Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization.

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization. HIGHLIGHTS: SAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages. Knockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization.

Missed Visits Predict Recurrence in Idiopathic Clubfoot.

BACKGROUND: Congenital talipes equinovarus, also known as "clubfoot," is a common congenital deformity. While reported relapse rates vary widely, relapse continues to be a common problem faced in the treatment of this condition. The objective of this study is to assess relationships between demographic/socioeconomic factors, follow-up, and rates of relapse in our population of clubfoot patients. METHODS: Retrospective chart review was conducted for patients undergoing treatment for idiopathic clubfoot from February 2012 to December 2022 at a tertiary children's hospital. Records were analyzed for follow-up adherence and recurrence in the Ponseti method, in addition to patient demographic and socioeconomic factors. Statistical analysis was performed to evaluate associations between recurrence, missed clinical visits, and demographic/socioeconomic factors of interest. RESULTS: Ninety-five patients were included in the study [74.7% male (N=71) and 25.2% female (N=24)]. A total of 64.2% (N=61) of patients developed recurrence during their treatment. Recurrence rates differed significantly by reported bracing noncompliance >1 month (35/46 vs. 26/49, P=0.019), having missed 1 or more clinical visits (38/61 vs. 8/34, P < 0.001), Medicaid or equivalent insurance type (41/56 vs. 20/39, P=0.028), non-white race (47/66 vs. 14/29, P=0.032, higher Social Deprivation Index score (56.13 vs. 41.06, P=0.019). Significant variables were analyzed using a multivariate logistic regression analysis (MVLR). After MVLR, having 1 or more missed clinical visits (OR 4.462, 95% CI: 1.549-12.856) remained significantly associated with increased rates of recurrence. Primary language preference and distance to the hospital were not associated with recurrence. CONCLUSIONS: Higher SDI scores, non-white race, Medicaid insurance, and missed clinical follow-up visits were all associated with increased rates of recurrence for clubfoot patients. Using an MVLR model, missed clinical follow-up visits remained independently associated with increased recurrence rates. LEVEL OF EVIDENCE: Level 2-retrospective, prognostic study.

Higher Cumulative Dose of Opioids and Other Sedatives are Associated with Extubation Failure in Norwood Patients.

BACKGROUND: The primary purpose of this study is to evaluate the relationship between sedation usage and extubation failure, and to control for the effects of hemodynamic, oximetric indices, clinical characteristics, ventilatory settings pre- and post-extubation, and echocardiographic (echo) findings in neonates with hypoplastic left heart syndrome (HLHS) post-Norwood procedure. METHODS: Single-center, retrospective analysis of Norwood patients during their first extubation post-surgery from January 2015 to July 2021. Extubation failure was defined as reintubation within 48 h of extubation. Demographics, clinical characteristics, ventilatory settings, echo findings (right ventricular function, tricuspid regurgitation), and cumulative dose of sedation medications before extubation were compared between patients with successful or failed extubation. RESULTS: The analysis included 130 patients who underwent the Norwood procedure with 121 (93%) successful and 9 (7%) failed extubations. Univariate analyses showed that vocal cord anomaly (p = 0.05), lower end-tidal CO2 (p < 0.01), lower pulse-to-respiratory quotient (p = 0.02), and ketamine administration (p = 0.04) were associated with extubation failure. The use of opioids, benzodiazepines, dexmedetomidine, and ketamine are mutually correlated in this cohort. On multivariable analysis, the vocal cord anomaly (OR = 7.31, 95% CI 1.25-42.78, p = 0.027), pre-extubation end-tidal CO2 (OR = 0.80, 95% CI 0.65-0.97, p = 0.025), and higher cumulative dose of opioids (OR = 10.16, 95% CI 1.25-82.43, p = 0.030) were independently associated with extubation failure while also controlling for post-extubation respiratory support (CPAP/BiPAP/HFNC vs NC), intubation length, and echo results. CONCLUSION: Higher cumulative opioid doses were associated with a greater incidence of extubation failure in infants post-Norwood procedure. Therefore, patients with higher cumulative doses of opioids should be more closely evaluated for extubation readiness in this population. Low end-tidal CO2 and low pulse-to-respiratory quotient were also associated with failed extubation. Consideration of the pulse-to-respiratory quotient in the extubation readiness assessment can be beneficial in the Norwood population.

