Systemic Cisplatin Does Not Affect the Bone Regeneration Process in a Critical Size Defect Murine Model.

Osteosarcoma (OS) is the most common primary malignant bone tumor, and the current standard of care for OS includes neoadjuvant chemotherapy, followed by an R0 surgical resection of the primary tumor, and then postsurgical adjuvant chemotherapy. Bone reconstruction following OS resection is particularly challenging due to the size of the bone voids and because patients are treated with adjuvant and neoadjuvant systemic chemotherapy, which theoretically could impact bone formation. We hypothesized that an osteogenic material could be used in order to induce bone regeneration when adjuvant or neoadjuvant chemotherapy is given. We utilized a biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of systemic chemotherapy in a murine critical size defect model. We found that in the presence of neoadjuvant or adjuvant chemotherapy, MHA/Coll is able to enhance and increase bone formation in a murine critical size defect model (11.16 ± 2.55 or 13.80 ± 3.18 versus 8.70 ± 0.81 mm3) for pre-op cisplatin + MHA/Coll (p-value = 0.1639) and MHA/Coll + post-op cisplatin (p-value = 0.1538), respectively, at 12 weeks. These findings indicate that neoadjuvant and adjuvant chemotherapy will not affect the ability of a biomimetic scaffold to regenerate bone to repair bone voids in OS patients. This preliminary data demonstrates that bone regeneration can occur in the presence of chemotherapy, suggesting that there may not be a necessity to modify the current standard of care concerning neoadjuvant and adjuvant chemotherapy for the treatment of metastatic sites or micrometastases.

Otto Aufranc Award: Intraosseous Vancomycin in Total Hip Arthroplasty - Superior Tissue Concentrations and Improved Efficiency.

BACKGROUND: Literature shows that intraosseous (IO) infusions are capable of providing increased local concentrations compared to those administered via intravenous (IV) access. Successes while using the technique for antibiotic prophylaxis administration in total knee arthroplasty (TKA) prompted consideration for use in total hip arthroplasty (THA) however; no study exists for the use of IO vancomycin in THA. METHODS: This single-blinded randomized control trial was performed from December 2020 to May 2022. Twenty patients were randomized into 1 of 2 groups: IV vancomycin (15 mg/kg) given routinely, or IO vancomycin (500 mg/100cc of NS) injected into the greater trochanter during incision. Serum vancomycin levels were collected at incision and closure. Soft tissue vancomycin levels were taken from the gluteus maximus (at start and end of case), and acetabular pulvinar tissue. Bone vancomycin levels were taken from the femoral head, acetabular reamings, and intramedullary bone. Adverse local/systemic reactions, 30-day complications, and 90-day complications were also tracked. RESULTS: A statistically significant reduction in serum vancomycin levels was seen when comparing IO to IV vancomycin at both the start and at the end of the procedure. All local tissue samples had higher concentrations of vancomycin in the IO group. Statistically significant increases were present within the acetabular bone reamings, and approached significance in intramedullary femoral bone. CONCLUSION: This study demonstrates the utility of IO vancomycin in primary THA with increased local tissue and decreased systemic concentrations. With positive findings in an area without tourniquet use, IO may be considered for antibiotic delivery for alternative procedures.

Osteogenesis in the presence of chemotherapy: A biomimetic approach.

Osteosarcoma (OS) is the most common bone tumor in pediatrics. After resection, allografts or metal endoprostheses reconstruct bone voids, and systemic chemotherapy is used to prevent recurrence. This urges the development of novel treatment options for the regeneration of bone after excision. We utilized a previously developed biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of chemotherapy. We also performed experiments to determine if human mesenchymal stem cells (hMSCs) seeded on MHA/Coll scaffold migrate less toward OS cells, suggesting that hMSCs will not contribute to tumor growth and therefore the potential of oncologic safety in vitro. Also, hMSCs seeded on MHA/Coll had increased expression of osteogenic genes (BGLAP, SPP1, ALP) compared to hMSCs in the 2D condition, even when exposed to chemotherapeutics. This is the first study to demonstrate that a highly osteogenic scaffold can potentially be oncologically safe because hMSCs on MHA/Coll tend to differentiate and lose the ability to migrate toward tumor cells. Therefore, hMSCs on MHA/Coll could potentially be utilized for bone regeneration after OS excision.

