Background Osteosarcoma is the most common primary malignant bone tumor in many countries, with metastatic disease responsible for most patient deaths. This study compares the prevalence of metastatic osteosarcoma at diagnosis across countries to inform the critical question of whether diagnostic delay or tumor biology drives metastases development prior to diagnosis. Procedure A literature search of the PubMed database was conducted to compare the prevalence of metastatic disease at the time of OS diagnosis between countries. A pooled prevalence with 95% confidence intervals was calculated for each study meeting inclusion criteria. Studies were grouped for analysis based on human development index (HDI) scores. Results Our analysis found an 18% (95% CI: 15%, 20%) average global pooled proportion of metastasis at osteosarcoma diagnosis. The average prevalence of metastasis at diagnosis increased as HDI groupings decreased, with very high HDI, high HDI, and medium/ low HDI groups found to be 15% (95% CI: 13%, 17%), 20% (95% CI: 14%, 28%), and 31% (95% CI: 15%, 52%), respectively. Conclusions Our evidence suggests there is a biological baseline for metastatic OS at diagnosis, which is observed in countries with very high HDI. In countries with medium/ low HDI, where there are more barriers to accessing healthcare, the higher prevalence of metastasis may result from treatment delay or an artificial prevalence inflation due to patients with less severe symptoms not presenting to clinic. Additional research in countries with medium/ low HDI may reveal that earlier detection and treatment could improve patient outcomes in those countries.
Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.
Osteosarcomas are characterized by highly disrupted genomes. Although osteosarcomas lack common fusions, we find evidence of many tumour specific gene-gene fusion transcripts, likely due to chromosomal rearrangements and expression of transcription-induced chimeras. Most of the fusions result in out-of-frame transcripts, potentially capable of producing long novel protein sequences and a plethora of neoantigens. To identify fusions, we explored RNA-sequencing data to obtain detailed knowledge of transcribed fusions, by creating a novel program to compare fusions identified by deFuse to de novo transcripts generated by Trinity. This allowed us to confirm the deFuse results and identify unusual splicing patterns associated with fusion events. Using various existing tools combined with this custom program, we developed a pipeline for the identification of fusion transcripts applicable as targets for immunotherapy. In addition to identifying candidate neoantigens associated with fusions, we were able to use the pipeline to establish a method for measuring the frequency of fusion events, which correlated to patient outcome, as well as highlight some similarities between canine and human osteosarcomas. The results of this study of osteosarcomas underscores the numerous benefits associated with conducting a thorough analysis of fusion events within cancer samples.
Background Canine osteosarcoma (OS) is a relevant spontaneous model for human OS. Identifying similarities in clinical characteristics associated with metastasis at diagnosis in both species may substantiate research aimed at using canine OS as a model for identifying mechanisms driving distant spread in the human disease. Methods This retrospective study included dog OS cases from three academic veterinary hospitals and human OS cases from the Surveillance, Epidemiology, and End Results program. Associations between clinical factors and metastasis at diagnosis were estimated using logistic regression models. Results In humans, those with trunk tumors had higher odds of metastasis at diagnosis compared to those with lower limb tumors (OR = 2.38, 95% CI: 1.51, 3.69). A similar observation was seen in dogs with trunk tumors compared to dogs with forelimb tumors (OR = 3.28, 95% CI 1.36, 7.50). Other associations were observed in humans but not in dogs. Humans aged 20‐29 years had lower odds of metastasis at diagnosis compared to those aged 10‐14 years (OR = 0.67, 95% CI: 0.47, 0.96); every 1‐cm increase in tumor size was associated with a 6% increase in the odds of metastasis at diagnosis (95% CI: 1.04, 1.08); compared to those with a white, non‐Hispanic race, higher odds were observed among those with a black, non‐Hispanic race (OR: 1.51, 95% CI: 1.04, 2.16), and those with a Hispanic origin (OR 1.35, 95% CI: 1.00, 1.81). Conclusion A common mechanism may be driving trunk tumors to progress to detectable metastasis prior to diagnosis in both species.
Introduction: Active Compression Decompression cardiopulmonary resuscitation with an impedance threshold device (ACD+ITD CPR) is available for use in the United States. However, little is known regarding integration of this CPR system into a large urban prehospital system with short response times, routine use of mechanical CPR and ITD, and transport of patients to cardiac arrest centers. This is an ongoing before and after study of the implementation of ACD+ITD CPR in non-traumatic cardiac arrest cases 6 months pre and post protocol change. Hypothesis: Neurologically intact rates of survival, defined by Cerebral Performance Category (CPC) score of 1 or 2, would be higher post protocol. Methods: Basic life support first responders (n = 420) and paramedics (n = 207) underwent training including didactic and hands-on sessions to learn ACD+ITD CPR. The protocol included ACD+ITD CPR initially, with the option to transition to mechanical CPR at 15 minutes. Demographics, response time, CPR duration, initial rhythm, signs of perfusion during CPR, and return of spontaneous circulation (ROSC) were recorded prospectively by first responders. Chart review was performed to determine survival to hospital admission and CPC score at discharge. Results: Training occurred October 2016 to March 2017, with protocol change on May 1, 2017. Cases from November 2016-April 2017 (n = 136) and May 2017-November 2017 (n= 103) were reviewed. Complete data were available for 128 subjects pre-protocol change (94%) and 96 subjects (94%) post. Age, gender, response time, rhythm, total CPR time, and rates of bystander CPR and witnessed arrest were similar between groups. Post protocol change, 87% (89/102) received ACD+ITD CPR with median ACD+ITD CPR time of 15 minutes (range 2-300). Pre-protocol, 6/128 (4.7%) subjects survived with CPC score 1 or 2, versus 8/96 (13.5%) subjects post (difference 8.8%, 95% CI 1%-17%). ROSC rates were similar (pre: 54/127, 42.5% post: 44/93, 47%, difference 4.8%, 95% CI -8% - 18%) Conclusions: The change in protocol was straightforward with a high rate of adherence of the system for the recommended duration of therapy. Results are suggestive of a higher rate of neurological survival with the routine use of ACD+ITD CPR in a small cardiac arrest patient population.
