An Insert Goniometer Can Help Select the Optimal Insert Thickness When Performing Kinematically Aligned Total Knee Arthroplasty with a Medial 1:1 Ball-in-Socket and Lateral Flat Surface Insert and Posterior Cruciate Ligament Retention.

Current surgical practices in total knee arthroplasty (TKA) have advanced and include significant changes and improvements in alignment philosophies, femorotibial implant conformities, and ligament management to replicate in vivo knee kinematics. While corrective measures have emphasized sagittal plane alignment to restore normal flexion-extension (F-E) motion and coronal plane ligament balance, internal-external (I-E) rotation kinematics in the axial plane have been largely neglected. Recent in vivo evidence indicates that the combination of factors necessary to closely restore native tibial rotation as the knee flexes and extends is kinematic alignment (KA), which resurfaces the patient's pre-arthritic knee without releasing ligaments, an insert with medial 1:1 ball-in-socket conformity and a lateral flat surface, and posterior cruciate ligament (PCL) retention. However, the inherent anterior-posterior (A-P) stability provided by the medial 1:1 ball-in-socket limits the surgeon's ability to select the correct insert thickness using manual laxity testing. Accordingly, this review presents the design and validation of an instrument called an insert goniometer that measures I-E tibial rotation for inserts that differ in thickness by 1 mm and uses rotation limits at extension and 90° flexion to select the optimal insert thickness. The optimal thickness is the one that provides the greatest external tibial orientation in extension and internal tibial orientation at 90° flexion without lift-off of the insert.

A bone graft from the tibial resection or patella that rectified a tibial over-resection reliably healed and improved clinical outcome scores: A retrospective study of kinematically aligned TKA.

PURPOSE: During kinematically aligned (KA) total knee arthroplasty (TKA), the surgeon may need to rectify an over-resection of the medial, lateral or posterior tibia. This study tested the hypothesis that a bone graft taken from the tibial resection or patella and impacted beneath a tibial baseplate would heal, regardless of whether the tibial component and knee were in outlier ranges according to mechanical alignment (MA) criteria. The study also tested the hypothesis that the Oxford Knee Score (OKS) and Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR) would improve beyond the substantial clinical benefit and that the source and thickness of the bone graft would not influence their improvement. METHODS: This retrospective study radiographically assessed the healing of a bone graft from the tibial resection (n = 19) or patella (n = 10) in 29 KA TKAs (18 females, mean age 65 years). The tibial component and knee alignment were categorized as in-range or outliers based on reported MA criteria for bone graft healing and implant survival. The one-sample t test identified differences in the improvement of the OKS and KOOS JR from their reported substantial clinical benefit of 16 and 20 points, respectively. RESULTS: At an average follow-up of 37 months, all bone grafts healed even though ≥55% of tibial components and 34% of knees were varus outliers according to MA criteria for bone healing and implant survival. Amongst the 29 patients, the mean OKS and KOOS JR improvements of 25 ± 11 and 47 ± 21 points, respectively, surpassed the threshold of their respective substantial clinical benefit (p < 0.01) and were not influenced by the bone graft's source and thickness (p ≥ 0.51). CONCLUSIONS: During cemented KA TKA, the surgeon can use a bone graft from the tibial resection or patella to rectify a tibial over-resection. This technique led to consistent bone healing and improved outcome scores. LEVEL OF EVIDENCE: Level IV.

No Radiographic Evidence of Medial Collateral Ligament Elongation in Valgus Osteoarthritic Knees Enables Treatment with Kinematically Aligned Total Knee Arthroplasty.