Comparison Between Cancellous Trabecular and Cortical Specimens from Human Lumbar Spine Samples as an Alternative Source of Mesenchymal Stromal Cells.

Due to their immunosuppressive potential and ability to differentiate into multiple musculoskeletal cell lineages, mesenchymal stromal cells (MSCs) became popular in clinical trials for the treatment of musculoskeletal disorders. The aim of this study was to isolate and characterize native populations of MSCs from human cortical and cancellous bone from the posterior elements of the lumbar spine and determine what source of MSCs yields better quality and quantity of cells to be potentially used for spinal fusion repair. We were able to show that MSCs from trabecular and cortical spine had the typical MSC morphology and expression markers; the ability to differentiate in adipocyte, chondrocyte, or osteoblast but they did not have a consistent pattern in the expression of the specific differentiation lineage genes. Moreover, MSCs from both sites demonstrated an immune suppression profile suggesting that these cells may have a more promising success in applications related to immunomodulation more than exploring their ability to drive osteogenesis to prevent nonunion in spine fusion procedures.

Evaluation of local tissue peri-implant reaction in total knee arthroplasty failure cases.

Introduction: Implant-related hypersensitivity is emerging as a causative factor as a potential source of total knee arthroplasty (TKA) failure. Mechanistically, this type IV hypersensitivity reaction (T4HR) is mediated by effector T-cells, macrophages, and leukocytes that infiltrate to the site of implant and react to metal exposure and induce inflammatory tissue damage. Methods: A case-control study was performed where cortical bone was taken at the time of revision surgery for all patients operated on for primary TKA in which metal allergy was suspected and for revision TKA cases done for presumed metal allergy. Cytof was used to determine the cell density of inflammatory cells, specifically Th1, Th2, M1, and M2 cells. Results: Comparing the mean cell density of primary versus revision TKA, revision TKA patients had significantly higher number of Th2 cells compared with Th1 cells (p = 0.0043). Among revision cases, there were significantly more M1 versus M2 macrophages (p = 0.034) within a patient. When comparing mean cell density of M1 versus M2 macrophages, there was a significant difference in both primary and revision TKA surgeries (p = 0.0041 primary, p < 0.001 revision). Among revision patients who had a predominance of Th2 cells, four (44%) of nine patients had a negative LTT/patch test. Conclusion: These data support metal hypersensitivity, mediated by a T4HR, for some cases of TKA failure. Current methods to screen patients for metal hypersensitivity prior to primary TKA have been inclusive. This study demonstrates the need for a more sensitive screening test from specimens in the knee joint, to more accurately identify patients who will exhibit a T4HR to metal.

Intraosseous Morphine Decreases Postoperative Pain and Pain Medication Use in Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial.

BACKGROUND: Intraosseous (IO) infusion of medication is a novel technique for total knee arthroplasty (TKA) antibiotic prophylaxis. To decrease postoperative pain in TKA patients, we investigated addition of morphine to a standard IO antibiotic injection. METHODS: A double-blind, randomized controlled trial was performed on 48 (24 each) consecutive patients undergoing primary TKA. The control group received an IO injection of antibiotics as per the standard protocol. The experimental group received an IO antibiotic injection with 10 mg of morphine. Pain, nausea, and opioid use were assessed up to 14 days postoperatively. Morphine and interleukin-6 serum levels were obtained 10 hours postoperatively in a subgroup of 20 patients. RESULTS: The experimental group had lower Visual Analog Scale pain score at 1, 2, 3, and 5 hours postoperatively (P = .0032, P = .005, P = .020, P = .010). This trend continued for postoperative day 1, 2, 8, and 9 (40% reduction, P = .001; 49% reduction, P = .036; 38% reduction, P = .025; 33% reduction, P = .041). The experimental group had lower opioid consumption than the control group for the first 48 hours and second week postsurgery (P < .05). Knee Injury and Osteoarthritis Outcome Score for Joint Replacement scores for the experimental group showed significant improvement at 2 and 8 weeks postsurgery (P < .05). Serum morphine levels in the experimental group were significantly less than the control group 10 hours after IO injection (P = .049). CONCLUSION: IO morphine combined with a standard antibiotic solution demonstrates superior postoperative pain relief immediately and up to 2 weeks. IO morphine is a safe and effective method to lessen postoperative pain in TKA patients. LEVEL OF EVIDENCE: Therapeutic, Level 1.

