Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.

Rapid excision of oxidized adenine by human thymine DNA glycosylase.

Oxidation of DNA bases generates mutagenic and cytotoxic lesions that are implicated in cancer and other diseases. Oxidative base lesions, including 7,8-dihydro-8-oxoguanine, are typically removed through base excision repair. In addition, oxidized deoxynucleotides such as 8-oxo-dGTP are depleted by sanitizing enzymes to preclude DNA incorporation. While pathways that counter threats posed by 7,8-dihydro-8-oxoguanine are well characterized, mechanisms protecting against the major adenine oxidation product, 7,8-dihydro-8-oxoadenine (oxoA), are poorly understood. Human DNA polymerases incorporate dGTP or dCTP opposite oxoA, producing mispairs that can cause A→C or A→G mutations. oxoA also perturbs the activity of enzymes acting on DNA and causes interstrand crosslinks. To inform mechanisms for oxoA repair, we characterized oxoA excision by human thymine DNA glycosylase (TDG), an enzyme known to remove modified pyrimidines, including deaminated and oxidized forms of cytosine and 5-methylcystosine. Strikingly, TDG excises oxoA from G⋅oxoA, A⋅oxoA, or C⋅oxoA pairs much more rapidly than it acts on the established pyrimidine substrates, whereas it exhibits comparable activity for T⋅oxoA and pyrimidine substrates. The oxoA activity depends strongly on base pairing and is 370-fold higher for G⋅oxoA versus T⋅oxoA pairs. The intrinsically disordered regions of TDG contribute minimally to oxoA excision, whereas two conserved residues (N140 and N191) are catalytically essential. Escherichia coli mismatch-specific uracil DNA-glycosylase lacks significant oxoA activity, exhibiting excision rates 4 to 5 orders of magnitude below that of its ortholog, TDG. Our results reveal oxoA as an unexpectedly efficient purine substrate for TDG and underscore the large evolutionary divergence of TDG and mismatch-specific uracil DNA-glycosylase.

The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).

Mini-open Femoroacetabular Osteoplasty in Patients With Tönnis Grade 2 or Higher Osteoarthritis is Associated With a Higher Risk of Subsequent Conversion to THA.