When performing caliper-verified kinematically aligned total knee arthroplasty (KA TKA) in the osteoarthritic (OA) knee with valgus deformity, an elongated medial collateral ligament (MCL) could result in a valgus setting of the tibial component. The present study analyzed KA TKA in patients with valgus deformities (i.e., tibiofemoral angle > 10 degrees of valgus) and determined (1) the occurrence of radiographic MCL elongation, (2) the incidence of lateral collateral ligament (LCL) and posterior cruciate ligament (PCL) release and the use of constrained components, and (3) whether the 1-year Forgotten Joint Score (FJS), Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR), and Likert satisfaction score were comparable to KA TKAs for OA deformities ≤10 degrees of valgus. One hundred and two consecutive patients who underwent KA TKA by a single surgeon were analyzed radiographically and clinically at a minimum follow-up of 1 year. Radiographic MCL elongation was identified by a greater than 1 degree of valgus orientation of the tibial component relative to the OA tibial joint line. Twenty-six patients had a radiographic anatomic tibiofemoral angle greater than 10 degrees of valgus (range of OA deformity: 11-23 degrees of valgus). Seventy-six had an OA deformity ≤10 degrees of valgus (10-degree valgus to -14-degree varus). No patient had MCL elongation or a ligament release, or required constrained components. The median FJS of 78, OKS of 42, and KOOS JR of 76, and the 85% satisfaction rate of the patients with greater than 10 degrees of OA valgus deformity were not significantly different from those with ≤10 degrees of OA valgus deformity (p ≥ 0.17). Because MCL elongation was not detected in OA deformities up to 23 degrees of valgus, the risk of under-correcting the valgus deformity leading to instability and poor outcome scores is low when performing KA TKA using primary components without releasing the LCL and/or PCL. LEVEL OF EVIDENCE:: IV.

The AKT inhibitor AZD5363 elicits synthetic lethality in ARID1A-deficient gastric cancer cells via induction of pyroptosis.

BACKGROUND: Gastric cancer (GC) is a deadly disease with poor overall survival and limited therapeutic options. Genetic alterations such as mutations and/or deletions in chromatin remodeling gene AT-rich interactive domain 1 A (ARID1A) occur frequently in GC. Although ARID1A mutations/deletions are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach may be effective for the treatment of ARID1A-deficient cancers. METHODS: A kinase inhibitor library containing 551 compounds was screened in ARID1A isogenic GC cells for the ability to induce synthetic lethality effect. Selected hits' activity was validated, and the mechanism of the most potent candidate drug, AKT inhibitor AD5363 (capivasertib), on induction of the synthetic lethality with ARID1A deficiency was investigated. RESULTS: After robust vulnerability screening of 551 diverse protein kinase inhibitors, we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A-/- cells. A synthetic lethality between loss of ARID1A expression and AKT inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through activation of the Caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed increased expression and phosphorylation of AKT. CONCLUSIONS: Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment.

Similar Recovery Rate for Patients Aged between 50 and 89 Years That Go Home on the Surgery Day and Self-Administer Their Rehabilitation after Kinematically Aligned Total Knee Arthroplasty.

BACKGROUND: for kinematic alignment (KA) total knee arthroplasty (TKA), it was unknown whether 'the pace of recovery' at six weeks was different for patients with ages ranging between 50-59, 60-69, 70-79, and 80-89 years who were discharged on the surgery day and self-administered their rehabilitation. METHODS: a single surgeon treated 206 consecutive patients with a KA-designed femoral component and an insert with a medial ball-in-socket, lateral flat articulation, and PCL retention. Each filled out preoperative and six-week Oxford Knee Score (OKS), Knee Society Score (KSS), Knee Function Score (KFS), and Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR) questionnaires. The six-week minus preoperative value indicated improvement. RESULTS: between age cohorts, the improvement was not different (p = 0.2319 to 0.9888). The mean improvement/six-week postoperative value was 6°/-2° for knee extension, 0°/119° for knee flexion, 7/31 for the OKS, 39/96 for the KSS, 7/64 for the KFS, and 13/62 for the KOOS. The 30-day hospital readmission rate was 1%. CONCLUSION: surgeons who perform KA TKA can counsel 50 to 89-year-old patients that they can be safely discharged home on the surgery day with a low risk of readmission and can achieve better function at six weeks than preoperatively when performing exercises without a physical therapist.

Correcting for asymmetry of the proximal tibial epiphysis is warranted to determine postoperative alignment deviations in kinematic alignment from planned alignment of the tibial component on the native tibia.