Biomimetic Scaffolds Modulate the Posttraumatic Inflammatory Response in Articular Cartilage Contributing to Enhanced Neoformation of Cartilaginous Tissue In Vivo.

Focal chondral lesions of the knee are the most frequent type of trauma in younger patients and are associated with a high risk of developing early posttraumatic osteoarthritis. The only current clinical solutions include microfracture, osteochondral grafting, and autologous chondrocyte implantation. Cartilage tissue engineering based on biomimetic scaffolds has become an appealing strategy to repair cartilage defects. Here, a chondrogenic collagen-chondroitin sulfate scaffold is tested in an orthotopic Lapine in vivo model to understand the beneficial effects of the immunomodulatory biomaterial on the full chondral defect. Using a combination of noninvasive imaging techniques, histological and whole transcriptome analysis, the scaffolds are shown to enhance the formation of cartilaginous tissue and suppression of host cartilage degeneration, while also supporting tissue integration and increased tissue regeneration over a 12 weeks recovery period. The results presented suggest that biomimetic materials could be a clinical solution for cartilage tissue repair, due to their ability to modulate the immune environment in favor of regenerative processes and suppression of cartilage degeneration.

High Variability of Mesenchymal Stem Cells Obtained via Bone Marrow Aspirate Concentrate Compared With Traditional Bone Marrow Aspiration Technique.

BACKGROUND: Bone marrow aspirate (BMA) is a common source for harvesting mesenchymal stem cells (MSCs), other progenitor cells, and associated cytokines and growth factors to be used in the biologic treatment of various orthopaedic pathologies. The aspirate is commonly centrifuged into a concentrated volume that can be immediately administered to a patient using commercially available kits. However, the handling and efficacy of BMA concentrate (BMAC) are still controversial. PURPOSE: To characterize BMA versus BMAC for MSC quantity, potency, and cytokine profile. STUDY DESIGN: Controlled laboratory study. METHODS: From 8 participants (age, 17-68 years), 30 mL of bone marrow was aspirated by a single surgeon from either the proximal humerus or distal femur and was separated into 2 equal samples. One sample was kept as BMA, and the other half was centrifuged into BMAC. The 2 samples then underwent flow cytometry for detection of MSCs, cell analysis for colony-forming units (CFUs), and cytokine profiling. A 2-tailed t test was used to detect differences between MSCs, CFUs, and cytokine density concentrations between BMA and BMAC. RESULTS: The average concentration of MSCs in both BMA and BMAC was 0.001%. Average MSC events detected by flow cytometry were significantly higher in BMA versus BMAC (15.1 and 8.1, respectively; P < .045). Expanded MSCs demonstrated similar phenotypes, but CFUs were significantly increased in BMA compared with BMAC (104 vs 68 CFUs, respectively; P < .001). Total protein concentration and cytokine profiling demonstrated great variability between BMA and BMAC and between patients. Most importantly, BMAC failed to concentrate MSCs in 6 of 8 samples. CONCLUSION: There is great variability in MSC concentration, total protein concentration, and cytokine profile between BMA and BMAC. CLINICAL RELEVANCE: When studying the clinical efficacy of BMAC, one must also evaluate the sample itself to determine the presence, concentration, and potency of MSCs if this is to be considered a cell-based therapy. Further standard operating procedures need to be investigated to ensure reproducible results and appropriate treatments.