Bone Metastasis Initiation Is Coupled with Bone Remodeling through Osteogenic Differentiation of NG2+ Cells.

The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2+ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2+ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2+ BMSCs are recruited to remodeling sites. Ablation of NG2+ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2+ BMSCs, especially when undergoing osteodifferentiation, enhanced cancer cell proliferation and migration. Knockout of N-cadherin in NG2+ cells abolished these effects in vitro and phenocopied NG2+ lineage depletion in vivo. These findings uncover dual roles of NG2+ cells in metastasis and remodeling and indicate that osteodifferentiation of BMSCs promotes metastasis initiation via N-cadherin-mediated cell-cell interaction. SIGNIFICANCE: The bone colonization of cancer cells occurs in an environment that undergoes constant remodeling. Our study provides mechanistic insights into how bone homeostasis and pathologic repair lead to the outgrowth of disseminated cancer cells, thereby opening new directions for further etiologic and epidemiologic studies of tumor recurrences. This article is highlighted in the In This Issue feature, p. 247.

Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.

Inflammation has a role in the pathogenesis of childhood malnutrition. We investigated the effect of malnutrition and inflammatory challenge on bone marrow composition and bone health. We studied an established murine model of moderate acute malnutrition at baseline and after acute inflammatory challenge with bacterial lipopolysaccharide (LPS), a surrogate of Gram-negative bacterial sepsis, or Leishmania donovani, the cause of visceral leishmaniasis. Both of these infections cause significant morbidity and mortality in malnourished children. Of the 2 stimuli, LPS caused more pronounced bone marrow changes that were amplified in malnourished mice. LPS challenge led to increased inflammatory cytokine expression (Il1b, Il6, and Tnf), inflammasome activation, and inflammatory monocyte accumulation in the bone marrow of malnourished mice. Depletion of inflammatory monocytes in Csfr1-LysMcre-DT malnourished mice significantly reduced the inflammasome activation and IL1-ß production after LPS challenge. The inflammatory challenge also led to increased expansion of mesenchymal stem cells (MSCs), bone marrow adiposity, and expression of genes (Pparg, Adipoq, and Srbp1) associated with adipogenesis in malnourished mice. This suggests that inflammatory challenge promotes differentiation of BM MSCs toward the adipocyte lineage rather than toward bone-forming osteoblasts in the malnourished host. Concurrent with this reduced osteoblastic potential there was an increase in bone-resorbing osteoclasts, enhanced osteoclast activity, upregulation of inflammatory genes, and IL-1B involved in osteoclast differentiation and activation. The resulting weakened bone formation and increased bone resorption would contribute to the bone fragility associated with malnutrition. Lastly, we evaluated the effect of replacing lipid rich in omega-6 fatty acids (corn oil) with lipid-rich in omega-3 fatty acids (fish oil) in the nutrient-deficient diet. LPS-challenged malnourished mice that received dietary fish oil showed decreased expression of inflammatory cytokines and Rankl and reduced osteoclast differentiation and activation in the bone marrow. This work demonstrates that the negative effect of inflammatory challenge on bone marrow is amplified in the malnourished host. Increasing dietary intake of omega-3 fatty acids may be a means to reduce inflammation and improve bone health in malnourished children.

Optimization and Characterization of a Bone Culture Model to Study Prostate Cancer Bone Metastasis.