BACKGROUND: The severity of degenerative changes of the hip is known to adversely impact the outcomes of the treatment of femoroacetabular impingement (FAI). Although the operative indications for FAI have expanded to include patients with moderate degrees of hip osteoarthritis, the exact stage of hip osteoarthritis at which surgery for FAI can offer clinical benefits is still uncertain. QUESTIONS/PURPOSES: (1) How does the survivorship free from conversion to THA and survivorship free from revision differ between patients with preexisting Tönnis Grades 2 or 3 changes and those without advanced degenerative changes (Tönnis Grade 0 or 1) after mini-open femoroacetabular osteoplasty? (2) What are the differences in hip-specific and general-health outcome scores between the two groups after mini-open femoroacetabular osteoplasty? METHODS: From December 2003 to April 2019, we treated 901 patients for FAI, and their clinical data were systematically recorded in a longitudinally maintained database. Mini-open femoroacetabular osteoplasty was our preferred surgical approach because of the surgeon's extensive experience with the technique. Among the entire dataset, 6% of patients (51 individuals) had Tönnis Grade 2 or higher hip osteoarthritis, while the remaining 94% (850 patients) had no or mild degenerative changes (Tönnis Grade 0 or 1). In the Tönnis Grade 2 or 3 group, three patients were lost before the minimum 2-year follow-up duration, leaving 4% (48 patients) who qualified for inclusion in the study. For the matched group with Tönnis Grade 0 or 1, 5% (45 patients) were excluded because of incomplete data, and a further 7% (58 patients) were excluded because they did not have 2 years of follow-up, leaving 83% (747 patients) who were eligible for the matching process. Matching was based on patient age (within 1 year), gender, and BMI (within one unit). Matching resulted in the inclusion of 144 randomly selected control patients in this retrospective, comparative study. General indications for femoroacetabular osteoplasty included symptoms of pain and restricted hip motion in young, active patients with signs of FAI evident on physical examination and radiographs. Patient demographics, medical history, radiographic parameters, and intraoperative findings were compared between the two groups to establish baseline differences and identify potential confounding variables. There was no difference in the mean ± standard deviation age between the cohort of interest and control group (39 ± 10 years and 38 ± 11 years, respectively; p = 0.67). There was no difference in the mean follow-up duration (7 ± 3 years versus 8 ± 2 years; p = 0.25) or the preoperative symptomatic period between the study and control groups (2 ± 2 years versus 3 ± 6 years; p = 0.09). There was no difference in the prevalence of dysplasia, slipped capital femoral epiphysis, Perthes disease, or avascular necrosis of the hip between the two groups. Intraoperatively, the groups did not differ in terms of labral repair (65% [31 of 48] versus 78% [113 of 144]; p = 0.08) and labral transplantation (2%; p > 0.99 for both); however, labral resection was performed more frequently in the study group (63% [30 of 48] versus 42% [60 of 144]; p = 0.002). At a minimum of 2 years of follow-up, survivorship free from conversion to THA and survivorship free from revision surgeries, as well as the latest clinical and functional outcome scores (SF-36, Hip Disability and Osteoarthritis Outcome Score, and modified Harris hip score), were compared between groups. RESULTS: Survivorship free from conversion to THA at 5 years was lower among patients with preexisting Tönnis Grades 2 or 3 changes than it was among patients matched for age, gender, and BMI who did not have advanced degenerative changes (Tönnis Grade 0 or 1) after mini-open femoroacetabular osteoplasty (75% [95% confidence interval 64% to 88%] versus 92% [95% CI 87% to 96%]; p < 0.001). No patients in either group underwent reoperation other than conversion to THA. Although the groups did not differ at baseline in terms of their outcomes scores, the group with more visible arthritis had lower postoperative Hip Disability and Osteoarthritis Outcome Scores than the control group (60 ± 21 points versus 86 ± 11 points, mean difference 26 points [95% CI 10 to 41]; p =0.004). There were no other between-group differences in outcome scores after surgery. CONCLUSION: In our study, approximately 25% of patients undergoing mini-open femoroacetabular osteoplasty with Tönnis Grade 2 or higher osteoarthritis underwent conversion to THA within 5 years. Some postoperative functional scores were lower in patients with advanced arthritis than in matched patients with no or mild arthritis. We emphasize the importance of exercising caution when considering femoroacetabular osteoplasty in patients in whom advanced arthritis is already evident at the time of presentation. LEVEL OF EVIDENCE: Level III, therapeutic study.

Development and Validation of a Risk Calculator for Intensive Care Unit Admission After Total Hip Arthroplasty.

BACKGROUND: The purpose of this study was to develop and validate a risk stratification calculator to determine the risk of a patient requiring intensive care unit (ICU) admission following primary and revision total hip arthroplasty (THA). METHODS: Using a database of 12,342 THA procedures, with 132 ICU admissions, from 2005 to 2017, we developed models of ICU admission risk based on previously identified preoperative factors including age, heart disease, neurologic disease, renal disease, unilateral versus bilateral surgery, preoperative hemoglobin, blood glucose, and smoking status. Prior to developing the calculator, a set of logistic regressions were analyzed to determine weight and scoring for each variable. Once developed, we validated the risk calculator using a second independent institution. RESULTS: A separate risk calculator was developed for primary and revision THA. The area under the curve (AUC) for primary THA was 0.808 (95% confidence interval 0.740 to 0.876) and revision THA was AUC 0.795 (confidence interval 0.740 to 0.850). As an example, the primary THA risk calculator had a Total Points scale of 220, with 50 points associated with a 0.1% chance of ICU admission and 205 points associated with a 95% chance of ICU admission. Validation with an external cohort demonstrated satisfactory AUCs, sensitivities, and specificities for both primary THA (AUC 0.794, sensitivity 0.750, and specificity 0.722) and revision THA (AUC 0.703, sensitivity 0.704, and specificity 0.671) CONCLUSION: The externally validated risk calculators developed in this study can accurately predict ICU admission following primary and revision THA based on a number of readily available preoperative factors.

