Disparities in clinical trial enrollment at a Canadian comprehensive cancer center: A 15-year retrospective study.

INTRODUCTION: Disparities in clinical trials (CTs) enrollment perpetuate inequities in treatment access and outcomes, but there is a paucity of Canadian data. The objective of this study was to examine disparities in cancer CT enrollment at a large Canadian comprehensive cancer center. METHODS: Retrospective study of CT enrollment among new patient consultations from 2006 to 2019, with follow-up to 2021 (N = 154,880), with the primary outcome of enrollment as a binary variable. Factors associated with CT enrollment were evaluated using multivariable Bayesian hierarchical logistic regression with random effects for most responsible physician (MRP) and geography, adjusted for patient characteristics (sex, age, language, geography, and primary care provider [PCP]), area-level marginalization (residential instability, material deprivation, dependency, and ethnic concentration), disease (cancer site and stage), and MRP (department, sex, language, and training). A sensitivity analysis of the cumulative incidence of enrollment was conducted to account for differences in disease type and follow-up length. RESULTS: CT enrollment was 11.2% overall, with a 15-year cumulative incidence of 18%. Lower odds of enrollment were observed in patients who were female (adjusted odds ratio [AOR], 0.82; 95% confidence interval [CI], 0.78-0.86), ≥65 years (AOR vs. <40, 0.61; 95% CI, 0.56-0.66), non-English speakers (0.72; 95% CI, 0.67-0.77), living ≥250 km away (AOR vs. <15 km, 0.71; 95% CI, 0.62-0.80), and without a PCP. Disease characteristics accounted for the largest proportion of observed variation (20.8%), with significantly greater odds of enrollment in patients with genitourinary cancers and late-stage disease. CONCLUSION: Significant sociodemographic disparities were observed, suggesting the need for targeted strategies to increase diversity in access to cancer CTs in Canada.

High grade adverse event reporting and enrolment in gynecologic oncology clinical trials.

OBJECTIVE: The primary objective is to assess factors associated with treatment related high grade (CTCAE grade ≥ 3) adverse event (AE) reporting among participants in gynecologic oncology clinical trials. METHODS: All AEs recorded in the Princess Margaret Clinical Trial adverse event database between 01/2016 and 12/2018 were evaluated. Gynecologic oncology clinical trials assessing systemic therapy were included. Inferential statistics on risk factors of related grade ≥ 3 adverse event reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariable analysis adjusting for age, clinical trial phase, sponsor, and therapy type. RESULTS: The gynecology cancer clinical trials accrued 317 unique patients (359 nested on trials) in 42 systemic therapy trials. In the period, 17,175 related AEs were reported in the gynecological cancer trials, 7.4% were grade ≥ 3. On multivariable analysis, no odds differences of grade ≥ 3 related AEs were detected according to study phase. Patients in immunotherapy clinical trials had lower odds of related grade ≥ 3 AEs than patients on targeted or other therapy (adjusted OR [aOR] 0.43; 95% CI 0.24-0.75). There was greater odds of related grade ≥ 3 AEs in clinical trials assessing combination vs single therapeutics (aOR 2.26, 95% CI 1.34-3.80). Patients aged ≥65 (aOR 1.77; 95% CI 1.08-2.89) had greater odds of related grade ≥ 3 AEs than patients aged 50 to 65 years. When compared to other disease sites, the odds of having a grade  ≥ 3 related AE reported in gynecology clinical trials was no different. CONCLUSIONS: In this cohort, factors influencing the odds of related grade ≥ 3 AE reporting in gynecologic trials included type of therapy and age. The study phase did not correlate with odds of high-grade AE reporting.

Comparison of Slate Safety Wearable Device to Ingestible Pill and Wearable Heart Rate Monitor.