The purpose of this study is to characterize the role of Slit-Robo GTPase-Activating Protein 2 (SRGAP2) in osteosarcoma (OS) metastasis. OS is the most common primary bone tumor and the eighth leading pediatric cancer. Despite combined therapies, treatment failure is experienced within 5 years of diagnosis by over 40% of patients, generally due to metastatic disease. Using the conditional Sleeping Beauty transposon mutagenesis system, our laboratory recently identified candidate tumor promoting genes in transgenic mice that develop OS, including the potential tumor suppressor SRGAP2 involved in regulating actin dynamics. We hypothesized that loss of SRGAP2 would increase the metastatic potential of OS cell lines in vitro and in vivo, whereas gain would decrease metastatic potential. Gene expression was amplified with a stably integrated, tetracycline-inducible over expression vector containing SRGAP2 cDNA and gene silencing was accomplished with a clustered regularly interspaced short palindromic repeat (CRISPR) targeting the gene. Studies were conducted in the well-characterized murine osteosarcoma cell lines K12 and its more aggressive derivative K7M2 and human osteosarcoma cell lines HOS and its more aggressive derivative 143B. Compared to luciferase-controls, overexpression and knockout of SRGAP2 had no effect on cell proliferation in K12, K7M2, HOS, and 143B (n = 4). A reduction of soft agar colony formation was observed in knockout cell lines but not in cell lines with SRGAP2 overexpression for K12 and 143B (n = 3); HOS cell lines did not form colonies in soft agar. Interestingly, overexpression of SRGAP2 decreased wound-healing closure in 143B and K12 lines, but increased closure time in HOS (n = 4). Tail vein injections in NRG mice are currently being investigated. Overexpression of SRGAP2 in K12 decreased development of macrometastases in lungs, whereas knockout of SRGAP2 eliminated gross detection of lung masses (n = 3). Future studies include imaging fixed cells to determine if SRGAP2 knockout and overexpression affects cell morphology and completing studies with K7M2 lines. These results suggest that SRGAP2 has a biphasic phenotype in osteosarcoma cell lines, with an optima in expression for efficient metastasis. It's dual role of deforming cell membranes independent of its ability to activate Rac GTPases and alter actin dynamics may be responsible for the observed results. Citation Format: Tracy Marko, Ghaidan Shamsan, David Largaespada. SRGAP2 expression levels may induce a biphasic metastatic phenotype in osteosarcoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1621.
Background: Rates of neurologically intact survival after cardiac arrest remain abysmal. Neuro-prognostication intra-arrest is challenging, with few real-time factors that can be used to determine patient prognosis. During the implementation of a new cardiopulmonary resuscitation (CPR) protocol in a large urban pre-hospital system, first responders prospectively recorded the presence of signs of perfusion during CPR. Hypothesis: Positive signs of perfusion would be a predictor of a good neurologic outcome in this observational study, as defined by Cerebral Performance Category (CPC) Score of 1 or 2. Methods: Basic life support first responders (n = 420) and paramedics (n = 207) underwent training including didactic and hands-on sessions to learn the new protocol, which included active compression-decompression CPR with an impedance threshold device. In addition to patient demographics and circumstances of cardiac arrest, signs of perfusion during CPR were prospectively recorded and included improved color, pulse during CPR, gasping, and movement during CPR. Chart review was performed to determine CPC score at discharge. Data were analyzed using descriptive statistics and calculation of unadjusted odds ratios. Results: The new protocol began May 1, 2017. Cases from May 2017-November 2017 (n= 102) were reviewed, with complete data available for 96 patients (94%). The median age was 56 (range 25-97), 54/91 (59%) male, 43/102 (42%) witnessed, 31/90 (34%) shockable rhythm, and 51/102 (50%) receiving bystander CPR. Improved color during CPR was seen in 23/102 (23%), pulse during CPR in 17/102 (17%), gasping in 18/102 (18%), and movement during CPR in 5/102 (5%). Any sign of perfusion during CPR was seen in 47/102 (46%), and 13/96 (13.5%) had a CPC score of 1 or 2 at discharge. The unadjusted OR for any sign of perfusion during CPR for a CPC score of 1 or 2 was 26 (95% CI 3 - 213) and for any sign of perfusion during CPR for ROSC was 9 (95% CI 3 - 24). Conclusions: Positive signs of perfusion during CPR noted by first responders strongly predicted ROSC and neurologically intact survival in this small sample. This suggests the importance of prospectively recording signs of perfusion during resuscitation, and communicating these observations during transfer of care.
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