Neonatal osteoblastic tumor with a novel PTBP1::FOSB fusion.

Congenital/neonatal bone neoplasms are extremely rare. We present the case of a patient with a neonatal bone tumor of the fibula that had osteoblastic differentiation and a novel PTBP1::FOSB fusion. FOSB fusions are described in several different tumor types, including osteoid osteoma and osteoblastoma; however, these tumors typically present in the second or third decade of life, with case reports as young as 4 months of age. Our case expands the spectrum of congenital/neonatal bone lesions. The initial radiologic, histologic, and molecular findings supported the decision for close clinical follow-up rather than more aggressive intervention. Since the time of diagnosis, this tumor has undergone radiologic regression without treatment.

Tibial Osteolysis After Long-Term Isolated Polyethylene Patellar Resurfacing.

Isolated patellar resurfacing served as an early treatment for patellofemoral arthritis but was abandoned because of erosion of the native femoral trochlear groove over time. We present the case of a large native tibial osteolytic lesion 20 years after isolated patellar resurfacing with a cemented polyethylene component. The patient had severe tricompartmental arthritic changes. The patellar component was very worn, and the resultant particle debris produced a large cavitary lesion in the proximal tibia. Osteolysis is a rare complication in patellofemoral arthroplasty, and, to our knowledge, this is the first reported case of native tibial osteolysis after isolated patellar resurfacing. The patient was treated with initial curettage and bone grafting of the lesion followed by total knee arthroplasty with a tibial cone and stemmed tibial fixation.

The Distribution of Underrepresented Minorities in U.S. Orthopaedic Surgery Residency Programs.

BACKGROUND: Orthopaedic surgery has generally lagged behind other surgical subspecialties with respect to racial and ethnic diversity in its U.S. residency programs. Efforts have been made to increase the number of underrepresented minorities (URMs) applying to orthopaedic surgery residencies; however, the impact on diversity at the residency program level is unknown. The purpose of this study was to determine whether orthopaedic surgery residency programs have become more racially diverse over time. METHODS: The Graduate Medical Education Track database was queried for individual racial/ethnic identification of orthopaedic surgery residents in U.S. Accreditation Council for Graduate Medical Education (ACGME)-accredited programs for 15 consecutive years (2002-2003 through 2016-2017). The number of URMs in each residency program during each academic year was recorded. The number of programs per year with no URMs, 1 URM, 2 URMs, and >2 URMs was recorded, and the change over time was assessed. RESULTS: The number of programs per year with >1 URM resident decreased over time, from 61 programs in 2002 to 53 programs in 2016, with the trough being 31 programs in 2010 (p < 0.0001). The number of programs per year without any URM residents increased over the period of study, from 40 programs in 2002 to 60 programs in 2016, with the peak being 76 programs in 2011 (p < 0.0001). CONCLUSIONS: The number of residency programs with >1 URM resident has decreased significantly over time, suggesting that diversity at the program level is limited. Program-level diversity should be further examined as a potential barrier to the recruitment of URMs to orthopaedics. Difficulty attracting URM residents to certain programs may have the unintended consequence of effectively limiting potential positions for these candidates, which can decrease the odds of minority students matching into orthopaedics and, therefore, perpetuate the cycle of lack of diversity in our field.

Intimate Partner Violence-Related Fractures in the United States: An 8 Year Review.

BACKGROUND: Fractures associated with intimate partner violence (IPV) are devastating injuries that can have lifelong implications. With exception to the facial region, there are very limited epidemiological reports describing the types and location of IPV-related fractures. The objective of this study is to review a national database and describe trends associated with IPV-related fractures. METHODS: An analysis of all adults was performed using the National Trauma Data Bank from 2007 through 2014.Data including demographics, age, location of fracture, and drug/alcohol use were described and analyzed. FINDINGS: There were 1,352 records identified where the patient was diagnosed with an IPV-related fracture. Women accounted for 83% of the population and the mean age was 37.5 years. Approximately 30% of the population was diagnosed with vertebral, trunk, and rib fractures. Variances among fracture location were observed across age groups. Facial fractures were recorded more in the younger population (18-39 years) when compared to other age groups (40-59 years; 60+ years), p<0.0001. Alternatively, rib and femur fractures were more common among survivors aged 60+ when compared to the younger age groups, p<0.0001. INTERPRETATION: The ability to identify and respond to survivors of IPV in the healthcare setting is critically important. While facial fractures are common, they are not the only type of fractures that are seen. In many cases, healthcare professionals are the first line of defense in identifying suspected IPV cases. The findings of this paper build upon existing literature while also describing IPV-related fractures across the age spectrum.