BACKGROUND: In total knee arthroplasty, unrestricted kinematic alignment aims to restore pre-arthritic lower limb alignment and joint lines. Joint line orientations of the contralateral healthy proximal tibia might be used to evaluate accuracy of tibial component alignment post-operatively if asymmetry is minimal. Our objective was to evaluate left-to-right asymmetry of the proximal tibial epiphysis in posterior tibial slope and varus-valgus orientation as related to unrestricted kinematic alignment principles. METHODS: High resolution CT images (0.5 mm slice thickness) were acquired from bilateral lower limbs of 11 skeletally mature subjects with no skeletal abnormalities. Images were segmented to generate 3D tibia models. Asymmetry was quantified by differences in orientations required to shape-match the proximal epiphysis of the mirror 3D tibia model to the proximal epiphysis of the contralateral 3D tibia model. FINDINGS: Systematic and random differences (i.e. mean ± standard deviation) in tibial slope and varus-valgus orientation were - 0.8° ± 1.2° and - 0.2° ± 0.8°, respectively. Ninety five percent confidence intervals on the means included 0° indicating that systematic differences were minimal. INTERPRETATION: Since random differences due to asymmetry are substantial in relation to random surgical deviations from pre-arthritic joint lines previously reported, post-operative computer tomograms of the contralateral healthy tibia should not be used to directly assess accuracy of tibial component alignment on a group level without correcting for differences in tibial slope and varus-valgus orientation due to asymmetry.

Risk of tibial baseplate loosening is low in patients following unrestricted kinematic alignment total knee arthroplasty using a cruciate-retaining medial conforming insert: A study using radiostereometric analysis at 2 years.

PURPOSE: Assessing the risk of tibial baseplate loosening in patients after unrestricted kinematically aligned (unKA) total knee arthroplasty (TKA) using a medially conforming insert is important because baseplates generally are aligned in varus which has been linked to an increased incidence of aseptic loosening following mechanically aligned TKA. Two limits that indicate long-term stability in patients are a change in maximum total point motion between 1 and 2 years (ΔMTPM) < 0.2 mm and anterior tilt at 2 years < 0.8°. The purposes were to determine: (1) the number of patients with ΔMTPM > 0.2 mm, (2) the number of patients with anterior tilt > 0.8° and (3) whether increased varus baseplate and limb alignment were associated with increased migration. METHODS: Thirty-five patients underwent cemented, caliper-verified, unKA TKA using a medially conforming tibial insert with posterior cruciate ligament (PCL) retention. Biplanar radiographs acquired on the day of surgery and at 1.5, 3, 6, 12 and 24 months were processed with model-based radiostereometric analysis (RSA) software to determine migration and the number of patients with migration above the two stability limits. Medial proximal tibial angle (MPTA), hip-knee-ankle angle (HKAA) and posterior slope angle (PSA) were analyzed for an association with migration in six degrees of freedom and in MTPM. RESULTS: Thirty-two of 35 patients were available for analysis at 2 years. One patient exhibited ΔMTPM > 0.2 mm. The same patient exhibited anterior tilt > 0.8°. Varus rotation (p = 0.048, r ≤ 0.34) and medial translation (p = 0.0273, r ≤ 0.29) increased with increased varus baseplate alignment. CONCLUSION: The results indicate low risk of long-term baseplate loosening in patients. Although varus rotation and medial translation increased with increased varus baseplate alignment, the magnitudes of the migrations were minimal and did not increase ΔMTPM and anterior tilt. LEVEL OF EVIDENCE: Level II, therapeutic prospective cohort study.

Public Health Informatics and the Perioperative Physician: Looking to the Future.

The role of informatics in public health has increased over the past few decades, and the coronavirus disease 2019 (COVID-19) pandemic has underscored the critical importance of aggregated, multicenter, high-quality, near-real-time data to inform decision-making by physicians, hospital systems, and governments. Given the impact of the pandemic on perioperative and critical care services (eg, elective procedure delays; information sharing related to interventions in critically ill patients; regional bed-management under crisis conditions), anesthesiologists must recognize and advocate for improved informatic frameworks in their local environments. Most anesthesiologists receive little formal training in public health informatics (PHI) during clinical residency or through continuing medical education. The COVID-19 pandemic demonstrated that this knowledge gap represents a missed opportunity for our specialty to participate in informatics-related, public health-oriented clinical care and policy decision-making. This article briefly outlines the background of PHI, its relevance to perioperative care, and conceives intersections with PHI that could evolve over the next quarter century.

