HER2 antibody-drug conjugates are active against desmoplastic small round cell tumor.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation with very poor outcomes. Herein, we leveraged ERBB2/HER2 expression in DSRCT as a therapeutic target. EXPERIMENTAL DESIGN: ERBB2/HER2 expression was evaluated in clinical samples and patient-derived xenografts (PDX) using RNA-seq, RT-qPCR, and a newly developed HER2 IHC assay (Clone 29D8). Responses to HER2 antibody-drug conjugates (ADC) -trastuzumab deruxtecan (DS-8201, T-DXd) and trastuzumab emtansine (T-DM1)- were evaluated in DSRCT-PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays. RESULTS: ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity of RNA assays and improved IHC detectability using Clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or T-DM1 resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2-ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status. Conclusions ERBB2/HER2 is a therapeutic target for DSRCT. HER2-ADCs are novel options for managing this exceptionally aggressive sarcoma and may fulfill its urgent and historically unmet need for more effective clinical therapy.

CCN6 suppresses metaplastic breast carcinoma by antagonizing WNT/ß-catenin signaling to inhibit EZH2-driven EMT.

Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation. Inactivation of the tumor suppressor gene CCN6 (also known as WISP3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with EMT. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. Here, we showed that CCN6 interacts with the Wnt receptor FZD8 and co-receptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of ß-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a ß-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/ß-catenin/TCF signaling in Ccn6-KO mBrCa cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacological inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated ß-catenin and high EZH2 in human spindle mBrCAs compared to other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a ß-catenin/TCF-EZH2 axis and highlight inhibition of ß-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs.

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography.

Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

Half-dose direct oral anticoagulation versus warfarin for atrial fibrillation following cardiac surgery.

BACKGROUND: Optimal anticoagulation strategies have not been defined for patients with atrial fibrillation following cardiac surgery. METHODS: From a total cohort of 228 patients with pre-existing or new onset atrial fibrillation following coronary artery bypass grafting and/or valve surgery, we compared in-hospital and 30-day outcomes in 119 patients treated with low-dose aspirin and a half-dose direct oral anticoagulant (DOAC) versus 109 treated with low-dose aspirin and warfarin. RESULTS: DOAC patients were older (73.1±7.0 vs. 68.7±11.4 years, P<0.001) and had a lower incidence of preoperative atrial fibrillation (37 [31.1%] vs. 69 [63.3%], P<0.001). Otherwise, the two cohorts were well matched for baseline demographics, cardiovascular risk factors, comorbidities, prior cardiac history and STS Risk Score. In comparison to Warfarin patients, DOAC patients had a shorter length of post-surgical stay (6 [5-8] vs. 7 [5-10] days, P=0.037). The two cohorts, however, had a similar incidence of stroke, transient ischemic attack, reoperation for bleeding and postoperative blood bank product usage. Follow-up 30-day outcomes did not differ between the two groups with respect to mortality (0 [0.0%] vs. 0 [0.0%], P=1.000) and hospital readmission (16 [13.4%] vs. 14 [12.8%], P=0.893), although two DOAC patients required drainage of sanguineous pericardial effusions. CONCLUSIONS: In comparison to warfarin, half-dose DOAC anticoagulation in patients with atrial fibrillation following cardiac surgery is associated with a shorter postoperative length of stay, without a significant increase in stroke/transient ischemic attack, reoperation for bleeding or postoperative blood product transfusion. Follow-up echocardiography in anticoagulated patients is recommended to rule out significant sanguineous pericardial effusions in the early postoperative period following hospital discharge.

Illumination of understudied ciliary kinases.

