A single-center retrospective review of metastatic prostate cancer on PSMA position emission tomography/computed tomography: Beyond lymph nodes and bones.

BACKGROUND: Prostate-specific membrane antigen (PSMA) Positron emission tomography/computed tomography (PET/CT) has become a crucial imaging modality for the staging of patients with prostate cancer. The purpose of this study is to retrospectively determine the frequency, anatomical distribution, and clinical-pathologic correlates of extra-nodal and extra-osseous metastatic prostate cancer detected on PSMA PET/CT. METHODS: All available 650 PSMA PET/CT performed in patients with biopsy-proved prostate cancer in our institution between September 2021 and December 2023 were reviewed for the presence of extra-nodal and extra-osseous metastatic disease (M1C disease). Thirty-four patients with M1C disease were identified. RESULTS: The most frequent sites of visceral/soft tissue metastases were the lungs (58.8%), liver (23.5%) and adrenal glands (20.6%). 75% of patients with lung metastases detected on PSMA PET/CT had concurrent intrathoracic lymph node involvement. A higher frequency of patients with M1C disease (55.9%) had a high Gleason score. The median prostate-specific antigen (PSA) level at the time of the PSMA scan was 20.16 ng/mL. There was a statistically significant association between PSA level and osseous disease (p = 0.004), as well as PSA level and nodal disease (p = 0.008). While a large number of patients had concurrent osseous and nodal disease (82.4% and 79.4%, respectively), no visceral/soft tissue sites demonstrated a significant association with the presence of osseous or nodal involvement. CONCLUSIONS: Given the increasing utilization of PSMA PET/CT, increased knowledge of the location and pattern of distribution of visceral/soft tissue metastatic sites is crucial not only for staging but also to better understand patterns of therapeutic response. We identified the lungs, liver and adrenal glands as the most common visceral/soft tissue metastatic sites from prostate cancer. We found that higher PSA levels at the time of PSMA PET/CT imaging were positively associated with concurrent osseous and nodal involvement.

Liposomal bupivacaine provides superior pain control compared to bupivacaine with adjuvants in interscalene block for total shoulder replacement: a prospective double-blinded, randomized controlled trial.

INTRODUCTION: Optimal pain control methods after total shoulder arthroplasty (TSA) achieve reduced opioid consumption, shortened hospital stay, and improved patient satisfaction in addition to adequate analgesia. Interscalene brachial plexus block is the gold standard for TSA, yet it typically does not provide pain relief lasting beyond 24 hours. Liposomal bupivacaine (LB) purportedly provides prolonged analgesia, yet it has been minimally explored for interscalene block, and it is significantly more expensive than standard bupivacaine. METHODS: This is a prospective, 2-arm, double-blinded randomized controlled trial. Subjects presenting for anatomic or reverse TSA were randomized in a 1:1 ratio to receive interscalene brachial plexus block with either LB plus bupivacaine (LBB group) or bupivacaine plus dexamethasone and epinephrine (BDE group). The primary outcome was 120-hour postoperative opioid consumption. Secondary outcomes were pain scores up to 96 hours postoperatively, pain control satisfaction, complications, level of distress from block numbness, and hospital stay. RESULTS: Ninety patients, 45 per group, were included in the intention-to-treat analysis and randomized. Because of withdrawal of consent and loss to follow-up, 40 in each group completed enrollment through postoperative day 60. Total 120-hour postoperative opioid consumption was similar between groups (P = .127), with no differences within 24- or 48-hour time intervals. Postoperative pain scores at 24-48 hours, 48-72 hours, 72-96 hours, and day 60 were significantly lower for the LBB group. DISCUSSION: LB interscalene brachial plexus block before total shoulder arthroplasty did not reduce 120-hour postoperative opioid consumption but significantly reduced postoperative pain between 24 and 96 hours and at postoperative day 60.

Descriptive Epidemiology From the Research in Osteochondritis Dissecans of the Knee (ROCK) Prospective Cohort.

