Measuring clinically relevant endpoints in a serum-free, three-dimensional, primary cell culture system of human osteoarthritic articular chondrocytes.

Osteoarthritis (OA) is characterized by degeneration of articular cartilage within the joint, inflammation and pain. The purpose of this study was to develop a primary, serum free cell culture system of human osteoarthritic articular chondrocytes (HOACs) with which to study manifestations of the disease process. Joint tissues were obtained from OA patients undergoing total knee arthroplasty (TKA). HOACs isolated from the femoral condyles and tibial plateau of the same side were combined, plated in three-dimensional, alginate beads and cultured for five days in serum, hormone and protein free medium. More living cells were obtained from the femoral condyles than the tibial plateau. The optimal plating density was 2.5 × 106 cells/ml of alginate. The amounts of DNA, RNA, proteoglycans and total collagen were similar in cultures prepared from the sides of least and greatest pathology. More type 1 than type 2 collagen was detected in the medium on days 2 and 5. A greater percentage of type 1 than type 2 collagen was degraded. The inflammatory cytokine interleukin-1 beta was present in the medium and alginate associated matrix. Although variation in the metabolic profiles between subjects was observed, HOACs from all patients continued to reflect the OA phenotype for five days in culture. This serum free, three-dimensional primary culture system of HOACs provides a platform with which to measure clinically relevant endpoints of OA and screen potential disease modifying OA therapeutics.

Multidisciplinary Approach to Treatment of Soft Tissue Sarcomas Requiring Complex Oncologic Resections.

BACKGROUND: To review the experience and outcome of utilizing a multidisciplinary team, including vascular surgery and orthopedic surgery, in the operative treatment of soft tissue sarcomas (STSs) at an academic, tertiary care hospital. METHODS: A retrospective review was performed of all patients who underwent elective STS resection between July 1, 2012 and January 31, 2015, since the addition of a specialized cancer treatment center and a dedicated oncologic division of orthopedic surgery. Surgical cases performed in conjunction with both orthopedic and vascular surgery were reviewed. RESULTS: Sixty-three patients underwent 66 surgical resections for STS during the study period. There were no perioperative deaths. Fifty-two lower-extremity resections (78.8%), 6 upper-extremity resections (9.1%), and 8 pelvic resections (12.1%) were performed. Sixteen cases required a vascular intervention (24.2%). These interventions included bypass in 2 patients (12.5%), primary repair of a named vessel in 4 patients (25%), and ligation of a named vessel in 10 patients (62.5%). Three patients had local recurrence of their tumor (4.5%), requiring further resection during the follow-up period. Seven patients required a primary amputation (10.6%). The average size of the tumor removed was 1,776 mL, ranging from 5 mL to 36,300 mL. CONCLUSIONS: The quality of surgical resection is paramount in optimal treatment of STS; however, wide resection of STS can result in prolonged operative times, significant blood loss, vascular complications, and functional deficits. A multidisciplinary surgical team including orthopedic and vascular teams may improve the treatment by optimizing complex resections that may require involved vascular control or reconstruction.

Surgical management of metastatic long bone fractures: principles and techniques.

Management of metastatic long bone fractures requires identification of the lesion and the use of sound fracture fixation principles to relieve pain and restore function. The treating surgeon must understand the principles of pathologic fracture fixation before initiating treatment. Because these fractures occur in the context of a progressive systemic disease, management typically involves a multidisciplinary approach. When considering surgical stabilization of these fractures, the abnormal (or absent) healing environment associated with diseased bone and the overall condition of the patient must be taken into account. The goal of surgery is to obtain a rigid mechanical construct, which allows for early mobility and weight bearing. This can be achieved using internal fixation with polymethyl methacrylate cement or segmental resection and joint reconstruction. Prosthetic joint arthroplasty is a more reliable means of fracture management when insufficient bone is present for fixation. Prophylactic stabilization of impending pathologic fractures can reduce the morbidity associated with metastatic lesions.