Return to Sport After Unicompartmental Knee Arthroplasty and Patello-Femoral Arthroplasty.

BACKGROUND: Data on sports/physical activity participation following unicompartmental knee arthroplasty (UKA) and patello-femoral arthroplasty (PFA) is variable and limited. The purpose of this study was to assess participations, outcomes, and limitations in sports following UKA and PFA. METHODS: Patients who underwent UKA and PFA at a single institution from 2015 to 2020 were surveyed on sports participation before and after surgery. Data was correlated with perioperative patient characteristics and outcome scores. Among 776 patients surveyed, 356 (50%) patients responded. Of respondents, 296 (83.1%) underwent UKA, 44 (12.6%) underwent PFA, and 16 (4.5%) underwent both UKA/PFA. RESULTS: Activity participation rates were 86.5, 77.3, and 87.5% five years prior, and 70.9, 61.4, and 75% at one year prior to UKA, PFA, and UKA/PFA, respectively. Return to sports rates were 81.6, 64.7, and 62.3% at mean 4.6 years postoperatively, respectively. The most common activities were recreational walking, swimming, cycling, and golf. Patients returned to a similar participation level for low-impact activities, whereas participation decreased for intermediate- and high-impact activities. Patients participating in activities had higher postoperative Knee Injury and Osteoarthritis Outcome Score Joint Replacement (P < .001), 12-Item Short Form Physical Component Score (P = .045) and Mental Component Score (P = .012). Activity restrictions were reported among 25, 36.4, and 25% of UKA, PFA, and UKA/PFA patients, respectively, and were more commonly self-imposed than surgeon-directed. CONCLUSIONS: Though UKA patients' postoperative sports participation may improve compared to one year preoperatively, participation for patients surgically treated for isolated osteoarthritis is decreased compared to 5 years preoperatively and varies among patient subsets.

Joint line position change in primary total knee arthroplasty: a radiographic analysis comparing conventional and robotic techniques.

PURPOSE: Joint line (JL) position change in total knee arthroplasty (TKA) may alter knee biomechanics and impact function. The purpose of this study was to compare the change in JL position between robotic-assisted TKA (RA-TKA) and conventional TKA (C-TKA). METHODS: A retrospective, radiographic analysis was conducted of patients who underwent RA-TKA and C-TKA to compare JL position change. JL position was measured in consecutive RA-TKAs and C-TKAs performed by four fellowship-trained arthroplasty surgeons. Statistical analysis was done utilizing t-tests and Mann Whitney U tests, with statistical significance being defined as a p value < 0.05. RESULTS: Six hundred total RA-TKAs and 400 total C-TKAs were included in the analysis. There were no significant differences in patient baseline characteristics such as body mass index, range of motion, and tibiofemoral coronal alignment. RA-TKAs were associated with an average of 0.04 (2.2) mm JL position change, and C-TKAs were associated with an average 0.5 (3.2) mm JL position change (p = 0.030). There were inter-surgeon differences when comparing the change in JL position for RA-TKAs and C-TKAs between the four participating surgeons. CONCLUSION: RA-TKA leads to better preservation of the JL position than C-TKA, and this seems to be dependent on the arthroplasty surgeon's preferences and techniques during TKA. Whether this statistically significant difference is clinically relevant needs to be further investigated.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.

BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).

Anti-FHL1 autoantibodies in juvenile myositis are associated with anti-Ro52 autoantibodies but not with severe disease features.