Cilia are cellular signaling hubs. Given that human kinases are central regulators of signaling, it is not surprising that kinases are key players in cilia biology. In fact, many kinases modulate ciliogenesis, which is the generation of cilia, and distinct ciliary pathways. Several of these kinases are understudied with few publications dedicated to the interrogation of their function. Recent efforts to develop chemical probes for members of the cyclin-dependent kinase like (CDKL), never in mitosis gene A (NIMA) related kinase (NEK), and tau tubulin kinase (TTBK) families either have delivered or are working toward delivery of high-quality chemical tools to characterize the roles that specific kinases play in ciliary processes. A better understanding of ciliary kinases may shed light on whether modulation of these targets will slow or halt disease onset or progression. For example, both understudied human kinases and some that are more well-studied play important ciliary roles in neurons and have been implicated in neurodevelopmental, neurodegenerative, and other neurological diseases. Similarly, subsets of human ciliary kinases are associated with cancer and oncological pathways. Finally, a group of genetic disorders characterized by defects in cilia called ciliopathies have associated gene mutations that impact kinase activity and function. This review highlights both progress related to the understanding of ciliary kinases as well as in chemical inhibitor development for a subset of these kinases. We emphasize known roles of ciliary kinases in diseases of the brain and malignancies and focus on a subset of poorly characterized kinases that regulate ciliary biology.

Variable Phenotype of Congenital Corneal Opacities in Biallelic CYP1B1 Pathogenic Variants.

PURPOSE: The aim of this study is to describe the variable phenotype of congenital corneal opacities occurring in patients with biallelic CYP1B1 pathogenic variants. METHODS: A retrospective chart review was conducted to identify patients with congenital corneal opacities and CYP1B1 pathogenic variants seen at UPMC Children's Hospital of Pittsburgh. Ophthalmic examination, high-frequency ultrasound, anterior segment optical coherence tomography, histopathologic images, and details of genetic testing were reviewed. RESULTS: Three children were identified. All presented with raised intraocular pressure. Two patients showed bilateral limbus-to-limbus avascular corneal opacification that did not resolve with intraocular pressure control; 1 showed unilateral avascular corneal opacity with a crescent of clear cornea, iridocorneal adhesions, iridolenticular adhesions, and classical features of congenital glaucoma in the fellow eye (enlarged corneal diameter, Haab striae, and clearing of the corneal clouding with appropriate intraocular pressure control). The first 2 patients were visually rehabilitated with penetrating keratoplasty. Histopathology revealed distinct features: a variably keratinized epithelium; a thick but discontinuous Bowman-like layer with areas of disruption and abnormal cellularity; Descemet membrane, when observed, showed reduced endothelial cells; and no pathological changes of Haab striae were identified. Two patients had compound heterozygous pathogenic variants in CYP1B1 causing premature stop codons, whereas 1 was homozygous for a pathogenic missense variant. CONCLUSIONS: Congenital corneal opacities seen in biallelic CYP1B1 pathogenic variants have a variable phenotype. One is that commonly termed as Peters anomaly type 1 (with iridocorneal adhesions, with or without iridolenticular adhesions) and the other is a limbus-to-limbus opacity, termed CYP1B1 cytopathy. Clinicians should be aware of this phenotypic variability.

Eight-Year Outcomes of Bilateral Lateral Rectus Recessions versus Unilateral Recession-Resection in Childhood Basic-Type Intermittent Exotropia.

