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2.  Editorial: Limb Preservation: Past and Present 
PMCID: PMC3563813  PMID: 23344850
3.  EWSR1-PBX3: A Novel Gene Fusion in Myoepithelial Tumors 
Genes, chromosomes & cancer  2014;54(2):63-71.
The genetics of myoepithelial tumors (ME) of soft tissue and bone have recently been investigated, with EWSR1 related gene fusions being seen in approximately half of the tumors. The fusion partners of EWSR1 so far described include POU5F1, PBX1, ZNF444 and, in a rare case, ATF1. We investigated by RNA sequencing an index case of EWSR1-rearranged ME of the tibia, lacking a known fusion partner, and identified a novel EWSR1-PBX3 fusion. The fusion was further validated by reverse transcriptase polymerase chain reaction (RT-PCR) and Fluorescence In Situ hybridization (FISH). To evaluate if this is a recurrent event, an additional cohort of 22 EWSR1-rearranged ME cases lacking a fusion partner were screened by FISH for abnormalities in PBX3 gene. Thus 2 additional cases were identified showing an EWSR1-PBX3 gene fusion. One of them was also intra-osseous involving the ankle, while the other occurred in the soft tissue of the index finger. The morphology of the EWSR1-PBX3 fusion positive cases showed similar findings, with nests or sheets of epithelioid to spindle cells in a partially myxoid to collagenous matrix. All the 3 cases showed expression of S100 and EMA by immunohistochemistry. In summary, we report a novel EWSR1-PBX3 gene fusion in a small subset of ME, thereby expanding the spectrum of EWSR1-related gene fusions seen in these tumors. This gene fusion seems to occur preferentially in skeletal ME, with 2 of the 3 study cases occurring in intraosseous locations.
PMCID: PMC4268355  PMID: 25231231
Myoepithelial tumor; EWSR1; PBX3
4.  Randomized Controlled Trial of Interval-Compressed Chemotherapy for the Treatment of Localized Ewing Sarcoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2012;30(33):4148-4154.
Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.
Patients and Methods
This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750 × 106/L and a platelet count greater than 75 × 109/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at (identifier: NCT00006734).
Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P = .048). The toxicity of the regimens was similar.
For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.
PMCID: PMC3494838  PMID: 23091096
5.  Erratum to: Kevin D. Harrington MD (1938–2013) 
PMCID: PMC3773114
7.  Obituary: Kevin D. Harrington MD (1938–2013) 
PMCID: PMC3705034
9.  Surgical Technique: Computer-generated Custom Jigs Improve Accuracy of Wide Resection of Bone Tumors 
Manual techniques of reproducing a preoperative plan for primary bone tumor resection using rudimentary devices and imprecise localization techniques can result in compromised margins or unnecessary removal of unaffected tissue. We examined whether a novel technique using computer-generated custom jigs more accurately reproduces a preoperative resection plan than a standard manual technique.
Description of Technique
Using CT images and advanced imaging, reverse engineering, and computer-assisted design software, custom jigs were designed to precisely conform to a specific location on the surface of partially skeletonized cadaveric femurs. The jigs were used to perform a hemimetaphyseal resection.
We performed CT scans on six matched pairs of cadaveric femurs. Based on a primary bone sarcoma model, a joint-sparing, hemimetaphyseal wide resection was precisely outlined on each femur. For each pair, the resection was performed using the standard manual technique on one specimen and the custom jig-assisted technique on the other. Superimposition of preoperative and postresection images enabled quantitative analysis of resection accuracy.
The mean maximum deviation from the preoperative plan was 9.0 mm for the manual group and 2.0 mm for the custom-jig group. The percentages of times the maximum deviation was greater than 3 mm and greater than 4 mm was 100% and 72% for the manual group and 5.6% and 0.0% for the custom-jig group, respectively.
Our findings suggest that custom-jig technology substantially improves the accuracy of primary bone tumor resection, enabling a surgeon to reproduce a given preoperative plan reliably and consistently.