OBJECTIVES: Four-and-a-half LIM domains 1 (FHL1) is a muscle-specific protein. Autoantibodies against FHL1 were recently discovered in adults with idiopathic inflammatory myopathies (IIMs) and were found to be associated with clinical features and outcomes indicative of increased disease severity. Anti-FHL1 autoantibodies have not been described in children. Here, the prevalence and clinical features associated with anti-FHL1 autoantibodies were examined in a large North American cohort of juvenile patients with IIM. METHODS: Sera from 338 juvenile IIM patients and 91 juvenile healthy controls were screened for anti-FHL1 autoantibodies by ELISA. Clinical characteristics and HLA alleles of those with and without anti-FHL1 autoantibodies were compared among those with juvenile IIM. RESULTS: Anti-FHL1 autoantibodies were present in 10.9% of juvenile IIM patients and 1.1% of controls. The frequency of anti-FHL1 autoantibodies among clinical and serologic subgroups did not differ. A higher percentage of Asian patients had anti-FHL1 autoantibodies (11% vs 0.7%; P = 0.002). Myositis-associated autoantibodies (MAAs) [odds ratio (OR) 2.09 (CI 1.03, 4.32)], anti-Ro52 autoantibodies specifically [OR 4.17 (CI 1.83, 9.37)] and V-sign rash [OR 2.59 (CI 1.22, 5.40)] were associated with anti-FHL1 autoantibodies. There were no differences in other features or markers of disease severity. No HLA associations with anti-FHL1 autoantibodies in Caucasian myositis patients were identified. CONCLUSION: Anti-FHL1 autoantibodies are present in ∼11% of juvenile IIM patients and commonly co-occur with MAAs, including anti-Ro52 autoantibodies. In contrast to adult IIM, anti-FHL1 autoantibodies in juvenile myositis are associated with V-sign rash but not with other distinctive clinical features or worse outcomes.

Distressed communities demonstrate increased readmission and health care utilization following shoulder arthroplasty.

BACKGROUND: Socioeconomic status (SES) has been shown to affect outcomes following total shoulder arthroplasty (TSA), but little is known regarding how SES and the communities in which patients reside can affect postoperative health care utilization. With the growing use of bundled payment models, understanding what factors put patients at risk for readmission and the ways in which patients utilize the health care system postoperatively is crucial for preventing excess costs for providers. This study helps surgeons predict which patients are high-risk and may require additional surveillance following shoulder arthroplasty. METHODS: A retrospective review of 6170 patients undergoing primary shoulder arthroplasty (anatomic and reverse; Current Procedural Terminology code 23472) from 2014-2020 at a single academic institution was performed. Exclusion criteria included arthroplasty for fracture, active malignancy, and revision arthroplasty. Demographics, patient zip code, and Charlson Comorbidity Index were attained. Patients were classified according to the Distressed Communities Index (DCI) score of their zip code. The DCI combines several metrics of socioeconomic well-being to generate a single score. Zip codes are then classified by scores into 5 categories based on national quintiles. The primary outcome of interest was 90-day readmissions. Secondary outcomes included number of postoperative medication prescriptions, patient telephone calls to the office, and follow-up office visits. RESULTS: Among all patients undergoing total shoulder arthroplasty, individuals from distressed communities were more likely than their prosperous counterparts to experience an unplanned readmission (odds ratio = 1.77, P = .045). Patients from comfortable (relative risk [RR] = 1.12, P < .001), midtier (RR = 1.13, P < .001), at-risk (RR = 1.20, P < .001), and distressed (RR = 1.17, P < .001) communities were all more likely to use more medications compared to those from prosperous communities. Likewise, those from comfortable (RR = 0.92, P < .001), midtier (RR = 0.88, P < .001), at-risk (RR = 0.93, P = .008), and distressed (RR = 0.93, P = .033) communities, respectively, were at a lower risk of making calls compared to prosperous communities. CONCLUSIONS: Following primary total shoulder arthroplasty, patients who reside in distressed communities are at significantly increased risk of experiencing an unplanned readmission and increased health care utilization postoperatively. This study revealed that patient socioeconomic distress is more associated with readmission than race following TSA. Increased awareness and employing strategies to maintain and ultimately improve communication with patients offers a potential solution to reduce excessive health care utilization, benefiting both patients and providers alike.

Factors associated with functional improvement after posteriorly augmented total shoulder arthroplasty.

