Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we ...report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.
*The superficial medial collateral ligament and other medial knee stabilizers-i.e., the deep medial collateral ligament and the posterior oblique ligament-are the most commonly injured ligamentous ...structures of the knee. *The main structures of the medial aspect of the knee are the proximal and distal divisions of the superficial medial collateral ligament, the meniscofemoral and meniscotibial divisions of the deep medial collateral ligament, and the posterior oblique ligament. *Physical examination is the initial method of choice for the diagnosis of medial knee injuries through the application of a valgus load both at full knee extension and between 20 degrees and 30 degrees of knee flexion. *Because nonoperative treatment has a favorable outcome, there is a consensus that it should be the first step in the management of acute isolated grade-III injuries of the medial collateral ligament or such injuries combined with an anterior cruciate ligament tear. *If operative treatment is required, an anatomic repair or reconstruction is recommended.
Background
There is a lack of knowledge on the primary and secondary static stabilizing functions of the posterior oblique ligament (POL), the proximal and distal divisions of the superficial medial ...collateral ligament (sMCL), and the meniscofemoral and meniscotibial portions of the deep medial collateral ligament (MCL).
Hypothesis
Identification of the primary and secondary stabilizing functions of the individual components of the main medial knee structures will provide increased knowledge of the medial knee ligamentous stability.
Study Design
Descriptive laboratory study.
Methods
Twenty-four cadaveric knees were equally divided into 3 groups with unique sequential sectioning sequences of the POL, sMCL (proximal and distal divisions), and deep MCL (meniscofemoral and meniscotibial portions). A 6 degree of freedom electromagnetic tracking system monitored motion after application of valgus loads (10 N·m) and internal and external rotation torques (5 N·m) at 0°, 20°, 30°, 60°, and 90° of knee flexion.
Results
The primary valgus stabilizer was the proximal division of the sMCL. The primary external rotation stabilizer was the distal division of the sMCL at 30° of knee flexion. The primary internal rotation stabilizers were the POL and the distal division of the sMCL at all tested knee flexion angles, the meniscofemoral portion of the deep MCL at 20°, 60°, and 90° of knee flexion, and the meniscotibial portion of the deep MCL at 0° and 30° of knee flexion.
Conclusion
An intricate relationship exists among the main medial knee structures and their individual components for static function to applied loads.
Clinical Significance: Interpretation of clinical knee motion testing following medial knee injuries will improve with the information in this study. Significant increases in external rotation at 30° of knee flexion were found with all medial knee structures sectioned, which indicates that a positive dial test may be found not only for posterolateral knee injuries but also for medial knee injuries.
Radiographic landmarks for medial knee attachment sites during anatomic repairs or reconstructions are unknown. If identified, they could assist in the preoperative evaluation of structure location ...and allow for postoperative assessment of reconstruction tunnel placement.
Radiopaque markers were implanted into the femoral and tibial attachments of the superficial medial collateral ligament and the femoral attachments of the posterior oblique and medial patellofemoral ligaments of eleven fresh-frozen, nonpaired cadaveric knee specimens. Both anteroposterior and lateral radiographs were made. Structures were assessed within quadrants formed by the intersection of reference lines projected on the lateral radiographs. Quantitative measurements were performed by three independent examiners. Intraobserver reproducibility and interobserver reliability were determined with use of intraclass correlation coefficients.
The overall intraclass correlation coefficients for intraobserver reproducibility and interobserver reliability were 0.996 and 0.994, respectively. On the anteroposterior radiographs, the attachment sites of the superficial medial collateral ligament, posterior oblique ligament, and medial patellofemoral ligament were 30.5 +/- 2.4 mm, 34.8 +/- 2.7 mm, and 42.3 +/- 2.1 mm from the femoral joint line, respectively. On the lateral femoral radiographs, the attachment of the superficial medial collateral ligament was 6.0 +/- 0.8 mm from the medial epicondyle and was located in the anterodistal quadrant. The attachment of the posterior oblique ligament was 7.7 +/- 1.9 mm from the gastrocnemius tubercle and was located in the posterodistal quadrant. The attachment of the medial patellofemoral ligament was 8.9 +/- 2.0 mm from the adductor tubercle and was located in the anteroproximal quadrant. On the lateral tibial radiographs, the proximal and distal tibial attachments of the superficial medial collateral ligament were 15.9 +/- 5.2 and 66.1 +/- 3.6 mm distal to the tibial inclination, respectively.