Safe Positioning for Sexual Intercourse After Proximal Femoral Replacement.

Hip arthroplasty is a common procedure used for the treatment of fractures and degenerative processes affecting the hip. Proximal femoral replacement is an uncommon type of hip arthroplasty used for reconstruction after extensive bone loss. Proximal femoral replacement is used most commonly after the resection of the proximal femur for malignancies and for extensive bone loss encountered in revision hip arthroplasty and occasionally for extensive bone loss after fractures. The authors present a case of a female patient who sustained a prosthetic dislocation of her proximal femoral replacement during sexual intercourse. Standard hip arthroplasty itself can pose a risk factor for dislocation associated with certain sexual positions. Proximal femoral replacement surgery likely carries an increased risk for dislocation, given the magnitude of soft tissue loss at the time of resection. The authors believe that routine perioperative conversations for sexually active patients with proximal femur replacements should include this potential risk and discuss appropriate positioning to prevent a potential dislocation. [Orthopedics. 2018; 41(2):e292-e294.].

Extensive Remineralization of Large Pelvic Lytic Lesions Following Total Therapy Treatment in Patients With Multiple Myeloma.

Osteolytic bone lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely imbalanced bone remodeling, secondary to increased osteoclastogenesis and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and are known to contribute to the increased morbidity because of the high risk of fracture, which frequently demands extensive surgical intervention. After observing unexpected radiological improvement in serial large pelvic CT assessment in a patient treated in a total therapy protocol, the radiographic changes of pelvic osteolytic lesions by PET/CT scanning in patients who received Total Therapy 4 (TT4) treatment for myeloma were retrospectively analyzed. Sixty-two (62) patients with lytic pelvic lesions >1 cm in diameter were identified at baseline PET/CT scanning. Follow-up CT studies showed that 27 of 62 patients (43%) with large baseline pelvic lesions achieved significant reaccumulation of radiodense mineralization at the lytic cortical site. The average size of lytic lesions in which remineralization occurred was 4 cm (range, 1.3 to 10 cm). This study clearly demonstrates that mineral deposition in large pelvic lesions occurs in a significant proportion of MM patients treated with TT4, potentially affecting patient outcomes, quality of life, and future treatment strategies. © 2017 American Society for Bone and Mineral Research.

Bilateral multifocal upper extremity atypical granular cell tumors presenting as long-standing right wrist and left hand masses in a 15-year-old African-American female.

Granular cell tumor (GrCT) is a benign nerve sheath tumor. Atypical and malignant variants of GrCT are rare but have been well described. We report a case of multifocal symmetric atypical GrCT in the bilateral hand/wrists of a 15-year-old African-American female. The initial clinical impression for both masses was favored to be ganglion cysts. Ultrasound findings of both masses revealed hypoechoic soft tissue lesions with some internal echogenicity favoring complex cysts. On excision, both masses were histologically circumscribed, lobulated and attached to tendon. Large epithelioid cells with abundant granular eosinophilic cytoplasm arranged in syncytial cords and trabeculae percolated through collagen. Many cells had pleomorphism and/or prominent nucleoli. Mitotic figures, spindling, high nuclear-to-cytoplasmic ratio and necrosis were absent. Both masses showed diffuse S100 protein but negative desmin and pancytokeratin expression. Ki-67 index was 1% to 2%. p53 was positive in 5% to 10% of nuclei. Both masses met criteria for atypical (but not malignant) GrCT. Our case shows that atypical GrCT may be not only multifocal but also symmetric. We speculate that migration of defective neural crest stem cells along both upper limb buds during embryogenesis may have allowed these essentially identical tumors to arise in similar locations bilaterally simultaneously.