Is a cancer diagnosis a teachable moment for the patient's relative who smokes?

PURPOSE: This study examined a cancer diagnosis, versus orthopedic surgery, as a teachable moment for recruiting smokers and treating nicotine dependence among patients' relatives. METHODS: Cancer patients and, for comparison, orthopedic patients at the University of Pennsylvania Health System were approached for referrals of relatives for a smoking cessation program, which involved behavioral counseling and nicotine patches. Primary outcomes were rate of program enrollment and rate of smoking abstinence. Potential mediators of smoking cessation were explored (e.g., treatment adherence, depression, anxiety). Two hundred and thirty-four relatives (113 cancer, 121 orthopedic) were considered eligible for the cessation program and comprised the study sample. RESULTS: Relatives of oncology patients were significantly more likely to enroll in the smoking cessation program, vs. orthopedic relatives (75 % vs. 60%; OR = 1.96, 95% CI 1.07-3.61, p = .03), but they were not significantly more likely to remain in the program (61% vs. 52%) or quit smoking (19% vs. 26%; p's > .05). Compared to orthopedic relatives, oncology relatives showed significantly lower nicotine patch adherence and significantly greater levels of negative affect and depression and anxiety symptoms during treatment (p's < .05). Further, orthopedic relatives, compared to oncology relatives, showed a greater reduction in the perceived benefits of smoking (p = .06), which was significantly associated with abstinence (p = .02). CONCLUSIONS: While a family member's cancer diagnosis may serve as a teachable moment for a smoker to enroll in a smoking cessation treatment program, high levels of psychological distress and perceptions of the benefits of smoking and low levels of treatment adherence may undermine successful abstinence among this population.

Impact of close surgical margin on local recurrence and survival in osteosarcoma.

PURPOSE: Whether neoadjuvant chemotherapy safely allows close margins in osteosarcoma patients is still unknown. This study investigates the impact of close margins on local recurrence (LR) and overall survival (OS) for osteosarcoma patients treated with neoadjuvant chemotherapy. METHODS: We retrospectively reviewed 47 cases of conventional osteosarcoma who were treated at our institution. Patient and treatment factors such as age, gender, MSTS stage, tumour site, surgery type, pathological type, tumour size, surgical margin, tumour necrosis rate, chemotherapy regimens and cycles were recorded. A close margin was defined as tumour present less than 5 mm from the closest resection margin. The average followup was 87.6 months (range, 25-135 months). RESULTS: Twenty-five patients were alive, 22 patients had died, and eight had LR. Twenty-eight patients had wide margins, seven had positive margins and 12 had close margins. Positive margins had a greater risk of LR (57.1%) than wide margins and close margins. There was no difference in LR (8.3% vs 10.7%) between close margins and wide margins. Margin status was not correlated with OS. CONCLUSION: Compared with wide margins, close margins did not lead to increased local recurrence in our study group. Whether close margins, as defined in our study, are just as acceptable as wide margins in terms of patient outcomes for osteosarcoma patients with neoadjuvant chemotherapy needs to be further confirmed in the future.

Preoperative Stereotactic Body Radiation Therapy for Soft-Tissue Sarcoma: Results of Phase 2 Study.

Purpose: Preoperative radiation followed by surgical resection is a standard treatment for soft-tissue sarcomas (STS). We report on 2 consecutive, phase 2, single-arm studies evaluating 5 fraction stereotactic body radiation therapy (SBRT) treatments followed by surgical resection for STS (clinical trails.gov NCT02706171). Methods and Materials: A total of 16 patients were treated with preoperative SBRT. Tumor size in the greatest dimension was a median 6.7 cm (maximum: 14 cm) and the majority of STS were in the extremities. SBRT consisted of 35 to 40 Gy in 5 fractions every other day. Results: Median follow-up time was 1719 days (4.7 years). Grade ≥3 acute toxicity occurred in 1 patient (grade 3 skin changes). Fifteen patients proceeded with surgical resection. Three patients had a wound complication after surgery, 1 patient had grade ≥3 late toxicity (grade 4 requiring surgical intervention). There was 1 local recurrence and 5 distant recurrences. Conclusions: Long-term follow-up on SBRT for STS found acceptable control and toxicity rates, and warrants further evaluation.

