Novel candidate metastasis-associated genes for synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with poor prognosis due to late recurrence and metastasis. Metastasis is an important prognostic factor of SS. This study aimed to identify the core genes and mechanisms associated with SS metastasis. Microarray data for GSE40021 and GSE40018 were obtained from the Gene Expression Omnibus database. 186 differentially expressed genes (DEGs) were identified. The biological functions and signalling pathways closely associated with SS metastasis included extracellular matrix (ECM) organization and ECM-receptor interaction. Gene set enrichment analysis showed that the terms cell cycle, DNA replication, homologous recombination and mismatch repair were significantly enriched in the metastasis group. Weighted gene co-expression network analysis identified the most relevant module and 133 hub genes, and 31 crossover genes were identified by combining DEGs. Subsequently, four characteristic genes, EXO1, NCAPG, POLQ and UHRF1, were identified as potential biomarkers associated with SS metastasis using the least absolute shrinkage and selection operator algorithm and validation dataset verification analysis. Immunohistochemistry results from our cohort of 49 patients revealed visible differences in the expression of characteristic genes between the non-metastatic and metastatic groups. Survival analysis indicated that high expression of characteristic genes predicted poor prognosis. Our data revealed that primary SS samples from patients who developed metastasis showed activated homologous recombination and mismatch repair compared to samples from patients without metastasis. Furthermore, EXO1, NCAPG, POLQ and UHRF1 were identified as potential candidate metastasis-associated genes. This study provides further research insights and helps explore the mechanisms of SS metastasis.

Fluoroscopic Percutaneous Fixation of Periacetabular Metastatic Cancer: The Tripod Technique.

There are an increasing number of patients who present with metastatic bone disease as the survival of patients with cancer improves in recent decades. The pelvis is the second most common site for skeletal metastases. Metastatic lesions in the pelvis can be largely divided into periacetabular lesions (Enneking zone II) and non-periacetabular lesions (zones I, III, and IV). Traditionally, patients with a symptomatic zone II lesion are treated with a cemented total hip arthroplasty (THA) using variations on the traditional Harrington method. These open surgeries are accompanied by many inherent risks. Both a prolonged recovery and wide range of potential complications may delay or interrupt the adjuvant radiation and systemic therapy. It was observed that the articular surface of the hip joint was often intact and that the femoral side was frequently not involved in these patients. A novel minimally invasive technique for hip joint preservation has recently been developed. Three large-bore cannulated screws are placed percutaneously under fluoroscopy in a tripod configuration to reinforce the mechanical axis of the acetabulum. Increased stability improves pain control and permits immediate weight bearing. When the disease progresses, this construct can be easily converted to a cemented THA using the tripod screws as rebar to support an acetabular cup, as part of a staged Harrington procedure. This approach is technically demanding. A detailed guide for the tripod technique should encompass indications, preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, modifications, postoperative care, and subsequent conversion to a cemented THA, if needed.

A graphic guide to the percutaneous tripod acetabular reconstruction for metastatic cancer.

Symptomatic peri-acetabular metastatic lesions are often treated with open surgery such as modified Harrington procedures. In an effort to avoid surgical complications inherently associated with open surgical approaches, we developed and recently reported a novel Tripod percutaneous screw technique. The tripod technique is minimally invasive and was found to yield excellent outcomes regarding both pain control and functionality. The procedure is performed in a standard operative theater using fluoroscopic guided percutaneous screws. Despite the simplicity of intraoperative set-up and instrumentation, it is technically demanding. Obtaining the correct fluoroscopic views and troubleshooting intraoperative hurdles can be challenging for even an experienced orthopedic surgeon. The technique and bony conduits were previously described in the trauma literature, however, there are key points of difference in the setting of metastatic disease. Here we provide a compilation of a stepwise graphic guide for the tripod model in the setting of metastatic peri-acetabular lesions, as well as the tips and tricks based on our own experience. These encompass preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, postoperative care, and subsequent conversion to a cemented total hip arthroplasty, if needed.

Wnt Signaling in Osteosarcoma.