PMCID: PMC3706671  PMID: 23292886
10.  Trends in the Surgical Treatment of Pathologic Proximal Femur Fractures Among Musculoskeletal Tumor Society Members 
Several strategies for the treatment of pathologic proximal femur fractures are practiced but treatment outcomes have not been rigorously compared.
Major variations in the use of intramedullary fixation, extramedullary/plate-screw fixation, and endoprosthetic reconstruction techniques for pathologic proximal femur fractures in patients with skeletal metastases are reported. The clinical and surgical variables that influence this choice differ among treating surgeons. To characterize the technique preferences and to identify areas of consensus regarding specific clinical presentations, we administered an online survey to the Musculoskeletal Tumor Society (MSTS) membership. We also tested whether responses correlated with the respondents’ years in practice and asked about the indications for wide tumor resection and the role of tumor debulking and adjuvant cementation.
A 10-minute, web-based survey was sent via email to 244 MSTS members. The survey queried participants’ musculoskeletal oncology training and experience and presented case scenarios illustrating different combinations of four variables that influence decision-making: cancer type, estimated patient survival, fracture displacement, and anatomic region of involvement.
Forty-one percent (n = 98) of MSTS members completed the survey. Intramedullary nail fixation (IMN; 45%) and proximal femur resection and reconstruction (34%) were the most commonly recommended techniques followed by long-stem cemented hemiarthroplasty/cemented hemiarthroplasty (15%) and open reduction and internal fixation (7%). Most respondents (56%) recommended use of cementation with IMN. Differences of opinion on recommended treatment were associated with variations in cancer type, fracture displacement, and anatomic region of involvement.
Our online survey showed a trend among MSTS members for selecting IMN and arthroplasty-related techniques to treat pathologic fractures of the proximal femur, but major differences in preferred operative technique exist. Prospective studies are needed to develop consistent, evidence-based treatment recommendations.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-012-2724-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3706680  PMID: 23247815
11.  Histopathologic and Radiologic Assessment of Chemotherapeutic Response in Ewing's Sarcoma: A Review 
Sarcoma  2012;2012:357424.
Ewing's sarcoma is a highly malignant tumor that metastasizes rapidly and is thus associated with a low survival rate. The intensification of chemotherapy has been shown to improve the overall survival of patients with Ewing's sarcoma. However, intensified chemotherapy can lead to increased toxicity or even the development of secondary malignancies. The stratification of patients with Ewing's sarcoma into “good” and “poor” responders may help guide the administration of progressively more intensified chemotherapy. Thus, an accurate assessment of the chemotherapeutic response, as well as the extent of chemotherapy-induced tumor necrosis, is critical for avoiding potential treatment-related complications in these patients. This paper reviews the methods currently used to evaluate chemotherapeutic response in Ewing's sarcoma, focusing specifically on histopathologic and imaging analyses, and discusses novel therapies and imaging methods that may help improve the overall survival of these patients.
PMCID: PMC3329737  PMID: 22550418
12.  Making a Case for the Socioeconomic Determinacy of Survival in Osteosarcoma 
The literature on osteosarcoma survival generally focuses on tumor and treatment variables, although it is unclear whether and how ethnic and socioeconomic factors might influence survival.
We therefore investigated the relative contribution of socioeconomic influences together with more traditional tumor-specific factors on osteosarcoma survival.
We performed survival analyses on two national databases in two countries. Using multivariable analyses, we compared these with corresponding institution-specific survival to determine if socioeconomic factors might impact osteosarcoma survival.
East Asian descent, state-specific treatment, female sex, treatment in the 1990s, low-grade disease, intracompartmental disease, small size, wide resections as opposed to forequarter or hindquarter amputations, and single primaries were good prognostic factors. Survival was better in the more affluent states. Males were affected at an older age than females. Blacks tended to have larger tumors, although their overall survival was similar to whites. East Asians were more likely to be treated in the 1990s with wide resections for smaller tumors and were located around states associated with good treatment. East Asians in Singapore and the United States had the same survival. Survival in East Asians in Singapore was similar to that of other races. The provision of health care for osteosarcoma varies greatly across the United States but is uniform in the socialized medical system in Singapore. Hence, the observed differences in the United States were likely the result of socioeconomic factors.