BACKGROUND: With the increase in concern for deaths and illness related to the increase in temperature globally, there is a growing need for real-time monitoring of workers for heat stress indicators. The purpose of this study was to determine the usability of the Slate Safety (SS) wearable physiological monitoring system. METHODS: Twenty nurses performed a common task in a moderate or hot environment while wearing the SS device, the Polar 10 monitor, and having taken the e-Celsius ingestible pill. Data from each device was compared for correlation and accuracy. RESULTS: High correlation was determined between the SS wearable device and the Polar 10 system (0.926) and the ingestible pill (0.595). The SS was comfortable to wear and easily monitored multiple participants from a distance. CONCLUSIONS: The Slate Safety wearable device demonstrated accuracy in measuring core temperature and heart rate while not restricting the motion of the worker, and provided a remote monitoring platform for physiological parameters.

Determining Clinical Judgment Among Emergency Nurses During a Complex Simulation.

INTRODUCTION: Clinical judgment is imperative for the emergency nurse caring for the acutely ill patients often seen in the emergency department. Without optimal clinical judgment in the emergency department, patients are at risk of medical errors and a failure to rescue. METHODS: A descriptive observational approach using the Lasater Clinical Judgment Rubric evaluated nurses during a task that required recognition of clinical signs of deterioration and appropriate clinical care for simulated patients. RESULTS: A total of 18 practicing emergency nurses completed only 44.6% of the patient assessments leading to low levels of clinical judgment throughout the simulation. Nurses expressed 4 levels of clinical judgment: exemplary (n = 1), accomplishing (n = 6), developing (n = 9), and beginning (n = 2). On average, nurses completed 69% of required tasks. DISCUSSION: Assessments were completed less than half the time, demonstrating a breakdown in the noticing phase of clinical judgment. The nurses shifted to task completion focus with minimal use of clinical judgment. As the nurses remained task oriented, several medication and medical errors were noted while caring for the simulated patients. Experience and education did not influence observed clinical judgment among the participants. Given the extreme demands placed on the emergency nurse, it cannot be assumed that nurses have developed or can use clinical judgment when caring for their patients. Time and training targeting clinical judgment are essential for emergency nurse development.

Examining the use of geriatric standardized patients with baccalaureate nursing students.

The need for clinical placements for undergraduate nursing programs heightened during the COVID-19 pandemic as nursing schools across the country faced restrictions with the high-risk geriatric client population. Nursing students experienced increased anxiety levels, decreased learning opportunities, and uncertainties about the decision to enter the workforce as healthcare professionals. In turn, this amplified the need for faculty support and feedback imperative for student success. One method for mitigating the gap between didactic content and clinical placement is using simulation-based learning experiences. The purpose of this observational study was to examine the impact of a newly developed home health geriatric simulation on student satisfaction and self-confidence in learning among 133 senior-level Baccalaureate nursing students from a large public university. Study measures included the National League of Nursing's Self-Confidence in Learning Scale (SCLS) and Simulation Design Scale (SDS). The primary outcome was satisfaction and self-confidence in learning. Higher SDS component scores were significantly correlated with higher SCLS scores (all p = <.0001), indicating that high satisfaction among Baccalaureate nursing students in simulation design relates to increased satisfaction and self-confidence in learning. Study findings support using standardized geriatric simulation scenarios to prepare students to communicate and care for older adults.

Development and implementation of a novel peer mentoring program for undergraduate nursing students.