BACKGROUND: Osteochondritis dissecans (OCD) occurs most commonly in the knees of young individuals. This condition is known to cause pain and discomfort in the knee and can lead to disability and early knee osteoarthritis. The cause is not well understood, and treatment plans are not well delineated. The Research in Osteochondritis Dissecans of the Knee (ROCK) group established a multicenter, prospective cohort to better understand this disease. PURPOSE: To provide a baseline report of the ROCK multicenter prospective cohort and present a descriptive analysis of baseline data for patient characteristics, lesion characteristics, and clinical findings of the first 1000 cases enrolled into the prospective cohort. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients were recruited from centers throughout the United States. Baseline data were obtained for patient characteristics, sports participation, patient-reported measures of functional capabilities and limitations, physical examination, diagnostic imaging results, and initial treatment plan. Descriptive statistics were completed for all outcomes of interest. RESULTS: As of November 2020, a total of 27 orthopaedic surgeons from 17 institutions had enrolled 1004 knees with OCD, representing 903 patients (68.9% males; median age, 13.1 years; range, 6.3-25.4 years), into the prospective cohort. Lesions were located on the medial femoral condyle (66.2%), lateral femoral condyle (18.1%), trochlea (9.5%), patella (6.0%), and tibial plateau (0.2%). Most cases involved multisport athletes (68.1%), with the most common primary sport being basketball for males (27.3% of cases) and soccer for females (27.6% of cases). The median Pediatric International Knee Documentation Committee (Pedi-IKCD) score was 59.9 (IQR, 45.6-73.9), and the median Pediatric Functional Activity Brief Scale (Pedi-FABS) score was 21.0 (IQR, 5.0-28.0). Initial treatments were surgical intervention (55.4%) and activity restriction (44.0%). When surgery was performed, surgeons deemed the lesion to be stable at intraoperative assessment in 48.1% of cases. CONCLUSION: The multicenter ROCK group has been able to enroll the largest knee OCD cohort to date. This information is being used to further understand the pathology of OCD, including its cause, associated comorbidities, and initial presentation and symptoms. The cohort having been established is now being followed longitudinally to better define and elucidate the best treatment algorithms based on these presenting signs and symptoms.

Efficacy and Safety of Locally Injected Tranexamic Acid in Hip Fracture Patients: A Retrospective Review.

OBJECTIVE: To determine whether locally injected tranexamic acid (TXA) used in the surgical treatment of fragility hip fractures can lower transfusion rates without increasing the risk of complications. DESIGN: Retrospective comparative cohort. SETTING: Tertiary referral orthopaedic specialty hospital, Level I trauma center. PATIENTS/PARTICIPANTS: A total of 490 patients (252 patients received TXA) 50 years of age and older who underwent surgery for a low-energy fragility fracture of the proximal femur between March 2018 and February 2020 were included in this study. INTERVENTION: Use of locally injected TXA at the time of wound closure. MAIN OUTCOME: The main outcomes of this study were the number of patients requiring postoperative blood transfusions, incidences of venous thromboembolism, and surgical site infections. RESULTS: A statistically significant difference was noted in the frequency of transfusion between patients who received TXA compared with those who did not receive TXA (33% vs. 43%, respectively) (P = 0.034). There were no significant differences in venous thromboembolism incidence (0.4% vs. 0.8% TXA vs. No TXA) (P = 0.526) or infections (0.4% vs. 0.4% TXA vs. No TXA) (P = 0.965). Regression analysis indicated that the use of TXA reduced the need for postoperative blood transfusion by 31% (odds ratio: 0.688, 95% CI: 0.477-0.993, P = 0.045). CONCLUSION: Locally injected TXA significantly reduced the need for postoperative transfusion in the surgical treatment of fragility hip fractures. In addition, there was no increased risk of complications in those receiving TXA versus those who did not. Locally injected TXA seems to be both a safe and effective way to reduce postoperative blood transfusions in patients with fragility hip fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A novel urinary biomarker protein panel to identify children with ureteropelvic junction obstruction - A pilot study.

