A Systematic Review of Short-Term Outcomes of Minimally Invasive Thoracoscopic Surgery for Lung Cancer after Neoadjuvant Systemic Therapy.

BACKGROUND: Minimally invasive surgeries for non-small cell lung cancers (NSCLCs) such as video-assisted thoracoscopic surgeries (VATSs) and robotic-assisted thoracoscopic surgeries (RATSs) have become standard of care for patients needing surgical resection in early stages. The role for neoadjuvant systemic therapy has increased with patients receiving neoadjuvant systemic chemotherapy and immunotherapy. However, there has been some equipoise over the intraoperative and overall outcomes for these patients. Here, we review the current data regarding outcomes of patients undergoing minimally invasive thoracic surgical resection after systemic chemotherapy, immunotherapy, or both. METHODS: A systematic literature review of randomized controlled trials and observational studies presenting data on patients with NSCLC that underwent neoadjuvant systemic therapy followed by minimally invasive surgery was performed assessing complications, conversion rates, and lymph node yield. RESULTS: Our search strategy and review of references resulted in 239 publications to screen with 88 full texts assessed and 21 studies included in our final review. VATS had a statistically significant higher lymph node yield in five studies. The reported conversion rates ranged from 0 to 54%. Dense adhesions, bleeding, and difficult anatomy were the most common reported reasons for conversion to open surgeries. The most common complications between both groups were prolonged air leak, arrythmia, and pneumonia. VATS was found to have significantly fewer complications in three papers. CONCLUSIONS: The current literature supports VATS as safe and feasible for patients with NSCLC after neoadjuvant systemic treatment. Surgeons should remain prepared to convert to open surgeries in those patients with dense adhesions and bleeding risk.

Elastofibroma Dorsi: Case Series of a Rare Chest Wall Pseudotumor.

BACKGROUND: Elastofibroma dorsi (EFD) is a pseudotumor of the thoracic wall that can be difficult to diagnose due to its rarity. Prompt recognition can limit unnecessary workup and expedite treatment. This study retrospectively analyzed patients with a diagnosis of EFD, discussing clinical presentations and surgical outcomes. METHODS: This is an IRB-approved single-center retrospective study of all patients with a diagnosis of elastofibroma at our institution between 2000 and 2022. RESULTS: Ten patients were identified to have a pathologic diagnosis of EFD since 2000, with half presenting in the last 5 years. Our cohort had an average age of 56.8 years and was 50% female. The average age of male subjects was younger than females, 49.6-64.0 years, respectively (p = 0.10). Eighty percent (8/10) of patients had unilateral EFDs and symptoms lasted 27.1 months on average prior to diagnosis. Surgical resection was performed on 66.67% (8/12) of masses, with 87.5% (7/8) of patients who underwent surgery reporting complete resolution of their symptoms and none reporting recurrence. CONCLUSIONS: Although EFD is a rare pseudotumor, its incidence may be increasing. As such, surgeons should be aware of the typical clinical presentation; specifically, a slow growing, predominantly unilateral, painful, subscapular mass with an inhomogeneous pattern on imaging. Originally thought to predominantly affect elderly women, our study shows that younger men may be at risk as well. If patients present with EFD, complete surgical resection should be performed to achieve favorable outcomes and resolution of symptoms.

A novel mouse model of hindlimb joint contracture with 3D-printed casts.

Stiff joints formed after trauma, surgery or immobilization are frustrating for surgeons, therapists and patients alike. Unfortunately, the study of contracture is limited by available animal model systems, which focus on the utilization of larger mammals and joint trauma. Here we describe a novel mouse-based model system for the generation of joint contracture using 3D-printed clamshell casts. With this model system we are able to generate both reversible and irreversible contractures of the knee and ankle. Four- or 8-month-old female mice were casted for either 2 or 3 weeks before liberation. All groups formed measurable contractures of the knee and ankle. Younger mice immobilized for less time formed reversible contractures of the knee and ankle. We were able to generate irreversible contracture with either longer immobilization time or the utilization of older mice. The contracture formation translated into differences in gait, which were detectable using the DigiGait® analysis system. This novel model system provides a higher throughput, lower cost and more powerful tool in studying the molecular and cellular mechanisms considering the large existing pool of transgenic/knockout murine strains.