Perioperative infection rate in patients with osteosarcomas treated with resection and prosthetic reconstruction.

BACKGROUND: The incidence of perioperative infection after segmental tumor endoprosthetic replacement in previous reports varies from a high of 7.4% to a low of 2.6%. Appropriate antibiotic use for this group is unknown and controversial, whereas the relationship of antibiotic use and perioperative infection is unclear. QUESTIONS/PURPOSES: We determined the incidence of perioperative infection in patients with osteosarcoma treated with segmental prosthetic replacement using a standard perioperative antibiotic regimen and the incidence of late infections and wound complications. PATIENTS AND METHODS: We retrospectively reviewed the records of 53 patients with osteosarcoma undergoing segmental prosthetic replacements from 1993 to 2008. There were 30 males and 23 females ranging from 10 to 78 years of age. All patients were given intraoperative antibiotics (intravenous cefazolin), continued for 3 days postoperatively and then given orally for 5 days. Patients who were allergic to penicillin or cefazolin were given vancomycin followed by clindamycin. A perioperative infection was defined as a deep infection within 2 months after prosthetic reconstruction. The minimum followup was 1 year (range, 1-15 years). RESULTS: We identified one confirmed perioperative prosthetic infection (1/53; 1.9%) (Enterobacter cloacae and methicillin-resistant Staphylococcus) in a 78-year-old woman after proximal tibial replacement, gastrocnemius flap, and skin graft. Her infection was controlled with débridement, drainage, and intravenous antibiotics. Three patients had late infections, two of which were culture negative. Four patients had wound complications that required further surgery. CONCLUSION: The antibiotic regimen we used is longer than that recommended for patients having routine total joint arthroplasty. Its appropriateness will require comparison with alternate regimens, including those of shorter duration. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Curettage and graft alleviates athletic-limiting pain in benign lytic bone lesions.

BACKGROUND: Solitary bone cysts (SBC), nonossifying fibromas (NOF), and fibrous dysplasia (FD) create benign intramedullary lytic bone lesions. They are typically asymptomatic and treated conservatively. We present a series of lesions that caused performance-limiting pain in young athletes, a symptom phenomenon and possible treatment indication that has been poorly described in the literature. QUESTIONS/PURPOSES: We asked whether intralesional curettage and defect grafting of these lesions would alleviate pain in young athletes and permit their return to unrestricted athletic activities. PATIENTS AND METHODS: We retrospectively identified 29 patients (30 lesions) who underwent curettage and grafting for SBC (12 patients), NOF (nine), or FD (eight). All patients had pain predominantly with athletic involvement. The mean age of the patients was 18 years (range, 12-31 years). Tumor locations were the femur (eight lesions), humerus (seven), tibia (six), fibula (five), pubic ramus (two), ulna (one), and calcaneus (one). Signs/symptoms were pain alone (24 patients) and pain plus fracture (five). Surgery involved curettage and packing with allograft cancellous chips, bone substitute, or demineralized bone matrix. Two patients required internal fixation. The mean followup was 21 months (range, 2-114 months). RESULTS: Twenty-four patients had no pain and five had occasional mild pain at last followup. All patients resumed full activity at a mean of 3.3 months (range, 1.5-8.3 months), excluding two who required repeat surgery. CONCLUSIONS: Our observations suggest curettage and packing with bone graft/substitute can provide pain relief and allow full athletic recovery for young athletes with benign lytic bone lesions. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

The relation of tumour necrosis and survival in patients with osteosarcoma.

