Outpatient Bryant's Overhead Traction Does Not Affect the Rate of Open Reduction or Avascular Necrosis in Developmental Dislocation of the Hip.

BACKGROUND: The efficacy of preliminary traction to increase the likelihood of closed reduction and/or decrease the incidence of avascular necrosis in the management of developmental dysplasia of the hip (DDH) is controversial. We sought to document compliance with and effectiveness of Bryant's outpatient traction in patients with idiopathic DDH. METHODS: Patients presenting between 6 and 24 months of age with idiopathic irreducible DDH were prospectively enrolled in the study. Prereduction outpatient traction was prescribed at participating surgeons' preference and parents' expressed willingness to comply with a traction protocol of at least 14 hours/day for 4 weeks. Traction hours were documented using a validated monitor; parents also reported average daily usage. Rate of successful closed reduction and evidence of capital epiphyseal growth disturbance 1 year' and 2 years' postreduction were documented. RESULTS: Ninety-six patients with 115 affected hips were enrolled. Reliable recorded traction hours were obtained in 31 patients with 36 affected hips. Defining compliance as 14 hours/day average use, 14 of 31 patients (45.2%) were compliant, 2 (6.5%) admitted noncompliance, while 15 (48.2%) claimed to be compliant, but were not. Overall, 68/115 hips (59.0%) were closed reduced. Age at treatment was the only demographic characteristic associated with an increased incidence of closed reduction (11.7 vs. 14.6 mo, P<0.01). Successful closed reduction was achieved in 10/16 hips (62.5%) of compliant patients, 12/20 (60.0%) of noncompliant patients, and 43/72 (59.7%) of no-traction patients. Irregular ossific nucleus development was noted 1-year postindex reduction in 5/16 (31.3%) of complaint-patient hips and 25/92 (27.2%) of noncomplaint and no-traction hips. Distorted proximal femoral epiphysis was noted at 2 years postreduction in 2/15 hips (13.3%) of compliant patients and 15/52 hips (28.8%) in noncompliant and no-traction patients. None of these differences was statistically significant. CONCLUSIONS: Parent-reported use of outpatient traction is unreliable. Four weeks of outpatient overhead Bryant's traction did not affect the rate of closed reduction or avascular necrosis in late-presenting DDH in this cohort. LEVEL OF EVIDENCE: Level II-prospective cohort.

Progressive long-term spatial memory loss following repeat concussive and subconcussive brain injury in mice, associated with dorsal hippocampal neuron loss, microglial phenotype shift, and vascular abnormalities.

There is considerable concern about the long-term deleterious effects of repeat head trauma on cognition, but little is known about underlying mechanisms and pathology. To examine this, we delivered four air blasts to the left side of the mouse cranium, a week apart, with an intensity that causes deficits when delivered singly and considered "concussive," or an intensity that does not yield significant deficits when delivered singly and considered "subconcussive." Neither repeat concussive nor subconcussive blast produced spatial memory deficits at 4 months, but both yielded deficits at 14 months, and dorsal hippocampal neuron loss. Hierarchical cluster analysis of dorsal hippocampal microglia across the three groups based on morphology and expression of MHCII, CX3CR1, CD68 and IBA1 revealed five distinct phenotypes. Types 1A and 1B microglia were more common in sham mice, linked to better neuron survival and memory, and appeared mildly activated. By contrast, 2B and 2C microglia were more common in repeat concussive and subconcussive mice, linked to poorer neuron survival and memory, and characterized by low expression levels and attenuated processes, suggesting they were de-activated and dysfunctional. In addition, endothelial cells in repeat concussive mice exhibited reduced CD31 and eNOS expression, which was correlated with the prevalence of type 2B and 2C microglia. Our findings suggest that both repeat concussive and subconcussive head injury engender progressive pathogenic processes, possibly through sustained effects on microglia that over time lead to increased prevalence of dysfunctional microglia, adversely affecting neurons and blood vessels, and thereby driving neurodegeneration and memory decline.

Do We Really Need to Worry About Calcaneocuboid Subluxation During Lateral Column Lengthening for Planovalgus Foot Deformity?