Intravenous lidocaine in spine surgery: A meta-analysis of randomized controlled trials.

BACKGROUND: This study aimed to evaluate the role of intravenous lidocaine as a supplemental pain control modality in patients undergoing spine surgery. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) involving the use of supplemental intravenous lidocaine in spine surgery. We developed a comprehensive search strategy to adequately screen for randomized controlled trials involving intravenous lidocaine in spine surgery. Continuous outcomes included postoperative opiate consumption and postoperative pain scores. Dichotomous outcomes included nausea, vomiting, pneumonia, delirium, and wound infection. RESULTS: A total of 3 RCTs comprising 235 patients were selected for inclusion in the meta-analysis. Cumulative morphine consumption at 48 h was not statistically significant between lidocaine and control groups. Postoperative pain was not statistically significant at any measured time points in the first and second day postoperatively. There was no statistical difference in postoperative complications including nausea, vomiting, pneumonia, delirium, or surgical site infection. CONCLUSION: Our results indicated that current literature does not support the use of intravenous lidocaine as an adjunctive measure of pain management after spine surgery. Given the relatively few numbers of studies in this field, further randomized controlled trials are needed to make a definitive conclusion on the effectiveness of lidocaine in spine surgery patients.

Human Rotator Cuff Tears Have an Endogenous, Inducible Stem Cell Source Capable of Improving Muscle Quality and Function After Rotator Cuff Repair.

BACKGROUND: The muscle quality of the rotator cuff (RC), measured by atrophy and fatty infiltration (FI), is a key determinant of outcomes in RC injury and repair. The ability to regenerate muscle after repair has been shown to be limited. PURPOSE: To determine if there is a source of resident endogenous stem cells, fibroadipogenic progenitor cells (FAPs), within RC injury patients, and if these cells are capable of adipogenic, fibrogenic, and pro-myogenic differentiation. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 20 patients between the ages of 40 and 75 years with partial- or full-thickness RC tears of the supraspinatus and evidence of atrophy and FI Goutallier grade 1, 2, or 3 were selected from 2 surgeons at an orthopaedic center. During the surgical repair procedure, supraspinatus muscle biopsy specimens were obtained for analysis as were deltoid muscle biopsy specimens to serve as the control. FAPs and satellite cells were quantified using fluorescence-activated cell sorting. Muscle FI and fibrosis was quantified using Oil Red O and Masson trichrome staining. FAP differentiation and gene expression profiles were compared across tear sizes after culture in adipogenic, fibrogenic, and beta-3 agonist (amibegron) conditions. Analysis of variance was used for statistical comparisons between groups, with P < .05 as statistically significant. RESULTS: Histologic analysis confirmed the presence of fat in biopsy specimens from patients with full-thickness tears. There were more FAPs in the full-thickness tear group compared with the partial-thickness tear group (9.43% ± 4.25% vs 3.84% ± 2.54%; P < .01). Full-thickness tears were divided by tear size, with patients with larger tears having significantly more FAPs than those with smaller tears. FAPs from muscles with full-thickness tendon tears had more adipogenic and fibrogenic potential than those with partial tears. Induction of a beige adipose tissue (BAT) phenotype in FAPs was possible, as demonstrated by increased expression of BAT markers and pro-myogenic genes including insulin-like growth factor 1 and follistatin. CONCLUSION: Endogenous FAPs are present within the RC and likely are the source of FI. These FAPs were increased in muscles with in larger tears but are capable of adopting a pro-myogenic BAT phenotype that could be utilized to improve muscle quality and patient function after RC repair.

Beige FAPs Transplantation Improves Muscle Quality and Shoulder Function After Massive Rotator Cuff Tears.

