone-seeking radiopharmaceuticals, the side effects of treatment are minimized, therapeutic effects are sustained, and concomitant use with other modalities may have synergistic effects. These new radiopharmaceuticals, such as strontium 89 and samarium 153-ethylene diamine tetramethylene phosphate, have been used as palliative treatment for patients with bone pain from osseous metastases. Excellent clinical responses with acceptable hematologic toxicity have been observed, and clinical results rival those of external beam radiation therapy. Radiosynovectomy has become a procedure of choice at many institutions to treat recurrent hemarthrosis and chronic synovitis in patients whose hemophilia is poorly controlled with medical management. Radiosynovectomy also remains a viable option to treat chronic synovitis secondary to inflammatory arthropathies, particularly rheumatoid arthritis.

Management of open wounds: lessons from orthopedic oncology.

The management of complex wounds remains a challenge, and although there have been many promising advances, patients often undergo a morbid and lengthy process to obtain sufficient, satisfactory healing. Sarcoma patients are especially vulnerable to soft tissue wound-healing complications. These patients are often treated with neoadjuvant radiation and/or chemotherapy and have compromised local vascularity to healing tissue. The advent and refinement of wound vacuum-assisted closure technology have been shown to have a tremendous impact. This article reviews the benefits of some novel technologies currently undergoing investigation in orthopedic oncology that will likely have applications in wound management from other causes.

Intracranial meningeal hemangiopericytoma metastatic to the scapula.

Meningeal hemangiopericytomas are rare vascular tumors that have a propensity for recurrence and metastasis. Intracranial hemangiopericytomas are rare vascular tumors. They account for 0.5% of primary central nervous system tumors and 2% of meningiomas. Unlike usual benign meningiomas, which rarely metastasize extracranially, meningeal hemangiopericytoma has a high rate of local recurrence and distant metastasis. The treatment paradigms for hemangiopericytomas and meningiomas differ based on their biological behaviors. Hemangiopericytomas have higher rates of recurrence and metastasis compared with meningiomas. Intracranial meningeal hemangiopericytoma is characterized by clinically repeated local recurrences at the primary site. Bone, liver, lung, central nervous system, and abdominal cavity are the most commonly reported sites of metastasis in hemangiopericytomas.This article describes a case of bone metastasis with extensive involvement of the scapula from intracranial hemangiopericytoma. Bone metastasis can be seen in a relatively late phase of the disease, with metastasis to other organs. Although radiation therapy is effective in controlling pain from bone metastases in unresectable disease and those with extensive visceral metastases, aggressive local surgical control of a solitary bone metastasis may be an option for patients with limited distant disease. The diagnosis may be initially confused with clear cell meningioma and benign meningiomas. The management of bone metastasis is not well reported in the orthopedic literature.