All bone metastases are not created equal: Revisiting treatment resistance in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common malignancy of the kidney, representing 80-90% of renal neoplasms, and is associated with a five-year overall survival rate of approximately 74%. The second most common site of metastasis is bone. As patients are living longer due to new RCC targeting agents and immunotherapy, RCC bone metastases (RCCBM) treatment failure is more prevalent. Bone metastasis formation in RCC is indicative of a more aggressive disease and worse prognosis. Osteolysis is a prominent feature and causes SRE, including pathologic fractures. Bone metastasis from other tumors such as lung, breast, and prostate cancer, are more effectively treated with bisphosphonates and denosumab, thereby decreasing the need for palliative surgical intervention. Resistance to these antiresportives in RCCBM reflects unique cellular and molecular mechanisms in the bone microenvironment that promote progression via inhibition of the anabolic reparative response. Identification of critical mechanisms underlying RCCBM induced anabolic impairment could provide needed insight into how to improve treatment outcomes for patients with RCCBM, with the goals of minimizing progression that necessitates palliative surgery and improving survival.

Bioinspired Extracellular Vesicles: Lessons Learned From Nature for Biomedicine and Bioengineering.

Efficient communication is essential in all layers of the biological chain. Cells exchange information using a variety of signaling moieties, such as small molecules, proteins, and nucleic acids. Cells carefully package these messages into lipid complexes, collectively named extracellular vesicles (EVs). In this work, we discuss the nature of these cell carriers, categorize them by their origin, explore their role in the homeostasis of healthy tissues, and examine how they regulate the pathophysiology of several diseases. This review will also address the limitations of using EVs for clinical applications and discuss novel methods to engineer nanoparticles to mimic the structure, function, and features of EVs. Using lessons learned from nature and understanding how cells use EVs to communicate across distant sites, we can develop a better understanding of how to tailor the fundamental features of drug delivery carriers to encapsulate various cargos and target specific sites for biomedicine and bioengineering.

Improving the immunosuppressive potential of articular chondroprogenitors in a three-dimensional culture setting.

Cartilage repair in osteoarthritic patients remains a challenge. Identifying resident or donor stem/progenitor cell populations is crucial for augmenting the low intrinsic repair potential of hyaline cartilage. Furthermore, mediating the interaction between these cells and the local immunogenic environment is thought to be critical for long term repair and regeneration. In this study we propose articular cartilage progenitor/stem cells (CPSC) as a valid alternative to bone marrow-derived mesenchymal stem cells (BMMSC) for cartilage repair strategies after trauma. Similar to BMMSC, CPSC isolated from osteoarthritic patients express stem cell markers and have chondrogenic, osteogenic, and adipogenic differentiation ability. In an in vitro 2D setting, CPSC show higher expression of SPP1 and LEP, markers of osteogenic and adipogenic differentiation, respectively. CPSC also display a higher commitment toward chondrogenesis as demonstrated by a higher expression of ACAN. BMMSC and CPSC were cultured in vitro using a previously established collagen-chondroitin sulfate 3D scaffold. The scaffold mimics the cartilage niche, allowing both cell populations to maintain their stem cell features and improve their immunosuppressive potential, demonstrated by the inhibition of activated PBMC proliferation in a co-culture setting. As a result, this study suggests articular cartilage derived-CPSC can be used as a novel tool for cellular and acellular regenerative medicine approaches for osteoarthritis (OA). In addition, the benefit of utilizing a biomimetic acellular scaffold as an advanced 3D culture system to more accurately mimic the physiological environment is demonstrated.

Gastric Siderosis and Ulceration from Intravenous Iron Supplementation Manifesting as Chronic Upper Gastrointestinal Bleeding: A Case Report and Review of the Literature.

Iron deficiency is the most common etiology of anemia worldwide and is often managed with varying methods of iron supplementation. Although rare, oral iron supplementation can perpetuate iron deficiency anemia by causing gastric ulceration and upper gastrointestinal bleeding in high-risk populations. However, this complication has not been previously described with intravenous iron supplementation. We present a case of a 63-year-old male with severe iron deficiency anemia on biweekly intravenous iron infusions and weekly packed red blood cell transfusions who presented with melena over several months. Upper endoscopy demonstrated a clean-based gastric body ulcer and nonbleeding gastric varices. Histology of the gastric ulcer was suggestive of iron-induced gastric mucosal injury. This case demonstrates that frequent utilization of intravenous iron and packed red blood cell transfusions may predispose certain patients to the development of iron-induced gastritis and ulceration.