PURPOSE: To report 8-year outcomes from a randomized controlled trial (RCT) comparing bilateral lateral rectus muscle recession (BLRc) with unilateral recession-resection (R&R) for childhood intermittent exotropia (IXT). DESIGN: Eight-year follow-up of RCT cohort. PARTICIPANTS: Of 197 randomized participants, 123 agreed to continue follow-up after the 3-year outcome visit (baseline age, 3-< 11 years; basic-type IXT, 15-40 prism diopters [Δ] by prism and alternate cover test [PACT]; baseline stereoacuity, ≤ 400 arcsec; no prior surgery). METHODS: After the RCT primary outcome at 3 years, annual follow-up from 4 through 8 years with treatment at investigator discretion. MAIN OUTCOME MEASURES: Suboptimal surgical outcome by 8 years after randomization, defined as any of the following at any visit: exotropia of 10 Δ or more by simultaneous prism cover test (SPCT) at distance or near, constant esotropia (ET) of 6 Δ or more by SPCT at distance or near, loss of near stereoacuity by 0.6 log arcsec or more from baseline, or reoperation. Secondary outcomes included (1) reoperation by 8 years and (2) complete or near-complete resolution at 8 years, defined as exodeviation of less than 10 Δ by SPCT and PACT at distance and near and 10 Δ or more reduction from baseline by PACT at distance and near, ET of less than 6 Δ at distance and near, no decrease in stereoacuity by 0.6 log arcsec or more from baseline, and no reoperation or nonsurgical treatment for IXT. RESULTS: The Kaplan-Meier cumulative probability of suboptimal surgical outcome through 8 years was 68% (55 events among 101 at risk) for BLRc and 53% (42 events among 96 at risk) for R&R (difference, 15%; 95% confidence interval [CI], -2% to 32%; P = 0.08). Complete or near-complete resolution at 8 years occurred in 15% (7/46) for BLRc and 37% (16/43) for R&R (difference, -22%; 95% CI, -44% to -0.1%; P = 0.049). The cumulative probability of reoperation was 30% for BLRc and 11% for R&R (difference, 19%; 95% CI, 2%-36%; P = 0.049). CONCLUSIONS: Despite no significant difference for the primary outcome, the 95% CI did not exclude a moderate benefit of R&R, which together with secondary outcomes suggests that unilateral R&R followed by usual care may yield better long-term outcomes than BLRc followed by usual care for basic-type childhood IXT using these surgical doses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Glaucoma Following Cataract Surgery: Pearls for Success Manuscript from the 2022 AOC/AACO/AAO Sunday Symposium.

Glaucoma Following Cataract Surgery (GFCS) remains a menace, so parents must be counseled prior to cataract removal in children. Age less than 7 months at the time of surgery increases this risk, and IOL placement has no effect. To lower IOP in GFCS, start with drops and before you escalate to surgery, consider phospholine iodide. Then, proceed cautiously with angle surgery and shunts, mixing in cycloablative procedures where appropriate in your hands. With patient-centered models for access, follow-up & adherence to treatment, GFCS can be controlled. Partnering with our certified orthoptist colleagues, we can achieve excellent results for the "whole patient" spanning cataracts, glaucoma, strabismus, and amblyopia.

Tenosynovial giant cell tumours: experience at an Australian tertiary referral centre for musculoskeletal tumours with minimum two-year follow-up.

Aims: Tenosynovial giant cell tumour (TGCT) is a rare benign tumour of the musculoskeletal system. Surgical management is fraught with challenges due to high recurrence rates. The aim of this study was to describe surgical treatment and evaluate surgical outcomes of TGCT at an Australian tertiary referral centre for musculoskeletal tumours and to identify factors affecting recurrence rates. Methods: A prospective database of all patients with TGCT surgically managed by two orthopaedic oncology surgeons was reviewed. All cases irrespective of previous treatment were included and patients without follow-up were excluded. Pertinent tumour characteristics and surgical outcomes were collected for analysis. Results: There were 111 total cases included in the study; 71 (64%) were female, the mean age was 36 years (SD 13.6), and the knee (n = 64; 57.7%) was the most commonly affected joint. In all, 60 patients (54.1%) had diffuse-type (D-TGCT) disease, and 94 patients (84.7%) presented therapy-naïve as "primary cases" (PC). The overall recurrence rate was 46.8% for TGCT. There was a statistically significant difference in recurrence rates between D-TGCT and localized disease (75.0% vs 13.7%, relative risk (RR) 3.40, 95% confidence interval (CI) 2.17 to 5.34; p < 0.001), and for those who were referred in the "revision cases" (RC) group compared to the PC group (82.4% vs 48.9%, RR 1.68, 95% CI 1.24 to 2.28; p = 0.011). Age, sex, tumour volume, and mean duration of symptoms were not associated with recurrence (p > 0.05). Conclusion: Recurrence rates remain high even at a tertiary referral hospital. Highest rates are seen in D-TGCT and "revision cases". Due to the risks of recurrence, the complexity of surgery, and the need for adjuvant therapy, this paper further supports the management of TGCT in a tertiary referral multi-disciplinary orthopaedic oncology service.

Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes.

DNA methylation is a vital early step in carcinogenesis. Most findings of aberrant DNA methylation in head and neck squamous cell carcinomas (HNSCC) are array based with limited coverage and resolution, and mainly explored by human papillomavirus (HPV) status, ignoring the high heterogeneity of this disease. In this study, we performed whole-genome bisulfite sequencing on a well-studied HNSCC cohort (n = 36) and investigated the methylation changes between fine-scaled HNSCC subtypes in relation to genomic instability, repetitive elements, gene expression, and key carcinogenic pathways. The previously observed hypermethylation phenotype in HPV-positive (HPV+) tumors compared with HPV-negative tumors was robustly present in the immune-strong (IMU) HPV+ subtype but absent in the highly keratinized (KRT) HPV+ subtype. Methylation levels of IMU tumors were significantly higher in repetitive elements, and methylation showed a significant correlation with genomic stability, consistent with the IMU subtype having more genomic stability and better prognosis. Expression quantitative trait methylation (cis-eQTM) analysis revealed extensive functionally-relevant differences, and differential methylation pathway analysis recapitulated gene expression pathway differences between subtypes. Consistent with their characteristics, KRT and HPV-negative tumors had high regulatory potential for multiple regulators of keratinocyte differentiation, which positively correlated with an expression-based keratinization score. Together, our findings revealed distinct mechanisms of carcinogenesis between subtypes in HPV+ HNSCC and uncovered previously ignored epigenomic differences and clinical implications, illustrating the importance of fine-scale subtype analysis in cancer. Significance: This study revealed that the previously observed hypermethylation of HPV(+) HNSCC is due solely to the IMU subtype, illustrating the importance of fine-scale subtype analysis in such a heterogeneous disease. Particularly, IMU has significantly higher methylation of transposable elements, which can be tested as a prognosis biomarker in future translational studies.

Changes in an Enzyme Ensemble During Catalysis Observed by High Resolution XFEL Crystallography.

Enzymes populate ensembles of structures with intrinsically different catalytic proficiencies that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL) to observe catalysis in a designed mutant (G150T) isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations and formation of the thioimidate catalytic intermediate selects for catalytically competent substates. A prior proposal for active site cysteine charge-coupled conformational changes in ICH is validated by determining structures of the enzyme over a range of pH values. A combination of large molecular dynamics simulations of the enzyme in crystallo and time-resolved electron density maps shows that ionization of the general acid Asp17 during catalysis causes additional conformational changes that propagate across the dimer interface, connecting the two active sites. These ionization-linked changes in the ICH conformational ensemble permit water to enter the active site in a location that is poised for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

Opioid-Free Analgesia Provides Pain Control Following Thumb Carpometacarpal Joint Arthroplasty.