Our analysis suggests ethnic and economic bias may influence survival in osteosarcoma and should receive greater attention in the collective literature on survival analyses.
Level of Evidence
Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3563779  PMID: 22972655
13.  Treating Metastatic Disease: Which Survival Model Is Best Suited for the Clinic? 
To avoid complications associated with under- or overtreatment of patients with skeletal metastases, doctors need accurate survival estimates. Unfortunately, prognostic models for patients with skeletal metastases of the extremities are lacking, and physician-based estimates are generally inaccurate.
We developed three types of prognostic models and compared them using calibration plots, receiver operating characteristic (ROC) curves, and decision curve analysis to determine which one is best suited for clinical use.
A training set consisted of 189 patients who underwent surgery for skeletal metastases. We created models designed to predict 3- and 12-month survival using three methods: an Artificial Neural Network (ANN), a Bayesian Belief Network (BBN), and logistic regression. We then performed crossvalidation and compared the models in three ways: calibration plots plotting predicted against actual risk; area under the ROC curve (AUC) to discriminate the probability that a patient who died has a higher predicted probability of death compared to a patient who did not die; and decision curve analysis to quantify the clinical consequences of over- or undertreatment.
All models appeared to be well calibrated, with the exception of the BBN, which underestimated 3-month survival at lower probability estimates. The ANN models had the highest discrimination, with an AUC of 0.89 and 0.93, respectively, for the 3- and 12-month models. Decision analysis revealed all models could be used clinically, but the ANN models consistently resulted in the highest net benefit, outperforming the BBN and logistic regression models.
Our observations suggest use of the ANN model to aid decisions about surgery would lead to better patient outcomes than other alternative approaches to decision making.
Level of Evidence
Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC3563791  PMID: 22983682
14.  Haptic Robot-assisted Surgery Improves Accuracy of Wide Resection of Bone Tumors: A Pilot Study 
Accurate reproduction of the preoperative plan at the time of surgery is critical for wide resection of primary bone tumors. Robotic technology can potentially help the surgeon reproduce a given preoperative plan, but yielding control of cutting instruments to a robot introduces potentially serious complications. We developed a novel passive (“haptics”) robot-assisted resection technique for primary bone sarcomas that takes advantage of robotic accuracy while still leaving control of the cutting instrument in the hands of the surgeon.
We asked whether this technique would enable a preoperative resection plan to be reproduced more accurately than a standard manual technique.
A joint-sparing hemimetaphyseal resection was precisely outlined on the three-dimensionally reconstructed image of a representative Sawbones femur. The indicated resection was performed on 12 Sawbones specimens using the standard manual technique on six specimens and the haptic robotic technique on six specimens. Postresection images were quantitatively analyzed to determine the accuracy of the resections compared to the preoperative plan, which included measuring the maximum linear deviation of the cuts from the preoperative plan and the angular deviation of the resection planes from the target planes.
Compared with the manual technique, the robotic technique resulted in a mean improvement of 7.8 mm of maximum linear deviation from the preoperative plan and 7.9° improvement in pitch and 4.6° improvement in roll for the angular deviation from the target planes.
The haptic robot-assisted technique improved the accuracy of simulated wide resections of bone tumors compared with manual techniques.
Clinical Relevance
Haptic robot-assisted technology has the potential to enhance primary bone tumor resection. Further bench and clinical studies, including comparisons with recently introduced computer navigation technology, are warranted.
PMCID: PMC3563824  PMID: 22911372
15.  Highlights of the ISOLS/MSTS 2009 Meeting: Editorial Comment 
PMCID: PMC2947666  PMID: 20706809
16.  Targeting the Giant Cell Tumor Stromal Cell: Functional Characterization and a Novel Therapeutic Strategy 
PLoS ONE  2013;8(7):e69101.