Wnt molecules are a class of cysteine-rich secreted glycoproteins that participate in various developmental events during embryogenesis and adult tissue homeostasis. Since its discovery in 1982, the roles of Wnt signaling have been established in various key regulatory systems in biology. Wnt signals exert pleiotropic effects, including mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway in humans has been shown to be involved in a wide variety of disorders including colon cancer, sarcoma, coronary artery disease, tetra-amelia, Mullerian duct regression, eye vascular defects, and abnormal bone mass. The canonical Wnt pathway functions by regulating the function of the transcriptional coactivator ß-catenin, whereas noncanonical pathways function independent of ß-catenin. Although the role of Wnt signaling is well established in epithelial malignancies, its role in mesenchymal tumors is more controversial. Some studies have suggested that Wnt signaling plays a pro-oncogenic role in various sarcomas by driving cell proliferation and motility; however, others have reported that Wnt signaling acts as a tumor suppressor by committing tumor cells to differentiate into a mature lineage. Wnt signaling pathway also plays an important role in regulating cancer stem cell function. In this review, we will discuss Wnt signaling pathway and its role in osteosarcoma.

Epidemiology, Therapeutic Strategies, Outcomes, and Complications of Pathologic Fractures.

Much can be learned about the epidemiology of metastatic disease of bone through large databases. Secondary data analyses add substantial knowledge of the incidence, prevalence, cost, complications, risk factors, and treatment variability by using modern statistical methods in a large patient cohort. Investigators must be aware of the intentions of these data sources as well as the limitations in any conclusions drawn. Large databases are primarily beneficial in generating hypotheses and will likely continue to be an important source of information. For the general orthopaedist, surgical management of metastatic skeletal disease can be a challenging problem with many potential risks. Complications are often encountered and can be influenced by the patient's medical conditions, stage of disease, and the selected surgical procedure. Patients diagnosed with skeletal metastases are often at higher risk of having perioperative complications, such as infection and thromboembolism, than is the general population. A case-based approach highlights potential risks with examples of common scenarios that can arise.

Neoadjuvant radiation therapy for the management of myoepithelial carcinoma of the upper extremity.

Myoepithelial tumors of the soft tissue are a rare tumor displaying myoepithelial elements and lacking obvious ductal differentiation. The rarity of these precludes any evidence-based consensus regarding optimal management. Nevertheless, the current approach to these lesions begins with amputation or complete excision. The efficacy of neoadjuvant or adjuvant radiation therapy or chemotherapy has not been established. Here, we present the first report to the authors' knowledge of neoadjuvant radiation therapy for the treatment of this rare soft tissue neoplasm and review the management and outcomes of published cases of myoepithelial carcinoma. A patient with a soft tissue myoepithelial carcinoma that declined both amputation and chemotherapy was treated with neoadjuvant radiation therapy and wide surgical excision followed by a brachytherapy boost to the resected tumor bed. Neoadjuvant radiation therapy resulted in an excellent response with extensive treatment-related changes consisting predominantly of fibrosis, hyalinization and hemorrhage and only 10% residual viable myoepithelial carcinoma present in the surgical specimen.

Pediatric oncologist willingness to offer germline TP53 testing in osteosarcoma.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by mutations in the tumor-suppressor gene TP53. Osteosarcoma is a sentinel cancer in LFS. Prior studies using Sanger sequencing platforms have demonstrated that 3% of individuals with osteosarcoma harbor a mutation in TP53. New data from next-generation sequencing have demonstrated that 3.8% of patients with osteosarcoma have a known pathogenic variant, and an additional 5.7% carry exonic variants of unknown significance in TP53. METHODS: Pediatric oncologists were e-mailed an anonymous 18-question survey assessing their willingness to offer TP53 germline testing to a child with osteosarcoma with or without a family history, and they were evaluated for changes in their choices with the prior data and the new data. RESULTS: One hundred seventy-seven pediatric oncologists (22%) responded to the survey. Respondents were more likely to offer TP53 testing to a patient with a positive family history (77.4% vs 12.4%; P < .0001). Significantly more providers responded that they would offer TP53 testing once they were provided with the new data (25.4% vs 12.4%; P = .0038). The proportion of providers who responded that they were unsure increased significantly when they were presented with the new data (25.4% vs 10.2%; P = .0002). Potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage were important factors influencing a provider's decision to offer TP53 testing. CONCLUSIONS: Recent data increase the proportion of providers willing to offer testing, and this suggests concern on the part of pediatric oncologists that variants of unknown significance may be disease-defining in rare cancers. Cancer 2018;124:1242-50. © 2018 American Cancer Society.

Provider views on the management of Ewing sarcoma of the spine and pelvis.