BACKGROUND: We hypothesized that an opioid-free (OF), multimodal pain management pathway for thumb carpometacarpal (CMC) joint arthroplasty would not have inferior pain control compared with that of a standard opioid-containing (OC) pathway. METHODS: This was a single-center, randomized controlled clinical trial of patients undergoing primary thumb CMC joint arthroplasty. Patients were randomly allocated to either a completely OF analgesic pathway or a standard OC analgesic pathway. Patients in both cohorts received a preoperative brachial plexus block utilizing 30 mL of 0.5% ropivacaine that was administered via ultrasound guidance. The OF group was given a combination of cryotherapy, anti-inflammatory medications, acetaminophen, and gabapentin. The OC group was only given cryotherapy and opioid-containing medication for analgesia. Patient-reported pain was assessed with use of a 0 to 10 numeric rating scale at 24 hours, 2 weeks, and 6 weeks postoperatively. We compared the demographics, opioid-related side effects, patient satisfaction, and Veterans RAND 12-Item Health Survey (VR-12) results between these 2 groups. RESULTS: At 24 hours postoperatively, pain scores in the OF group were statistically noninferior to, and lower than, those in the OC group (median, 2 versus 4; p = 0.008). Pain scores continued to differ significantly at 2 weeks postoperatively (median, 2 versus 4; p = 0.001) before becoming more similar at 6 weeks (p > 0.05). No difference was found between groups with respect to opioid-related side effects, patient satisfaction, or VR-12 results. CONCLUSIONS: A completely opioid-free perioperative protocol is effective for the treatment of pain following thumb CMC joint arthroplasty in properly selected patients. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Conformationally Selective 2-Aminotetralin Ligands Targeting the alpha2A- and alpha2C-Adrenergic Receptors.

Many important physiological processes are mediated by alpha2A- and alpha2C-adrenergic receptors (α2Rs), a subtype of class A G protein-coupled receptors (GPCRs). However, α2R signaling is poorly understood, and there are few approved medications targeting these receptors. Drug discovery aimed at α2Rs is complicated by the high degree of binding pocket homology between α2AR and α2CR, which confounds ligand-mediated selective activation or inactivation of signaling associated with a particular subtype. Meanwhile, α2R signaling is complex and it is reported that activating α2AR is beneficial in many clinical contexts, while activating α2CR signaling may be detrimental to these positive effects. Here, we report on a novel 5-substituted-2-aminotetralin (5-SAT) chemotype that, depending on substitution, has diverse pharmacological activities at α2Rs. Certain lead 5-SAT analogues act as partial agonists at α2ARs, while functioning as inverse agonists at α2CRs, a novel pharmacological profile. Leads demonstrate high potency (e.g., EC50 < 2 nM) at the α2AR and α2CRs regarding Gαi-mediated inhibition of adenylyl cyclase and production of cyclic adenosine monophosphate (cAMP). To help understand the molecular basis of 5-SAT α2R multifaceted functional activity, α2AR and α2CR molecular models were built from the crystal structures and 1 µs molecular dynamics (MD) simulations and molecular docking experiments were performed for a lead 5-SAT with α2AR agonist and α2CR inverse agonist activity, i.e., (2S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), in comparison to the FDA-approved (for opioid withdrawal symptoms) α2AR/α2CR agonist lofexidine. Results reveal several interactions between FPT and α2AR and α2CR amino acids that may impact the functional activity. The computational data in conjunction with experimental in vitro affinity and function results provide information to understand ligand stabilization of functionally distinct GPCR conformations regarding α2AR and α2CRs.

Evaluation of Long-term Performance of the GORE SYNECOR Intraperitoneal Biomaterial in the Treatment of Inguinal Hernias.

BACKGROUND: The objective of this study was to analyze device safety and clinical outcomes of inguinal hernia repair with the GORE SYNECOR Intraperitoneal Biomaterial device, a hybrid composite mesh. METHODS: This retrospective case review analyzed device/procedure endpoints beyond 1 year in patients treated for inguinal hernia repair with the device. Three objectives were evaluated: procedural endpoint-incidence through 30 days of surgical site infection, surgical site occurrence (SSO), ileus, readmission, reoperation, and death; device endpoint-serious device incidence of mesh erosion, infection, excision/removal, exposure, migration, shrinkage, device-related bowel obstruction and fistula, and hernia recurrence through 12 months; and patient-reported outcomes of the bulge, physical symptoms, and pain. RESULTS: A total of 157 patients (mean age: 67±13 y) with 201 inguinal hernias (mean size: 5.1±5 cm 2 ) were included. Laparoscopic approach and bridging repair were performed in 99.4% of patients. All device location was preperitoneal. No procedure-related adverse events within 30 days were reported. No surgical site infection or SSO events or device-related hernia recurrence occurred through 12 months. Procedure-related serious adverse events occurred in 6 patients; 5 recurrent inguinal hernias (at 1 and 2 y) and 1 scrotal hematoma (at 6 mo). Through 24 months, no SSO events requiring procedural intervention occurred. Through 50 months, 6 (2.98%) patients had confirmed hernia recurrence and 4 (1.99%) patients had hernia reoperation. The patient-reported outcome for pain was reported by 7.9% (10/126) of patients who completed the questionnaire. CONCLUSIONS: In this study, inguinal hernia repair with the hybrid composite mesh was successful in most patients and the rate of recurrence was low, further supporting the long-term safety and device performance.