BACKGROUND: Posteriorly augmented glenoid components in anatomic total shoulder arthroplasty (TSA) address posterior glenoid bone loss with inconsistent results. The purpose of this study was to identify preoperative and postoperative factors that impact range of motion (ROM) and function after augmented TSA in patients with type B2 or B3 glenoid morphology. METHODS: This was a retrospective review of all patients who underwent TSA with a step-type augmentation performed by a single surgeon between 2009 and 2018. Patients with Walch type B2 or B3 glenoids were included. Outcomes included forward elevation (FE), external rotation (ER), internal rotation (IR), Single Assessment Numeric Evaluation (SANE) score, and visual analog scale pain score. Preoperative imaging was reviewed to assess glenoid retroversion and posterior humeral head subluxation relative to the scapular body and midglenoid face. Postoperative measurements included glenoid retroversion, subluxation relative to the scapular body, subluxation relative to the central glenoid peg, and center-peg osteolysis. Measurements were performed by investigators blinded to ROM and functional outcome scores. RESULTS: Fifty patients (mean age, 68.1 ± 8.0 years) with a mean follow-up period of 42.0 months (range, 24-106 months) were included. Glenoid morphology included type B2 glenoids in 41 patients and type B3 glenoids in 9. One patient had center-peg osteolysis, and 1 patient had glenoid component loosening. Average preoperative FE, ER, and IR were 110°, 21°, and S1, respectively. Average postoperative FE, ER, and IR were 155°, 42°, and L1, respectively. The mean postoperative visual analog scale score was 0.5 ± 0.8, and the mean SANE score was 94.5 ± 5.6. Type B3 glenoids were associated with better postoperative IR compared with type B2 glenoids (T10 vs. L1, P = .024), with no other differences in ROM between the glenoid types. Preoperative glenoid retroversion did not significantly impact postoperative ROM. Postoperative glenoid component retroversion and residual posterior subluxation relative to the scapular body or glenoid face did not correlate with ROM in any plane. However, posterior subluxation relative to the glenoid face was moderately associated with lower SANE scores (r = -0.448, P = .006). CONCLUSION: Patients achieved excellent functional outcomes and pain improvement after TSA with an augmented glenoid component. Postoperative ROM and function showed no clinically important associations with preoperative or postoperative glenoid retroversion or humeral head subluxation in our cohort of posteriorly augmented TSAs, except for worse functional scores with increased humeral head subluxation in relation to the glenoid surface.

Routine Use of Closed Suction Drains Following Revision Arthroplasty May Not be Necessary.

BACKGROUND: There are numerous studies demonstrating that closed suction drainage (CSD) usage after primary total joint arthroplasty (TJA) has little to no benefit. There are little data on the role of CSDs after revision TJA. The purpose of our study was to evaluate whether there is any clinical advantage to CSD usage after revision TJA. METHODS: This retrospective study evaluated the clinical records of 2,030 patients undergoing revision TJA between 2007 and 2021. CSD was used in 472 patients and not used in 1,558 patients. Primary outcome was blood transfusion rate and secondary outcomes included total blood loss (TBL), as determined by Gross formula, wound complications (hematoma, infection, and dehiscence), and length of hospital stay. Patients undergoing revision TJA for oncologic reasons or those with incomplete datasets were excluded. RESULTS: There were no statistically significant differences in rates of allogeneic blood transfusion, TBL, and wound complications (hematoma, infection, and dehiscence) between the two groups (P = .159, .983, .192, .334, and .548, respectively). When adjusted for demographic and surgical confounders, there was no difference in transfusion and TBL rates between groups (Odds Ratio 1.04, 95% Confidence Interval 0.78-1.38, P = .780 and estimate -105.71 mL, 95% confidence interval -333.96 to 122.55, P = .364, respectively). CSD cohort had a shorter length of stay (4.30 versus 5.82 days, P < .001). CONCLUSION: We acknowledge that there is a role for CSD usage in a selected group of patients. Nevertheless, our study revealed that routine use of CSD after revision TJA does not provide an additional clinical benefit.

Mortality and Complications Following Early Conversion Arthroplasty for Failed Hip Fracture Surgery.