Treatment of subperiosteal abscesses in children: is drainage of the intramedullary canal required?

Acute osteomyelitis can be successfully treated with antibiotics alone. Surgery is utilized after failure of antibiotic treatment or if an abscess is present. Limited evidence exists with regard to whether intramedullary drainage is required in addition to the drainage of the subperiosteal abscess. We reviewed our 9-year experience of treating subperiosteal abscesses identifying 68 patients. Thirty patients underwent both intramedullary and abscess drainage, whereas 38 patients underwent drainage of the abscess alone at the initial procedure. Our analysis demonstrated a statistical significance (P=0.012) and odds ratio of 6.46 in favor of an intramedullary drainage to decrease risk for need for repeat surgical treatment.

Presentation and Management of Venomous Snakebites: Should All Patients Be Transferred to a Tertiary Referral Hospital?

Venomous snakebites may be difficult to manage because of the varied clinical presentations that may lead to uncertainty regarding the most appropriate medical and surgical management. Frequently, snakebite victims are referred from smaller rural hospitals to larger tertiary centers offering more specialized services and care. A retrospective chart review was performed using medical records from both adult and pediatric hospitals in a rural state over a 7-year period (January 2004 to January 2011) to investigate the utility of intensive care and specialized medical services offered at tertiary referral centers. The results demonstrated that presentation of venomous snakebites is the same in adults and children as well as the management. The results also demonstrated that the use of supportive care and antivenin alone was successful in the management of the vast majority of snakebites. Most snakebite victims recovered with nonsurgical care; thus surgical intervention is rarely warranted. These findings demonstrate that snakebite victims may not need referral to a tertiary center, if the primary local hospital has supportive care capacity and familiarity with antivenin usage.

High Relative Expression of Pannexin 3 (PANX3) in an Axillary Sweat Gland Carcinoma With Osteosarcomatous Transformation.

Primary cutaneous sweat gland carcinomas (SGCs) are rare tumors that commonly involve axillae, have a high local recurrence rate, and rarely show sarcomatoid transformation. A 68-year-old man presented with rapid enlargement of a previously stable, asymptomatic pea-sized nodule in the left axilla. Initial excision (with positive surgical margins) at another institution showed characteristic histologic features of a high-grade osteosarcoma and molecular analysis using a 92-gene real-time quantitative reverse transcription-polymerase chain reaction assay confirmed a diagnosis of osteosarcoma with 96% certainty. Notably, the molecular assay demonstrated consistently high relative expression of pannexin 3 (PANX3), a gene involved in normal osteoblast differentiation which, when highly expressed, strongly predicts osteosarcoma per the assay's algorithm. However, on further histologic review, the tumor also contained focal cystic areas, nests, and ducts composed of malignant epithelial cells reminiscent of SGC; these areas directly transitioned into the osteosarcomatous component and were strongly positive for pancytokeratin, CK7, and p63. Within 2 weeks, the lesion recurred and grew rapidly, prompting complete resection, histologic sections of which showed high-grade osteosarcoma without residual epithelial elements. This is the fifth report, to our knowledge, of osteosarcomatous transformation in a SGC, and the only report to date including molecular data. This case demonstrates that osteosarcoma arising from a SGC has a similar molecular profile to de novo primary osteosarcoma of bone. It also emphasizes the importance of histopathologic findings as the established diagnostic gold standard and the need to interpret molecular results within the clinical context.

Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity.

The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity (p < 0.01-0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1716-1724, 2016.

The best of both worlds - managing the cancer, saving the bone.