Evaluation of long-term performance of an intraperitoneal biomaterial in the treatment of ventral hernias.

BACKGROUND: One-year device safety and clinical outcomes of ventral hernia repair with the GORE® SYNECOR Intraperitoneal Biomaterial, a hybrid composite mesh was evaluated. METHODS: This retrospective, multicenter, case review analyzed device/procedure endpoints and patient-reported outcomes in patients treated for hernia repair ≥ 1 year from study enrollment. RESULTS: Included were 459 patients (with 469 ventral hernias) with a mean age of 58 ± 15 years; 77.1% met Ventral Hernia Working Group 2 (VHWG2) classification. Mean hernia size was 18.9 cm2 and 57.3% of hernias were incisional. Laparoscopic or robotic approach was utilized in 95.4% of patients. Mesh location was intraperitoneal for 75.6% and bridging repair was performed in 57.3%. Procedure-related adverse events within 30-days occurred in 5.0% of patients and included surgical site infection (SSI), surgical site occurrence (SSO), ileus, readmission, and re-operation. Procedure-related SSI or SSO events were 3.8% through 12 months. SSO events requiring procedural intervention (SSOPI) were 2.6% through 24 months. Four patients (0.9%) had confirmed hernia recurrence through the study (the mean follow-up was 32-months, range 14-53 months). Subgroup comparisons were conducted for all type recurrence; only diabetes was found to be statistically significant (p = .0506). CONCLUSION: In this analysis, ventral hernia repair with hybrid, composite mesh results in successful outcomes in most patients. This study represents a heterogeneous patient population undergoing repair using various approaches, mesh fixation, and mesh placement locations. These data appear to confirm long-term acceptable safety and device performance with a low rate of recurrence in a predominantly VHWG2 population.

Impact of Ticagrelor Versus Clopidogrel on Bleeding Outcomes of Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Increased bleeding risks have been documented in patients exposed to P2Y12 inhibitors within 5 days of coronary artery bypass surgery (CABG). This study aimed to determine the relative CABG bleeding risks of clopidogrel versus ticagrelor exposure and the proper time course of ticagrelor discontinuation prior to surgery. METHODS: Clinical outcomes were assessed in 2075 isolated CABG patients, including 375 who had received P2Y12 inhibitors within 5 days of surgery (155 clopidogrel, 213 ticagrelor, 7 prasugrel). BARC-4 CABG bleeding complications and perioperative blood product usage were assessed in propensity-matched P2Y12-inhibited and non-P2Y12-inhibited cohorts. RESULTS: P2Y12-inhibited patients (n = 375) in comparison to matched non-P2Y12-inhibited patients (n = 1138) had higher rates of re-operation for bleeding (3.8 % vs 1.3 %, p = 0.003), postoperative red blood cell transfusion ≥5 units (5.7 % vs 2.7 %, p = 0.007), and intraoperative and postoperative blood product utilization (42.3 % vs 27.1 %, p < 0.001; 41.8 % vs 32.2 %, p < 0.001, respectively). Univariate predictors of BARC-4 bleeding included clopidogrel (OR: 2.145, 95 % CI: 1.131-4.067, p = 0.019) and ticagrelor discontinued within 3 days of surgery (OR: 2.153, 95 % CI: 1.003-4.169, p = 0.049). Multivariate logistic regression demonstrated that only clopidogrel exposure was an independent BARC-4 bleeding predictor (OR: 1.850, 95 % CI: 1.007-3.398, p = 0.048). Unadjusted ticagrelor patients with drug discontinuation 4-5 days prior to CABG only demonstrated higher rates of perioperative platelet transfusion, without additional signs of excessive bleeding. CONCLUSIONS: Clopidogrel exposure within 5 days of CABG is an independent predictor of BARC-4 bleeding, whereas major ticagrelor bleeding effects are confined to drug exposure within 3 days of surgery.