BACKGROUND: Hip fracture in older patients leads to high morbidity and mortality. Patients who are treated surgically but fail acutely face a more complex operation with conversion total hip arthroplasty (THA). This study investigated mortalities and complications in patients who experienced failure within one year following hip fracture surgery requiring conversion THA. METHODS: Patients aged 60 years or more undergoing conversion THA within one year following intertrochanteric or femoral neck fracture were identified and propensity-matched to patients sustaining hip fractures treated surgically but not requiring conversion within the first year. Patients who had two-year follow-up (91 conversions; 247 comparisons) were analyzed for 6-month, 12-month, and 24-month mortalities, 90-day readmissions, surgical complications, and medical complications. RESULTS: Nonunion and screw cutout were the most common indications for conversion THA. Mortalities were similar between groups at 6 months (7.7% conversion versus 6.1% nonconversion, P = .774), 12 months (11% conversion versus 12% nonconversion, P = .999), and 24 months (14% conversion versus 22% nonconversion, P = .163). Survivorships were similar between groups for the entire cohort and by fracture type. Conversion THA had a higher rate of 90-day readmissions (14% versus 3.2%, P = .001), and medical complications (17% versus 6.1%, P = .006). Inpatient and 90-day orthopaedic complications were similar. CONCLUSION: Conversion THA for failed hip fracture surgery had comparable mortality rates to hip fracture surgery, with higher rates of perioperative medical complications and readmissions. Conversion THA following hip fracture represents a potential "second hit" that both surgeons and patients should be aware of with initial decision-making.

For Patients With Acute PJI Treated With Debridement, Antibiotics, and Implant Retention, What Factors Are Associated With Systemic Sepsis and Recurrent or Persistent Infection in Septic Patients?

BACKGROUND: Periprosthetic joint infection (PJI) can lead to a severe systemic inflammatory response and may result in systemic sepsis. However, little is known about how often systemic sepsis may occur in patients with PJI, and whether sepsis is associated with a greater likelihood of persistent or recurrent PJI. QUESTIONS/PURPOSES: (1) Among patients who present with acute or acute hematogenous PJI and who were treated with debridement, antibiotics, and implant retention (DAIR), what proportion have sepsis and what factors are associated with a presentation with sepsis? (2) For patients presenting with sepsis, what factors are associated with persistent or recurrent PJI? METHODS: In all, 320 patients who underwent DAIR for the treatment of acute postoperative or acute hematogenous PJI between January 2000 and December 2019 were included in this study. Exclusion criteria were patients with other known sources of infection, such as pneumonia or urinary tract infections, which could contribute to systemic sepsis (6% [18 of 320]), patients with chronic PJI, and those with less than 6 months of follow-up (21% [66 of 320]). Our final cohort consisted of 236 patients presenting with an acute postoperative or acute hematogenous PJI who underwent an irrigation and debridement procedure. Sepsis was defined by the criteria for systemic inflammatory response syndrome (SIRS) or bacteria-positive blood culture results. Inclusion of patients with positive blood culture by organisms that caused their joint infection was important as all patients presented with fulminant acute infection of a prosthetic joint. Data, including vital signs, surgical variables, and treatment outcomes, were collected retrospectively through a chart review of an electronic medical record system. The statistical analysis comparing patients with sepsis versus patients without sepsis consisted of logistic regression to identify factors associated with sepsis. After confirming its ability to identify patients with a higher association with the development of sepsis through area under the curve models, a nomogram was generated to standardize our results from the regression, which was supported by the area under the curve model, to help readers better identify patients who are more likely to develop sepsis. RESULTS: A total of 44% (103 of 236) of patients had infections that met the criteria for sepsis. After controlling for confounding variables, including congestive heart failure, anemia, serum C-reactive protein (CRP), and the male sex, it was revealed that serum CRP (odds ratio 1.07 [95% confidence interval 1.04 to 1.11]; p < 0.001) and male sex (OR 1.96 [95% CI 1.03 to 3.81]; p = 0.04) were associated with the development of systemic sepsis. For patients presenting with sepsis, persistent or recurrent PJI were associated with an increased CRP level (OR 1.06 [95% CI 1.02 to 1.11]; p = 0.01) and number of prior surgical procedures on the joint (OR 2.30 [95% CI 1.21 to 4.89]; p = 0.02). CONCLUSION: Overall, our findings support that patients with systematic sepsis may benefit from two-stage revision rather than DAIR to decrease the bioburden more effectively, especially in those with methicillin-resistant Staphylococcus aureus and polymicrobial infections. High serum CRP levels and a history of prior surgical procedures on the involved joint should trigger prompt, aggressive surgical treatment if the patient's overall clinical status can tolerate such an intervention. LEVEL OF EVIDENCE: Level III, therapeutic study.