INTRODUCTION AND OBJECTIVE: Reliable urinary biomarker proteins would be invaluable in identifying children with ureteropelvic junction obstruction (UPJO) as the existing biomarker proteins are inconsistent in their predictive ability. Therefore, the aim of this study was to identify consistent and reliable urinary biomarker proteins in children with UPJO. METHODS: To identify candidate biomarker proteins, total protein from age-restricted (<2 years) and sex-matched (males) control (n = 22) and UPJO (n = 21) urine samples was analyzed by mass spectrometry. Proteins that were preferentially identified in UPJO samples were selected (2-step process) and ranked according to their diagnostic odds ratio value. The top ten proteins with highest odds ratio values were selected and tested individually by ELISA. The total amount of each protein was normalized to urine creatinine and the median with interquartile ranges for control and UPJO samples was determined. Additionally, fold change (UPJO/Control) of medians of the final panel of 5 proteins was also determined. Finally, we calculated the average + 3(SD) and average + 4(SD) values of each of the 5 proteins in the control samples and used it as an arbitrary cutoff to classify individual control and UPJO samples. RESULTS: In the first step of our selection process, we identified 171 proteins in UPJO samples that were not detected in the majority of the control samples (16/22 samples, or 72.7%). Of the 171 proteins, only 50 proteins were detected in at least 11/21 (52.4%) of the UPJO samples and hence were selected in the second step. Subsequently, these 50 proteins were ranked according to the odds ratio value and the top 10 ranked proteins were validated by ELISA. Five of the 10 proteins - prostaglandin-reductase-1, ficolin-2, nicotinate-nucleotide pyrophosphorylase [carboxylating], immunoglobulin superfamily-containing leucine-rich-repeat-protein and vascular cell adhesion molecule-1 were present at higher levels in the UPJO samples (fold-change of the median protein concentrations ranging from 2.9 to 9.4) and emerged as a panel of biomarkers to identify obstructive uropathy. Finally, the order of prevalence of the 5 proteins in UPJO samples is PTGR1>FCN2>QPRT>ISLR>VCAM1. CONCLUSION: In summary, this unique screening strategy led to the identification of previously unknown biomarker proteins that when screened collectively, may reliably distinguish between obstructed vs. non-obstructed infants and may prove useful in identifying informative biomarker panels for biological samples from many diseases.

In Vitro Cytotoxicity, Adhesion, and Proliferation of Human Vascular Cells Exposed to Zinc.

Zinc (Zn) and its alloys have recently been introduced as a new class of biodegradable metals with potential application in biodegradable vascular stents. Although an in vivo feasibility study pointed to outstanding biocompatibility of Zn-based implants in vascular environments, a thorough understanding of how Zn and Zn2+ affect surrounding cells is lacking. In this comparative study, three vascular cell types-human endothelial cells (HAEC), human aortic smooth muscle cells (AoSMC), and human dermal fibroblasts (hDF)-were studied to advance the understanding of Zn/Zn2+-cell interactions. Aqueous cytotoxicity using a Zn2+ insult assay resulted in LD50 values of 50 µM for hDF, 70 µM for AoSMC, and 265 µM for HAEC. Direct cell contact with the metallic Zn surface resulted initially in cell attachment, but was quickly followed by cell death. After modification of the Zn surface using a layer of gelatin-intended to mimic a protein layer seen in vivo-the cells were able to attach and proliferate on the Zn surface. Further experiments demonstrated a Zn dose-dependent effect on cell spreading and migration, suggesting that both adhesion and cell mobility may be hindered by free Zn2+.

Biodegradable Metals for Cardiovascular Stents: from Clinical Concerns to Recent Zn-Alloys.

Metallic stents are used to promote revascularization and maintain patency of plaqued or damaged arteries following balloon angioplasty. To mitigate the long-term side effects associated with corrosion-resistant stents (i.e., chronic inflammation and late stage thrombosis), a new generation of so-called "bioabsorbable" stents is currently being developed. The bioabsorbable coronary stents will corrode and be absorbed by the artery after completing their task as vascular scaffolding. Research spanning the last two decades has focused on biodegradable polymeric, iron-based, and magnesium-based stent materials. The inherent mechanical and surface properties of metals make them more attractive stent material candidates than their polymeric counterparts. A third class of metallic bioabsorbable materials that are based on zinc has been introduced in the last few years. This new zinc-based class of materials demonstrates the potential for an absorbable metallic stent with the mechanical and biodegradation characteristics required for optimal stent performance. This review compares bioabsorbable materials and summarizes progress towards bioabsorbable stents. It emphasizes the current understanding of physiological and biological benefits of zinc and its biocompatibility. Finally, the review provides an outlook on challenges in designing zinc-based stents of optimal mechanical properties and biodegradation rate.