OBJECTIVES: Given the dynamic and high-stress environment of nursing education today, the need arose for the development and implementation of a novel peer mentoring program to support undergraduate nursing students. Peer mentoring refers to a network of support in which a more skilled or experienced person serves as a role model for a less skilled person for professional development and personal growth. Peer mentoring provides a support system that encourages self-confidence and increases self-worth for both the mentee and the mentor. The undergraduate student peer mentoring program in a large, Southeastern United States, university-based, 4-year school of nursing was created in response to a desire for more support conveyed by upper-level nursing students. METHODS: A model was developed whereby each incoming nursing student (Semester 1) would be paired with a senior nursing student (Semesters 3, 4, or 5). This mentoring dyad was then assigned to a faculty mentor who ensured that the mentoring relationship was functioning in accordance with established guidelines and provided support to both the student mentee and the student mentor. RESULTS: The first cohort was comprised of 20 mentoring dyads. Subsequent cohorts have ranged from 20 to 45 mentoring dyads. To date, over 300 nursing students have participated in the undergraduate peer mentoring program. Based on feedback from student evaluation surveys, both mentors and mentees appreciate and find value in the program. Approximately 93% of student mentors indicated that they would have appreciated such a program when they were first semester nursing students. CONCLUSION: Some of the challenges of navigating nursing programs are not related to lack of academic aptitude. Rather, other challenges, including lack of social support and soft skills needed to successfully complete the first and second semesters of nursing school. These are critical challenges that a peer mentor could help to meet.

Factors Associated With Radioactive Iodine Therapy-Acquired Nasolacrimal Duct Obstruction.

OBJECTIVE: To identify factors associated with radioactive iodine (RAI)-acquired nasolacrimal duct obstruction (NLDO). METHODS: Retrospective chart review and telephone surveys of patients who received RAI therapy for thyroid carcinoma at an academic institution were conducted. Telephone surveys were used to screen for post-RAI NLDO diagnoses. Databases were reviewed for documented NLDO, demographics, RAI dose, total number of RAI treatments, and sialadenitis. Routine post-RAI whole-body scintigraphy (WBS) images were analyzed for the presence or absence of 131I sodium iodide (I-131) in the nasolacrimal duct. Intranasal I-131 activity was graded as none, low, moderate, and high; those with moderate or high activity were considered to have "increased" activity. Logistic and ordinal logistic regression models were used to evaluate the associations with NLDO while adjusting for I-131 dose. RESULTS: Of the 209 patients who completed the survey, 15 (7%) had NLDO diagnoses. Increased intranasal I-131 activity on WBS, presence of nasolacrimal I-131 WBS activity, presence of documented post-RAI sialadenitis, and history of >1 RAI treatment were associated with the development of NLDO from univariate analyses (P ≤ .013). After adjusting for the administered dose of I-131, the presence of sialadenitis and nasolacrimal I-131 activity on WBS were the remaining 2 factors significantly associated with NLDO development (P < .001 and P = .01, respectively). CONCLUSIONS: The presence of sialadenitis and nasolacrimal I-131 activity on WBS are I-131 dose-independent correlative factors for RAI-associated NLDO. Patients with these characteristics should be counseled on their increased risk of NLDO after RAI therapy for thyroid carcinoma.

Bone Fracture Acute Phase Response-A Unifying Theory of Fracture Repair: Clinical and Scientific Implications.

Bone fractures create five problems that must be resolved: bleeding, risk of infection, hypoxia, disproportionate strain, and inability to bear weight. There have been enormous advancements in our understanding of the molecular mechanisms that resolve these problems after fractures, and in best clinical practices of repairing fractures. We put forth a modern, comprehensive model of fracture repair that synthesizes the literature on the biology and biomechanics of fracture repair to address the primary problems of fractures. This updated model is a framework for both fracture management and future studies aimed at understanding and treating this complex process. This model is based upon the fracture acute phase response (APR), which encompasses the molecular mechanisms that respond to injury. The APR is divided into sequential stages of "survival" and "repair." Early in convalescence, during "survival," bleeding and infection are resolved by collaborative efforts of the hemostatic and inflammatory pathways. Later, in "repair," avascular and biomechanically insufficient bone is replaced by a variable combination of intramembranous and endochondral ossification. Progression to repair cannot occur until survival has been ensured. A disproportionate APR-either insufficient or exuberant-leads to complications of survival (hemorrhage, thrombosis, systemic inflammatory response syndrome, infection, death) and/or repair (delayed- or non-union). The type of ossification utilized for fracture repair is dependent on the relative amounts of strain and vascularity in the fracture microenvironment, but any failure along this process can disrupt or delay fracture healing and result in a similar non-union. Therefore, incomplete understanding of the principles herein can result in mismanagement of fracture care or application of hardware that interferes with fracture repair. This unifying model of fracture repair not only informs clinicians how their interventions fit within the framework of normal biological healing but also instructs investigators about the critical variables and outputs to assess during a study of fracture repair.