The attachment locations of the main medial knee structures can be qualitatively and quantitatively correlated to osseous landmarks and projected radiographic lines, with close agreement among examiners.
Background There is limited information regarding load responses of the posterior oblique and superficial medial collateral ligaments
to applied loads.
Hypotheses The degree of knee flexion affects ...loads experienced by the posterior oblique ligament and both divisions of the superficial
medial collateral ligament. The posterior oblique ligament provides significant resistance to valgus and internal rotation
forces near knee extension. Different load responses are experienced by proximal and distal divisions of the superficial medial
collateral ligament.
Study Design Descriptive laboratory study.
Methods Twenty-four nonpaired, fresh-frozen cadaveric knees were tested. Buckle transducers were applied to the proximal and distal
divisions of the superficial medial collateral and posterior oblique ligaments. Applied loads at 0°, 20°, 30°, 60°, and 90°
of knee flexion consisted of 10 N·m valgus loads, 5 N·m internal and external rotation torques, and 88 N anterior and posterior
drawer loads.
Results External rotation torques produced a significantly higher load response on the distal superficial medial collateral ligament
than did internal rotation torques at all flexion angles with the largest difference at 90° (96.6 vs 22.5 N). For an applied
valgus load at 60° of knee flexion, loads on the superficial medial collateral ligament were significantly higher in the distal
division (103.5 N) than the proximal division (71.9 N). The valgus load response of the posterior oblique ligament at 0° of
flexion (19.1 N) was significantly higher than at 30° (10.6 N), 60° (7.8 N), and 90° (6.8 N) of flexion. At 0° of knee flexion,
the load response to internal rotation on the posterior oblique ligament (45.8 N) was significantly larger than was the response
on both divisions of the superficial medial collateral ligament (20 N for both divisions). At 90° of flexion, the load response
to internal rotation torques reciprocated between these structures with a significantly higher response in the distal superficial
medial collateral ligament division (22.5 N) than the posterior oblique ligament (9.1 N).
Conclusion The superficial medial collateral ligament experienced the largest load response to applied valgus and external rotation
torques; the posterior oblique ligament observed the highest load response to internal rotation near extension.
Clinical Relevance This study provides new knowledge of the individual biomechanical function of the main medial knee structures in an intact
knee and will assist in the interpretation of clinical knee motion testing and provide evidence for techniques involving repair
or reconstruction of the posterior oblique ligament and both divisions of the superficial medial collateral ligament.
Background
The amount of medial compartment opening for medial knee injuries determined by valgus stress radiography has not been well documented. The purpose of this study was to develop clinical ...guidelines for diagnosing medial knee injuries using valgus stress radiography.
Hypothesis
Measurements of medial compartment gapping can accurately differentiate between normal and injured medial structure knees on valgus stress radiographs.
Study Design
Controlled laboratory study.
Methods
Valgus stress radiographs were obtained on 18 adult lower extremities using 10-N·m and clinician-applied valgus loads at 0° and 20° of flexion to intact knees and after sequential sectioning of the superficial medial collateral ligament proximally and distally, the meniscofemoral and meniscotibial portions of the deep medial collateral ligament, the posterior oblique ligament, and the cruciate ligaments. Three independent observers of different experience levels measured all of the radiographs during 2 separate occasions to determine intraobserver repeatability and interobserver reproducibility.
Results
Compared with the intact knee, significant medial joint gapping increases of 1.7 mm and 3.2 mm were produced at 0° and 20° of flexion, respectively, by a clinician-applied load on an isolated grade III superficial medial collateral ligament simulated injury. A complete medial knee injury yielded gapping increases of 6.5 mm and 9.8 mm at 0° and 20°, respectively, for a clinician-applied load. Intraobserver repeatability and interobserver reproducibility intraclass correlation coefficients were .99 and .98, respectively.
Conclusion
Valgus stress radiographs accurately and reliably measure medial compartment gapping but cannot definitively differentiate between meniscofemoral- and meniscotibial-based injuries. A grade III medial collateral ligament injury should be suspected with greater than 3.2 mm of medial compartment gapping compared to the contralateral knee at 20° of flexion, and this injury will also result in gapping in full extension.
Clinical Significance
Valgus stress radiographs provide objective and reproducible measurements of medial compartment gapping, which should prove useful for definitive diagnosis, management, and postoperative follow-up of patients with medial knee injuries.
Highlights • Instrumented treadmill running analysis was conducted on kids ages 6–18. • Kinematics, kinetics and EMG were collected and compared to matched overground data. • Kinematics collected in ...the two conditions were similar except at the feet. • Kinetics collected in the two conditions showed important differences.
