Static stability of novel uncemented elbow hemiarthroplasty stabilized with ligament reconstruction.

BACKGROUND: The purpose of this study was to create a model to simulate treatment of unreconstructable distal humerus fractures with hemiarthroplasty. Stability was restored with a latest plate-system that simultaneously tensions medial and lateral collateral ligament grafts. MATERIALS AND METHODS: Static varus and valgus elbow stability was tested in 11 cadaver elbows with intact ligaments and capsule at 5 flexion angles (0°, 30°, 60°, 90°, 120°). The elbows were then destabilized via release of all ligaments and capsular attachments. The distal humerus articular cartilage was excised and replaced with an uncemented hemiarthroplasty. Ligament reconstruction was subsequently performed, and elbow stability was measured and compared to the native state. Dimensions of the hemiarthroplasty component were compared to native elbow dimensions to assess and quantify any existing relationship to elbow stability. RESULTS: A hemiarthroplasty was implanted in all specimens. A size mismatch occurred between the distal humerus trochlea and the olecranon fossa in all specimens and averaged 6.3 mm. Following ligament reconstruction, specimens reproduced the flexion angle-dependent stability of native elbows to both varus and valgus stress. On the medial side, elbow joint stability in mid-flexion was approximately 7% tighter after hemiarthroplasty. Laterally, the elbow was approximately 15% tighter after hemiarthroplasty and demonstrated peak stability in full flexion. The 3 assessed hemiarthroplasty components and bony dimensions did not exhibit any relationship between implant-bone mismatch and elbow stability after ligamentous reconstruction. CONCLUSION: Cadaveric elbow specimens underwent uncemented hemiarthroplasty with soft tissue stabilization with a novel technique for ligament reconstruction. Following hemiarthroplasty and ligament reconstruction, these specimens maintained secure fixation between ligament and bone. Static stability was maintained at varying degrees of elbow flexion regardless of variable mismatch between the hemiarthroplasty component and the native olecranon fossa.

Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer.

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations. METHODS: We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019. RESULTS: Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use. CONCLUSION: Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.

Liver 'organ on a chip'.

The liver plays critical roles in both homeostasis and pathology. It is the major site of drug metabolism in the body and, as such, a common target for drug-induced toxicity and is susceptible to a wide range of diseases. In contrast to other solid organs, the liver possesses the unique ability to regenerate. The physiological importance and plasticity of this organ make it a crucial system of study to better understand human physiology, disease, and response to exogenous compounds. These aspects have impelled many to develop liver tissue systems for study in isolation outside the body. Herein, we discuss these biologically engineered organoids and microphysiological systems. These aspects have impelled many to develop liver tissue systems for study in isolation outside the body. Herein, we discuss these biologically engineered organoids and microphysiological systems.

Statin drugs to reduce breast cancer recurrence and mortality.

Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers. In this context, statin use has been correlated, variably, with a decrease in deaths from breast cancer. However, there is no extant model for this effect, and the extent of efficacy is open to question.The overarching goal of this article is to communicate to the reader of the potential of statins to reduce breast cancer progression and mortality. This is the use as a secondary prevention measure, and not as a therapy to directly counter active cancer. First, salient aspects of statin pharmacology, as relates to cardiovascular disease, will be discussed. Second, the basic and clinical research studies that investigate statin usage in breast cancer will be presented. Additionally, statin effects in other cancer types will be included for context. Finally, proposals for future basic and clinical research studies to determine the role of statins in breast cancer management will be presented.

Statins attenuate outgrowth of breast cancer metastases.