BACKGROUND: Although lengthening of the lateral column through an osteotomy of the anterior calcaneus is an integral component of flatfoot reconstruction in younger patients with flexible planovalgus deformities, the procedure has been implicated in iatrogenic calcaneocuboid (CC) subluxation and subsequent degenerative changes at the CC articulation. The purpose of this study is to characterize alterations at the CC joint after lateral column lengthening (LCL) and determine if Steinmann pin stabilization of the CC joint before distraction maintains a normal relationship. METHODS: Seven matched pairs of fresh-frozen cadaveric feet underwent preprocedure plain radiography and cross-sectional computed tomography (CT) imaging. LCL by osteotomy through the anterior calcaneus was then performed. One foot of each matched pair had a single smooth Steinmann pin placed centrally across the CC joint before osteotomy distraction. Distraction across each osteotomy was then performed and maintained with a 12-mm porous titanium wedge. Repeat imaging was obtained and compared with preprocedure studies to quantify sagittal and rotational differences at the CC articulation. RESULTS: Following LCL, plain radiography demonstrated statistically significant increases in the percentage of the calcaneal articular surface dorsal to the superior aspect of the cuboid in both the pinned (8.2% vs. 17.6%, P=0.02) and unpinned (12.5% vs. 16.3%, P=0.04) specimens. No difference in the percentage of subluxation was found between the 2 groups after LCL. CT imaging demonstrated statistically significant increases in rotation between the calcaneus and cuboid after LCL in both the pinned (7.6±5.6 degrees, P=0.01) and unpinned (17±12.3 degrees, P=0.01) specimens. The degree of rotation was greater in unpinned specimens after LCL (P=0.043). CONCLUSIONS: Both sagittal and rotatory subluxation seem to occur at the CC joint after LCL regardless of pin stabilization. As a single pin would be expected to limit pure translation while having little effect on rotation, it is possible that the rotational changes identified on 3-dimensional imaging are interpreted as dorsal translation when viewed 2 dimensionally using plain radiography. Consideration should therefore be given to CC stabilization with 2 pins during LCL to prevent this rotatory subluxation. LEVEL OF EVIDENCE: Level V-cadaver study.

Biomechanical Analysis of Retrograde Flexible Intramedullary Nail Constructs in a Simulated Pediatric Femur Fracture Model.

BACKGROUND: Various flexible intramedullary nail (FIMN) constructs for pediatric femur fractures are described; however, no biomechanical study has compared stability of medial-lateral entry versus all-lateral entry retrograde nailing. Our purpose is to compare the rotational and bending stiffness of 2 different FIMN constructs and 2 different materials in a simulated pediatric femur fracture model. METHODS: Eighty adolescent-sized composite femurs were used to simulate transverse (40 femurs) and oblique (40 femurs) mid-diaphyseal fractures. Retrograde FIMN of the femurs was performed using either 3.5 mm titanium (Ti) or 3.5 mm stainless-steel (SS) flexible nails in 2 configurations: 2 "C"-shaped nails (CC) placed through medial and lateral entry sites or 1 "C"-shaped nail and 1 "S"-shaped nail (CS) placed through a single lateral entry site. Models were first tested in 10 cycles of axial rotation to ±1 N m of torque at a rate of 0.5 degrees/s under 36 kg of compression. Axial compression was performed and bending stiffness defined as the force required to achieve 10 degrees varus at the fracture site. RESULTS: No differences were noted in rotational stiffness comparing Ti and SS nails regardless of nail configuration or fracture pattern. Comparable rotational stability was found for CC and CS configurations with SS implants for both fracture patterns. The CS construct (0.60 N m/degree) was stiffer in rotation than the CC construct (0.41 N m/degree) with Ti implants in the transverse fracture model (P<0.005). SS nails provided greater bending stiffness than Ti nails in both oblique and transverse fracture patterns, regardless of nail construct. The all-lateral entry (CS) construct demonstrated statistically significant greater bending stiffness regardless of implant material or fracture pattern (P<0.03). CONCLUSIONS: An all-lateral entry (CS) FIMN construct demonstrated greater bending stiffness in both fracture patterns and materials. Ti and SS implants have comparable rotational stiffness in all fracture patterns and materials; however, SS nails were superior at resisting bending forces in both fracture patterns. CS nail configuration and SS implants demonstrated superior bending stiffness and rotational stiffness when compared with the more commonly used CC construct and Ti implants. LEVEL OF EVIDENCE: NA (biomechanical study).

