Retention of the posterior cruciate ligament stabilizes the medial femoral condyle during kneeling using a tibial insert with ball-in-socket medial conformity.

PURPOSE: Resecting the posterior cruciate ligament (PCL) increases posterior laxity and increases the flexion gap more than the extension gap in the native (i.e. healthy) knee. These two effects could lead to significant anterior displacement of the medial femoral condyle in kneeling following total knee arthroplasty even when using a tibial insert with a high degree of medial conformity. Using an insert with ball-in-socket medial conformity and a flat lateral articular surface, the primary purpose was to determine whether the medial femoral condyle remained stable with and without PCL retention during kneeling. METHODS: Two groups of patients were studied, one with PCL retention (22 patients) and the other with PCL resection (25 patients), while kneeling at 90º flexion. Following 3D model-to-2D image registration, A-P displacements of both femoral condyles were determined relative to the dwell point of the medial socket. RESULTS: With PCL resection versus PCL retention, the medial femoral condyle was 5.1 ± 3.7 mm versus 0.8 ± 2.1 mm anterior of the dwell point (p < 0.0001). Patient-reported function scores were comparable (p ≥ 0.1610) despite a significantly shorter follow-up of 7.8 ± 0.9 months with PCL retention than 19.6 ± 4.9 months with PCL resection (p < 0.0001). Range of motion was 126 ± 8° versus 122 ± 6° with and without PCL retention, respectively (p = 0.057). CONCLUSION: Surgeons that use a highly conforming tibial insert design can stabilize the medial femoral condyle during kneeling by retaining the PCL. In patients with PCL resection, the 9 mm high anterior lip of the insert with ball-in-socket medial conformity was insufficient to prevent significant anterior displacement of the medial femoral condyle when weight-bearing on the anterior tibia.

A new tibial insert design with ball-in-socket medial conformity and posterior cruciate ligament retention closely restores native knee tibial rotation after unrestricted kinematic alignment.

PURPOSE: In total knee arthroplasty (TKA) with posterior cruciate ligament (PCL) retention, the medial and lateral insert conformity that restores in vivo native (i.e., healthy) knee tibial rotation and high function without causing stiffness is unknown. The purpose was to determine whether a ball-in-socket (B-in-S) medially conforming (MC) and flat lateral insert implanted with unrestricted kinematic alignment (KA) TKA and PCL retention restores tibial rotation to native. METHODS: One group of 25 patients underwent unrestricted KA TKA with manual instruments. Another group of 25 patients had native knees. Single-plane fluoroscopy imaged each knee while patients performed step-up and chair rise activities. Following 3D model-to-2D image registration, anterior-posterior (A-P) positions of the femoral condyles were determined. Changes in A-P positions with flexion were used to determine tibial rotation. RESULTS: At maximum flexion, mean tibial rotations of KA TKA knees were comparable to native knees (Step up: 12.3° ± 4.4° vs. 13.1° ± 12.0°, p = 0.783; Chair Rise: 12.7° ± 6.2° vs. 12.6° ± 9.5º, p = 0.941). However, paths of rotation differed in that screw home motion was less evident in KA TKA knees. At 8 months follow-up, the median Forgotten Joint Score was 69 points (range 65 to 85), the median Oxford Knee Score was 43 points (range 40 to 46), and mean knee flexion was 127º ± 8°. CONCLUSIONS: The ball-in-socket medial, flat lateral insert and PCL retention implanted with unrestricted KA TKA restored in vivo native knee tibial rotation at maximum flexion for each activity and high function without stiffness. Providing high A-P stability, this implant design might benefit patients desiring to return to demanding work and recreational activities. LEVEL OF EVIDENCE: Therapeutic - Level II.

Posterior cruciate ligament retention with medial ball-in-socket conformity promotes internal tibial rotation and knee flexion while providing high clinical outcome scores.