Surface Defection Reduces Cytotoxicity of Zn(2-methylimidazole)2 (ZIF-8) without Compromising its Drug Delivery Capacity.

Zn(2-methylimidazole)2 (ZIF-8), as one of the most important metal-organic framework (MOF) molecules, is a promising candidate for drug delivery due to its low-density structure, high surface area, and tunable frameworks. However, ZIF-8 exhibits a high cytotoxicity associated with its external hydrophobic surface, which significantly restricts its application in drug delivery and other biomedical applications. Commonly used chemical functionalization methods would convert the hydrophobic surface of ZIF-8 to hydrophilic, but the generated functional groups on its internal surface may reduce its pore sizes or even block its pores. Herein, a surface defection strategy was applied on the external surface of ZIF-8 to enhance its hydrophilicity without reducing or blocking the internal pores. In this approach, mechanical ball-milling was used to incur defects on the external surface of ZIF-8, leading to unsaturated Zn-sites and N-sites which subsequently bound H2O molecules in an aqueous environment. Furthermore, hydroxyurea delivery and cell cytotoxicity of ZIF-8 with and without the external surface treatment were evaluated. It was found that 5-min ball milling changed the hydrophobic-hydrophilic balance of ZIF-8, resulting in significantly higher cell viability without compromising its hydroxyurea loading and release capacity. Such a simple mechanical ball-milling followed by water-treatment provides a general technique for surface-modification of other MOF molecules, which will undoubtedly magnify their biomedical applications.

Physiologically Low Oxygen Enhances Biomolecule Production and Stemness of Mesenchymal Stem Cell Spheroids.

Multicellular human mesenchymal stem cell (hMSC) spheroids have been demonstrated to be valuable in a variety of applications, including cartilage regeneration, wound healing, and neoangiogenesis. Physiological relevant low oxygen culture can significantly improve in vitro hMSC expansion by preventing cell differentiation. We hypothesize that hypoxia-cultured hMSC spheroids can better maintain the regenerative properties of hMSCs. In this study, hMSC spheroids were fabricated using hanging drop method and cultured under 2% O2 and 20% O2 for up to 96 h. Spheroid diameter and viability were examined, as well as extracellular matrix (ECM) components and growth factor levels between the two oxygen tensions at different time points. Stemness was measured among the spheroid culture conditions and compared to two-dimensional cell cultures. Spheroid viability and structural integrity were studied using different needle gauges to ensure no damage would occur when implemented in vivo. Spheroid attachment and integration within a tissue substitute were also demonstrated. The results showed that a three-dimensional hMSC spheroid cultured at low oxygen conditions can enhance the production of ECM proteins and growth factors, while maintaining the spheroids' stemness and ability to be injected, attached, and potentially be integrated within a tissue.

Corrosion Characteristics Dictate the Long-Term Inflammatory Profile of Degradable Zinc Arterial Implants.

There has been considerable recent interest to develop a feasible bioresorbable stent (BRS) metal. Although zinc and its alloys have many potential advantages, the inflammatory response has not been carefully examined. Using a modified wire implantation model, we characterize the inflammatory response elicited by zinc at high purity (4N) [99.99%], special high grade (SHG)[∼99.7%], and alloyed with 1 wt % (Zn-1Al), 3% (Zn-3Al), and 5.5% (Zn-5Al) aluminum. We found that inflammatory cells were able to penetrate the thick and porous corrosion layer that quickly formed around SHG, Zn-1Al, Zn-3Al, and Zn-5Al implants. In contrast, a delayed entrance of inflammatory cells into the corrosion layer around 4N zinc due to a significantly lower corrosion rate was associated with greater fibrous encapsulation, appearance of necrotic regions, and increased macrophage labeling. Interestingly, cell viability at the interface decreased from SHG, to Zn-1Al, and then Zn-3Al, a trend associated with an increased CD68 and CD11b labeling and capsule thickness. Potentially, the shift to intergranular corrosion due to the aluminum addition increased the activity of macrophages. We conclude that the ability of macrophages to penetrate and remain viable within the corrosion layer may be of fundamental importance for eliciting biocompatible inflammatory responses around corrodible metals.