In the context of breast cancer, the importance of the skeleton in the regulation of primary tumour development and as a site for subsequent metastasis is well characterized. Our understanding of the contributions made by the host bone and bone marrow cells increasingly demonstrates the extent of the interaction between tumour cells and normal host cells. As a result, the need to develop and utilize therapies that can impede the growth and/or function of tumour cells while sparing normal host bone and bone marrow cells is immense and expanding. The need for these new treatments is, however, superimposed on the orthopaedic management of patients' quality of life, where pain control and continued locomotion are paramount. Indeed, the majority of the anticancer therapies used to date often result in direct or indirect damage to bone. Thus, although the bone microenvironment regulates tumour cell growth in bone, cells within the bone marrow niche also mediate many of the orthopaedic consequences of tumour progression as well as resistance to the antitumour effects of existing therapies. In this Review, we highlight the effects of existing cancer treatments on bone and the bone marrow microenvironment as well as the mechanisms mediating these effects and the current utility of modern orthopaedic interventions.

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans.

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

Cisplatin inhibits bone healing during distraction osteogenesis.

Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p < 0.001). Further, no significant inhibitory effects from the five-dose CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP.

Concurrent septic arthritis and osteomyelitis in children.

INTRODUCTION: Septic arthritis and osteomyelitis can both independently cause substantial morbidity. With concomitant septic arthritis and osteomyelitis, the septic arthritis may be treated without knowledge of the adjacent osteomyelitis resulting in delayed treatment. This study aims to identify factors that may help to diagnosis concurrent infections (CI) earlier. METHODS: A retrospective chart review of 200 patients with septic arthritis was performed. Patients with CI were compared with patients with septic arthritis alone using tests determined by the nature of the variable being analyzed (the χ test, the Fisher exact test, the Cochran-Armitage trend test, and the Kruskal-Wallis test.). RESULTS: Two hundred patients were eligible and analyzed, of which 43 (21.5%) had CI. On the basis of age, CI were most common in newborns and adolescents (P<0.0001). On the basis of location, 72% of shoulder infections (P<0.0001) were concurrent, whereas <50% of elbows, hips, knees, and ankle were CI. The most common infective organism was methicillin-sensitive Staphylococcus aureus (P<0.0001). CI were significantly associated with increased median (6) days of clinical symptoms before presentation (P<0.0001), increased duration of median (6) days of hospital stay (P<0.0001), increased number of operative procedures (P=0.005), and increased need for ICU admission (P=0.024). CONCLUSIONS: Utilizing advanced imaging (CT scan, bone scan, and/or MRI) in patients with septic arthritis who are younger than 4 months of age, between ages 13 and 20 years, with septic arthritis involving the shoulder, and with symptoms for more than 6 days may shorten hospital stays, decrease the number of operative procedures required, and possibly limit infection-related sequelae by identifying CI earlier. LEVEL OF EVIDENCE: III.

Proteomic technologies for the study of osteosarcoma.

Osteosarcoma is the most common primary bone cancer of children and is established during stages of rapid bone growth. The disease is a consequence of immature osteoblast differentiation, which gives way to a rapidly synthesized incompletely mineralized and disorganized bone matrix. The mechanism of osteosarcoma tumorogenesis is poorly understood, and few proteomic studies have been used to interrogate the disease thus far. Accordingly, these studies have identified proteins that have been known to be associated with other malignancies, rather than being osteosarcoma specific. In this paper, we focus on the growing list of available state-of-the-art proteomic technologies and their specific application to the discovery of novel osteosarcoma diagnostic and therapeutic targets. The current signaling markers/pathways associated with primary and metastatic osteosarcoma that have been identified by early-stage proteomic technologies thus far are also described.

Early complications of high-dose-rate brachytherapy in soft tissue sarcoma: a comparison with traditional external-beam radiotherapy.