PURPOSE: We investigated whether tumour necrosis was associated with disease-free survival (DFS) and overall survival (OS) of osteosarcoma patients treated in our institution. METHODS: We retrospectively studied the predictive value of percentage of necrosis in 40 cases of IIB osteosarcoma treated from 1999 to 2008 in our institution. Patient and treatment factors such as age, gender, tumour site, surgery type, pathological type, tumour size, margin status, percentage of tumour necrosis, chemotherapy regimens and cycles were recorded. The average follow-up was 85.9 months (range, 25-135 months). RESULTS: Two patients had local recurrence (LR) alone, five patients had both LR and metastasis, 14 patients had metastasis alone. Twenty-four patients were alive and 16 had died. The five-year DFS and OS were 47.8% and 65.9%, respectively. Tumour necrosis grouped by 90% was not associated with DFS and OS. Patients with greater than 70% necrosis rate had a significantly higher DFS than those with less than 70%. CONCLUSION: We found no survival advantage at 90% tumour necrosis in our study. Further study with more patients should be performed to evaluate the predictive value of necrosis rate at the cutoff of 70%.

Induction of Myogenic Differentiation Improves Chemosensitivity of Chemoresistant Cells in Soft-Tissue Sarcoma Cell Lines.

Rhabdomyosarcoma (RMS) and rhabdoid tumors (RT) are rare soft-tissue malignancies with the highest incidence in infants, children, and adolescents. Advanced, recurrent, and/or metastatic RMS and RT exhibit poor response to treatment. One of the main mechanisms behind resistance to treatment is believed to be intratumoral heterogeneity. In this study, we investigated the myogenic determination factor 1 (MYOD1) and Noggin (NOG) markers in an embryonal RMS (ERMS) cell line and an RT cell line and the differential response of the MYOD1 and NOG expressing subpopulations to chemotherapy. Importantly, we found that these markers together identify a subpopulation of cells (MYOD1+ NOG+ cells) with primary resistance to Vincristine and Doxorubicin, two commonly used chemotherapies for ERMS and RT. The chemoresistant MYOD1+ NOG+ cells express markers of undifferentiated cells such as myogenin and ID1. Combination of Vincristine with TPA/GSK126, a drug combination shown to induce differentiation of RMS cell lines, is able to partially overcome MYOD1/NOG cells chemoresistance.

Conservative treatment of Campanacci grade III proximal humerus giant cell tumors.

UNLABELLED: Management of large giant cell tumors of the proximal humerus is controversial because wide resection with reconstruction results in a poor functional outcome for most patients. We retrospectively reviewed the cases of six patients with Campanacci Grade III giant cell tumors of the proximal humerus to determine the feasibility of avoiding en bloc resections for large giant cell tumors in this location. We evacuated the tumor through curettage and then used burring (unless the remaining cavity was thinned and at risk for fracture) and phenolization, followed by packing of the defect with allograft cancellous bone. The mean age of the patients at surgery was 30 years, and the minimum followup was 2.5 years (mean, 5.6 years; range, 2.5-9.7 years). One of the six patients had local recurrence 1.2 years postoperatively and was treated with repeat intralesional surgery with no additional recurrence 5 years later. No other patient required additional treatment, had pulmonary metastases develop, or had progression to osteoarthritis. The mean Musculoskeletal Tumor Society and Toronto Extremity Salvage Score functional scores at last followup were 26 of 30 (range, 21-30) and 95% (range, 90%-100%), respectively. These functional scores are higher than reported scores for patients with segmental resection and reconstruction of the proximal humerus. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Internal hemipelvectomy for pelvic sarcomas using a T-incision surgical approach.