BACKGROUND: Curative therapy for ES requires both chemotherapy and local control of primary tumor. There is no universally accepted standard approach to local control modalities. This survey was conducted to determine practice patterns and factors influencing the choice to offer various local control modalities to patients with ES of the spine and pelvis. METHODS: The survey consisted of four scenarios involving a 15-year-old girl who presented with Ewing sarcoma of thoracic vertebra, sacrum, iliac wing, and acetabulum with or without neurologic compromise. The questionnaire was sent to oncologists, orthopedic surgeons, and radiation oncologists, asking their recommendations for local control modality. RESULTS: Among 94 respondents, radiotherapy was most frequently chosen for sacral tumors (68.1%) and T10 vertebral tumors (46.2%) whereas surgery was preferred for iliac wing pelvic tumors (45.7%) and acetabular tumors (43.6%). Orthopedic surgeons were significantly more likely to offer surgery than radiation oncologists (OR 3.07, 95%CI 1.37-6.88, P = 0.007). Providers outside North America were more likely to offer combined surgery plus radiotherapy (OR 10.58, 95%CI 5.41-20.70, P < 0.001). CONCLUSION: Considerable heterogeneity exists in local control modalities for Ewing sarcoma of the spine and pelvis. Specialty and location of practice may influence treatment recommendations.

Can Navigation-assisted Surgery Help Achieve Negative Margins in Resection of Pelvic and Sacral Tumors?

BACKGROUND: Navigation-assisted resection has been proposed as a useful adjunct to resection of malignant tumors in difficult anatomic sites such as the pelvis and sacrum where it is difficult to achieve tumor-free margins. Most of these studies are case reports or small case series, but these reports have been extremely promising. Very few reports, however, have documented benefits of navigation-assisted resection in series of pelvic and sacral primary tumors. Because this technology may add time and expense to the surgical procedure, it is important to determine whether navigation provides any such benefits or simply adds cost and time to an already complex procedure. QUESTIONS/PURPOSES: (1) What proportion of pelvic and sacral bone sarcoma resections utilizing a computer-assisted resection technique achieves negative margins? (2) What are the oncologic outcomes associated with computer-assisted resection of pelvic and sacral bone sarcomas? (3) What complications are associated with navigation-assisted resection? METHODS: Between 2009 and 2015 we performed 24 navigation-assisted resections of primary tumors of the pelvis or sacrum. Of those, four were lost to followup after the 2-year postoperative visit. In one patient, however, there was a failure of navigation as a result of inadequate imaging, so nonnavigated resection was performed; the remaining 23 were accounted for and were studied here at a mean of 27 months after surgery (range, 12-52 months). During this period, we performed navigation-assisted resections in all patients presenting with a pelvis or sacral tumor; there was no selection process. No patients were treated for primary tumors in these locations without navigation during this time with the exception of the single patient in whom the navigation system failed. We retrospectively evaluated the records of these 23 patients and evaluated the margin status of these resections. We calculated the proportion of patients with local recurrence, development of metastases, and overall survival at an average 27-month followup (range, 12-52 months). We queried a longitudinally maintained surgical database for any complications and noted which, if any, could have been directly related to the use of the navigation-assisted technique. RESULTS: In our series, 21 of 23 patients had a negative margin resection. In all patients the bone margin was negative, but two with sacral resections had positive soft tissue margins. Six of 23 patients experienced local recurrence within the study period. Three patients died during the study period. Seventeen patients demonstrated no evidence of disease at last recorded followup. We noted three intraoperative complications: one dural tear, one iliac vein laceration, and one bladder injury. Eight patients out of 23 had wound complications resulting in operative débridement. Two patients in the series developed transient postoperative femoral nerve palsy, which we believe were caused by stretch of the femoral nerve secondary to the placement of the reference array in the pubic ramus. CONCLUSIONS: Navigation-assisted resection of pelvic and sacral tumors resulted in a high likelihood of negative margin resection in this series, and we observed relatively few complications related specifically to the navigation. We have no comparison group without navigation, and future studies should indeed compare navigated with nonnavigated resection approaches in these anatomic locations. We did identify a potential navigation-related complication of femoral nerve palsy in this series and suggest careful placement and observation of the reference array during the operative procedure to lessen the likelihood of this previously unreported complication. We suggest it is worthwhile to consider the use of navigation-assisted surgery in resection of tumors of the pelvis and sacrum, but further study will be needed to determine its precise impact, if any, on local recurrence and other oncologic outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Longitudinal follow-up of adult survivors of Ewing sarcoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. METHODS: This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. CONCLUSIONS: With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.

Mechanical analysis of the vascularized fibular graft prosthetic composite (VFGPC) for internal hemipelvectomy reconstruction.