BACKGROUND: Metastasis in breast cancer foreshadows mortality, as clinically evident disease is aggressive and generally chemoresistant. Disseminated breast cancer cells often enter a period of dormancy for years to decades before they emerge as detectable cancers. Harboring of these dormant cells is not individually predictable, and available information suggests that these micrometastatic foci cannot be effectively targeted by existing therapies. As such, long-term, relatively non-toxic interventions that prevent metastatic outgrowth would be an advance in treatment. Epidemiological studies have found that statins reduce breast cancer specific mortality but not the incidence of primary cancer. However, the means by which statins reduce mortality without affecting primary tumor development remains unclear. METHODS: We examine statin efficacy against two breast cancer cell lines in models of breast cancer metastasis: a 2D in vitro co-culture model of breast cancer cell interaction with the liver, a 3D ex vivo microphysiological system model of breast cancer metastasis, and two independent mouse models of spontaneous breast cancer metastasis to the lung and liver, respectively. RESULTS: We demonstrate that statins can directly affect the proliferation of breast cancer cells, specifically at the metastatic site. In a 2D co-culture model of breast cancer cell interaction with the liver, we demonstrate that atorvastatin can directly suppress proliferation of mesenchymal but not epithelial breast cancer cells. Further, in an ex vivo 3D liver microphysiological system of breast cancer metastasis, we found that atorvastatin can block stimulated emergence of dormant breast cancer cells. In two independent models of spontaneous breast cancer metastasis to the liver and to the lung, we find that statins significantly reduce proliferation of the metastatic but not primary tumor cells. CONCLUSIONS: As statins can block metastatic tumor outgrowth, they should be considered for use as long-term adjuvant drugs to delay clinical emergence and decrease mortality in breast cancer patients.

Biomarker identification for statin sensitivity of cancer cell lines.

Statins are potent cholesterol reducing drugs that have been shown to reduce tumor cell proliferation in vitro and tumor growth in animal models. Moreover, retrospective human cohort studies demonstrated decreased cancer-specific mortality in patients taking statins. We previously implicated membrane E-cadherin expression as both a marker and mechanism for resistance to atorvastatin-mediated growth suppression of cancer cells; however, a transcriptome-profile-based biomarker signature for statin sensitivity has not yet been reported. Here, we utilized transcriptome data from fourteen NCI-60 cancer cell lines and their statin dose-response data to produce gene expression signatures that identify statin sensitive and resistant cell lines. We experimentally confirmed the validity of the identified biomarker signature in an independent set of cell lines and extended this signature to generate a proposed statin-sensitive subset of tumors listed in the TCGA database. Finally, we predicted drugs that would synergize with statins and found several predicted combination therapies to be experimentally confirmed. The combined bioinformatics-experimental approach described here can be used to generate an initial biomarker signature for anticancer drug therapy.

Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells.

BACKGROUND: Our understanding of the multiple roles exosomes play during tumor progression is still very poor and the contribution of the normal tissue derived exosomes in distant seeding and tumor outgrowth has also not been widely appreciated. METHODS: Using our all-human liver microphysiological system (MPS) platform as a model to closely recapitulate the early metastatic events, we isolated exosomes from both tumor cells and liver microenvironment. RESULTS: We observed that while priming of the hepatic niche (HepN) with MDA-231 breast cancer derived exosomes facilitated seeding of the cancer cells in the liver, subsequent tumor outgrowth was diminished; this was consistent with increased entry into dormancy. We found that hepatic niche (HepN) derived exosomes contribute significantly to the exosome pool and are distinguished from cancer derived exosomes based on their size, protein and miRNA content. By Ingenuity Pathway Analysis (IPA) of the miRNA content of the HepN, MDA-231/HepN and MDA-231 cells we showed that the HepN derived exosomes affect the breast cancer cells by suppressing pathways involved in cancer cell proliferation and invasion. More importantly exposure of MDA-231 and MDA-468 cells to purified normal HepN derived exosomes, induced changes in the cells consistent with a Mesenchymal to Epithelial reverting Transition (MErT). miRNA arrays performed on MDA-231 treated with Hum Hep/NPC derived exosomes showed significant changes in the levels of a select number of miRNAs involved in epithelial cell differentiation and miRNAs, such as miR186, miR23a and miR205, from our top and bottom bins have previously been reported to regulate E-cadherin transcription and MErT induction in various cancer types. Consistently HepN derived exosome treatment of breast and prostate cancer lines lead to a transient induction of E-cadherin and ZO-1 at the protein level and a more epithelial-like morphology of the cells. CONCLUSIONS: Collectively our data revealed a novel mechanism of regulation of the metastatic cascade, showing a well-orchestrated, timely controlled crosstalk between the cancer cells and the HepN and implicating for the first time the normal tissue/HepN derived exosomes in enabling seeding and entry into dormancy of the cancer cells at the metastatic site.

Subjective and Objective Differences in Patients with Unilateral and Bilateral Carpal Tunnel Syndrome and the Role of Obesity in Syndrome Severity.