Rotator cuff (RC) tears are a common cause of upper extremity disability. Any tear size can result in subsequent muscle atrophy and fatty infiltration (FI). Preoperative muscle degeneration can predict repair and postoperative functional outcomes. Muscle residential fibro-adipogenic progenitors (FAPs) are found to be capable of differentiating into beige adipocytes that release factors to promote muscle growth. This study evaluated the regenerative potential of local cell transplantation of beige FAPs to mitigate muscle degeneration in a murine massive RC tear model. Beige FAPs were isolated from muscle in UCP-1 reporter mice by flow cytometry as UCP-1+ /Sca1+ /PDGFR+ /CD31- /CD45- /integrin α7- . C57/BL6J mice undergoing supraspinatus tendon tear with suprascapular nerve transection (TT + DN) received either no additional treatment, phosphate-buffered saline injection, or beige FAP injection 2 weeks after the initial injury. Forelimb gait analysis was used to assess shoulder function with DigiGait. Mice were sacrificed 6 weeks after cell transplantation. FI, fibrosis, fiber size, vascularity were analyzed and quantified via ImageJ. Our results showed that beige FAP transplantation significantly decreased fibrosis, FI, and atrophy, enhanced vascularization compared with saline injection and non-treatment groups. Beige FAP transplantation also significantly improved shoulder function as measured by gait analysis. This study suggests that beige-differentiated FAPs may serve as a treatment option for RC muscle atrophy and FI, thus improving shoulder function in patients with massive RC tendon tears. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1159-1166, 2020.

Rotator Cuff Fibro-Adipogenic Progenitors Demonstrate Highest Concentration, Proliferative Capacity, and Adipogenic Potential Across Muscle Groups.

Fatty infiltration (FI) of rotator cuff (RC) muscles is common in patients with RC tears. Studies have demonstrated that fibro-adipogenic progenitors (FAPs), a population of resident muscle stem cells, are the main contributors of FI, which adversely affects muscle quality and RC repair success. Although FI is common in RC injuries, it is not frequently reported after other musculotendinous injuries. Additionally, studies have shown the development of different pathology patterns across muscle groups suggestive of intrinsic differences in cellular composition and behavior. This study evaluates FAP distribution and differentiation properties across anatomic locations in mice. Muscles from seven different anatomic locations were harvested from PDGFRα-eGFP FAP reporter mice. FAPs were quantified using histology and FACS sorting with BD Aria II with CD31- /CD45- /Integrinα7- /Sca-1+ and PDGFRα reporter signal (n = 3 per muscle). The cells were analyzed for adipogenesis using immunocytochemistry and for proliferation properties with Brdu-Ki67 staining. In a separate group of mice, RC and tibialis anterior muscles received glycerol injection and were harvested after 2 weeks for FI quantification (n = 4). One-way analysis of variance was used for statistical comparisons among groups, with significance at p < 0.05. FAPs from the RC, masseter, and paraspinal muscles were more numerous and demonstrated greater proliferative capacity and adipogenic potency than those from the tibialis anterior and gastrocnemius. The RC demonstrated significantly greater levels of FI than the tibialis anterior after glycerol-injection injury. Clinical Significance: This study suggests differences in FAP distribution and differentiation characteristics may account for the propensity to develop FI in RC tears as compared with other musculotendinous injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1113-1121, 2020.

Beige fibro-adipogenic progenitor transplantation reduces muscle degeneration and improves function in a mouse model of delayed repair of rotator cuff tears.