INTRODUCTION: The vascularized fibular graft prosthetic composite (VFGPC) is used for reconstruction after internal hemipelvectomy. The purpose of this study was to create a mathematical model that calculates the mechanical effects of the vascularized fibular graft on the VFGPC. METHODS: The effects of the VFG positioning were calculated based on three-dimensional static analyzes to determine the direction, magnitude, and distribution of the forces through the prosthesis and VFG. The shear stress (SS) and cyclic loads to failure (CLF) were calculated. By varying the location of the VFG on the sacrum the zone of acceptable placement was calculated. RESULTS: Utilization of the VFG decreased the forces through the implant by 15-35% and decreased SS 20-54%, depending on stance. The CLF improved by 94%. The zone of acceptable placement for the VFG was found to be between 0° and 15° of the vertical axis in the sagittal plane and 0° and 30° of the posterior axis in coronal plane. CONCLUSION: Determining the position of the VFG pre-operatively allows for the creation of a customized cutting jig can be utilized to create graft allowing for accurate fibular osteotomies, minimization of ischemia time, and decreased intra-operative handling of the graft.

A case of severe nephrotoxicity associated with long-term dietary supplement use.

Dietary supplements are widely used for their perceived health benefits without side effects and hence have minimal regulation. However, they have been associated with various toxicities including kidney disease. We report a 65-year-old male who had very heavy daily intake of dietary supplements for 3 years. He presented with acute kidney injury and nephrotic-range proteinuria. The renal biopsy showed acute tubular necrosis with vacuolization, acute interstitial nephritis, and secondary membranous nephropathy, consistent with an non-steroidal anti-inflammatory drug (NSAID)-like nephropathy. This was postulated to be related to the cyclooxygenase (COX) inhibitors (anthocyanins) in cherry extract that was a significant part of the patient's dietary supplement use. His proteinuria completely resolved and serum creatinine stabilized after discontinuation of all dietary supplements and a prolonged (5 months) course of prednisone. Clinicians are advised to specifically inquire about dietary supplements, especially cherry extract, as a potential cause of new-onset renal failure and proteinuria.
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Pediatric Oncology Provider Views on Performing a Biopsy of Solid Tumors in Children with Relapsed or Refractory Disease for the Purpose of Genomic Profiling.

BACKGROUND: Patients with relapsed and refractory solid tumors have a poor prognosis. Recent advances in genomic technology have made it feasible to screen tumors for actionable mutations, with the anticipation that this may provide benefit to patients. METHODS: Pediatric oncologists were emailed an anonymous 34-question survey assessing their willingness to offer a rebiopsy to patients with relapsed disease for the purpose of tumor genomic profiling. They were presented with two scenarios evaluating morbidity and invasiveness of the procedures using the clinical examples of medulloblastoma and Ewing sarcoma. RESULTS: A total of 195 pediatric oncologists responded to the questionnaire. Morbidity and invasiveness of the procedure demonstrated significant differences in provider willingness to refer their patients for rebiopsy. The pretest probability was a major variable influencing provider willingness to offer a rebiopsy. Respondents were more likely to offer a rebiopsy if the likelihood was high that the results would have an impact on clinical management than if the biopsy was for histologic confirmation alone (mean 89 vs. 56 %; p = 0.017). Compared with the rate of a rebiopsy for histologic confirmation, significantly fewer providers were willing to offer a rebiopsy if they were led to believe the likelihood of finding an actionable mutation was low (mean 45 vs. 56 %; p = 0.021). CONCLUSION: The scenario showed that the pretest probability of finding an actionable mutation was influential in determining provider willingness to offer a rebiopsy for the purpose of tumor genomic profiling. Further research is warranted to evaluate the benefit of tumor genomic profiling in terms of patient outcomes.

New Developments in the Genetics of Hypertension: What Should Clinicians Know?

It has long been known that genetic factors play a major role in determining an individual's propensity to hypertension. In recent years, there has been major progress towards realizing the goal of identifying the specific genetic factors that lead to alterations in blood pressure. Of particular note, new genes regulating renal sodium handling and aldosterone regulation have been discovered via the study of rare Mendelian disorders. Similarly, a number of large genome-wide association studies have been completed, which have added to our understanding as well. Here, recent progress in the genetics of hypertension will be reviewed, with an emphasis towards highlighting specific areas where clinical practice has already or will soon be affected.

Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.

The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.

SKP2 Knockout in Rb1/p53-Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis.

