Benjamin J. Miller

Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database

BACKGROUND The current study aims to determine cause-specific survival in patients with Ewings sarcoma while reporting clinical risk factors for survival. METHODS The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify patients with osseous Ewings sarcoma from 1991 to 2010. Patient, tumor, and socioeconomic variables were analyzed to determine prognostic factors for survival. RESULTS There were 1163 patients with Ewings sarcoma identified in the SEER Program database. The 10-year cause-specific survival for patients with non-metastatic disease at diagnosis was 66.8% and 28.1% for patients with metastatic disease. Black patients demonstrated reduced survival at 10 years with an increased frequency of metastatic disease at diagnosis as compared to patients of other race, while Hispanic patients more frequently presented with tumor size>10cm. Univariate analysis revealed that metastatic disease at presentation, tumor size>10cm, axial tumor location, patient age≥20 years, black race, and male sex were associated with decreased cause-specific survival at 10 years. Metastatic disease at presentation, axial tumor location, tumor size>10cm, and age≥20 years remained significant in the multivariate analysis. CONCLUSIONS Patients with Ewings sarcoma have decreased cause-specific survival at 10 years when metastatic at presentation, axial tumor location, tumor size>10cm, and patient age≥20 years.

Minimizing Blood Transfusion in Total Hip and Knee Arthroplasty Through a Multimodal Approach

BACKGROUND We introduced a multimodal, multidisciplinary approach to perioperative blood management aimed at reducing blood transfusions in primary knee (TKA) and hip (THA) arthroplasty. The protocol included (1) preoperative hemoglobin optimization through a multidisciplinary approach, (2) minimization of perioperative blood loss, and (3) adherence to evidence-based transfusion guidelines. METHODS Evaluation of 1010 consecutive patients undergoing primary TKA (488) or THA (522) was performed. RESULTS A significant reduction in the overall transfusion rate (1.4% vs 17.9%, P<.0001) resulted after algorithm introduction, when compared with the 1814 previous patients. Zero (0%) TKA and 4 (0.8%) THA patients adherent to protocol, and 4/488 (0.8%) TKA and 10/522 (1.9%) THA patients overall received transfusions. CONCLUSION Adoption of a multimodal blood management algorithm can significantly reduce blood transfusions in primary joint arthroplasty.

Risk factors for metastatic disease at presentation with osteosarcoma: an analysis of the SEER database.

BACKGROUND Osteosarcoma is the most common primary bone sarcoma and affects all ages. There are substantial differences in management and outcomes for patients who have localized disease compared with distant spread at the time of diagnosis. Our goal was to examine potential risk factors predictive of metastatic disease at presentation. METHODS The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify all patients diagnosed with osteosarcoma from 2000 to 2008 and to classify each patient as having metastatic or localized disease at the time of diagnosis. Patient-based characteristics, tumor characteristics, and county-level socioeconomic measures were analyzed to determine which factors were predictive of an increased rate of distant metastatic disease at presentation. These factors were analyzed as univariate characteristics as well as in a multivariate logistic regression model. RESULTS We identified 2017 cases of high-grade osteosarcoma, and 464 (23.0%) of the patients presented with metastatic disease. In the unadjusted logistic regression analysis, patients had increased odds of metastatic disease at presentation if they had an age of sixty years or more (odds ratio [OR] = 2.22; 95% confidence interval [CI], 1.71 to 2.89), had a tumor located in the axial skeleton (OR = 2.47; 95% CI, 1.88 to 3.26), and lived in a county with low socioeconomic status (OR = 1.59; 95% CI, 1.08 to 2.35). These factors remained significant when combined in multivariate models controlling for age, location, and socioeconomic status. For patients with recorded tumor size information (n = 1398), the odds of metastasis at presentation increased by 10% with each additional centimeter of tumor size (OR = 1.10; 95% CI, 1.08 to 1.13). When the patients with missing tumor size information were excluded, socioeconomic status was no longer a significant risk factor for metastasis at presentation in the multivariate model. CONCLUSIONS Osteosarcoma patients with advanced age, a tumor in the axial skeleton, a larger tumor size, and a residence in a less affluent county were more likely to have metastatic disease at presentation.