Background: The fibular collateral ligament is the primary stabilizer to varus instability of the knee. Untreated fibular collateral
ligament injuries can lead to residual knee instability and can ...increase the risk of concurrent cruciate ligament reconstruction
graft failures. Anatomic reconstructions of the fibular collateral ligament have not been biomechanically validated.
Purpose: To describe an anatomic fibular collateral ligament reconstruction using an autogenous semitendinosus graft and to test the
hypothesis that using this reconstruction technique to treat an isolated fibular collateral ligament injury will restore the
knee to near normal stability.
Study Design: Controlled laboratory study.
Methods: Ten nonpaired, fresh-frozen cadaveric knees were biomechanically subjected to a 10 N·m varus moment and 5 N·m external and
internal rotation torques at 0°, 15°, 30°, 60°, and 90° of knee flexion. Testing was performed with an intact and sectioned
fibular collateral ligament, and also after an anatomic reconstruction of the fibular collateral ligament with an autogenous
semitendinosus graft. Motion changes were assessed with a 6 degree of freedom electromagnetic motion analysis system.
Results: After sectioning, we found significant increases in varus rotation at 0°, 15°, 30°, 60°, and 90°, external rotation at 60°
and 90°, and internal rotation at 0°, 15°, 30°, 60°, and 90° of knee flexion. After reconstruction, there were significant
decreases in motion in varus rotation at 0°, 15°, 30°, 60°, and 90°, external rotation at 60° and 90°, and internal rotation
at 0°, 15°, and 30° of knee flexion. In addition, we observed a full recovery of knee stability in varus rotation at 0°, 60°,
and 90°, external rotation at 60° and 90°, and internal rotation at 0° and 30° of knee flexion.
Conclusion: An anatomic fibular collateral ligament reconstruction restores varus, external, and internal rotation to near normal stability
in a knee with an isolated fibular collateral ligament injury.
Clinical Significance: An anatomic reconstruction of the fibular collateral ligament with an autogenous semitendinosus graft is a viable option
to treat nonrepairable acute or chronic fibular collateral ligament tears in patients with varus instability.
Keywords:
fibular collateral ligament
anatomic reconstruction
semitendinosus graft
biomechanics
Background It is often difficult to identify the attachment sites of the fibular collateral ligament, popliteus tendon, and popliteofibular
ligament for chronic posterolateral knee injuries or during ...revision surgeries. Descriptions of radiographic landmarks for
these attachment sites would assist in the intraoperative identification of their locations and also allow for postoperative
assessment of the placement of reconstruction tunnels.
Hypothesis Identification of qualitative and quantitative radiographic landmarks for the attachments of the main posterolateral knee
structures are reproducible among observers of various experience levels and allow for improved intraoperative and postoperative
identification of these attachment sites.
Study Design Descriptive laboratory study.
Methods Dissections were performed on 11 cadaveric knee specimens. The attachments and locations of the investigated structures were
labeled with radiopaque markers. The positions of the attachments relative to other attachment sites, labeled bony landmarks,
and superimposed reference lines were quantified on anteroposterior and lateral radiographs. Measurements were performed by
3 independent examiners. Intraobserver and interobserver reliability was determined using intraclass correlation coefficients.
Results Overall intraclass correlation coefficients for intraobserver reproducibility and interobserver reliability were calculated
to be 0.981 and 0.983, respectively. On the anteroposterior view, the perpendicular distances from a line intersecting the
femoral condyles to the popliteus tendon, proximal fibular collateral ligament, and lateral gastrocnemius tendon were 14.5,
27.1, and 34.5 mm, respectively. On the lateral view, the femoral attachments of the fibular collateral ligament, popliteus
tendon, and lateral gastrocnemius tendon were 4.3, 12.2, and 13.1 mm, respectively, from the lateral epicondyle. In addition,
the fibular collateral ligament and popliteus tendon were located within 1 mm of a reference line projected along the posterior
femoral cortex distally, and also were located within the posteroinferior quadrant bound by the posterior femoral cortex extension
reference line and another reference line perpendicular to it at the posterior margin of Blumensaatâs line.
Conclusion Comprehensive qualitative and quantitative guidelines for assessing posterolateral knee structures on both anteroposterior
and lateral knee radiographs were described.
Clinical Significance This radiographic information regarding the attachment sites of posterolateral structures can serve as a valuable reference
for preoperative, intraoperative, and postoperative assessments of surgical reconstructions.
PDF