BACKGROUND: Muscle atrophy and fatty infiltration (FI) are common occurrences following rotator cuff (RC) tears. Tears of all sizes are subject to muscle degeneration. The degree of muscle degeneration following RC tears is highly correlated with repair success and functional outcomes. We have recently discovered that muscle fibro-adipogenic progenitors (FAPs) can differentiate into uncoupling protein 1 (UCP-1)-expressing beige adipocytes and induce muscle regeneration. This study evaluated the potential of local cell transplantation of beige adipose FAPs (BAT-FAPs) to treat RC muscle degeneration in a murine model of RC repair. METHODS: BAT-FAPs were isolated from muscle in UCP-1 reporter mice by flow cytometry as UCP-1+/Sca1+/PDGFR+/CD31-/CD45-/integrin α7-. C57/BL6J mice underwent supraspinatus tendon tear with suprascapular nerve transection followed by repair 2 or 6 weeks after the initial injury. At the time of repair, mice received either no additional treatment, phosphate-buffered saline injection, or BAT-FAP injection. Functional outcomes were assessed by gait analysis. Mice were humanely killed at 6 weeks after cell transplantation. Supraspinatus muscle FI, fibrosis, muscle fiber size, and vascularity were analyzed and quantified via ImageJ. Analysis of variance with post hoc Tukey test and P <.05 was used to determine statistical significance. RESULTS: Cell transplantation diminished fibrosis, FI, and atrophy and enhanced vascularization in both delayed repair models. Cell transplantation resulted in improved shoulder function as assessed with gait analysis in both the delayed repair models. CONCLUSIONS: BAT-FAPs significantly reduced muscle degeneration and improved shoulder function after RC repair. BAT-FAPs hold significant promise as a therapeutic adjunct to repair for patients with advanced RC pathology.

3D printed PLA Army-Navy retractors when used as linear retractors yield clinically acceptable tolerances.

BACKGROUND: Modern low-cost 3D printing technologies offer the promise of access to surgical tools in resource scarce areas, however optimal designs for manufacturing have not yet been established. We explore how the optimization of 3D printing parameters when manufacturing polylactic acid filament based Army-Navy retractors vastly increases the strength of retractors, and investigate sources of variability in retractor strength, material cost, printing time, and parameter limitations. METHODS: Standard retractors were printed from various polylactic acid filament spools intra-manufacturer and inter-manufacturer to measure variability in retractor strength. Printing parameters were systematically varied to determine optimum printing parameters. These parameters include retractor width, thickness, infill percentage, infill geometry, perimeter number, and a reinforced joint design. Estimated retractor mass from computer models allows us to estimate material cost. RESULTS: We found statistically significant differences in retractor strength between spools of the same manufacturer and between manufacturers. We determined the true strength optimized retractor to have 30% infill, 3 perimeters, 0.25 in. thickness, 0.75 in. width, and has "Triangle" infill geometry and reinforced joints, failing at more than 15X the threshold for clinically excessive retraction and costs $1.25 USD. CONCLUSIONS: The optimization of 3D printed Army-Navy retractors greatly improve the efficacy of this instrument and expedite the adoption of 3D printing technology in many diverse fields in medicine not necessarily limited to resource poor settings.

Role of pulsed electromagnetic fields (PEMF) on tenocytes and myoblasts-potential application for treating rotator cuff tears.

The post-surgery integrity of the tendons and muscle quality are the two major factors in success of rotator cuff (RC) repair. Though surgical techniques for rotator cuff repair have significantly improved in the past two decades, there are no effective treatments to improve tendon-to-bone healing and muscle quality after repair at this point in time. Pulsed electromagnetic fields (PEMF) have previously been used for promoting fracture healing. Previous studies have shown that PEMF has a positive role in promoting osteoblast precursors proliferation and differentiation. However, PEMFs effect on tenocytes and muscle cells has not been determined fully yet. The purpose of this study is to define the role of a commercially available PEMF on tenocytes and myoblasts growth and differentiation in vitro. Human rotator cuff tenocytes and C2C12 murine myoblasts were cultured and treated with PEMF for 2 weeks under regular and inflammatory conditions. Our results showed that 2 weeks treatment of PEMF enhanced gene expressions of growth factors in human rotator cuff tenocytes under inflammatory conditions. PEMF significantly enhanced C2C12 myotube formation under normal and inflammatory conditions. Results from this study suggest that PEMF has a positive role in promoting tenocyte gene expression and myoblast differentiation. Therefore, PEMF may potentially serve as a non-operative treatment to improve clinical incomes rotator cuff tendon repairs. Results © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:956-964, 2017.

Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration.

Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen's ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that use the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine.

Return to sport after muscle injury.