Giant cell tumor of bone (GCTB) is a benign, locally destructive neoplasm, with tumors comprised of mesenchymal fibroblast-like stromal cells; monocytic, mononuclear cells of myeloid lineage; and the characteristic osteoclast-like, multinucleated giant cells. Hampering the study of the complex interaction of its constituent cell types is the propensity of longstanding, repeatedly passaged cell cultures to undergo phenotypic alteration and loss of osteoclast-inducing capacities. In this study, we employed a novel, single-step technique to purify freshly harvested stromal cells using a CD14-negative selection column. Using 9 freshly harvested GCTB specimens and the purified stromal cell component, we performed analyses for markers of osteoblast lineage and analyzed the capacity of the stromal cells to undergo osteoblastic differentiation and induce osteoclastogenesis in co-cultures with monocytic cells. Successful purification of the CD14-negative stromal cells was confirmed via flow cytometric analysis and immunocytochemistry. Osteogenic media upregulated the expression of osteocalcin, suggesting an osteoblastic lineage of the GCTB stromal cells. The effects of the Wnt pathway agonist, SB415286, and recombinant human bone morphogenetic protein (BMP)-2 on osteoblastogenesis varied among samples. Notably, osteogenic media and SB415286 reversed the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) expression ratio resulting in diminished osteoclastogenic capacity. Recombinant human BMP2 had the opposite effect, resulting in enhanced and sustained support of osteoclastogenesis. Targeting the giant cell tumor stromal cell may be an effective adjunct to existing anti-resorptive strategies.
PMCID: PMC3724882  PMID: 23922683
17.  Epithelioid Hemangioma of Bone and Soft Tissue: A Reappraisal of a Controversial Entity 
The controversy surrounding diagnosis of an epithelioid hemangioma (EH), particularly when arising in skeletal locations, stems not only from its overlapping features with other malignant vascular neoplasms, but also from its somewhat aggressive clinical characteristics, including multifocal presentation and occasional lymph node involvement. Specifically, the distinction from epithelioid hemangioendothelioma (EHE) has been controversial. The recurrent t(1;3)(p36;q25) chromosomal translocation, resulting in WWTR1-CAMTA1 fusion, recently identified in EHE of various anatomic sites, but not in EH or other epithelioid vascular neoplasms, suggests distinct pathogeneses.
We investigated the clinicopathologic and radiologic characteristics of bone and soft tissue EHs in patients treated at our institution with available tissue for molecular testing.
Patients and Methods
Seventeen patients were selected after confirming the pathologic diagnosis and fluorescence in situ hybridization analysis for the WWTR1 and/or CAMTA1 rearrangements. Four patients had multifocal presentation. Most patients with EH of bone were treated by intralesional curettage. None of the patients died of disease and only four patients had a local recurrence.
Our results, using molecular testing to support the pathologic diagnosis of EH, reinforce prior data that EH is a benign lesion characterized by an indolent clinical course with an occasional multifocal presentation and rare metastatic potential to locoregional lymph nodes.
These findings highlight the importance of distinguishing EH from other malignant epithelioid vascular tumors as a result of differences in their management and clinical outcome.
Level of Evidence
Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3314752  PMID: 21948309
Medicine & Public Health; Conservative Orthopedics; Orthopedics; Sports Medicine; Surgery; Surgical Orthopedics; Medicine/Public Health, general
18.  Endoprosthetic Treatment is More Durable for Pathologic Proximal Femur Fractures 
Pathologic proximal femur fractures result in substantial morbidity for patients with skeletal metastases. Surgical treatment is widely regarded as effective; however, failure rates associated with the most commonly used operative treatments are not well defined.
We therefore compared surgical treatment failure rates among intramedullary nailing, endoprosthetic reconstruction, and open reduction-internal fixation when applied to impending or displaced pathologic proximal femur fractures.