Prevalence of Hypertension in Pediatric Tibia Vara and Slipped Capital Femoral Epiphysis.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) and tibia vara (Blount disease) are associated with childhood obesity. However, the majority of obese children do not develop SCFE or tibia vara. Therefore, it is hypothesized that other obesity-related biological changes to the physis, in addition to increased biomechanical stress, potentiate the occurrence of SCFE and tibia vara. Considering that hypertension can impose pathologic changes in the physis similar to those observed in these obesity-related diseases we set out to determine the prevalence of hypertension in patients with SCFE and tibia vara. METHODS: Blood pressure measurements were obtained in 44 patients with tibia vara and 127 patients with SCFE. Body mass index and blood pressure were adjusted for age, sex, and height percentiles utilizing normative distribution data from the CDC. These cohorts were compared with age-matched and sex-matched cohorts derived from an obesity clinic who did not have either bone disease. A multivariable proportional odds model was used to determine association. RESULTS: The prevalence of prehypertension/hypertension was significantly higher in the tibia vara (64%) and SCFE cohort (64%) compared with respective controls (43%). Patients diagnosed with either SCFE or tibia vara had 2.5-fold higher odds of having high blood pressure compared with age-matched and sex-matched obese patients without bone disease. Sex, age, and race did not have a significant effect on a patient's blood pressure. CONCLUSIONS: This is the first study to establish that the obesity-related bone diseases, SCFE and tibia vara, are significantly associated with high blood pressure. These data have immediate clinical impact as they demonstrate that children with obesity-related developmental bone disease have increased prevalence of undiagnosed and untreated hypertension. Furthermore, this prevalence study supports the hypothesis that hypertension in conjunction with increased biomechanical forces together potentiate the occurrence of SCFE and tibia vara. If proven true, it is plausible that hypertension may represent a modifiable risk factor for obesity-related bone disease. LEVEL OF EVIDENCE: Level III-case-control study.

OTO: Ontology Term Organizer.

BACKGROUND: The need to create controlled vocabularies such as ontologies for knowledge organization and access has been widely recognized in various domains. Despite the indispensable need of thorough domain knowledge in ontology construction, most software tools for ontology construction are designed for knowledge engineers and not for domain experts to use. The differences in the opinions of different domain experts and in the terminology usages in source literature are rarely addressed by existing software. METHODS: OTO software was developed based on the Agile principles. Through iterations of software release and user feedback, new features are added and existing features modified to make the tool more intuitive and efficient to use for small and large data sets. The software is open source and built in Java. RESULTS: Ontology Term Organizer (OTO; http://biosemantics.arizona.edu/OTO/ ) is a user-friendly, web-based, consensus-promoting, open source application for organizing domain terms by dragging and dropping terms to appropriate locations. The application is designed for users with specific domain knowledge such as biology but not in-depth ontology construction skills. Specifically OTO can be used to establish is_a, part_of, synonym, and order relationships among terms in any domain that reflects the terminology usage in source literature and based on multiple experts' opinions. The organized terms may be fed into formal ontologies to boost their coverage. All datasets organized on OTO are publicly available. CONCLUSION: OTO has been used to organize the terms extracted from thirty volumes of Flora of North America and Flora of China combined, in addition to some smaller datasets of different taxon groups. User feedback indicates that the tool is efficient and user friendly. Being open source software, the application can be modified to fit varied term organization needs for different domains.

Epidemiology, diagnosis, and treatment of pericapsular pyomyositis of the hip in children.