Nearly 90% of patients with advanced prostate cancer manifest bone metastases. Distinct from the osteolytic metastasis mostly observed in other cancer types, prostate cancer bone metastasis is typically more osteoblastic, which is relatively understudied due to the lack of reliable and efficient models to resemble the indolent cellular growth and complexity of metastatic progression. In our previous studies, we developed bone-in-culture array (BICA) to primarily model the osteoblast-involved, pre-osteolytic stage of breast cancer bone metastasis. Given that the progression of prostate cancer bone metastasis is largely osteoblastic, it is reasonable to speculate that the original BICA model can be adjusted to investigate prostate cancer bone metastases. In this study, we refined BICA by reducing the surgical labor and improving its reproducibility and capacity. The optimized BICA can successfully recapitulate important features of prostate cancer bone metastasis such as the osteoblastic phenotype, indolent growth, cancer-niche interactions, and response to hormones. Our efforts address the long-standing need for reliable and efficient models to study prostate cancer bone metastasis.

Acute and severe trabecular bone loss in a rat model of critical illness myopathy.

Prolonged mechanical ventilation for critically ill patients with respiratory distress can result in severe muscle wasting with preferential loss of myosin. Systemic inflammation triggered by lung mechanical injury likely contributes to this myopathy, although the exact mechanisms are unknown. In this study, we hypothesized that muscle wasting following mechanical ventilation is accompanied by bone loss. The objective was to determine the rate, nature, and extent of bone loss in the femora of rats ventilated up to 10 days and to relate the bone changes to muscle deterioration. We have developed a rat model of ventilator-induced muscle wasting and established its feasibility and clinical validity. This model involves pharmacologic paralysis, parenteral nutrition, and continuous mechanical ventilation. We assessed the hindlimb muscle and bone of rats ventilated for 0, 2, 5, 8, and 10 days. Routine histology, microCT, and biomechanical evaluations were performed. Hindlimb muscles developed changes consistent with myopathy, whereas the femurs demonstrated a progressive decline in trabecular bone volume, mineral density, and microarchitecture beginning Day 8 of mechanical ventilation. Biomechanical testing showed a reduction in flexural strength and stiffness on Day 10. The bone changes correlated with the loss of muscle mass and myosin. These results demonstrate that mechanical ventilation leads to progressive trabecular bone loss parallel to muscle deterioration. The results of our study suggest that mechanically ventilated patients may be at risk of compromised bone integrity and muscle weakness, predisposing to post-ventilator falls and fractures, thereby warranting interventions to prevent progressive bone and muscle decline.

The Legal, Ethical, and Scientific Considerations for Returning Explanted Orthopaedic Hardware to the Patient.

ABSTRACT: Orthopaedic hardware explantation is a multifaceted topic with complex legal, ethical, and scientific aspects that require thorough exploration. Issues of device ownership, explant-induced disease propagation, and potential device resale pose legal risks to providers and health-care institutions. Ethically, implant removal highlights the potential that performing procedures at the request of the patient will incentivize patient compliance and strengthen the patient-surgeon relationship. However, the return of explanted hardware to patients could hinder scientific study and innovation, ultimately limiting advancement in risk reduction and patient outcomes. Continued research into these topics remains paramount to ensure that clinicians and institutions deliver optimal patient care while abiding with legal and ethical imperatives. This article addresses the legal, ethical, and scientific issues that are pertinent to returning an explanted orthopaedic implant to the patient and the potential ramifications of such practice.

A Population of M2 Macrophages Associated With Bone Formation.

We previously identified transient brown adipocyte-like cells associated with heterotopic ossification (HO). These ancillary cells support new vessel synthesis essential to bone formation. Recent studies have shown that the M2 macrophage contributes to tissue regeneration in a similar way. To further define the phenotype of these brown adipocyte-like cells they were isolated and characterized by single-cell RNAseq (scRNAseq). Analysis of the transcriptome and the presence of surface markers specific for macrophages suggest that these cells are M2 macrophages. To validate these findings, clodronate liposomes were delivered to the tissues during HO, and the results showed both a significant reduction in these macrophages as well as bone formation. These cells were isolated and shown in culture to polarize towards either M1 or M2 similar to other macrophages. To confirm that these are M2 macrophages, mice received lipopolysacheride (LPS), which induces proinflammation and M1 macrophages. The results showed a significant decrease in this specific population and bone formation, suggesting an essential role for M2 macrophages in the production of bone. To determine if these macrophages are specific to HO, we isolated these cells using fluorescence-activated cell sorting (FACS) from a bone defect model and subjected them to scRNAseq. Surprisingly, the macrophage populations overlapped between the two groups (HO-derived versus callus) suggesting that they may be essential ancillary cells for bone formation in general and not selective to HO. Of further note, their unique metabolism and lipogenic properties suggest the potential for unique cross talk between these cells and the newly forming bone.