Patients and Methods
We retrospectively compared the clinical course of 298 patients who underwent intramedullary nailing (n = 82), endoprosthetic reconstruction (n = 197), or open reduction-internal fixation (n = 19) from 1993 to 2008. Primary outcome was treatment failure, which was defined as reoperation for any reason. Treatment groups were compared for differences in demographic and clinical parameters.
The number of treatment failures in the endoprosthetic reconstruction group (3.1%) was significantly lower than in the intramedullary nailing (6.1%) and open reduction-internal fixation (42.1%) groups. The number of revisions requiring implant exchange also was significantly lower for endoprosthetic reconstruction (0.5%), compared with intramedullary nailing (6.1%) and open reduction-internal fixation (42.1%).
Endoprosthetic reconstruction is associated with fewer treatment failures and greater implant durability. Prospective studies are needed to determine the impact of operative strategy on function and quality of life.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3270160  PMID: 21879407
19.  Comparison between Constrained and Semiconstrained Knee Allograft-Prosthesis Composite Reconstructions 
Sarcoma  2013;2013:489652.
Allograft-prosthesis composite (APC) can restore capsular and ligamentous tissues of the knee sacrificed in a tumor extirpation. We asked if performing APC would restore knee stability and allow the use of nonconstrained arthroplasty while preventing aseptic loosening. We retrospectively compared 50 knee APCs performed with non-constrained revision knee prosthesis (Group 1) with 36 matched APCs performed with a constrained prosthesis (Group 2). In Group 1, the survival rate was 69% at five and 62% at ten years. Sixteen reconstructions were removed due to complications: eight deep infections, three fractures, two instabilities, one aseptic loosening, one local recurrence, and one nonunion. In Group 2, the survival rate was 80% at five and 53% at ten years. Nine reconstructions were removed: 3 due to deep infections, 3 to fractures, and 3 to aseptic loosening. In both groups, we observed more allograft fractures when the prosthetic stem does not bypass the host-donor osteotomy (P > 0.05). Both groups had mainly good or excellent MSTS functional results. Survival rate and functional scores and aseptic loosening were similar in both groups. A rotating-hinge APC is recommended when host-donor soft tissue reconstruction fails to restore knee instability. The use of a short prosthetic stem has a statistical relationship with APC fractures.
PMCID: PMC3586499  PMID: 23476114
20.  Monoclonality of Multifocal Epithelioid Hemangioendothelioma of the Liver by Analysis of WWTR1-CAMTA1 Breakpoints 
Cancer Genetics  2012;205(1-2):12-17.
Like other vascular tumors, epithelioid hemangioendothelioma (EHE) can have multifocal presentation in up to 50% of cases. However, whether multifocal EHE represents an unusual pattern of metastasis or multiple separate primary tumors remains to be elucidated. Our recent identification of WWTR1-CAMTA1 fusion as the genetic hallmark of EHE irrespective of anatomic location was used to clarify this question by comparing the similarity of translocation breakpoints. In our previous study, we found variability of the fusion transcripts of the t(1;3)(p36;q25) translocation among different patients with EHE. Thus, we undertook a molecular analysis of six samples from two patients with multicentric hepatic EHE to test our hypothesis that the presence of identical breakpoints in WWTR1 and CAMTA1 support the monoclonal nature of multifocal EHE. Using RT-PCR and subsequent sequencing we confirmed an identical WWTR1-CAMTA1 fusion transcript product from different nodules in each patient. Our results confirm that multifocal EHE are monoclonal and thus representing metastatic implants of the same neoplastic clone rather than a ‘field-effect’ or synchronous occurrence of multiple neoplastic clones.
PMCID: PMC3361903  PMID: 22429593
vascular tumor; epithelioid hemangioendothelioma; WWTR1-CAMTA1; metastasis; multifocality; monoclonality
21.  Additive Influence of Extracellular pH, Oxygen Tension, and Pressure on Invasiveness and Survival of Human Osteosarcoma Cells 
Frontiers in Oncology  2013;3:199.