Radiographic Severity May Not be Associated with Pain and Function in Glenohumeral Arthritis.

BACKGROUND: Despite the routine use of plain radiographs to stratify the severity of glenohumeral osteoarthritis, little is known about the relationship between radiographic measures and patient-perceived pain and function. QUESTIONS/PURPOSES: (1) What radiographic findings are associated with worse pain and function in patients with glenohumeral osteoarthritis? (2) What demographic factors are associated with worse pain and function in patients with glenohumeral osteoarthritis? METHODS: This retrospective study included patients presenting for an initial office visit for primary glenohumeral osteoarthritis. Patients with other concurrent shoulder pathologic findings, prior surgery, lack of pain and functional scores, recent injection, or inadequate radiographs were excluded. Between January 2017 and January 2019, 3133 patients were eligible based on these inclusion criteria; 59% (1860) had outcome assessments and 48% (893) of those had radiographs. An additional 42% (378) of those with radiographs were excluded because of other shoulder findings, recent injection, prior surgery, or inadequate radiographs, leaving 16% (515 of 3133) who were fully analyzed in this study. A radiographic review included the joint space width, posterior humeral head subluxation, inferior humeral head osteophyte size, cystic change, and head asphericity. Additionally, radiographic arthritis was classified according to the Walch, Samilson-Prieto, and Kellgren-Lawrence classifications by two separate reviewers. Radiographic and demographic criteria as well as the presence of psychologic or mental illness were correlated with VAS Pain (range 1-10; minimal clinically important difference [MCID] 1.6), American Shoulder and Elbow Surgeons (ASES; range 0-100; MCID 13.6), Single Assessment Numeric Evaluation (SANE; range 0-100; MCID 14), and Simple Shoulder Test (SST; range 0-12; MCID 1.5) scores using univariate and multivariable regression analyses. RESULTS: After accounting for age, gender, and psychologic illness in the multivariable analysis, we found that patients with Samilson-Prieto Grade 4 arthrosis had lower VAS Pain scores (ß = -1.9; p = 0.02) than those with Grade 0 or 1 did; however, no clinically important associations were found between Samilson-Prieto Grade 4 and ASES (ß = 7; p = 0.25), SANE (ß = 4; p = 0.63), or SST (ß = 0.5; p = 0.62) scores. No clinically important associations were found between Kellgren-Lawrence Grade 3 and VAS Pain (ß = 1.4; p = 0.10), ASES (ß = -8; p = 0.22), SANE (ß = -13; p = 0.11), or SST scores (ß = 0.4; p = 0.66). Radiographic joint space and posterior subluxation also did not have any clinically important associations with VAS Pain or functional scores. In assessing Walch glenoid type, there was no clinically important association between glenoid type and VAS Pain (F = 3.1; p < 0.01), ASES (F = 1.9; p = 0.15), SANE (F = 0.45; p = 0.66), or SST scores (F = 0.76; p = 0.71). Men had higher SST scores than women did (ß = 2.0; p < 0.01), but there were no clinically important differences in VAS Pain (ß = -0.4; p = 0.04), ASES (ß = 6; p < 0.01), or SANE (ß = 4; p = 0.07) scores. No clinically important association was found between age or the presence of any psychologic illness and VAS Pain or functional scores. CONCLUSION: In patients with glenohumeral arthritis, no consistent clinically important differences in pain or function were discovered with respect to radiographic or demographic factors. Surgeons should understand that the pain levels of patients with glenohumeral arthritis may not parallel radiographic severity. Future studies can build on these findings by examining other non-radiographic or demographic factors that affect pain in patients with shoulder arthritis, such as psychological factors. LEVEL OF EVIDENCE: Level III, prognostic study.