BACKGROUND: Radiotherapy and surgery are routinely utilized to treat extremity soft tissue sarcoma. Multiple radiation modalities have been described, each with advantages and disadvantages, without one modality demonstrating clear superiority over the others. QUESTIONS/PURPOSES: We determined the overall initial complication rate in patients receiving surgery and radiotherapy, which specific complications were found when comparing different modalities, and whether combination therapy increased the overall rate of complications compared with surgery and single-modality radiotherapy. PATIENTS AND METHODS: We retrospectively reviewed the records of 190 patients who received external-beam radiotherapy (141 patients), high-dose-rate brachytherapy (37 patients), or both (12 patients). We evaluated 100 men and 90 women (mean age, 57 years; range, 18-94 years) for tumor size and subtype, comorbidities, stage, grade, margin of resection, type of adjuvant treatment, and complications. Minimum followup was 3 months (mean, 40 months; range, 3-155 months). RESULTS: The most frequent early complications in the high-dose-rate brachytherapy cohort were infection, cellulitis, and seroma and/or hematoma. In the external-beam radiotherapy cohort, chronic edema, fibrosis, and chronic radiation dermatitis were more frequently encountered. The total number of early complications and overall incidence of major complications requiring further surgery were similar among the three cohorts, but a larger number of patients in the high-dose-rate brachytherapy group required subsequent surgery for infection compared with the external-beam radiotherapy group. CONCLUSIONS: High-dose-rate brachytherapy decreases radiation exposure and allows shorter duration of treatment compared with traditional external-beam radiotherapy but has a higher perioperative wound complication rate. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Increased risk of Blount disease in obese children and adolescents with vitamin D deficiency.

BACKGROUND: Poor dietary habits and decreased outdoor activity has led to an epidemic of obese children and vitamin D deficiency. The lack of vitamin D alters bone development and mineralization by diminishing physiological levels of calcium and phosphorus. Given vitamin D's role in bone and growth plate mineralization and regulation, we hypothesized that vitamin D deficiency would lead to higher rates of fractures, slipped capital femoral epiphysis (SCFE), and Blount disease in obese youth. METHODS: A retrospective review was performed at the obesity clinic using the obesity database (890 patients). Data obtained included body mass index (BMI), vitamin D levels (25-vitamin D), history of fractures, Blount disease, and/or SCFE. The chart review identified 2 populations of obese patients, those with vitamin D deficiency, <16 ng/mL (198 patients) and those not vitamin D deficient >16 ng/mL (692 patients). Fisher exact, χ², and 2-sample t tests along with logistic regression were used for statistical analysis. A P value ≤0.05 was considered statistically significant. RESULTS: Blount disease was found to have a statistically significant (P<0.05) positive association with patient's sex, BMI, and vitamin D level. Specifically, males were 8.16 times more likely than females to be observed with Blount disease (P=0.01). Patients with very low vitamin D levels were 7.33 times more likely to have Blount disease than patients with higher levels (P=0.002). Each whole number increase in BMI increases the likelihood of Blount disease by 3% (P=0.01). There was no association between increased number of fractures or SCFE with vitamin D deficiency in these obese patients. CONCLUSION: As our findings indicate, BMI and vitamin D levels have a strong association with Blount disease, which may be especially important among males. Ours is the first study to show a relationship between vitamin D deficiency and Blount disease, but further prospective studies are needed with larger numbers to confirm this independent association of vitamin D deficiency with Blount disease. LEVEL OF EVIDENCE: Level III retrospective study.

The promise of bone cancer proteomics.

Mass spectrometric analysis of the low-molecular-weight (LMW) range of the serum/plasma proteome is revealing the existence of large numbers of previously unknown peptides and protein fragments, predicted to be derived from circulating low-abundance proteins. While genomics and proteomics are the primary discovery research tool, recent innovations in high-throughput proteomics are now standard practice for biomarker and target discovery. Surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) is the current mainstay for serum or plasma analysis, although other methods are emerging as alternative high-throughput approaches. From a proteomics perspective, the bone cancers, such as myeloma, breast and prostate cancer bony metastases, and osteosarcoma, are likely among the least studied. As recent advances in proteomic technology have thrust the bone cancer field into the era of proteomics, a review of the current status of the proteome as it relates to the skeletal consequences of malignancy seems reasonable.