Biomechanical Assessment of Torsional Stiffness in a Supracondylar Humerus Fracture Model.

BACKGROUND: We assessed the effect on the torsional stability by different pin diameters and varied pin configurations in a biomechanical supracondylar humerus fracture model. METHODS: After scanning a model of a pediatric humerus, the image was imported into software. Variable pin trajectories were planned. Acrylonitrile butadiene styrene plastic models were 3-dimensionally printed with predetermined pin trajectories. Models were osteotomized and potted with a polyurethane resin. Five-pin configurations were designed to test coronal and sagittal patterns of pin placement. Each included 3 lateral pins and a medial pin. Pin diameters of 1.6, 2.0, and 2.4 mm were tested in all configurations. Three models for each pin diameter/configuration were tested to ensure uniformity. Stability of the construct was tested to determine the torque needed to deflect the osteotomy 10 degrees in internal/external rotation. Each model was tested 3 times. RESULTS: In all models/configurations, the 2.4 mm pin diameter was statistically stiffer than 1.6 mm diameter pins; this lost statistical significance in certain patterns when comparing 2.0- and 2.4-mm pins. When comparing a divergent to a parallel configuration in the coronal plane, there was no significant difference in stability when pin diameter or number were controlled. The convergent pin configuration was, in general, the least stable pattern. Use of a medial pin conferred statistically significant stiffness throughout most models as demonstrated with pin deletion. Use of 2 pins was significantly less stiff than most 3-pin models. CONCLUSIONS: Larger pin diameters confer greater stiffness among all patterns. The use of 3 lateral and 1 medial pin was not statistically different than 2 lateral and 1 medial pin in our models. Both patterns were stiffer than 3 lateral pins only or other fewer pin constructs. The alignment of pins in the sagittal plane did not affect overall construct stiffness.

Retrograde Stainless Steel Flexible Nails Have Superior Resistance to Bending in Distal Third Femoral Shaft Fractures.

BACKGROUND: It has been shown that retrograde titanium flexible intramedullary nails (Ti FIN) provide superior resistance to bending compared to antegrade Ti FIN in distal femur fractures. The purpose of this study was to compare resistance to torsional and bending forces of stainless steel (SS) FIN, with or without a locking screw, and Ti FIN in distal third femoral shaft fractures. We hypothesize that locked retrograde SS FIN will demonstrate greater resistance to both bending and torsional forces. METHODS: Thirty adolescent synthetic femur models were used to simulate transverse distal femoral fractures at either 60 mm or 90 mm proximal to the distal femoral physis. The femurs were instrumented with antegrade Ti FIN, antegrade SS FIN, retrograde Ti FIN, retrograde SS FIN, or retrograde locked SS FIN. Three models for each construct at both osteotomy levels were tested. Models were analyzed to determine maximum resistance to bending and torsion. RESULTS: In fractures 60 mm from the physis, retrograde SS FIN demonstrated statistically superior resistance to bending when compared with both antegrade and retrograde Ti FIN (P=0.001 and 0.008, respectively) and antegrade SS FIN (P=0.0001). Locked SS constructs showed a trend towards greater resistance to bending forces when compared with unlocked constructs (P>0.05). No significant difference was seen in resistance to bending when fractures were 90 mm proximal to the distal femoral physis between the five groups. No significant differences were observed in resistance to torsion in either the proximal or distal fracture models, regardless of construct type. CONCLUSIONS: Retrograde SS FIN confer significantly greater resistance to bending forces for fractures 60 mm proximal to the distal femoral physis compared with Ti FIN or antegrade entry SS FIN. In fractures 90 mm from the physis, no differences were noted in our model. Our results support the use of retrograde SS nails in the pediatric patient with distal femoral shaft fractures. LEVEL OF EVIDENCE: Level II-comparative biomechanical study.