BACKGROUND: It remains unclear whether physiologic differences exist in musculoskeletal ultrasound nerve measurements when comparing bilateral and unilateral carpal tunnel syndrome (CTS) patients. Similarly, the influence of body mass index on CTS severity is not well characterized. METHODS: Unilateral and bilateral CTS patients were seen from October of 2014 to February of 2021. Obese and nonobese CTS patients were compared. Median nerve cross-sectional area (CSA), Boston Carpal Tunnel Syndrome Questionnaire (BCTSQ), and six-item Carpal Tunnel Symptom Score (CTS-6) measures were obtained. Nerve conduction studies recorded distal motor latency (DML) and distal sensory latency (DSL). Statistical analysis used Wilcoxon signed rank testing for paired continuous variables, Mann-Whitney U testing for nonpaired continuous variables, and chi-square testing for continuous variables, with a significance level of P < 0.05. RESULTS: A total of 109 (218 nerves) bilateral and 112 (112 nerves) unilateral CTS patients were reviewed. Bilateral patients had larger median nerve CSAs on their more symptomatic side, when defined by BCTSQ score ( P < 0.0001), CTS-6 score ( P < 0.0001), DML ( P < 0.0001), and DSL ( P < 0.01). Bilateral patients also had higher symptom severity scale ( P < 0.01) and DSL ( P < 0.001) outcomes compared with unilateral patients. Obese patients had higher median nerve CSA ( P < 0.01), prolonged DML, and prolonged DSL ( P < 0.0001) values despite similar CTS severity (BCTSQ and CTS-6). CONCLUSIONS: Ultrasound identifies the more symptomatic side in bilateral patients, which correlates with increasing severity (NCS and BCTSQ). Obesity increases median nerve CSA and prolongs nerve conduction studies without influencing CTS severity. This information can be used when considering which diagnostic test to order for CTS.

Diabetes Increases Median Nerve Cross-Sectional Area but Not Disease Severity in Patients with Carpal Tunnel Syndrome.

Background: Ultrasonography (US) is a useful diagnostic modality for diagnosis of carpal tunnel syndrome (CTS). Diabetes mellitus is increasingly prevalent and is a risk factor for CTS. Given the increasing use of US in the diagnosis of CTS, our goal was to evaluate the influence of diabetes on CTS severity and the cross-sectional area (CSA) of the median nerve in patients with CTS. Methods: Patients with clinically diagnosed CTS were seen in the outpatient setting from October 2014 to February 2021. Median nerve CSA and patient reported severity measures were obtained: Boston Carpal Tunnel Syndrome Questionnaire (BCTSQ) and CTS-6. For patients with diabetes, additional parameters were collected including most recent A1c, insulin pharmacotherapy, and polypharmacy. Results: Ninety-nine patients (122 nerves) without diabetes and 55 patients (82 nerves) with diabetes were recruited for the study. Patients in the diabetes group were more obese and older and had a significantly increased median nerve CSA compared with patients without diabetes. Obesity was associated with higher median nerve CSA in all patients but not in patients with diabetes. There was no difference in disease severity in patients with and without diabetes as reported by BCTSQ or CTS-6 scores. In patients with diabetes, there was significantly decreased median nerve CSA with A1c of 6.5 or higher and a trend to decreased CSA with polypharmacy. There was no influence of insulin therapy on median nerve CSA. Conclusion: Diabetes is associated with higher median nerve CSA in patients with CTS of similar disease severity. The increased median nerve CSA in patients with diabetes may be reflective of diabetes-related microvascular changes. Interestingly, the trend to decreased median nerve CSA in patients with suboptimal diabetic control (A1c ≥ 6.5) may suggest eventual degenerative changes to the median nerve. In summary, clinicians should be cautious with interpreting a larger median nerve CSA as more severe CTS in patients with diabetes. Level of Evidence: Level 3 Diagnostic.

Elbow Uncemented Hemiarthroplasty: Surgical Technique.

Management of elbow arthritis in younger and higher demand patients is challenging and may benefit from a distal humerus hemiarthroplasty that employs a noncemented method of implant fixation and stabilizes the elbow through ligament reconstruction. By not replacing both articulating surfaces, hardware longevity may be improved. We describe a novel system that may be indicated for the treatment of posttraumatic or primary osteoarthritis of the distal humerus. The step-by-step technique for surgical implantation of this uncemented distal humerus hemiarthroplasty is described and illustrated.