Hypoxia Created Human Mesenchymal Stem Cell Sheet for Prevascularized 3D Tissue Construction.

3D tissue based on human mesenchymal stem cell (hMSC) sheets offers many interesting opportunities for regenerating multiple types of connective tissues. Prevascularizing hMSC sheets with endothelial cells (ECs) will improve 3D tissue performance by supporting cell survival and accelerating integration with host tissue. It is hypothesized that hypoxia cultured hMSC sheets can promote microvessel network formation and preserve stemness of hMSCs. This study investigates the vascularization of hMSC sheets under different oxygen tensions. It is found that the HN condition, in which hMSC sheets formed under physiological hypoxia (2% O2 ) and then cocultured with ECs under normoxia (20% O2 ), enables longer and more branched microvessel network formation. The observation is corroborated by higher levels of angiogenic factors in coculture medium. Additionally, the hypoxic hMSC sheet is more uniform and less defective, which facilitates fabrication of 3D prevascularized tissue construct by layering the prevascularized hMSC sheets and maturing in rotating wall vessel bioreactor. The hMSCs in the 3D construct still maintain multilineage differentiation ability, which indicates the possible application of the 3D construct for various connective tissues regeneration. These results demonstrate that hypoxia created hMSC sheets benefit the microvessel growth and it is feasible to construct 3D prevascularized tissue construct using the prevascularized hMSC sheets.

Metallic zinc exhibits optimal biocompatibility for bioabsorbable endovascular stents.

Although corrosion resistant bare metal stents are considered generally effective, their permanent presence in a diseased artery is an increasingly recognized limitation due to the potential for long-term complications. We previously reported that metallic zinc exhibited an ideal biocorrosion rate within murine aortas, thus raising the possibility of zinc as a candidate base material for endovascular stenting applications. This study was undertaken to further assess the arterial biocompatibility of metallic zinc. Metallic zinc wires were punctured and advanced into the rat abdominal aorta lumen for up to 6.5months. This study demonstrated that metallic zinc did not provoke responses that often contribute to restenosis. Low cell densities and neointimal tissue thickness, along with tissue regeneration within the corroding implant, point to optimal biocompatibility of corroding zinc. Furthermore, the lack of progression in neointimal tissue thickness over 6.5months or the presence of smooth muscle cells near the zinc implant suggest that the products of zinc corrosion may suppress the activities of inflammatory and smooth muscle cells.

Decellularization of fibroblast cell sheets for natural extracellular matrix scaffold preparation.

The application of cell-derived extracellular matrix (ECM) in tissue engineering has gained increasing interest because it can provide a naturally occurring, complex set of physiologically functional signals for cell growth. The ECM scaffolds produced from decellularized fibroblast cell sheets contain high amounts of ECM substances, such as collagen, elastin, and glycosaminoglycans. They can serve as cell adhesion sites and mechanically strong supports for tissue-engineered constructs. An efficient method that can largely remove cellular materials while maintaining minimal disruption of ECM ultrastructure and content during the decellularization process is critical. In this study, three decellularization methods were investigated: high concentration (0.5 wt%) of sodium dodecyl sulfate (SDS), low concentration (0.05 wt%) of SDS, and freeze-thaw cycling method. They were compared by characterization of ECM preservation, mechanical properties, in vitro immune response, and cell repopulation ability of the resulted ECM scaffolds. The results demonstrated that the high SDS treatment could efficiently remove around 90% of DNA from the cell sheet, but significantly compromised their ECM content and mechanical strength. The elastic and viscous modulus of the ECM decreased around 80% and 62%, respectively, after the high SDS treatment. The freeze-thaw cycling method maintained the ECM structure as well as the mechanical strength, but also preserved a large amount of cellular components in the ECM scaffold. Around 88% of DNA was left in the ECM after the freeze-thaw treatment. In vitro inflammatory tests suggested that the amount of DNA fragments in ECM scaffolds does not cause a significantly different immune response. All three ECM scaffolds showed comparable ability to support in vitro cell repopulation. The ECM scaffolds possess great potential to be selectively used in different tissue engineering applications according to the practical requirement.