BACKGROUND: The yield of synovial fluid cultures in patients meeting clinical criteria for septic hip arthritis remains low. In the presence of positive blood cultures, these patients are diagnosed and treated as "presumed septic arthritis." We hypothesized that some of these patients may instead have an extra-articular infection, such as pericapsular pyomyositis. METHODS: An IRB-approved prospective study of children with suspected septic hip arthritis at a tertiary care children's hospital over a 2-year time period was conducted. Children were evaluated with a previously published clinical algorithm with the addition of magnetic resonance imaging (MRI). RESULTS: Of the 53 patients presenting with an acutely irritable hip, 32% were found to have pericapsular pyomyositis, whereas 15% were diagnosed with septic arthritis. Although C-reactive protein (CRP, ≥33.1 mg/L) performed well at predicting infection, there were no significant differences in CRP, erythrocyte sedimentation rate, white blood cell count, temperature, or weight-bearing status in children with septic arthritis compared with pericapsular pyomyositis. In addition to MRI, there was a difference in the size of hip effusion on ultrasound, which was significantly smaller in cases of pericapsular pyomyositis. CRP (≥74.3 mg/L) was found to be predictive of need for surgical intervention in children with pericapsular pyomyositis. CONCLUSIONS: Correct anatomic diagnosis of the site of infection is essential for the efficient care of the child. Herein, we found that pericapsular pyomyositis is twice as common as septic arthritis in children presenting with an acutely irritable hip. Clinical algorithms are incapable of differentiating these pathologies suggesting that both be considered under the current diagnosis previously referred to as "presumed septic arthritis." Incorrect diagnosis of a septic arthritis in the presence of a pericapsular pyomyositis could potentially lead to unnecessary debridement of the joint in the presence of extra-articular infection, thus contaminating the joint. Conversely, debriding the joint instead of the epicenter of the infection can prolong the infectious process. For these reasons, we conclude that MRI has the potential to improve the clinical care of children by providing a more precise diagnosis. LEVEL OF EVIDENCE: Level II-"Diagnostic" [Development of diagnostic criteria on the basis of consecutive patients (with universally applied reference "gold" standard)].

Medial approach for drainage of the obturator musculature in children.

BACKGROUND: In a recent study designed to determine the anatomic location of infection in children presenting with acute hip pain, fever, and elevated inflammatory markers, we demonstrated the incidence of infection of the musculature surrounding the hip to be greater than twice that of septic arthritis. Importantly, the obturator musculature was infected in >60% of cases. Situated deep in the pelvis, surrounding the obturator foramen, debridement of these muscles and placement of a drain traditionally requires an extensive ilioinguinal or Pfannenstiel approach, placing significant risk to the surrounding neurovascular structures. We hypothesized that the obturator internus and externus could be successfully debrided using a limited medial approach. METHODS: An IRB-approved prospective study of children (0 to 18 y) evaluated in the pediatric emergency department by an orthopaedic surgeon to rule out septic hip arthritis at a tertiary care children's hospital (July 1, 2010 to June 30, 2012) was conducted. Infected obturator musculature was identified and confirmed using magnetic resonance imaging. Cadaveric dissection was performed comparing the ilioinguinal, Pfannenstiel, and proposed minimally invasive medial approach. The proposed approach was utilized to debride and place drains in 7 consecutive patients. RESULTS: Anatomic information gained from magnetic resonance images of patients with abscess within the obturator musculature, and from the results of cadaveric studies, allowed for planning of a novel surgical approach. We found that through the surgical approach used to perform an osteotomy of the ischium (Tonnis) the obturator externus could be debrided through the adductor brevis and the obturator internus could be debrided through the obturator foramen. Using our medial approach, resolution of symptoms in all children who underwent surgical drainage resulted without complication. CONCLUSIONS: Our medial approach can safely access the obturator musculature for abscess decompression and drain placement with successful results. Advantages to this approach include: lower risk to neurovascular structures within the pelvis, less soft tissue trauma, and similarity to current techniques used for adductor lengthening, medial reduction of the dislocated hip, and osteotomy of the ischium. LEVEL OF EVIDENCE: Level II.