Osteofibrous dysplasia and adamantinoma: A summary of diagnostic challenges and surgical techniques.

Osteofibrous dysplasia is an indolent benign fibro-osseous tumor, while adamantinoma is a locally aggressive biphasic malignancy with epithelial and fibro-osseous components. Predominantly arising in the tibial diaphysis of children and young adults, both tumors are resistant to chemotherapy and radiation. Wide surgical resection is regarded as the mainstay of therapy for adamantinoma, and limb-salvage reconstructive procedures can achieve good functional outcomes, albeit with non-negligible rates of complications. This review discusses emerging advances in the pathogenesis, histogenesis, and diagnosis of these entities and presents advantages and limitations of the most common surgical techniques used for their management.

The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells.

Estrogen receptor-positive (ER+) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.

A replicating stem-like cell that contributes to bone morphogenetic protein 2-induced heterotopic bone formation.

Bone morphogenetic protein 2 (BMP2)-induced heterotopic bone formation (HBF) starts synchronously from zero upon BMP2 induction, which is advantageous for lineage tracking. The studies reported here in GLAST-CreErt2 :tdTomato red (TR)floxSTOPflox mice during BMP2-induced HBF show 78.8 ± 11.6% of chondrocytes and 86.5 ± 1.9% of osteoblasts are TR+ after approximately 1 week. Clustering after single-cell RNAseq resulted in nine cell types, and analysis revealed one as a highly replicating stem-like cell (RSC). Pseudotiming suggested that the RSC transitions to a mesenchymal stem-like cell that simultaneously expresses multiple osteoblast and chondrocyte transcripts (chondro-osseous progenitor [COP]). RSCs and COPs were isolated using flow cytometry for unique surface markers. Isolated RSCs (GLAST-TR+ Hmmr+ Cd200- ) and COPs (GLAST-TR+ Cd200+ Hmmr- ) were injected into the muscle of mice undergoing HBF. Approximately 9% of the cells in heterotopic bone (HB) in mice receiving RSCs were GLAST-TR+ , compared with less than 0.5% of the cells in mice receiving COPs, suggesting that RSCs are many times more potent than COPs. Analysis of donor-derived TR+ RSCs isolated from the engrafted HB showed approximately 50% were COPs and 45% were other cells, presumably mature bone cells, confirming the early nature of the RSCs. We next isolated RSCs from these mice (approximately 300) and injected them into a second animal, with similar findings upon analysis of HBF. Unlike other methodology, single cell RNAseq has the ability to detect rare cell populations such as RSCs. The fact that RSCs can be injected into mice and differentiate suggests their potential utility for tissue regeneration.

Clinical Considerations for Return to Driving a Car following a Total Knee or Hip Arthroplasty: A Systematic Review.