Background/Purpose: The effects of chemical and physical interactions in the microenvironment of solid tumors have not been fully elucidated. We hypothesized that acidosis, hypoxia, and elevated interstitial fluid pressure (eIFP) have additive effects on tumor cell biology and lead to more aggressive behavior during tumor progression. We investigated this phenomenon using three human osteosarcoma (OS) cell lines and a novel in vitro cell culture apparatus.
Materials and Methods: U2OS, SaOS, and MG63 cell lines were cultured in media adjusted to various pH levels, oxygen tension (hypoxia 2% O2, normoxia 20% O2), and hydrostatic gage pressure (0 or 50 mmHg). Growth rate, apoptosis, cell cycle parameters, and expression of mRNA for proteins associated with invasiveness and tumor microenvironment (CA IX, VEGF-A, HIF-1A, MMP-9, and TIMP-2) were analyzed. Levels of CA IX, HIF-1α, and MMP-9 were measured using immunofluorescence. The effect of pH on invasiveness was evaluated in a Matrigel chamber assay.
Results: Within the acidic–hypoxic–pressurized conditions that simulate the microenvironment at a tumor’s center, invasive genes were upregulated, but the cell cycle was downregulated. The combined influence of acidosis, hypoxia, and IFP promoted invasiveness and angiogenesis to a greater extent than did pH, pO2, or eIFP individually. Significant cell death after brief exposure to acidic conditions occurred in each cell line during acclimation to acidic media, while prolonged exposure to acidic media resulted in reduced cell death. Furthermore, 48-h exposure to acidic conditions promoted tumor invasiveness in the Matrigel assay.
Conclusion: Our findings demonstrate that tumor microenvironmental parameters – particularly pH, pO2, and eIFP – additively influence tumor proliferation, invasion, metabolism, and viability to enhance cell survival and must be controlled in OS research.
PMCID: PMC3728769  PMID: 23914349
osteosarcoma; tumor microenvironment; hypoxia; acidity; elevated interstitial fluid pressure; carbonic anhydrase IX
22.  Quality of Life Following Amputation or Limb Preservation in Patients with Lower Extremity Bone Sarcoma 
Frontiers in Oncology  2013;3:210.
Purpose: Although functional differences have been described between patients with lower extremity bone sarcoma with amputation and limb-preservation surgery, differences have not clearly been shown between the two groups related to quality of life. The purpose of the study was to determine if there is a difference in overall quality of life in lower extremity bone sarcoma survivors related to whether they had an amputation or a limb-preservation procedure while identifying psychological differences for further evaluation. The main hypothesis was that sparing a person’s limb, as opposed to amputating it, would result in a better quality of life.
Patients and Methods: Eighty-two long-term survivors of lower extremity bone sarcoma were studied to make a comparison of the overall quality of life, pain assessment, and psychological evaluations in limb preservation and amputation patients. Forty-eight patients with limb preservation and thirty-four patients with amputations were enrolled in the study. Validated psychometric measures including the Quality of Life Questionnaire (QLQ), the Minnesota Multiphasic Personality Inventory, and visual analog scales were utilized.
Results: The overall quality of life of patients with limb preservation was significantly higher than patients with amputation (p-value < 0.01). Significant differences were noted in the categories of material well-being, job satisfiers, and occupational relations.
Conclusion: The overall quality of life of patients with limb-preservation appears to be better than for those patients with amputation based on the QLQ in patients surviving lower extremity bone sarcoma. Further analysis needs to verify the results and focus on the categories that significantly affect the overall quality of life.
PMCID: PMC3742996  PMID: 23967402
sarcoma; quality of life; amputation; limb salvage; orthopedic outcomes
23.  External validation of the Bayesian Estimated Tools for Survival (BETS) models in patients with surgically treated skeletal metastases 
BMC Cancer  2012;12:493.
We recently developed two Bayesian networks, referred to as the Bayesian-Estimated Tools for Survival (BETS) models, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases (BETS-3 and BETS-12, respectively). In this study, we attempted to externally validate the BETS-3 and BETS-12 models using an independent, international dataset.
Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centers between 1999 and 2009. These data were applied to the BETS-3 and BETS-12 models, which generated a probability of survival at 3 and 12 months for each patient. Model robustness was assessed using the area under the receiver-operating characteristic curve (AUC). An analysis of incorrect estimations was also performed.
Our dataset contained 815 records with adequate follow-up information to establish survival at 12 months. All records were missing data including the surgeon’s estimate of survival, which was previously shown to be a first-degree associate of survival in both models. The AUCs for the BETS-3 and BETS-12 models were 0.79 and 0.76, respectively. Incorrect estimations by both models were more commonly optimistic than pessimistic.
The BETS-3 and BETS-12 models were successfully validated using an independent dataset containing missing data. These models are the first validated tools for accurately estimating postoperative survival in patients with operable skeletal metastases of the extremities and can provide the surgeon with valuable information to support clinical decisions in this patient population.
PMCID: PMC3556063  PMID: 23098538
Bayesian analysis; Skeletal metastasis; Prognostic model; Postoperative survival
24.  Compress® Knee Arthroplasty Has 80% 10-year Survivorship and Novel Forms of Bone Failure 
Compliant, self-adjusting compression technology is a novel approach for durable prosthetic fixation of the knee. However, the long-term survival of these constructs is unknown.
We therefore determined the survival of the Compress® prosthesis (Biomet Inc, Warsaw, IN, USA) at 5 and 10 actuarial years and identified the failure modes for this form of prosthetic fixation.
We retrospectively reviewed clinical and radiographic records for all 82 patients who underwent Compress® knee arthroplasty from 1998 to 2008, as well as one patient who received the device elsewhere but was followed at our institution. Prosthesis survivorship and modes of failure were determined. Followup was for a minimum of 12 months or until implant removal (median, 43 months; range, 6–131 months); 28 patients were followed for more than 5 years.
We found a survivorship of 85% at 5 years and 80% at 10 years. Eight patients required prosthetic revision after interface failure due to aseptic loosening alone (n = 3) or aseptic loosening with periprosthetic fracture (n = 5). Additionally, five periprosthetic bone failures occurred that did not require revision: three patients had periprosthetic bone failure without fixation compromise and two exhibited irregular prosthetic osteointegration patterns with concomitant fracture due to mechanical insufficiency.
Compress® prosthetic fixation after distal femoral tumor resection exhibits long-term survivorship. Implant failure was associated with patient nonadherence to the recommended weightbearing proscription or with bone necrosis and fracture. We conclude this is the most durable FDA-approved fixation method for distal femoral megaprostheses.
Level of Evidence
Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-012-2635-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3563794  PMID: 23054526
25.  Evaluation of eIF4E Expression in an Osteosarcoma Specific Tissue Microarray 
The ability to define osteosarcoma (OS) patients at greatest risk for metastatic progression and non-responsiveness to conventional therapy is currently not possible. Such biomarkers are needed to predict overall prognosis, probability of metastases at diagnosis, and response to chemotherapy. The tissue microarray (TMA) serves as a powerful tool for detecting and validating protein biomarkers across a variety of patients. We constructed a novel outcome-linked TMA to add to and address shortcomings of currently available osteosarcoma tissue resources. To test the utility of our TMA we surveyed the expression of eukaryotic initiation factor 4E (eIF4E) in osteosarcoma patients using immunohistochemistry. Aberrant regulation of translation initiation is a feature of many cancers. eIF4E is central to initiation of protein synthesis. Its expression and activity have been implicated in tumor formation and potentially malignant and/or metastatic progression in some carcinomas. We found that eIF4E was uniformly expressed in osteosarcoma patient samples. No association was found between eIF4E and outcome in osteosarcoma patients. This novel osteosarcoma TMA provided a facile mechanism to assess the role of a relevant protein biomarker in osteosarcoma.
PMCID: PMC3179611  PMID: 21941146
Tissue microarray; osteosarcoma; eIF4E; immunohistochemistry

Results 1-25 (47)