The Pathway to Developing a Competency-based Tool for Entry-level Nursing Simulation: A Delphi Study.

BACKGROUND: Simulation-based learning experiences allow undergraduate nursing students to develop competence and confidence through deliberate practice with immediate feedback on the learner's performance through debriefing. With the transition to competency-based nursing education, nursing faculty need more guidance in implementing competency-based evaluations in the simulation setting. PURPOSE: This Delphi study aims to inform the future development of a competency-based tool - SimComp - based on the American Association of Colleges of Nursing (AACN) Essentials. METHODS: A Delphi framework was used to recruit expert nursing faculty to complete the surveys via an online platform. Data analysis occurred through open-ended questions and quantitative methods to ensure that the responses from expert panelists were used to form the results. RESULTS: After four rounds of this Delphi study, a consensus was achieved on 111 appropriate items for assessing competence in the simulation-based learning environment. CONCLUSION: While further research is warranted, this study provides insight for nursing institutions considering implementing or increasing the use of simulation within their program for competency-based evaluations.

Empowering nursing students through inclusivity training for LGBTQIA+ patients: A quasi-experimental study.

BACKGROUND: The current state of nursing education is concerning, with nearly two-thirds of the American Association of Colleges of Nursing (AACN) and Commission of Collegiate Nursing Education (CCNE) -accredited universities reporting that their nursing graduates are ill-prepared to care for the LGBTQIA+ community (Eickhoff, 2021). This lack of training is alarming, given the ongoing reports of LGBTQIA+ healthcare discrimination and the insufficient knowledge of nursing faculty to guide future nurses in caring for this patient population (Hughes et al., 2022). AIM: Our study sought to address this gap by developing and assessing the effectiveness of an LGBTQIA+ inclusivity training module for Baccalaureate nursing students. DESIGN: We employed a quasi-experimental pretest-posttest design, evaluating nursing students' knowledge and attitudes before and after the LGBTQIA+ inclusivity training. SETTING: The study was conducted in a four-year baccalaureate nursing program in the Southern United States. PARTICIPANTS: Junior-level baccalaureate nursing students. METHODS: Using a pre-test post-test method, we collected data that included the Gay Affirmative Practice Scale, an LGBTQIA+ knowledge assessment, and a computer-based LGBTQIA+ inclusivity training module. RESULTS: N = 30 students consented and completed all necessary study components. The findings revealed significant improvements in pre-test and post-test GAP and knowledge assessment scores following the LGBTQIA+ Inclusivity Training for baccalaureate nursing students. CONCLUSIONS: The results of our study underscore the effectiveness of an LGBTQIA+ computer-based simulation experience for baccalaureate nursing students, marking a significant step towards improving LGBTQIA+ healthcare inclusivity in nursing education.

Women in leadership matters: Achieving diversity in radiology residency recruitment.

RATIONALE AND OBJECTIVES: To assess whether academic radiology departments and residency programs with efforts toward supporting and augmenting Diversity, Equity, and Inclusion (DEI) are associated with a higher proportion of residents from diverse backgrounds. MATERIALS AND METHODS: Program Directors within the Radiology Residency Education Research Alliance were surveyed to gather information about program characteristics, incorporation of diversity in resident recruitment, the sponsoring department's commitment to efforts at expanding diversity, and a summary of their current and past residents, staff and faculty members (academic years 2020 and 2023) with respect to a list of diversity characteristics. RESULTS: Survey response rate was 51 %. Sixty-three percent (15/24) of participating programs have departmental committees dedicated to DEI work; 46 % (11/24) of programs' departments have a Vice Chair for DEI. Sixty percent (15/24) of programs use their social media accounts to advertise their DEI programming efforts. Ninety-six percent (23/24) of programs participating in the survey use diversity factors to select candidates for their program. Women Leadership was associated with above-median diversity of residents and faculty. CONCLUSION: This study of radiology residency programs encourages a more prominent role for women in leadership positions within academic radiology departments to drive diversity and inclusion efforts.

