An MITF- and mTOR-dependent FLCN pathway suppresses TFE3-driven metastasis in melanoma.

Cancer cells have remarkable plasticity allowing them to acquire many biological states. Melanoma cells have the ability to switch from a proliferative melanocytic state to an invasive mesenchymal state and back again resulting in intratumoral heterogeneity. While microphthalmia-associated transcription factor (MITF) promotes the melanocytic phenotype, it is unclear what transcription factors drive the mesenchymal phenotype, and what mechanisms regulate the switch from the proliferative state to the mesenchymal state. We show that nuclear localization of the MITF paralog TFE3 correlates positively with metastatic potential in melanoma cell lines and tumors, and that deletion of TFE3 in MITF-low melanoma cell lines eliminates migration and metastatic ability. Further, we find that MITF suppresses the mesenchymal phenotype by activating expression of FNIP2, which encodes a component of an mTORC1-stimulated pathway promoting cytoplasmic retention and lysosomal degradation of TFE3. These findings point to the mTOR pathway and TFE3 as key regulators of melanoma plasticity.

Effect of modeling femoral version and head-neck offset correction on computed contact mechanics in dysplastic hips treated with periacetabular osteotomy.

While correction of dysplastic acetabular deformity has been a focus of both clinical treatment and research, concurrent femoral deformities have only more recently received serious attention. The purpose of this study was to determine how including abnormalities in femoral head-neck offset and femoral version alter computationally derived contact stresses in patients with combined dysplasia and femoroacetabular impingement (FAI). Hip models with patient-specific bony anatomy were created from preoperative and postoperative CT scans of 20 hips treated with periacetabular osteotomy and femoral osteochondroplasty. To simulate performing only a PAO, a third model was created combining each patient's postoperative pelvis and preoperative femur geometry. These three models were initialized with the femur in two starting orientations: (1) standardized template orientation, and (2) using patient-specific anatomic landmarks. Hip contact stresses were computed in all 6 model sets during an average dysplastic gait cycle, an average FAI gait cycle, and an average stand-to-sit activity using discrete element analysis. No significant differences in peak contact stress (p = 0.190 to 1), mean contact stress (p = 0.273 to 1), or mean contact area (p = 0.050 to 1) were identified during any loading activity based on femoral alignment technique or inclusion of femoral osteochondroplasty. These findings suggest that presence of abnormal femoral version and/or head-neck offset deformities are not themselves predominant factors in intra-articular contact mechanics during gait and stand-to-sit activities. Inclusion of modified movement patterns caused by these femoral deformities may be necessary for models to adequately capture the mechanical effects of these clinically recognized risk factors for negative outcomes.

Sliding Hip Screw and Side Plate for Intertrochanteric Hip Fractures.

For stable intertrochanteric hip fractures, treatment commonly involves the use of a sliding hip screw. Intertrochanteric hip fractures are increasingly common as the population ages and lives longer. More than 250,000 hip fractures occur per year in the United States1. The mortality rate within the first year following operative treatment ranges from 14% to 27.3%2,3. Early surgical repair within 48 hours of injury is associated with a lower risk of mortality2,4,5. The goals of surgical treatment are restoration of coronal plane alignment without varus angulation and early patient mobilization. Description: The sliding hip screw procedure can be divided into (1) preoperative planning; (2) patient positioning; (3) C-arm setup; (4) closed reduction of fracture; (5) sterile preparation and draping; (6) lateral hip approach; (7) guide pin insertion; (8) triple-reaming the proximal aspect of the femur; (9) sliding hip screw insertion into the femoral neck and head; (10) side plate insertion, engaging the sliding hip screw, and fixation to the femur; (11) lag compression screw insertion (if appropriate); and (12) final fluoroscopic images and wound closure. Alternatives: Intertrochanteric hip fractures must be surgically treated to avoid morbidity and increased risk of mortality. Nonoperative treatment is occasionally indicated in nonambulatory patients or those with high perioperative risk. If treated surgically, a common alternative implant option includes the intramedullary nail. Finally, for severely comminuted fractures or failed internal fixation, total hip arthroplasty may be necessary. Rationale: Sliding hip screws are as effective as intramedullary nails and often less costly6. In general, the quality of fracture reduction is more critical than the choice of implant7. A prospective study found no significant difference in walking ability with either sliding hip screws or intramedullary nails for stable intertrochanteric fractures8. Expected Outcomes: By 6 months, the majority of fractures will have healed; according to a prospective randomized study, 91% of stable fractures and 85% of unstable fractures had achieved radiographic union by that time9. Another study showed radiographically healed fractures in all 106 patients treated with sliding hip screws at median follow-up of 13.6 months8. Important Tips: Watch out for comminution of the greater or lesser trochanter, which may require supplemental fixation.Prior to completely reflecting the vastus lateralis muscle, control the bleeding from any perforators with use of 2-0 silk ties. This prevents recurrent bleeding, which often occurs if only cautery is utilized to coagulate these vessels.Utilize a 4.5-mm drill hole in the lateral cortex of the femur in order to allow for minor adjustments of the anterior femoral neck guide pin; otherwise, the pin will be held tightly and continue to be bound in the same direction by the lateral cortex on repeated attempts.If the guide pin is inadvertently withdrawn along with the reamer after reaming, a lag screw may be placed backward in the newly reamed hole and the guide pin passed back through the lag screw to reposition it.Extracapsular hip fractures should be carefully scrutinized for signs of instability, such as lateral wall comminution or reverse obliquity. The fracture may displace posteriorly when the patient is supine on the fracture table.While placing the guidewire, multiple entry attempts can weaken the lateral cortex and propagate the fracture into the subtrochanteric region.Superior placement of the lag screw results in poor tip-apex distance and a higher chance of screw cut-out.Be careful to prevent guidewire penetration into the hip joint.Loss of reduction or femoral head malrotation may occur during lag screw insertion. Acronyms & Abbreviations: AP = anteroposteriorfx's = fracturesIMN = intramedullary nailIV = intravenousPDS = polydioxanone sutureSHS = sliding hip screwTFL = tensor fascia lata.