UNLABELLED: Internal hemipelvectomy is performed for pelvic sarcomas when the tumor can be safely resected without sacrificing the entire extremity. Wide exposure and awareness of major neurovascular structures are crucial to the success of this surgery. Various modifications on the standard utilitarian approach have been used to best achieve these goals. We reviewed our experience using the T-incision technique for 30 pelvic sarcoma resections. The minimum followup was 3.6 months (mean, 55 months; range, 3.6-185.4 months). Postoperative complications included minor complications (requiring no surgery or a simple incision and drainage with primary closure) in 27% of patients and major complications (involving a deep infection or more extensive surgical treatment) in 17%. Ninety-two percent of wound complications healed uneventfully with antibiotics and incision and drainage. The 2-, 5-, and 10-year patient survival rates were 67%, 59%, and 53%. The 2-, 5-, and 10-year disease-free survival rates were 68%, 42%, and 42%. The mean Musculoskeletal Tumor Society and Toronto Extremity Salvage Scores were 69% and 86%, respectively. We believe the T-incision technique for internal hemipelvectomy is an effective surgical approach for pelvic sarcomas when limb salvage is possible. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Ethanol sclerotherapy reduces pain in symptomatic musculoskeletal hemangiomas.

UNLABELLED: Hemangiomas, benign vascular lesions, require intervention if causing pain or functional limitations. Functional deficits are common after excision, favoring minimally invasive treatments. To determine whether ethanol sclerotherapy reduces pain and lesion size and to assess complications in symptomatic musculoskeletal hemangiomas, we retrospectively reviewed 19 patients (six males, 13 females; mean age, 34 years) meeting criteria of confirmed hemangioma, treatment with ethanol sclerotherapy, and minimum of 6 weeks of followup. Fourteen were primary lesions and five were recurrent; all were painful. Thirty-eight sclerotherapy procedures were performed, with each patient undergoing a maximum of three procedures. Mean followup was 24 months (range, 2-95 months). Four patients reported full pain relief, 11 had partial relief, and four had no relief. With recurrent lesions, one patient had full pain relief, one had partial relief, and three had no relief. For patients with lesions larger than 5 cm, two had full relief, six had partial relief, and three had no relief. Lesion shrinkage occurred in 12 patients. Temporary complications included paresthesiae (three), tendon contracture (one), skin breakdown (one), and deep vein thrombosis (one). Ethanol sclerotherapy afforded prompt pain relief in 15 of 19 patients with hemangioma, making it a reasonable option for initially avoiding surgical excision. However, the short followup of our patients requires additional long-term studies to assess the duration of the results. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Long-term results for limb salvage with osteoarticular allograft reconstruction.

UNLABELLED: Osteoarticular allograft reconstruction after extremity tumor resection has been shown to have a high rate of complications. Although good functional results have been seen, long-term outcomes have not been well studied. We performed a retrospective review of 20 patients who underwent primary osteoarticular allograft reconstruction after extremity sarcoma resection. All postoperative complications related to the allograft reconstruction were recorded. Musculoskeletal Tumor Society 1993 and Toronto Extremity Salvage Score scores were used for functional evaluation at last followup. Minimum followup was 10 years (mean, 16 years; range, 10-21 years). Seventy percent of patients experienced an event during the followup period. Recorded events were fracture (nine patients), progressive arthritis (five), nonunion (four), and infection (two). Sixty percent of allografts were removed at a mean of 5.2 years. Progressive arthritis led to total joint arthroplasty in five patients (25%). Mean Musculoskeletal Tumor Society and Toronto Extremity Salvage Score functional scores were 25 of 30 and 95% for patients who retained their original allograft. Osteoarticular allograft reconstruction for extremity sarcomas had a high rate of adverse events (70%) and allograft removal (60%) at long-term followup. Functional outcomes of patients with intact grafts were comparable to outcomes with segmental replacement prostheses reported in the literature. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Rhabdomyosarcoma and Wilms tumors contain a subpopulation of noggin producing, myogenic cells immunoreactive for lens beaded filament proteins.