Virtual Interviewing for Radiology Residency: Pluses, Minuses, and A Review of the Literature.

This article reviews current medical literature to assess the benefits and drawbacks of virtual interviews for radiology residencies as well as the downstream effects of these changes, best practices, and potential future recruitment methods. Topics covered include the effects of remote recruitment in promoting accessibility and applicant diversity and equality as well as fiscal, environmental, and time savings in combination with technical challenges, the complications of over application, challenges in assessment of program culture and location, impact on morale, and hidden financial and emotional costs. Learnings from other medical specialties are highlighted in addition to the process of signaling, guidelines for conducting and participating in virtual interviews, and matters for future consideration.

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo: procoagulant nature of osteosarcoma.

BACKGROUND: Procoagulant states, leading to activation of the coagulation protease thrombin, are common in cancer and portend a poor clinical outcome. Although procoagulant states in osteosarcoma patients have been described, studies exploring osteosarcoma cells' ability to directly contribute to procoagulant activity have not been reported. This study explores the hypothesis that osteosarcoma can regulate thrombin generation and proliferate in response to thrombin, and that attenuating thrombin generation with anticoagulants can slow tumor growth. METHODS: Pathologic analysis of osteosarcoma with adjacent venous thrombus was performed. In vitro proliferation assays, cell-based coagulant activity assays, and quantification of coagulation cofactor expression were performed on human and murine osteosarcoma cell lines with varying aggressiveness. The efficacy of low molecular weight heparin (LMWH) attenuation of tumor-dependent thrombin generation and growth in vitro and in vivo was determined. RESULTS: Venous thrombi adjacent to osteosarcoma were found to harbor tumor surrounded by fibrin expressing coagulation cofactors, a finding associated with poor clinical outcome. More aggressive osteosarcoma cell lines had greater surface expression of procoagulant factors and generated more thrombin than less aggressive cell lines and were found to proliferate in response to thrombin. Treatment with LMWH reduced in vitro osteosarcoma proliferation and procoagulant activity as well as tumor growth in vivo. CONCLUSIONS: These findings suggest that elements of the coagulation cascade may play a role in and represent a pharmaceutical target to disrupt osteosarcoma growth. They also have broader implications, as they suggest that, to be effective, dosing of anticoagulants must take into account an individual tumor's capacity to generate thrombin.

The Deleterious Effects of Impaired Fibrinolysis on Skeletal Development Are Dependent on Fibrin(ogen), but Independent of Interlukin-6.

Chronic diseases in growing children, such as autoimmune disorders, obesity, and cancer, are hallmarked by musculoskeletal growth disturbances and osteoporosis. Many of the skeletal changes in these children are thought to be secondary to chronic inflammation. Recent studies have likewise suggested that changes in coagulation and fibrinolysis may contribute to musculoskeletal growth disturbances. In prior work, we demonstrated that mice deficient in plasminogen, the principal protease of degrading and clearing fibrin matrices, suffer from inflammation-driven systemic osteoporosis and that elimination of fibrinogen resulted in normalization of IL-6 levels and complete rescue of the skeletal phenotype. Given the intimate link between coagulation, fibrinolysis, and inflammation, here we determined if persistent fibrin deposition, elevated IL-6, or both contribute to early skeletal aging and physeal disruption in chronic inflammatory conditions. Skeletal growth as well as bone quality, physeal development, and vascularity were analyzed in C57BL6/J mice with plasminogen deficiency with and without deficiencies of either fibrinogen or IL-6. Elimination of fibrinogen, but not IL-6, rescued the skeletal phenotype and growth disturbances in this model of chronic disease. Furthermore, the skeletal phenotypes directly correlated with both systemic and local vascular changes in the skeletal environment. In conclusion, these results suggest that fibrinolysis through plasmin is essential for skeletal growth and maintenance, and is multifactorial by limiting inflammation and preserving vasculature.