Acquired Von Willebrand Syndrome and Blood Pump Design.

The existence of acquired von Willebrand syndrome (AVWS) in patients with continuous flow left ventricular assist devices (LVADs) is well documented and has been verified by numerous investigators. AVWS has not been observed to occur in pulsatile devices such as the SynCardia total artificial heart (TAH), the HeartMate XVE, and the Thoratec pulsatile ventricular assist device (PVAD) used as a single pump. AVWS can also occur in patients with aortic stenosis, ventricular septal defect, mitral stenosis, and patent ductus arteriosus. It has been experimentally verified that supraphysiologic shear stress that occurs under these conditions can cleave the von Willebrand molecule, but the critical magnitude of stress and duration is unclear. Limited experimental results demonstrate that shear stresses as low as 5 Pa (50 dyne/cm2 ) can cause cleavage. Stresses in current centrifugal pumps can be as high as two orders of magnitude greater than this value. Pulsatile LVADs have stresses almost two orders of magnitude less than continuous flow LVADs. In order to improve continuous flow LVADs, the challenge for designers is to first determine the magnitude and duration of stress that is causing AVWS and then, if possible, design a pump below these stresses.

Multidomain, Surface Layer-associated Glycoside Hydrolases Contribute to Plant Polysaccharide Degradation by Caldicellulosiruptor Species.

The genome of the extremely thermophilic bacterium Caldicellulosiruptor kronotskyensisencodes 19 surface layer (S-layer) homology (SLH) domain-containing proteins, the most in any Caldicellulosiruptorspecies genome sequenced to date. These SLH proteins include five glycoside hydrolases (GHs) and one polysaccharide lyase, the genes for which were transcribed at high levels during growth on plant biomass. The largest GH identified so far in this genus, Calkro_0111 (2,435 amino acids), is completely unique toC. kronotskyensisand contains SLH domains. Calkro_0111 was produced recombinantly inEscherichia colias two pieces, containing the GH16 and GH55 domains, respectively, as well as putative binding and spacer domains. These displayed endo- and exoglucanase activity on the ß-1,3-1,6-glucan laminarin. A series of additional truncation mutants of Calkro_0111 revealed the essential architectural features required for catalytic function. Calkro_0402, another of the SLH domain GHs inC. kronotskyensis, when produced inE. coli, was active on a variety of xylans and ß-glucans. Unlike Calkro_0111, Calkro_0402 is highly conserved in the genus Caldicellulosiruptorand among other biomass-degrading Firmicutes but missing from Caldicellulosiruptor bescii As such, the gene encoding Calkro_0402 was inserted into the C. besciigenome, creating a mutant strain with its S-layer extensively decorated with Calkro_0402. This strain consequently degraded xylans more extensively than wild-typeC. bescii The results here provide new insights into the architecture and role of SLH domain GHs and demonstrate that hemicellulose degradation can be enhanced through non-native SLH domain GHs engineered into the genomes of Caldicellulosiruptorspecies.

A Novel Selectable Islet 1 Positive Progenitor Cell Reprogrammed to Expandable and Functional Smooth Muscle Cells.

Disorders affecting smooth muscle structure/function may require technologies that can generate large scale, differentiated and contractile smooth muscle cells (SMC) suitable for cell therapy. To date no clonal precursor population that provides large numbers of differentiated SMC in culture has been identified in a rodent. Identification of such cells may also enhance insight into progenitor cell fate decisions and the relationship between smooth muscle precursors and disease states that implicate differentiated SMC. In this study, we used classic clonal expansion techniques to identify novel self-renewing Islet 1 (Isl-1) positive primitive progenitor cells (PPC) within rat bone marrow that exhibited canonical stem cell markers and preferential differentiation towards a smooth muscle-like fate. We subsequently used molecular tagging to select Isl-1 positive clonal populations from expanded and de novo marrow cell populations. We refer to these previously undescribed cells as the PPC given its stem cell marker profile, and robust self-renewal capacity. PPC could be directly converted into induced smooth muscle cells (iSMC) using single transcription factor (Kruppel-like factor 4) knockdown or transactivator (myocardin) overexpression in contrast to three control cells (HEK 293, endothelial cells and mesenchymal stem cells) where such induction was not possible. iSMC exhibited immuno- and cytoskeletal-phenotype, calcium signaling profile and contractile responses similar to bona fide SMC. Passaged iSMC could be expanded to a scale sufficient for large scale tissue replacement. PPC and reprogramed iSMC so derived may offer future opportunities to investigate molecular, structure/function and cell-based replacement therapy approaches to diverse cardiovascular, respiratory, gastrointestinal, and genitourinary diseases that have as their basis smooth muscle cell functional aberrancy or numerical loss. Stem Cells 2016;34:1354-1368.