Republication of "Primary Ankle Arthrodesis vs ORIF for Severely Comminuted Pilon Fractures: A Comparative Retrospective Study".

Background: The treatment for highly comminuted pilon fractures remains controversial. The goal of this retrospective cohort study was to compare functional outcomes of primary arthrodesis of the tibiotalar joint (fusion) and open reduction internal fixation (ORIF). Methods: Patients who underwent primary ORIF or fusion for pilon fractures at our institution since 2000 were identified by Current Procedural Terminology (CPT) code. Inclusion criteria for the ORIF cohort were patients with an AO/Orthopaedic Trauma Association type C3 pilon fracture. Additional inclusion criteria for the fusion cohort were patients whose fractures were deemed non-reconstructable by the treating surgeon. Outcome assessment was determined by the Foot and Ankle Outcome Score (FAOS) and Short Form 36-item health survey (SF-36), time to radiographic union or fusion, and wound-healing complications at a minimum of 2 years after their surgery. Results: Nineteen ORIF and 16 fusion patients completed the study's outcome assessments. A higher rate of nonunion was observed in patients treated by primary ORIF than primary fusion (5/19 vs 1/16). Posttraumatic arthritis was observed in 11 of 19 primary ORIF patients. Primary fusion patients exhibited increased symptoms, pain, and physical role limits but were equivalent to primary ORIF patients on all other functional metrics examined. Conclusions: Primary ankle arthrodesis achieves a lower rate of nonunion and comparable functional outcomes to ORIF in patients with severely comminuted pilon fractures. The higher rate of nonunion observed in the primary ORIF group suggests that primary fusion should be considered an effective procedure for severe injuries to decrease the need for further operative intervention. Level of Evidence: Therapeutic Level III, retrospective cohort.

Computed Tomography-Based Humeral Templating for Uncemented Elbow Arthroplasty.

BACKGROUND: Intramedullary (IM) screw insertion into the distal humerus provides fixation for a novel, uncemented elbow arthroplasty. A multitude of screw sizes is required to accommodate variable humeral morphology. The goal of this study was to use computed tomography (CT) for IM screw sizing and to validate this templating by inserting screws into three-dimensionally (3D) printed models. METHODS: Computed tomography humerus scans for 30 patients were reformatted in the plane of the distal IM canal. Screw size was templated by measuring the canal diameter at 3 locations corresponding to the lengths of the screws being tested. Interrater and intrarater reliabilities of the measurements were assessed. Three-dimensional models of 5 humeri were printed, and IM screws were placed to achieve a secure endosteal fit. RESULTS: We identified combinations of body components and IM screw length and diameter for all patients to seat this uncemented elbow arthroplasty. The measurements and screw width determinations were reliable. Canal diameter correlated with age but was unrelated to sex. Screws were inserted into five 3D-printed models which matched the templates and demonstrated mechanical and radiographic evidence of secure fit. CONCLUSIONS: This study characterizes distal humerus anatomy in the context of IM screw fixation. Humerus CT scans of 30 patients were able to be templated, and validation via implantation of IM screws into 3D models was successful. Computed tomography templating will allow surgeons to predict the optimal screw size prior to implantation. A broad range of screw lengths and diameters is critical for implantation of this novel elbow arthroplasty.

Patients Prefer Ultrasound to Nerve Conduction Studies for the Diagnosis of Carpal Tunnel Syndrome.

Background: The net promoter score (NPS) allows analysis of patient satisfaction and preference between treatment and/or diagnostic testing. Electrodiagnostic testing (EDX) and ultrasound (US) are commonly used diagnostic tests for carpal tunnel syndrome. Although EDX is reliable for diagnosing carpal tunnel syndrome (CTS), it can be uncomfortable and inconvenient for patients. We aimed to determine whether patients preferred US or EDX studies for the diagnosis of CTS, using the NPS. Methods: Seventy-five patients presenting to the clinic for evaluation of CTS complaints who had EDX were prospectively studied. US evaluation of the median nerve was then completed at time of evaluation. Patient satisfaction was determined by asking, "how likely are you to recommend this procedure to a friend or relative?" for both EDX and US. Patient demographics, comorbidities, CTS-6 questionnaire (CTS-6), and functionality assessed through patient-reported qDASH were also recorded. Results: Sixty-five patients were included in the study. Most patients did not have any comorbidities and were nonsmokers. The gender composition was similar, and the average age of the enrolled patients was 58. The NPS for US was significantly higher than EDX (P < 0.0001). Patients with diabetes mellitus rated their EDX experience significantly lower than those without diabetes mellitus. Conclusions: Patients are more likely to recommend US instead of EDX in the evaluation of CTS complaints. This allows for shared decision-making between the patient and provider if ordering diagnostic testing for CTS.