The Trends in Treatment of Femoral Neck Fractures in the Medicare Population from 1991 to 2008

BACKGROUND We examined trends in the treatment of femoral neck fractures over the last two decades. METHODS We used Medicare Part A administrative data to identify patients hospitalized for closed femoral neck fracture from 1991 to 2008. We used codes from the International Classification of Diseases, Ninth Revision, to categorize treatment as nonoperative, internal fixation, hemiarthroplasty, and total hip arthroplasty. We examined differences in treatment according to hospital hip fracture volume, hospital location (rural or urban), and teaching status. RESULTS Our sample consisted of 1,119,423 patients with intracapsular hip fractures occurring from 1991 to 2008. We found a generally stable trend over time in the percentage of patients managed with nonoperative treatment, internal fixation, hemiarthroplasty, and total hip arthroplasty. We found little difference in surgical treatment across different groups of hospitals (high volume compared with low volume, urban compared with rural, and teaching compared with nonteaching). The percentage of acute care hospitals treating hip fractures remained fairly constant (74.8% in 1991 to 1993 and 69.0% in 2006 to 2008). The median number of hip fractures treated per hospital did not change (thirty-three in 1991 to 1993 and thirty-three in 2006 to 2008). There was no increase in the percentage of fractures treated in high-volume hospitals over time (57.7% in 1991 to 1993 and 57.1% in 2006 to 2008) and little reduction in the percentage of fractures treated in low-volume hospitals (5.8% in 1991 to 1993 and 5.5% in 2006 to 2008). CONCLUSIONS There has been little change in the trends of operative and nonoperative treatment for proximal femoral fractures over the last two decades, and there was little evidence of regionalization of hip fracture treatment to higher-volume hospitals.

Total Knee Arthroplasty Outcomes in Top-Ranked and Non–Top-Ranked Orthopedic Hospitals: An Analysis of Medicare Administrative Data

OBJECTIVE To examine outcomes of Medicare enrollees who underwent primary total knee arthroplasty (TKA) in top-ranked orthopedic hospitals identified through the U.S. News & World Report hospital rankings and 2 comparison groups of hospitals. PATIENTS AND METHODS We used Medicare Part A data to identify patients who underwent primary TKA between January 1, 2006, and December 31, 2006, in 3 groups of hospitals: (1) top-ranked according to U.S. News & World Report rankings; (2) not top-ranked, but eligible for ranking; and (3) not eligible for ranking by U.S. News & World Report. We compared the demographics and comorbidity of patients treated in the 3 hospital groups. We examined rates of postoperative adverse outcomes--a composite consisting of hemorrhage, pulmonary embolism, deep vein thrombosis, wound infection, myocardial infarction, or mortality within 30 days of surgery. We also compared 30-day all-cause readmission rates and hospital length of stay (LOS) across groups. RESULTS Our cohort consisted of 48 top-ranked hospitals (performing 10,477 primary TKAs), 288 eligible non-top-ranked hospitals (28,938 TKAs), and 481 hospitals not eligible for ranking (25,297 TKAs). Unadjusted rates of the composite outcome were modestly higher for top-ranked hospitals (4.3%, 455 patients) as compared with non-top-ranked hospitals (4.1%, 1191 patients) and hospitals ineligible for ranking (3.3%, 843 patients) (P<.001), but these differences were no longer significant after accounting for differences in patient complexity. Likewise, there were no significant differences in readmission rates or LOS across groups. CONCLUSION Rates of postoperative complications and readmission and hospital LOS were similar for Medicare patients who underwent primary TKA in top-ranked and non-top-ranked hospitals.

Mortality Rates are Similar after Hip Fractures for Rural and Urban Patients

BackgroundProximal femoral fractures are common in the elderly. The best care depends on expeditious presentation, medical stabilization, and treatment of the condition.Questions/purposesWe investigated the risk of increased mortality in residents of rural communities secondary to inaccessible facilities and treatment delays.Patients and MethodsWe used Medicare Provider Analysis and Review Part A data to identify 338,092 patients with hip fractures. Each patient was categorized as residing in urban, large rural, or small rural areas. We compared the distance traveled, mortality rates, time from admission to surgery, and length of stay for patients residing in each location.ResultsPatients in rural areas traveled substantially farther to reach their treating facility than did urban patients: mean, 34.4 miles for small rural, 14.5 miles for large rural, and 9.3 miles for urban. The adjusted odds ratios for mortality were similar but slightly better for urban patients for in-hospital mortality (small rural odds ratio, 1.05; large rural odds ratio, 1.13). Rural patients had a favorable adjusted odds ratio for 1-year mortality when compared with urban patients (small rural odds ratio, 0.93; large rural odds ratio, 0.96). Rural patients experienced no greater delay in time to surgery or longer hospital length of stay.ConclusionsAlthough patients living in rural areas traveled a greater distance than those living in urban centers, we found no increase in time to surgery, hospital length of stay, or mortality.Level of Evidence Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Intramedullary nails for long bone metastases: why do they fail?