Osteosarcoma is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in osteosarcoma is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that Skp2 knockout in murine osteosarcoma improved survival and delayed tumorigenesis. Here, we performed RNA sequencing (RNA-seq) on tumors from a transgenic osteosarcoma mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage ("DKO": Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout ("TKO": Osx1-Cre;Rb1lox/lox;p53lox/lox;Skp2-/-), followed by qPCR and immunohistochemistry validation. To investigate the clinical implications of our results, we analyzed a human osteosarcoma patient cohort ("NCI-TARGET OS") with RNA-seq and clinical data. We found large differences in gene expression after SKP2 knockout. Surprisingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors, especially the signature genes for macrophages and to a lesser extent, T cells, B cells, and vascular cells. We also uncovered a set of relevant transcription factors that may mediate these changes. In osteosarcoma patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET osteosarcoma and the TCGA Sarcoma cohorts. Overall, our findings indicate that SKP2 may mediate immune exclusion from the osteosarcoma tumor microenvironment, suggesting that SKP2 modulation in osteosarcoma may induce antitumor immune activation.

Artificial intelligence assisted preoperative planning and 3D-printing guiding frame for percutaneous screw reconstruction in periacetabular metastatic cancer patients.

Background: The percutaneous screw reconstruction technique, known as the "Tripod Technique," has demonstrated favorable clinical outcomes in the management of metastatic periacetabular lesions, as evidenced by our prior investigations and corroborated by independent studies. Nevertheless, there is a steep learning curve in handling this technique, with possible complications such as intraarticular screw placement. Methods: Preoperative pelvic CT scans were acquired before surgery and utilized for the guiding frame design. A convolutional neural network model was trained with annotated data to identify the starting point and trajectory of each potential screw. A model boundary intersection detection technology was used to determine the optimal diameter and length of each screw. A non-rigid registration technology was matched with a prefabricated model of the body surface to design personalized anchoring skin pads. Finally, a polylactic acid-based guiding frame for intraoperative was custom-made with a 3D printer. Results: 12 patients underwent a guiding frame-assisted Tripod procedure for treatment of periacetabular metastatic lesions. An intraoperative CT scan was performed in all cases to confirm screw trajectories. Among 36 screws that were implanted, 26 screws were implanted as designed. The remaining ten screws drifted, but all remained within the intra-osseous conduit without any complications. The mean surgical time was 1.22 h with the guiding frame compared with 2.3 h without the guiding frame. Following the surgical procedure, a noteworthy enhancement in pain management, as evidenced by a reduction in scores on the visual analog scale (p < 0.01), and an improvement in functional status, as assessed through the Eastern Cooperative Oncology Group score (p < 0.01), were observed when compared to the patient's pre-operative condition. Conclusion: This proof-of-concept investigation demonstrates that the amalgamation of AI-assisted surgical planning and additive manufacturing can improve surgical accuracy and shorten surgical duration. While access to this technology is currently constrained during its early stages of development, it is anticipated that these limitations will diminish as the potential of AI and additive manufacturing in facilitating complex orthopedic procedures becomes more evident, leading to a surge in interest and adoption of this approach.

Targeted inhibition of SCFSKP2 confers anti-tumor activities resulting in a survival benefit in osteosarcoma.

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2 triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2 also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

Current practice managements regarding thromboembolic prophylaxis within the pediatric sarcoma patient population.

OBJECTIVE: Children with cancer are approximately 600 times more likely to develop thromboses than the general pediatric population. Current management strategies for children have been extrapolated from adult studies and prophylaxis guidelines remain controversial. The purpose of this study is to survey the current thromboembolic prophylaxis practice methods of physicians treating pediatric sarcoma patients. METHODS: Physicians involved in the care of sarcoma patients were surveyed using a 5-question survey designed to evaluate current clinical practices. RESULTS: Of 107 responding physicians, 67 identified themselves as involved in the treatment of pediatric sarcoma patients. The providers most likely to use any form of deep vein thrombosis prophylaxis were orthopedic surgeons (60%), followed by general surgeons (45%), pediatric oncologists (30%), and medical oncologists (25%). Of the providers polled, 48% use mechanical forms, 20% use chemical forms, and 31% use a combination. CONCLUSIONS: Currently, there is a lack of consensus regarding thromboembolic prophylaxis for pediatric sarcoma patients.

Infection rate following total joint arthroplasty in the HIV population.

The purpose of this study is to review a large series of HIV-infected patients who underwent total joint arthroplasty and identify potential risk-factors for infection. Sixty-nine HIV-infected arthroplasty cases were analyzed with 138 matched controls. Deep infection rate following total hip or knee arthroplasty was 4.4% (3 of 69) among HIV cases compared to 0.72% (1 of 138) among controls, yielding a non-significant 6.22 times increased odds of infection (95% CI 0.64-61.0, P=0.11). Kaplan-Meier survival curves for infection free survival and revision free survival revealed non-significantly decreased survival in HIV cases compared to controls (P=0.06 and P=0.09). Our results suggest that the rate of early joint infection following primary total joint arthroplasty in the HIV-infected population is lower than reported in a number of previously published studies.