Primary CNS Lymphoma Arising from the 4th Ventricle: A Case Report and Review of the Literature.

A 65-year-old male with a history of ischemic strokes, seizures, and subarachnoid hemorrhage presented with a 4-week history of progressive diplopia, vertigo, nausea, and vomiting. Magnetic resonance imaging (MRI) revealed a 2.5 × 1.8 × 1.7 cm posterior fossa mass arising from the roof of the 4th ventricle extending into the cerebellar vermis. Posterior fossa craniotomy with stereotactic biopsy confirmed a locally invasive diffuse large B-cell lymphoma (DLBCL). Primary central nervous system lymphoma (PCNSL) arising from the 4th ventricle is a rare extranodal manifestation of non-Hodgkin lymphoma (NHL), with few cases documented in the literature. Review of available cases lends support that lymphoma arising from the 4th ventricle has a variable clinical presentation, occurs most commonly in immunocompetent males, and should be on the differential of any immunocompetent adult presenting with a posterior fossa mass. Optimal treatment modalities are based largely on phase 2 clinical trials, and recommended guidelines regardless of anatomic location should be adhered to.

Periprosthetic Fracture of Greater Trochanter in Total Hip Replacement Stemming from Pin Site Placement in Navigation-Assisted Surgery.

Surgeons are looking to use computer computer-assisted surgery (CAS) in total hip arthroplasty (THA) in order to quantify leg length measurement, angular cup placement, and enhance stability to provide enhanced accuracy in implant placement. As a result, CAS in THA is gaining popularity. This technology employs the use of pins and provides the surgeon with real-time feedback on positioning intraoperatively. Previous total knee arthroplasty (TKA) literature has reported pin-associated complications such as infections, neuropraxia, and suture abscess. To our knowledge, there have been reports of tibial stress fracture after CAS TKA, but this is the first report of a pin causing fracture of the greater trochanter leading to dislocation in THA. Further studies may be warranted to optimize pin placement for trackers to prevent fractures of the greater trochanter.

A Prospective, International Cohort Study of Invasive Mold Infections in Children.

BACKGROUND: Invasive mold infections (IMIs) are a leading cause of mortality in immunocompromised children, yet there has never been an international epidemiologic investigation of pediatric IMIs. METHODS: This international, prospective cohort study was performed to characterize the epidemiology, antifungal therapy, and outcomes of pediatric IMIs. Children (≤18 years) with proven or probable IMIs were enrolled between August 2007 and May 2011 at 22 sites. Risk factors, underlying diagnoses, and treatments were recorded. Outcomes were assessed at 12 weeks after diagnosis using European Organization for Research and Treatment of Cancer/Mycoses Study Group response criteria. RESULTS: One hundred thirty-one pediatric patients with IMIs were enrolled; the most common IMI was invasive aspergillosis ([IA] 75%). Children with IA and those with other types of IMIs had similar underlying risk factors, except that children with IMIs caused by non-Aspergillus species were more likely to have received mold-active antifungal agents preceding diagnosis. The most commonly used antifungal classes after diagnosis were triazoles (82%) and polyenes (63%). Combination therapy was used in 53% of patients. Use of combination therapy was associated with an increased risk of adverse events (risk ratio, 1.98; 95% confidence interval, 1.06-3.68; P = .031), although there was no detectable difference in outcome. CONCLUSIONS: Although risk factors for IMIs are similar across specific subtypes, preceding antifungal therapy may be an important modifier. Combination antifungal therapy requires further study to determine its true risks and benefits.

Health care-associated infections in children after cardiac surgery.