Cumulative Intraarticular Injections Are Not a Risk Factor for Periprosthetic Joint Infection Following total Knee Arthroplasty.

BACKGROUND: While injections within 90 days prior to total knee arthroplasty (TKA) are associated with an increased risk of periprosthetic joint infection (PJI), there is a paucity of literature regarding the impact of cumulative injections on PJI risk. This study was conducted to assess the association between cumulative corticosteroid and hyaluronic acid (HA) injections and PJI risk following TKA. METHODS: This retrospective study using an injection database included patients undergoing TKA with a minimum 1-year follow-up from 2015 to 2020. Patients with injections within 90 days prior to surgery were excluded. The sum of corticosteroid and HA injections within five years prior to TKA was recorded. The primary outcome was PJI within 90 days following TKA. Area under the curve (AUC) values were calculated for a cumulative number of injections. RESULTS: 648 knees with no injections and 672 knees with injections prior to TKA were included, among whom 243 received corticosteroids, 151 received HA, and 278 received both. No significant differences in early PJI rates existed between patients who received injections (0.60%) or not (0.93%) (P = .541). No significant differences existed in early PJI rates between patients injected with corticosteroids (0.82%), HA (0.66%), or both (0.36%) (P = .832). No cutoff number of injections was predictive for PJI. DISCUSSION: A cumulative amount of steroid or HA injections, if given more than 90 days prior to TKA, does not appear to increase the risk of PJI within 90 days postoperatively. Multiple intraarticular corticosteroid injections and HA injections may be safely administered before TKA, without increased risk for early PJI.

Routine Laboratory Tests are not Necessary After Primary Total Joint Arthroplasty: A Prospective Study Utilizing a Selective Algorithmic Approach.

BACKGROUND: Laboratory tests are obtained following total joint arthroplasty (TJA) despite a lack of supporting evidence. No prior study has prospectively analyzed the effect of discontinuing routine laboratory tests. This study aimed to determine whether discontinuing routine laboratory tests in TJA patients resulted in a difference in 90-day complications. METHODS: This was a prospective protocol change study at a high-volume center. Prior to protocol change, patients underwent routine laboratory tests following primary unilateral TJA (control group). After the change, an algorithmic approach was used to selectively order laboratory tests (protocol group). Patients with bleeding disorders, chronic obstructive pulmonary disease, arrhythmia, coronary artery disease, congestive heart failure, chronic renal failure, dementia, abnormal preoperative sodium, potassium, or hemoglobin <10 g/dL were excluded. In-hospital and 90-day data were collected. Student's t-test was used to analyze continuous variables and chi-squared test was used for categorical variables. A pre-hoc analysis examining the primary outcome required 607 patients per group to achieve 80% power. RESULTS: The protocol group included 937 patients, whereas the control group included 891 patients. The protocol group had fewer females and total hip arthroplasties. There were no differences in age, body mass index, American Society of Anesthesiologists classification, tranexamic acid administration, or estimated blood loss between the protocol and control groups. There were also no differences in transfusions, electrolyte corrections, unplanned consults, length of stay, or transfers. The protocol cohort had more fluid boluses and home discharges. There was no difference in 90-day complications between the 2 groups. CONCLUSIONS: This study utilizing an algorithmic approach to laboratory collection demonstrates that discontinuing routine laboratory tests following TJA is safe and effective. We believe this protocol can be implemented for most patients undergoing primary unilateral TJA.

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study.

BACKGROUND: Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. MATERIALS AND METHODS: Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. PERIOD: Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. RESULTS: Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3-4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. CONCLUSION: Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. IMPLICATIONS FOR PRACTICE: Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.

Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with ß-thalassemia.

ß-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with ß-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of ß-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.