Tapered vs Cylindrical Stem Fixation in a Model of Femoral Bone Deficiency in Revision Total Hip Arthroplasty.

BACKGROUND: Distal fixation achieved with a tapered stem design has demonstrated favorable clinical results in revision total hip arthroplasty in the setting of severe bone defects. However, stem subsidence is common with this stem design. PURPOSE: The purpose of this study is to compare the initial fixation stability of a tapered stem design to a fully porous-coated cylindrical stem design in a model of severe femoral bone deficiency. METHODS: Tapered and cylindrical stems (n = 8) were implanted into a model femur with progressively shorter segments for fixation (9, 6, or 3 cm). The stems were axially loaded, and the force to produce subsidence was recorded. RESULTS: Average loads to produce 150 µm of displacement with a 3-cm segment were higher for the tapered stem (393 N vs 221 N, P < .01). No difference was observed in the 6- or 9-cm models. Average loads to produce failure (>4-mm subsidence) were also higher for tapered stems with a 3-cm segment (1574 N vs 500 N, P < .0001). A regression analysis determined the minimum segment length of 1.5-2.5 cm to obtain stable fixation with a tapered stem design (R(2) = 0.78, P < .001). CONCLUSIONS: Tapered stems required higher loads to produce subsidence than cylindrical stems in a revision THA model. Revision tapered stems require a minimum intact segment of 1.5-2.5 cm to obtain adequate initial fixation stability. Revision tapered stems have superior initial fixation stability to cylindrical stems in the setting of severe bone loss.

Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone.

We examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome.

FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma.

On December 14, 2023, the United States Food and Drug Administration (FDA) approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 or programmed death-ligand 1 (PD-1/PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following both a PD-1/PD-L1 inhibitor and a VEGF-TKI. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS). A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [hazard ratio (HR)=0.75 (95% CI: 0.63, 0.90); 1-sided p-value=0.0008]. Kaplan-Meier curves reflected non-proportional hazards with similar median PFS estimates of 5.6 months (95% CI: 3.9, 7.0) in the belzutifan arm and 5.6 months (95% CI: 4.8, 5.8) in the everolimus arm. While not reaching full maturity, OS results appeared to show a favorable trend in the belzutifan arm compared to everolimus [HR=0.88 (95% CI: 0.73, 1.07)]. The confirmed objective response rate by BICR was 22% and 3.6% in belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower on the belzutifan arm compared to the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared to everolimus.

FDA Approval Summary: Capecitabine Labeling Update under Project Renewal.

On December 14, 2022, the U.S. Food and Drug Administration (FDA) approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase (DPD) deficiency, and edited other sections of the USPI to conform with FDA's current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA's Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal.

FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma.

On December 15, 2023, the FDA granted traditional approval to enfortumab vedotin-ejfv plus pembrolizumab (EV + Pembro) for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Substantial evidence of effectiveness was obtained from EV-302/KEYNOTE-A39 (NCT04223856), an open-label, randomized, trial evaluating EV + Pembro versus cisplatin or carboplatin plus gemcitabine (Plat + Gem) in patients with previously untreated la/mUC. A total of 886 patients were randomized (1:1) to receive EV 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles, or Plat + Gem for up to 6 cycles. Dual primary endpoints were progression-free survival (PFS) determined by blinded independent central review and overall survival (OS). Median PFS was 12.5 months (95% CI: 10.4, 16.6) in the EV + Pembro arm and 6.3 months (95% CI: 6.2, 6.5) in the Plat + Gem arm (HR 0.450 [95% CI: 0.377, 0.538]; p-value < 0.0001). Median OS was 31.5 months (95% CI: 25.4, NE) in the EV + Pembro arm and 16.1 months (95% CI: 13.9, 18.3) in the Plat + Gem arm (HR 0.468 [95% CI: 0.376, 0.582]; p-value < 0.0001). The safety profile of EV + pembrolizumab was similar to that observed in EV-103/KEYNOTE-869 in cisplatin-ineligible patients with la/mUC. This article summarizes the data and the FDA thought process supporting traditional approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by FDA.