Few recent studies have assessed the epidemiology of health care-associated infections (HAIs) in the pediatric population after cardiac surgery. A retrospective cohort study was performed to assess the epidemiology of several types of HAIs in children 18 years of age or younger undergoing cardiac surgery from July 2010 to June 2012. Potential pre-, intra-, and postoperative risk factors, including adherence to the perioperative antibiotic prophylaxis regimen at the authors' hospital, were assessed by multivariable analysis using Poisson regression models. Microorganisms associated with HAIs and their susceptibility patterns were described. Overall, 634 surgeries were performed, 38 (6 %) of which were complicated by an HAI occurring within 90 days after surgery. The HAIs included 7 central line-associated bloodstream infections (CLABSIs), 12 non-CLABSI bacteremias, 6 episodes of early postoperative infective endocarditis (IE), 9 surgical-site infections (SSIs), and 4 ventilator-associated pneumonias (VAPs). Mechanical ventilation (rate ratio [RR] 1.07 per day; 95 % confidence interval [CI] 1.03-1.11; p = 0.0002), postoperative transfusion of blood products (RR 3.12; 95 %, CI 1.38-7.06; p = 0.0062), postoperative steroid use (RR 3.32; 95 % CI 1.56-7.02; p = 0.0018), and continuation of antibiotic prophylaxis longer than 48 h after surgery (RR 2.56; 95 % CI 1.31-5.03; p = 0.0062) were associated with HAIs. Overall, 66.7 % of the pathogens associated with SSIs were susceptible to cefazolin, the perioperative antibiotic prophylaxis used by the authors' hospital. In conclusion, HAIs occurred after 6 % of cardiac surgeries. Bacteremia and CLABSI were the most common. This study identified several potentially modifiable risk factors that suggest interventions. Further studies should assess the role of improving adherence to perioperative antibiotic prophylaxis, the age of transfused red blood cells, and evidence-based guidelines for postoperative steroids.

Candida speciation, antifungal treatment and adverse events in pediatric invasive candidiasis: results from 441 infections in a prospective, multi-national study.

A multi-national prospective study of pediatric patients with invasive candidiasis between August 2007 and September 2012 was performed and included 441 infections. Variation in infecting Candida species and antifungals used was noted between US and non-US sites. Antifungal-associated adverse events were most common with polyene use.

Evaluation of an HIV adherence counseling program in La Romana, Dominican Republic.

Research has demonstrated that adherence to antiretroviral therapy (ART) results in lower rates of morbidity and mortality associated with HIV infection, yet adherence remains a challenge in resource-limited settings like the Dominican Republic. Clinica de Familia La Romana addressed this problem with an education-based adherence program for adult patients new to ART, and this retrospective cohort study aimed to evaluate the impact of this intervention. Appointment adherence and biological markers were assessed in cases and controls through 12 months. A total of 101 participants were included, with 61 controls and 40 cases. The baseline CD4 count was 162 and 157 cells/mm3 in controls and cases, respectively. Cases showed a 15-fold increase in CD4 count compared with a 2.5-fold increase in controls. Cases were more likelyto adhere to appointments with adherence rates of 86% versus 76% in controls. There was no difference between the rates of treatment abandonment, transfer of care, or death.

A multicenter study of initiation of antiretroviral therapy and transmitted drug resistance in antiretroviral-naive adolescents and young adults with HIV in New York City.

BACKGROUND: In December 2009, the Department of Health and Human Services guidelines for initiation of antiretroviral therapy (ART) changed to include patients with CD4 counts between 350 and 500 cells/µL. The aims of this study were to assess uptake of this recommendation in ART-naive youth with human immunodeficiency virus (HIV) and to describe the epidemiology of transmitted genotypic drug resistance mutations (DRMs) in this population. METHODS: A multicenter, retrospective cohort study of ART initiation in ART-naive youth was performed. Eligible subjects were 13-25 years of age, were diagnosed with HIV within 1 year of presentation to care at the study sites, and presented to care from January 2007 to June 2011. RESULTS: Of 685 potential subjects identified, 331 (49%) fulfilled inclusion criteria. Mean CD4 count at presentation to care was 452 cells/µL. Overall, 191 (58%) subjects started ART. The mean CD4 count at ART initiation was 261 cells/µL before and 363 cells/µL after the 2009 guideline change (P < .0001). Of 212 (64%) subjects with resistance testing available prior to ART initiation, 38 (18%) subjects had a major DRM and an increased proportion of resistance was seen in later study years. CONCLUSIONS: Our study demonstrated an uptake in recently changed guideline recommendations to treat HIV-infected individuals at higher CD4 counts and reinforces the importance of performing resistance testing at entry into care, as 18% of our population had major DRMs prior to initiation of ART.