AIM: The purpose of this study is to systematically review patient characteristics and clinical determinants that may influence return to driving status and time frames following a primary TKA or THA and provide an update of the current literature. METHODS: This review was completed per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Final electronic database searches were completed in October 2019 in Medline/PubMed, Medline/OVID, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Library using preselected search terms. Manuscripts of prospective and nonrandomized studies that examined the return to driving a car after a primary knee or hip arthroplasty patients were included. The Methodological Index for Non-Randomized Studies was used to measure study quality. Two authors selected studies and assessed their qualities. All disagreements were resolved through discussion and, as needed, a third reviewer. Data on study title, author(s), country, year, study design, sample size, inclusion and exclusion criteria, age, BMI, gender, statistical analyses, driving measure, follow-up time, surgical approach, laterality, and postoperative management were extracted from each study. RESULTS: A total of 23 studies were eligible, including 12 TKA studies (n = 654) with mean ages between 43 and 82 years, 9 THA studies (n = 922) with mean ages between 34 and 85 years, and 2 combined TKA and THA (TKA, n = 815; THA, n = 685), yielded MINORS scores between 6 and 12. Most patients achieved or exceeded preoperative response times between 1 and 8 weeks following a TKA and 2 days to 8 weeks following a THA, and/or self-reported return to driving between 1 week and 6 months. Influences on return to driving time included laterality and pain, but gender was mixed. Discussion/. CONCLUSIONS: Study results were consistent with previous systematic reviews in that return to driving a car after a primary TKA or THA is highly variable, and most commonly occurs around 4 weeks, but can range between 2 and 8 weeks. While various patient and clinical factors can influence return to driving for a TKA or THA, the most common contributing facts were pain and laterality. The heterogeneous nature of the studies prevented a meta-analysis for determining contributions of return to driving following a primary TKA or THA. Regardless, this study updates previous systematic reviews and presents insight on patient and clinical factors beyond generalized timeframes for return to driving a car. This information and results from future studies are essential to guide clinical recommendations and patient and clinician expectations for return to driving a car after a primary TKA or THA.

Clinical Characteristics of Patients with Type 2 Diabetes Mellitus Receiving a Primary Total Knee or Hip Arthroplasty.

AIM: The purpose of this study is to explore clinical characteristics of patients with T2DM receiving a primary knee (TKA) or hip (THA) arthroplasty to patients without T2DM receiving a TKA or THA and patients with T2DM with no history of osteoarthritis (OA). METHODS: The study included a retrospective database review of 500 consecutive primary TKA or THA identified with ICD-9 codes and 100 consecutive T2DM patients. Patients who received a TKA or THA were screened for inclusion and exclusion and divided into with or without T2DM groups. A comparison group of patients with T2DM only without arthroplasty was screened to exclude patients with a history of OA or arthroplasty. All groups were compared based on demographic and relevant comorbidity differences. OA characteristics, including OA and previous arthroplasty of the involved and contralateral joints, were compared between patients with and without T2DM receiving a TKA or THA. Finally, patients with T2DM with and without TKA or THA were compared for T2DM differences. RESULTS: Study results found that among those receiving a primary arthroplasty, patients with T2DM were more likely to be obese and older and reported cardiovascular, urinary, dyslipidemia, and peripheral neuropathy than those with T2DM. Among the T2DM individuals, those receiving an arthroplasty surgery were older and obese and more likely to report peripheral neuropathy; however, those with T2DM with no OA were more likely to report atherosclerosis and cardiovascular disease. Within the arthroplasty subgroup of individuals with T2DM, those requiring antidiabetic medication were 4.5 times more likely to have contralateral OA or arthroplasty. CONCLUSIONS: The results of this study suggest that patients with T2DM requiring a primary arthroplasty are a unique subgroup that requires careful considerations as they are often older, have obesity, and specific comorbidities predisposing to worse postoperative outcomes than their non-T2DM arthroplasty counterparts. Therefore, clinical practice and future studies must consider strategies that would limit OA and arthroplasty management delays while accounting for comorbidities and patient characteristics.

Biomechanical Evaluation of Dual Plate Configurations for Femoral Shaft Fracture Fixation.

AIM: This study aimed at comparing the mechanical properties of conventional and locking dual plates in adjacent and orthogonal orientations for the surgical fixation of transverse femoral shaft fractures. It also assessed the failure mechanics after dual adjacent and orthogonal locking plate removal. METHODS: Thirty-two composite femurs were transversally osteotomized and randomly assigned for fixation with either dual locking or compression plates in an adjacent or orthogonal configuration. Sixteen specimens were preloaded axially to 20 N and single-leg stance loads were simulated. The remaining sixteen constructs were subjected to torsional loads of 10 Nm at a rate of 10 Nm/s in external and internal rotation of the femoral head in relation to the knee. Overall combined rotational stiffness was calculated. Eight different specimens with no osteotomy underwent the same experiments after dual locked plate removal and were tested to failure in combined eccentric axial and torsional modes. Data were statistically processed using a two-tailed t-test and one-way analysis of variance for the comparison of means between two or more groups, respectively. RESULTS: Orthogonal constructs were statistically stiffer in axial loading compared to their adjacent counterparts in both conventional and locking configurations (p<0.001). Dual locking plates provided higher torsional stiffness than conventional ones within each plate orientation (p<0.01). Neither axial/torsional strength nor failure loads differed between constructs that had adjacent or orthogonal dual locking plates instrumented and then removed (p>0.05). CONCLUSIONS: In both orthogonal and adjacent orientations, double locking plates provide higher stability than their dual conventional counterparts. Orthogonal dual plate configuration is more stable and biomechanically superior to dual adjacent plating for constructs fixed with either standard compression or locking plates.