US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

US Food and Drug Administration Approval Summary: Elacestrant for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET). PATIENTS AND METHODS: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239). RESULTS: In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia. CONCLUSION: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Impact of tunnels and tenodesis screws on clavicle fracture: a biomechanical study of varying coracoclavicular ligament reconstruction techniques.

PURPOSE: The purpose of this study was to compare the load to fracture of distal clavicles with no tunnels, one tunnel, or 2 tunnels and to evaluate the effect of inserting tenodesis screws in the tunnels on load to fracture of the distal clavicle. METHODS: Fifty right sawbone clavicles were obtained and divided into 5 groups (n = 10): group 1, normal clavicle; group 2, one tunnel, no tenodesis screw; group 3, 2 tunnels, no tenodesis screws; group 4, one tunnel with tenodesis screw; and group 5, 2 tunnels with 2 tenodesis screws. Tunnels were created using a 5-mm-diameter reamer, and 5.5 × 10 mm polyethyl ethyl ketone tenodesis screws were used. A 4-point bending load was applied to the distal clavicles. Load to failure was noted for each specimen. RESULTS: Load to failure in clavicles without tunnels was significantly higher (1,157.18 ± 147.10 N) than in all other groups (P < .0005). No statistical differences were noted between groups 2, 3, 4, and 5. Load to failure was not statistically different in clavicles with one versus 2 tunnels. In addition, the use of tenodesis screws in the tunnels did not affect the load required to fracture. CONCLUSIONS: The use of tunnels in the clavicle for coracoclavicular (CC) ligament reconstruction significantly reduces the load required to fracture the distal clavicle. The addition of tenodesis screws does not appear to significantly increase the strength of the clavicle in this construct. CLINICAL RELEVANCE: CC ligament reconstruction techniques commonly use tunnels in the distal clavicle, which may render the clavicle more susceptible to fracture. This study helps quantify the effect of these tunnels on the strength of the distal clavicle.

Interference screw versus suture button fixation for tibialis anterior tendon transfer: a biomechanical analysis.

Tibialis anterior tendon (TAT) transfer to the lateral cuneiform is commonly utilized to treat dynamic supination for relapsed clubfoot deformity. Traditional suture button fixation (SBF) may lead to skin necrosis at the button/skin interface. While interference screw fixation (ISF) would mitigate this concern, this fixation method has not been investigated in clubfoot patients. This study aims to investigate the performance of ISF versus SBF for TAT transfer in a cadaveric model. Ten matched pairs of cadaveric feet were obtained. One of each matched specimen underwent TAT transfer to the lateral cuneiform using ISF and the other underwent TAT transfer using SBF. For each ISF specimen, the tension of the transferred TAT required to bring the ankle to neutral was measured. This tension was then applied to both matched specimens using an MTS machine. Tension dissipation was measured after a 20-minute interval. In specimens with SBF, a load cell was positioned between the plantar skin and suture button to determine plantar skin pressure at the time of initial tension application. Average tension necessary to achieve neutral dorsiflexion was 49.4 N. Average tension dissipation after 20 min was significantly less in the IFS group (20 N versus 23.6 N, P = 0.02). No fixation failures occurred in either group. Average plantar foot skin pressure was 196.5 mmHg at initial tension application, exceeding thresholds for tissue ischemia. ISF allows for tendon tensioning at forces beyond those expected to result in skin necrosis with SBF with less dissipation of tension over time.

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.

On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.