Outcomes After Use of the Induced Membrane Technique for Fractures of the Upper Extremity.

PURPOSE: The purpose of this study was to review a series of cases in which the induced membrane technique was used for fractures with segmental bone loss in the upper extremity. We aimed to examine patient indications, outcomes based on union rates, and complications associated with this technique. METHODS: An institutional review board-approved database at our institution was used to identify patients based on either diagnosis or procedure codes commonly used during the induced membrane treatment. The database was queried between 2003 and 2020 and included patients with segmental bone defects from acute trauma, nonunions, and infections. Demographic data, mechanism of injury, size and extent of the bone defect, treatment indication and methods along with intraoperative and postoperative complications were retrospectively reviewed. RESULTS: We identified 23 patients who met our inclusion criteria, including 15 patients with traumatic segmental bone loss and 8 patients with chronic nonunions and/or infections. Fourteen cases involving the bones of the forearm, 8 cases involving the metacarpals and 3 cases involving the phalanges were identified. Radiographic union was ultimately demonstrated in 21/23 patients (91.3%) with a median time to union of 20 weeks (range 13-29 weeks). A total of 10 patients required unplanned reoperation, with 4 nonunions requiring repeat plating and grafting procedures, and 1 patient ultimately underwent amputation for persistent infection. CONCLUSIONS: The induced membrane technique represents an effective treatment option for acute traumatic bone loss as well as chronic fracture nonunions. The technique has potential challenges, as 10 patients (43.5%) in our series required unplanned reoperations with 4 patients (17.4%) requiring a repeat intervention for persistent nonunion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Overlapping surgery in arthroplasty - a systematic review and meta-analysis.

BACKGROUND: Planned overlapping surgery can improve efficiency, reduce costs and help manage long waiting lists; yet, this practice has been questioned due to patient safety concerns. A systematic review and meta-analysis were performed to answer the question: (1) are there any differences in the risk of postoperative adverse outcomes; and (2) are there any differences in length of stay or length of surgery, in elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) performed either as non-overlapping surgery (NOS) or overlapping surgery (OS). PATIENTS AND METHODS: A systematic search of literature in the databases of MEDLINE, PubMed, Embase and Cochrane from dates of inception was performed. All studies published in English were included. Risk of Bias in Non-randomised Studies-of Interventions (ROBINS-I) and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework were utilised. Relative risk (RR) was used for dichotomous outcomes, while mean difference (MD) was used for continuous variables, with 95% confidence intervals. Alpha was set at 0.05. RESULTS: A total of nine studies with 120,625 patients were included for analyses. There were no statistically significant differences for overall rates of postoperative complications, dislocations, fractures, infections, readmissions or revision surgery nor with length of stay or length of surgery (p>0.05). Patient characteristics between groups were similar (p>0.05). DISCUSSION: There were no differences in postoperative adverse outcomes for elective orthopaedic THA and TKA performed as NOS when compared to OS. Operating schedules for OS in elective lower limb arthroplasty appear to be safe, given appropriate patient selection processes and may be a useful method to improve hospital efficiency. Informed consent and preoperative patient education should remain paramount. LEVEL OF EVIDENCE: IV.