Differences in Trochlear Morphology of a New Femoral Component Designed for Kinematic Alignment from a Mechanical Alignment Design.

Because kinematic alignment (KA) aligns femoral components in greater valgus and with less external rotation than mechanical alignment (MA), the trochlear groove of an MA design used in KA is medialized, which can lead to complications. Hence, a KA design has emerged. In this study, our primary objective was to quantify differences in trochlear morphology between the KA design and the MA design from which the KA design evolved. The KA and MA designs were aligned in KA on ten 3D femur-cartilage models. Dependent variables describing the morphology of the trochlea along the anterior flange, which extends proximal to the native trochlea, and along the arc length of the native trochlea, were determined, as was flange coverage. Along the anterior flange, the KA groove was significantly lateral proximally by 10 mm and was significantly wider proximally by 5 mm compared to the MA design (p < 0.0001). Along the arc length of the native trochlea, the KA groove was significantly lateral to the MA design by 4.3 mm proximally (p ≤ 0.0001) and was significantly wider proximally by 19 mm than the MA design. The KA design reduced lateral under-coverage of the flange from 4 mm to 2 mm (p < 0.0001). The KA design potentially mitigates risk of patellofemoral complications by lateralizing and widening the groove to avoid medializing the patella for wide variations in the lateral distal femoral angle, and by widening the flange laterally to reduce under-coverage. This information enables clinicians to make informed decisions regarding use of the KA design.

Reoperation, Implant Survival, and Clinical Outcome After Kinematically Aligned Total Knee Arthroplasty: A Concise Clinical Follow-Up at 16 Years.

BACKGROUND: The preceding study reported a 10-year follow-up of 222 kinematically aligned total knee arthroplasties (TKA) performed in 217 patients in 2007. As 35% of tibial components and 8% of limbs were in >3° varus, the present study assessed whether this adversely affected reoperation, implant survival, and function at 16 years. METHODS: We retrospectively reviewed a single surgeon's private practice database to determine the patients who underwent reoperation as well as Forgotten Joint Score and Oxford Knee Score. RESULTS: There were 7 patients who had a major reoperation (revision of a loose tibial component [n = 2], and revision of well-fixed component due to stiffness [n = 1], patella instability [n = 1], pain [n = 1], and infection [n = 2]). There were 5 who had a minor reoperation that retained the components, and 91 patients (94 TKAs) died. Implant survivorship was 93% using reoperation for any reason as the endpoint. The median (interquartile range) Forgotten Joint and Oxford Knee scores were 88 (57 to 100) and 45 (39 to 48) points, respectively. CONCLUSION: The kinematically aligned TKA had a 7% reoperation rate at 16 years follow-up, comparable to or lower than reports of mechanically aligned TKA, which supports the concept of the unrestricted version of kinematic alignment in which the patient's prearthritic alignment is fully restored regardless of deformity.

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.

Better forgotten joint scores when the angle of the prosthetic trochlea is lateral to the quadriceps vector in kinematically aligned total knee arthroplasty.