Chronically elevated contact stress exposure correlates with intra-articular cartilage degeneration in patients with concurrent acetabular dysplasia and femoroacetabular impingement.

Hip dysplasia is known to lead to premature osteoarthritis. Computational models of joint mechanics have documented elevated contact stresses in dysplastic hips, but elevated stress has not been directly associated with regional cartilage degeneration. The purpose of this study was to determine if a relationship exists between elevated contact stress and intra-articular cartilage damage in patients with symptomatic dysplasia and femoroacetabular impingement. Discrete element analysis was used to compute hip contact stresses during the stance phase of walking gait for 15 patients diagnosed with acetabular dysplasia and femoral head-neck offset deformity. Contact stresses were summed over the duration of the walking gait cycle and then scaled by patient age to obtain a measure of chronic cartilage contact stress exposure. Linear regression analysis was used to evaluate the relationship between contact stress exposure and cartilage damage in each of six acetabular subregions that had been evaluated arthroscopically for cartilage damage at the time of surgical intervention. A significant correlation (R2 = 0.423, p < 0.001) was identified between chondromalacia grade and chronic stress-time exposure above both a 1 MPa damage threshold and a 2 MPa-years accumulated damage threshold. Furthermore, an over-exposure threshold of 15% regional contact area exceeding the 1 and 2 MPa-years threshold values resulted in correct identification of cartilage damage in 83.3% (55/66) of the acetabular subregions loaded during gait. These results suggest corrective surgery to alleviate impingement and reduce chronic contact stress exposures below these damage-inducing thresholds could mitigate further cartilage damage in patients with hip dysplasia.

Changes in Muscle Volume and Composition After Treatment of Hip Dysplasia with Periacetabular Osteotomy.

Background: Periacetabular osteotomy (PAO) is a common treatment for pre-arthritic hip dysplasia in young adults. The purpose of this study was to better understand changes in muscle volume and composition after PAO visualized using magnetic resonance imaging (MRI). Methods: A prospectively collected series of individuals that underwent PAO for hip dysplasia were reviewed to identify subjects with pre- and postoperative MRI. In our practice, MRI was obtained preoperatively and greater than 6 months after PAO for persistent hip pain. MRI sequences were selected to optimize visualization of the muscle volume, fatty infiltration, and hip joint cartilage. MRI images were selected at predetermined bony landmarks and analyzed using 3D Slicer (©2021, www.slicer.org) software to measure muscle diameter and calculate muscle cross-sectional area (CSA) in 17 individual muscles surrounding the hip. Muscle atrophy was graded using the Goutallier classification for fatty infiltration and acetabular cartilage condition was graded using the Outerbridge classification. We compared pre- and postoperative muscle area and composition as well as cartilage for each case. Results: A series of six female patients met our inclusion criteria. Mean age was 26 years at time of surgery. All cases had MRI sequences adequate for muscle volume measurements. Fatty infiltration and cartilage changes were recorded in four subjects with appropriate MRI sequences. Separating muscle groups, external rotators underwent the largest volume increase. Hip flexors demonstrated mild volume decrease. CSA change among external rotators averaged +12%, hip flexors -9.3%, and hip abductors -9.2% after PAO. All muscles had either the same or increased fatty infiltration after surgery, with gluteus medius and iliacus undergoing the most average increase. Similarly, cartilage condition worsened by a small margin in this series. Conclusion: Our results provide preliminary indication that PAO may have noticeable effects on muscle characteristics and cartilage in the early postoperative period. This was a limited case series of subjects with adequate pre- and post-operative MRI imaging.Level of Evidence: IV.

Hip Arthroscopy: A Social Media Analysis of Patient Perception.

BACKGROUND: The rate of hip arthroscopy has increased significantly in recent years, although understanding of patient perception remains limited. PURPOSE: To analyze posts shared on Instagram and Twitter referencing hip arthroscopy to evaluate perspective, tone, timing, content, visibility, and location. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A search of public posts on Instagram and Twitter was performed over a 1-year period, selected through use of the following hashtags: #hiparthroscopy, #hipscope, and #labralrepair. A total of 1850 Instagram posts and 163 Twitter posts were included in the analysis. A categorical classification system was used for media format (picture or video), perspective (patient, family or friend, physician, hospital or physical therapy group, professional organization, news media, or industry), timing (preoperative, postoperative, nonoperative), perioperative period (within 1 week before or after surgery), tone (positive, negative, or neutral), and content (surgical site, hospital or surgeon, imaging, rehabilitation, activities of daily living (ADLs), return to work, surgical instruments, or education). Post popularity (number of likes) and geographic location were also recorded. RESULTS: Of the 1850 Instagram posts analyzed, 91.2% were made by patients, and 52.9% were positive. The most common content included in Instagram posts was rehabilitation, ADLs, and hospital or surgeon. A total of 163 Twitter posts were analyzed, with 59.0% of posts made by physicians. A majority of posts had a positive tone, and the most frequently referenced themes included education, hospital or surgeon, and rehabilitation. Overall, posts originated from 24 different countries. CONCLUSION: The majority of patients who undergo hip arthroscopy have a positive tone when discussing their procedure. Posts commonly focused on rehabilitation, ADLs, hospital or surgeon, and education. This analysis provides insight into patient perspectives toward hip arthroscopy.