Myo/Nog cells are identified by their expression of the skeletal muscle specific transcription factor MyoD and the bone morphogenetic protein inhibitor noggin, and binding of the G8 monoclonal antibody. Their release of noggin is critical for morphogenesis and skeletal myogenesis. In the adult, Myo/Nog cells are present in normal tissues, wounds and skin tumors. Myo/Nog cells in the lens give rise to myofibroblasts that synthesize skeletal muscle proteins. The purpose of this study was to screen human lens tissue, rhabdomyosarcoma cell lines, and tissue sections from rhabdomyosarcoma, Wilms and tumors lacking features of skeletal muscle for co-localization of antibodies to Myo/Nog cell markers and the lens beaded filament proteins filensin and CP49. Immunofluorescence localization experiments revealed that Myo/Nog cells of the lens bind antibodies to beaded filament proteins. Co-localization of antibodies to G8, noggin, filensin and CP49 was observed in most RC13 and a subpopulation of RD human rhabdomyosarcoma cell lines. Western blotting with beaded filament antibodies revealed bands of similar molecular weights in RC13 and murine lens cells. Human alveolar, embryonal, pleomorphic and spindle cell rhabdomyosarcomas and Wilms tumors contained a subpopulation of cells immunoreactive for G8, noggin, MyoD and beaded filaments. G8 was also co-localized with filensin mRNA. Staining for beaded filament proteins was not detected in G8 positive cells in leiomyosarcomas, squamous and basal cell carcinomas, syringocarciomas and malignant melanomas. Lens beaded filament proteins were thought to be present only in the lens. Myo/Nog-like cells immunoreactive for beaded filaments may be diagnostic of tumors related to the skeletal muscle lineage.

The measurement of physical functioning among patients with Tenosynovial Giant Cell Tumor (TGCT) using the Patient-Reported Outcomes Measurement Information System (PROMIS).

BACKGROUND: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size and location. The aim of this study was to identify relevant items, and demonstrate the content validity of custom measures of lower extremity PF from the Patient-Reported Outcomes Measurement Information System Physical Function Physical Function (PROMIS-PF) item bank among patients with TGCT. METHODS: Patients were recruited for qualitative research interviews to identify predominant TGCT symptoms and impacts. Patients completed a checklist to evaluate the relevance of each PROMIS-PF item. The publicly available PROMIS-PF item response theory (IRT) parameters were used to select items representing the range of the latent PF trait. RESULTS: Participants (n = 20) were 75% female, mean age 42.5 years. TGCTs were located in the knee (n = 15), hip (n = 3), and ankle (n = 2). Fifty-four PROMIS-PF items were identified as relevant by ≥20% of the participants. PF concepts discussed by participants during the qualitative interviews were also used to select relevant items. Selected items (n = 13) were used to create a physical function subscale specific to lower extremity tumors. CONCLUSIONS: We describe a novel method of combining qualitative research and IRT-based item information to select a relevant and content valid subset of PROMIS-PF items to assess heterogeneous impacts on PF in TGCT, a rare disease population.

Current surgical management of bone metastases in the extremities and pelvis.

Surgical management of metastases to the extremities and pelvis has benefited from advances in the technology of internal fixation, as well as the increased availability of options for large endoprostheses. Contoured periarticular plates and the screws that attach rigidly to the plates have made fixation into weakened bone more reliable and easier to provide. For massive bone loss, modular endoprostheses are now widely available. These options supplemented with bone cement (polymethylmethacrylate) give patients the ability to have most bone defects reinforced or replaced such that the patient can begin using the affected limb almost immediately.

Musculoskeletal desmoid tumors.

Desmoid tumors are benign tumors that exhibit varying degrees of local aggressiveness and diverse growth patterns. Magnetic resonance imaging remains the modality of choice for assessment of the nature and size of the soft-tissue lesion and involvement of surrounding structures. Treatment strategies include surgery, chemotherapy, hormonal therapy, and radiation therapy, either individually or in combination. Despite the benign nature of these tumors, multidisciplinary care is needed to provide combined treatment options. Chemotherapy in low doses is an excellent first-round treatment in any patient in whom contemplated local treatment may produce local morbidity and adjacent tissue injury.