PURPOSE: The primary aim was to analyze unrestricted kinematic alignment (unKA) total knee arthroplasty (TKA) and determine the frequency of medial deviation of the prosthetic trochlear angle (PTA) of the femoral component relative to the quadriceps vector (QV) that terminates at the anterior inferior iliac spine (AIIS), and whether patients with medial deviation had a worse Forgotten Joint Score (FJS) and Oxford Knee Score (OKS) relative to those with lateral deviation. The secondary aim was to determine the frequency of medial deviation for mechanical alignment (MA) TKA simulations. METHODS: From a database of a single surgeon, the study extracted de-identified data on 147 patients with a CT scanogram showing the pelvis and AIIS, a limb with an unKA TKA, and a native (i.e., healthy) opposite limb. On the scanogram, an examiner, blinded to the PROMs, measured the PTA-QV angle on the unKA TKA and on the opposite limb simulated MA TKA by drawing the PTA at 6° valgus relative to the femoral mechanical axis and measuring the PTA-QV angle. RESULTS: Medial deviation of the PTA occurred in 86% of patients with unKA TKA, and the 126 with medial deviation had a 17/1 point worse median FJS/OKS than the 21 with lateral deviation at a mean follow-up of 47 ± 8 months, respectively (p < 0.0001, p = 0.0053). In addition, 21%, 17%, and 8% of MA TKA had medial deviation after radiographic simulation using reported surgical errors for manual, patient-specific, and robotic instrumentation, respectively. CONCLUSION: In most patients with unKA TKA and a smaller proportion with MA TKA, a PTA of 6° valgus was medial to the QV, which, by excluding the patient's Q-angle, might alter patellofemoral kinematics like an incorrectly oriented trochleoplasty. The 17-point worse FJS in the patients with an unKA TKA and medial deviation of the PTA suggests the surgical target should be to orient the PTA lateral to the QV. LEVEL OF EVIDENCE: IV.

A Torn or Reconstructed Anterior Cruciate Ligament Does Not Adversely Affect Clinical Outcome Scores and the Incidence of Reoperation After Unrestricted Kinematically Aligned Total Knee Arthroplasty.

BACKGROUND: There are no reports as to whether the condition of the anterior cruciate ligament (ACL) adversely affects the 2 to 3 year function and reoperation risk of a kinematically aligned (KA) total knee arthroplasty (TKA) performed with posterior cruciate ligament (PCL) retention and an intermediate medial conforming (MC) insert. METHODS: A single surgeon's prospective database query identified 418 consecutive primary TKAs performed between January 2019 and December 2019. The surgeon recorded the ACL condition in the operative note. Patients filled out the Forgotten Joint Score (FJS), Oxford knee score (OKS), and Knee Injury and Osteoarthritis Outcome Scores for Joint Replacement at the final follow-up. There were 299 patients with an intact ACL, 99 with a torn ACL, and 20 with a reconstructed ACL. The mean follow-up was 31 months (range, 20 to 45). RESULTS: The median FJS, OKS, and Knee Injury and Osteoarthritis Outcome Score (KOOS) of the reconstructed/torn/intact KA TKAs were 90/79/67, 47/44/43, and 92/88/80 points, respectively. The median OKS and KOOS of the reconstructed ACL cohort were 4 and 11 points higher than in the intact ACL cohort (P = .003, .04). One patient who had a reconstructed ACL underwent manipulation under anesthesia (MUA) for stiffness. The 5 reoperations in the intact ACL cohort were for instability (n = 2), revision after failed MUA for stiffness (n = 2), and infection (n = 1). CONCLUSION: These results suggest that patients who have a torn and reconstructed ACL can expect high function and a low risk of reoperation comparable to patients who have an intact ACL when treated with unrestricted, caliper-verified KA, PCL retention, and an intermediate MC insert.

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.

Correcting for distal femoral asymmetry is necessary to determine postoperative alignment deviations from planned alignment of the femoral component.