Metastatic disease to long bones is common and often requires stabilization to treat or prevent fracture. Intramedullary fixation is used in many metaphyseal and diaphyseal lesions. The goal of this study was to investigate the causes of and risk factors for reconstructive failure in intramedullary fixation of metastatic disease. We performed a retrospective review of 112 consecutive reconstructions for metastatic disease treated with an isolated intramedullary nail. There were 81 reconstructions in the femur, 25 in the humerus, and 6 in the tibia. All included patients were followed until death or reconstructive failure. All surviving patients had a minimum 2-year follow-up.Ten failures required construct revision. Median time to revision was 17.9 months (range, 3-93 months). The causes of failure included surgeon error, tumor progression, nonunion, and hardware failure. Patients with short survival times (P<.001) or a diagnosis of lung cancer (P=.029) were unlikely to fail. Revision was required in 6 solitary lesions (P=.012), 3 cases of lymphoma (P=.002), 3 cases of progressive renal cell carcinoma (P=.040), and 2 radiation-associated fractures (P=.007).Intramedullary stabilization is a successful operation for appropriate lesions. Failures may be minimized with proper implant selection and surgical technique, resection or curettage of renal cell carcinoma, avoidance of radiation-associated fractures, and overestimating patient survival.

TAZ and YAP are frequently activated oncoproteins in sarcomas

TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP.

The use of locking plates in orthopedic oncology reconstructions.

Locking-plate systems are believed to provide better purchase in poor quality bone and equivalent purchase with fewer screws, and also to limit screw pullout by functioning as fixed-angle devices. This retrospective study examined 25 oncologic reconstructions involving locking plates. There were 8 cases of open reduction and internal fixation for pathologic fracture or nonunion and 17 limb-salvage reconstructions. Mean follow-up was 18.2 months with 92% of constructs intact (there were 2 implant-related failures). Locking plates offer advantages that can be useful in orthopedic oncology reconstructions. The long-term performance and mechanisms of failure of these implants remains to be defined.

Anchored multiplex PCR for targeted next-generation sequencing reveals recurrent and novel USP6 fusions and upregulation of USP6 expression in aneurysmal bone cyst

Primary aneurysmal bone cyst (ABC) is a neoplastic process due to recurrent translocations involving the USP6 gene. By fluorescence in situ hybridization, up to 69% of primary ABCs harbored USP6 translocations; no USP6 translocation was found in secondary ABC or giant cell tumor of bone (GCT). GCT can recur locally, metastasize to the lungs in some cases, and rarely undergo malignant transformation. Differentiating primary ABC from its mimics is important for treatment and prognosis. We evaluated USP6 fusion and expression in 13 cases of primary and 1 case of secondary ABC, and 9 cases of GCT using nucleic acid extracted from formalin‐fixed, paraffin‐embedded tissue and a next generation sequencing (NGS)‐based assay. USP6 fusions including 7 novel fusions and USP6 transcripts were identified in all 13 primary ABCs. Nine cases with strong evidence of fusions showed high levels of USP6 transcripts by reverse transcription‐PCR (RT‐PCR). The remaining four had no detectable USP6 expression by a first‐round of RT‐PCR but the presence of USP6 transcripts was identified by a second‐round, nested PCR. The major fusions were confirmed by RT‐PCR followed by Sanger sequencing. No USP6 fusion or transcript was detected in any of the GCTs or the case of secondary ABC by NGS or by two rounds of PCR. All USP6 translocations resulted in fusion of the entire USP6 coding sequence with promoters of the fusion gene leading to upregulation of USP6 transcription, which is likely the underlying mechanism for ABC oncogenesis.