Skeletal muscle injuries are among the most common sports-related injuries that result in time lost from practice and competition. The cellular response to muscle injury can often result in changes made to the muscle fibers as well as the surrounding extracellular matrix during repair. This can negatively affect the force and range of the injured muscle even after the patient's return to play. Diagnosis of skeletal muscle injury involves both history and physical examinations; imaging modalities including ultrasound and magnetic resonance imaging (MRI) can also be used to assess the extent of injury. Current research is investigating potential methods, including clinical factors and MRI, by which to predict a patient's return to sports. Overall, function of acutely injured muscles seems to improve with time. Current treatment methods for skeletal muscle injuries include injections of steroids, anesthetics, and platelet-rich plasma (PRP). Other proposed methods involve inhibitors of key players in fibrotic pathways, such as transforming growth factor (TGF)-ß and angiotensin II, as well as muscle-derived stem cells.

Differential spheroid formation by oral cancer cells.

Squamous cell carcinomas (SCC) make up 96% of all oral cancers. Most laboratory SCC studies grow cells as a monolayer, which does not accurately represent the disease in vivo. We used a more relevant multicellular spheroid (MCS) model to study this disease. The SCC9ß6KDFyn cell line, which expresses full-length ß6 and a kinase dead Fyn formed the largest MCS. Cell adhesive properties are dynamic and N-cadherin was increased in the largest MCS. c-Raf mediates the survival of tumor cells and was consistently expressed both in monolayers and in the MCS by SCC9ß6D1 cells which lack the ß6 cytoplasmic tail and, do not activate Fyn. SCC9ß6KDFyn cells also express high levels of c-Raf when grown as spheroids in which Fyn suppression stimulates MCS formation. Tumor microenvironment and growth patterns modulate cell behavior and suppression of Fyn kinase may promote MCS growth.

The cytoplasmic extension of the integrin ß6 subunit regulates epithelial-to-mesenchymal transition.

Prognosis for oral cancer patients has not improved in over 60 years due to invasion and recurrence. To understand the invasive behavior of this tumor, we evaluated the role of the αvß6 integrin. Invasive oral SCC cells express the αvß6 integrin, which contains an 11-amino-acid extension on its ß-subunit unique to the integrin family. We determined that this ß6 cytoplasmic extension regulates the composition of the intermediate filament network and the organization of signaling structures called focal contacts. The auto-phosphorylation of FAK, which is localized to focal contacts, was also regulated by the ß6-cytoplasmic tail, as were the transcription factors Notch and STAT3. Lastly, we also determined that activation of MAPK required the full-length ß6 integrin. Together these results indicate that the signaling critical to epithelial-to-mesenchymal transition (EMT) is regulated by the ß6 integrin cytoplasmic domain.

Expression of EMMPRIN modulates mediators of tumor invasion in oral squamous cell carcinoma.

Squamous cell carcinoma (SCC) accounts for 96 percent of all intraoral malignancies. The five-year survival rate is 50 percent and has not improved in 60 years. During SCC progression, subsets of SCC cells undergo an epithelial-to-mesenchymal transition (EMT) to become highly invasive. The extracellular matrix metalloproteinase inducer (EMMPRIN) contributes to EMT by activating local matrix metalloproteinases (MMPs). In this study, we found that EMMPRIN modulates the invasive phenotype and may be a potential therapeutic target.

Stem cell markers as predictors of oral cancer invasion.

We previously showed that within primary tumors there exist subpopulations of cells expressing stem cell markers. Using immunofluorescence and western blotting, we examined the expression of stem cell markers tumor-rejection antigen 1-60 (TRA1-60) and octamer-binding transcription factor 3/ 4 (OCT3/4) to determine their relationship with cell invasiveness. Six human oral cancer cell lines were examined and a direct correlation was found between expression of these stem cell markers and invasion. Poor expression of E-cadherin and increased expression of N-cadherin was also found in TRA1-60- and OCT3/4- expressing cells. Phosphorylation of the major signaling molecule mitogen activated protein kinase (MAPK) was greatest in the TRA1-60- and OCT3/4- expressing cells. These results suggest that expression of specific stem cell markers in tumors may help guide a clinician's choice of treatment.