BACKGROUND: One method for assessing the accuracy of manual, patient-specific, navigational, and robotic-assisted total knee arthroplasty (TKA) instrumentation is to use a post-operative computer tomogram and determine the deviation of the femoral component alignment relative to the planned alignment in the native (i.e. healthy) contralateral distal femoral epiphysis. However, side-to-side asymmetry might introduce errors which inflate alignment deviations. This study quantified asymmetry in the distal femoral epiphysis. METHODS: High resolution CT images (0.5 mm slice thickness) were acquired from bilateral lower limb specimens of 13 skeletally mature subjects with no skeletal abnormalities. Images were segmented to generate 3D femur models. Asymmetry was quantified by differences in positions and orientations required to shape-match the distal epiphysis of the mirror 3D femur model to the distal epiphysis of the contralateral 3D femur model. RESULTS: Asymmetry was due to random rather than systematic differences. Random differences (i.e. standard deviations) in proximal-distal (P-D) and anterior-posterior (A-P) positions were 1.1 mm and in varus-valgus (V-V) and internal-external (I-E) orientations were 0.9° and 1.3°, respectively. These represented substantial relative errors of up to 50 % in previously reported overall alignment deviations. CONCLUSIONS: Although small in an absolute sense, asymmetry of the distal femur epiphysis introduced substantial relative errors when assessing accuracy of femoral component alignment in TKA. When post-operative computer tomograms are used to assess the accuracy of manual, patient specific, navigational, and robotic-assisted TKA instrumentation, the overall deviation should be corrected for asymmetry to better indicate the accuracy of the surgical technique.

Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma.

Luxeptinib (LUX) is a novel oral kinase inhibitor that inhibits FLT3 and also interferes with signaling from the BCR and cell surface TLRs, as well as activation of the NLRP3 inflammasome. Ongoing clinical trials are testing its activity in patients with lymphoma and AML. This study sought to refine understanding of how LUX modulates the earliest steps downstream of the BCR following its activation by anti-IgM in lymphoma cells in comparison to ibrutinib (IB). LUX decreased anti-IgM-induced phosphorylation of BTK at Y551 and Y223 but its ability to reduce phosphorylation of kinases further upstream suggests that BTK is not the primary target. LUX was more effective than IB at reducing both steady state and anti-IgM-induced phosphorylation of LYN and SYK. LUX decreased phosphorylation of SYK (Y525/Y526) and BLNK (Y96) which are necessary regulators of BTK activation. Further upstream, LUX blunted the anti-IgM-induced phosphorylation of LYN (Y397) whose activation is required for phosphorylation of SYK and BLNK. These results indicate that LUX is targeting autophosphorylation of LYN or a step further upstream of LYN in the cascade of signal generated by BCR and that it does so more effectively than IB. The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells.

Exploiting the Receptor-Binding Domains of R-Spondin 1 to Target Leucine-Rich Repeat-Containin G-Coupled Protein Receptor 5-Expressing Stem Cells in Ovarian Cancer.

Leucine-rich repeat-containing G-protein-coupled receptor (LGR5) and LGR6 mark epithelial stem cells in normal tissues and tumors. They are expressed by stem cells in the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. High-grade serous ovarian cancer is unique in expressing unusually high levels of LGR5 and LGR6 mRNA. R-spondins are the natural ligands for LGR5 and LGR6 to which they bind with nanomolar affinity. To target stem cells in ovarian cancer, we used the sortase reaction to site-specifically conjugate the potent cytotoxin monomethyl auristatin E (MMAE) via a protease sensitive linker to the two furin-like domains of RSPO1 (Fu1-Fu2) that mediate its binding to LGR5 and LGR6 and their co-receptors Zinc And Ring Finger 3 and Ring Finger Protein 43 via a protease-cleavable linker. An immunoglobulin Fc domain added to the N-terminal end served to dimerize the receptor-binding domains so that each molecule carries two MMAE. The resulting molecule, FcF2-MMAE, demonstrated: 1) selective LGR5-dependent low nanomolar cytotoxicity against ovarian cancer cells in vitro; 2) selectivity that was dependent on binding to both the LGR receptors and ubiquitin ligase co-receptors; 3) favorable stability and plasma pharmacokinetic properties when administered intravenously with an elimination half-life of 29.7 hours; 4) selective inhibition of LGR5-rich as opposed to isogenic LGR5-poor tumors in vivo; and, 5) therapeutic efficacy in three aggressive wild-type human ovarian cancer xenograft models. These results demonstrate the successful use of the Fu1-Fu2 domain of RSPO1 as a drug carrier and the ability of FcF2-MMAE to target cells in tumors that express stem cell markers. SIGNIFICANCE STATEMENT: FcF2-MMAE is a novel cancer therapeutic that exploits the high-affinity binding domains of RSPO1 to target monomethyl auristatin E to tumor stem cells that express LGR5. FcF2-MMAE has low nanomolar LGR5-dependent cytotoxicity in vitro, favorable pharmacokinetics, and differential efficacy in an isogenic LGR5-poor versus LGR5-rich ovarian cancer xenograft model when given on a weekly schedule.