Mucin multilayers assembled through sugar-lectin interactions.

Multilayer films of biopolymers are attractive tools to exploit the extraordinary properties of certain biomacromolecules and introduce new functionalities to surfaces. Mucins, the gel-forming constituents of mucus, are versatile glycoproteins that have potential as new building blocks for biomaterial surface coatings. Multilayer films have mostly been assembled through the electrostatic pairing of polyelectrolytes, which results in limited pH and salt stability and screens charges otherwise available for useful payload binding. Here, we aim at assembling mucin multilayer films that differ from conventional paired polyelectrolyte assemblies to obtain highly stable and functional surface modifications. Using the lectin wheat germ agglutinin (WGA) to cross-link mucin-bound sugar residues, we show that (Mucin/WGA) films can grow into hydrated films and sustain exceptional resistance to extreme salt conditions and a large range of pH. Furthermore, we show that the addition of soluble N-acetyl-d-glucosamine can induce the controlled release of WGA from (Mucin/WGA) films. Last, we show that (Mucin/WGA) films can repeatedly incorporate and release a positively charged model cargo. The lubricating, hydration, barrier, and antimicrobial properties of mucins open multiple applicative perspectives for these highly stable mucin-based multilayer films.

Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling.

The HMG-CoA reductase inhibitors, statins, have been used as lipid lowering drugs for decades and several epidemiological studies suggest statin usage correlates with a decreased incidence of cancer specific mortality in patients. However, the mechanism of this mortality benefit remains unclear. Here, we demonstrate that statin drug lipophilicity and affinity for its target enzyme, HMGCR, determine their growth suppressive potency against various tumor cell lines. The lipophilic atorvastatin decreases cancer cell proliferation and survival in vitro. Statin sensitivity coincided with Ras localization to the cytosol instead of the membrane, consistent with a decrement in prenylation. To investigate signaling pathways that may be involved with sensitivity to statin therapy, we employed inhibitors of the PI3K-Akt and Mek-Erk signaling cascades. We found that inhibition of PI3K signaling through Akt potentiated statin sensitivity of breast cancer cells in vitro and in co-culture with primary human hepatocytes. The same effect was not observed with inhibition of Mek signaling through Erk. Moreover, the sensitivity of breast cancer cells to atorvastatin-mediated growth suppression correlated with a decrease in EGF-mediated phosphorylation of Akt. As an increase in Akt activity has been shown to be involved in the metastasis and metastatic outgrowth of many cancer types (including breast), these data suggest a mechanism by which statins may reduce cancer specific mortality in patients.

Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion.

The cholesterol reducing drugs, statins, exhibit anti-tumor effects against cancer stem cells and various cancer cell lines, exert potent additivity or synergy with existing chemotherapeutics in animal models of cancer and may reduce cancer incidence and cancer related mortality in humans. However, not all tumor cell lines are sensitive to statins, and clinical trials have demonstrated mixed outcomes regarding statins as anticancer agents. Here, we show that statin-induced reduction in intracellular cholesterol levels correlate with the growth inhibition of cancer cell lines upon statin treatment. Moreover, statin sensitivity segregates with abundant cytosolic vimentin expression and absent cell surface E-cadherin expression, a pattern characteristic of mesenchymal-like cells. Exogenous expression of cell surface E-cadherin converts statin- sensitive cells to a partially resistant state implying that statin resistance is in part dependent on the tumor cells attaining an epithelial phenotype. As metastasizing tumor cells undergo epithelial to mesenchymal transition during the initiation of the metastatic cascade, statin therapy may represent an effective approach to targeting the cells most likely to disseminate.