BACKGROUND: Although retaining the posterior cruciate ligament (PCL) is advantageous in unrestricted kinematically aligned TKA, it is often excised with a medial stabilized implant. The primary objectives were to determine whether PCL retention using an insert with ball-in-socket (B-in-S) medial conformity to maximize A-P stability promotes internal tibial rotation and flexion while providing high patient-reported outcome scores. METHODS: Two cohorts of 25 patients each were treated with unrestricted kinematically aligned (KA) TKA using a tibial insert with B-in-S medial conformity and a flat lateral articular surface. One cohort retained the PCL; the other had it excised. Patients performed deep knee bend and step-up exercises during fluoroscopic imaging. Following 3D model-to-2D image registration, anterior-posterior (A-P) positions of the femoral condyles and tibial rotation were determined. RESULTS: For deep knee bend, mean internal tibial rotation with PCL retention was significantly greater at maximum flexion (17.7° ± 5.7° versus 10.4° ± 6.5°, p < 0.001) and significantly greater at 30°, 60°, and 90° flexion as well (p ≤ 0.0283). For step-up, mean internal tibial rotation with PCL retention was significantly greater at at 15°, 30°, and 45° flexion (p ≤ 0.0049) but was marginally not significantly greater at 60° (i.e. maximum) flexion (12.3° ± 4.4° versus 10.1° ± 5.4°, p = 0.0794). Mean flexion during active knee flexion with PCL retention was significantly greater (127° ± 8° versus 122° ± 6°, p = 0.0400). Both cohorts had high median Oxford Knee, WOMAC, and Forgotten Joint Scores that were not significantly different (p = 0.0918, 0.1448, and 0.0855, respectively) CONCLUSION: Surgeons that perform unrestricted KA TKA should retain the PCL with an insert that has B-in-S medial conformity, as this maintains extension and flexion gaps while also promoting internal tibial rotation and knee flexion as well as providing high clinical outcome scores.

Ball-in-socket medial conformity with posterior cruciate ligament retention neither limits internal tibial rotation and knee flexion nor lowers clinical outcome scores after unrestricted kinematically aligned total knee arthroplasty.

PURPOSE: For a new tibial insert design with ball-in-socket (B-in-S) medial conformity (MC), posterior cruciate ligament (PCL) retention, and flat lateral articular surface (B-in-S MC + PCL), this study determined whether internal tibial rotation and knee flexion were limited and clinical outcome scores were lower during weight-bearing activities relative to an insert with intermediate (I) (i.e., less than ball-in-socket) medial conformity (I MC + PCL). METHODS: Twenty-five patients were treated with bilateral unrestricted, caliper-verified kinematic alignment (KA) total knee arthroplasty (TKA) with an I MC + PCL insert and B-in-S MC + PCL insert in opposite knees. Each patient performed weight-bearing deep knee bend, step up, and chair rise under single-plane fluoroscopy. Analysis following 3D model-to-2D image registration determined internal tibial rotation. For each TKA, knee flexion was measured and patients completed clinical outcome scoring questionnaires. RESULTS: Internal tibial rotation did not differ between conformities during chair rise and step up (p = 0.3419 and 0.1030, respectively). During deep knee bend, internal tibial rotation between 90° and maximum flexion was 3° greater in the B-in-S MC + PCL group (18° vs 15°) (p = 0.0290). Mean knee flexion (p = 0.3115) and median Forgotten Joint Score (FJS), Oxford Knee Score (OKS), and Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores (p = 0.2100, 0.2154, and 0.4542, respectively) did not differ between conformities. CONCLUSION: An insert with ball-in-socket medial conformity, which maximizes anteroposterior (AP) stability, did not limit internal tibial rotation and knee flexion and did not lower patient-reported outcomes when implanted with unrestricted caliper-verified KA and PCL retention. The high AP stability provided by the medial ball-in-socket might interest those surgeons exploring the treatment of the active patient with a desire to return to high-level and athletic activities.

Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.

Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API.

PURPOSE: The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization. METHODS: A crystal engineering approach was used to design and execute a cocrystal screen of the API. Hydrogen bonding between the API and pharmaceutically acceptable carboxylic acids was identified as a viable synthon for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for cocrystal formation with the API. RESULTS: A cocrystal containing the API and glutaric acid in a 1:1 molecular ratio was identified and the single crystal structure is reported. Physical characterization of the cocrystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The cocrystal solid is nonhygroscopic, and chemically and physically stable to thermal stress. Use of the cocrystal increased the aqueous dissolution rate by 18 times as compared to the homomeric crystalline form of the drug. Single dose dog exposure studies confirmed that the cocrystal increased plasma AUC values by three times at two different dose levels. CONCLUSIONS: APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. Cocrystals are an additional class of crystalline solid that can provide options for improved properties. In this case, a crystalline molecular complex of glutaric acid and an API was identified and used to demonstrate an improvement in the oral bioavailability of the API in dogs.