Adjusting Insert Thickness and Tibial Slope Do Not Correct Internal Tibial Rotation Loss Caused by PCL Resection: In Vitro Study of a Medial Constraint TKA Implanted with Unrestricted Calipered Kinematic Alignment.

Most medial stabilized (MS) total knee arthroplasty (TKA) implants recommend excision of the posterior cruciate ligament (PCL), which eliminates the ligament's tension effect on the tibia that drives tibial rotation and compromises passive internal tibial rotation in flexion. Whether increasing the insert thickness and reducing the posterior tibial slope corrects the loss of rotation without extension loss and undesirable anterior lift-off of the insert is unknown. In 10 fresh-frozen cadaveric knees, an MS design with a medial ball-in-socket (i.e., spherical joint) and lateral flat insert was implanted with unrestricted calipered kinematic alignment (KA) and PCL retention. Trial inserts with goniometric markings measured the internal-external orientation relative to the femoral component's medial condyle at maximum extension and 90 degrees of flexion. After PCL excision, these measurements were repeated with the same insert, a 1 mm thicker insert, and a 2- and 4-mm shim under the posterior tibial baseplate to reduce the tibial slope. Internal tibial rotation from maximum extension and 90 degrees of flexion was 15 degrees with PCL retention and 7 degrees with PCL excision (p < 0.000). With a 1 mm thicker insert, internal rotation was 8 degrees (p < 0.000), and four TKAs lost extension. With a 2 mm shim, internal rotation was 9 degrees (p = 0.001) and two TKAs lost extension. With a 4 mm shim, internal rotation was 10 degrees (p = 0.002) and five TKAs lost extension and three had anterior lift-off. The methods of inserting a 1 mm thicker insert and reducing the posterior slope did not correct the loss of internal tibial rotation after PCL excision and caused extension loss and anterior lift-off in several knees. PCL retention should be considered when using unrestricted calipered KA and implanting a medial ball-in-socket and lateral flat insert TKA design, so the progression of internal tibial rotation and coupled reduction in Q-angle throughout flexion matches the native knee, optimizing the retinacular ligaments' tension and patellofemoral tracking.

More passive internal tibial rotation with posterior cruciate ligament retention than with excision in a medial pivot TKA implanted with unrestricted caliper verified kinematic alignment.

PURPOSE: Excision of the posterior cruciate ligament (PCL) is recommended when implanting a medial pivot (MP) total knee arthroplasty (TKA) to reduce the risk of limiting flexion by over-tensioning the flexion space. The present study determined whether PCL retention (1) limits internal tibial rotation and (2) causes anterior lift-off of the insert in 90° flexion after implantation of an MP design with unrestricted caliper verified kinematic alignment (KA). METHODS: Four surgeons implanted an MP TKA design with medial ball-in-socket and lateral flat tibial insert in ten fresh-frozen cadaveric knees. Before and after PCL excision, trial inserts with medial goniometric markings measured the angular I-E tibial orientation relative to the trial femoral component's medial condyle in extension and at 90° flexion, and the surgeon recorded the occurrence of anterior lift-off of the insert at 90° flexion. RESULTS: PCL retention resulted in greater internal tibial rotation than PCL excision, with mean values of 15° vs 7° degrees from maximum extension to 90° flexion, respectively (p < 0.0007). At 90° flexion, no TKAs with PCL retention and one TKA with PCL excision had anterior lift-off of the insert (N.S.). CONCLUSIONS: This preliminary study of ten cadaveric knees showed that PCL retention restored more passive internal tibial rotation than PCL excision with a negligible risk of anterior lift-off. However, in vivo analysis from multiple authors with a larger sample size is required to recommend PCL retention with an MP TKA design implanted with unrestricted caliper verified KA.