Characterization of neuromas in peripheral nerves and their effects on heterotopic bone formation.

The formation of neuromas involves expansion of the cellular components of peripheral nerves. The onset of these disorganized tumors involves activation of sensory nerves and neuroinflammation. Particularly problematic in neuroma is arborization of axons leading to extreme, neuropathic pain. The most common sites for neuroma are the ends of transected nerves following injury; however, this rodent model does not reliably result in neuroma formation. In this study, we established a rodent model of neuroma in which the sciatic nerve was loosely ligated with two chromic gut sutures. This model formed neuromas reliably (∼95%), presumably through activation of the neural inflammatory cascade. Resulting neuromas had a disorganized structure and a significant number of replicating cells. Quantification of changes in perineurial and Schwann cells showed a significant increase in these populations. Immunohistochemical analysis showed the presence of ß-tubulin 3 in the rapidly expanding nerve and a decrease in neurofilament heavy chain compared to the normal nerve, suggesting the axons forming a disorganized structure. Measurement of the permeability of the blood-nerve barrier shows that it opened almost immediately and remained open as long as 10 days. Studies using an antagonist of the ß3-adrenergic receptor (L-748,337) or cromolyn showed a significant reduction in tumor size and cell expansion as determined by flow cytometry, with an improvement in the animal's gait detected using a Catwalk system. Previous studies in our laboratory have shown that heterotopic ossification is also a result of the activation of neuroinflammation. Since heterotopic ossification and neuroma often occur together in amputees, they were induced in the same limbs of the study animals. More heterotopic bone was formed in animals with neuromas as compared to those without. These data collectively suggest that perturbation of early neuroinflammation with compounds such as L-748,337 and cromolyn may reduce formation of neuromas.

Quadriceps augmentation of undersized hamstrings during ACL reconstruction.

BACKGROUND: Double hamstring autograft for anterior cruciate ligament (ACL) reconstruction is a well-established graft option; however, a major concern with this method arises when the prepared graft is too small. Resorting to allograft can be a solution to this problem, but some surgeons prefer to use autograft in particular situations and some patients may refuse allograft. We investigate the merits of using autogenous quadriceps tendons to augment the insufficient hamstrings and compare the autograft composite graft to a standard hamstrings graft of equal size. METHODS: Semitendinosus, gracilis, and quadriceps tendons were harvested from 10 matched pairs of human cadaver lower extremities. Within each pair, a routine hamstring ACL graft (control) consisting of the semitendinosus and gracilis tendons, and an quadriceps augmented hamstrings graft of equal size comprised of the semitendinosus and quadriceps tendons, were prepared. A freeze-clamp mount was used to biomechanically test each graft construct. Tensile failure load, displacement, energy absorbed, and stiffness were determined and statistically compared within each pair and mode of graft failure was established. RESULTS: No statistically significant differences were found between the quadriceps augmented hamstrings graft versus standard control grafts. Average values for peak failure load and graft displacement at the point of first failure were nearly identical. All ACL graft constructs failed at the mid-substance. CONCLUSIONS: This study demonstrates no statistical difference in the biomechanical properties of an isolated hamstring ACL autograft versus a quadriceps augmented ACL autograft of equal size at time zero. CLINICAL RELEVANCE: This is a potentially new and reliable method for quadriceps tendon autograft augmentation of hamstring autograft for ACL reconstruction.

The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability.

The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs.