Citations

OBJECTIVE The American Spine Registry (ASR) is a collaborative effort between the American Academy of Orthopaedic Surgeons and the American Association of Neurological Surgeons. The goal of this study was to evaluate how representative the ASR is of the national practice with spinal procedures, as recorded in the National Inpatient Sample (NIS). METHODS The authors queried the NIS and the ASR for cervical and lumbar arthrodesis cases performed during 2017–2019. International Classification of Diseases, 10th Revision and Current Procedural Terminology codes were used to identify patients undergoing cervical and lumbar procedures. The two groups were compared for the overall proportion of cervical and lumbar procedures, age distribution, sex, surgical approach features, race, and hospital volume. Outcomes available in the ASR, such as patient-reported outcomes and reoperations, were not analyzed due to nonavailability in the NIS. The representativeness of the ASR compared to the NIS was assessed via Cohen’s d effect sizes, and absolute standardized mean differences (SMDs) of < 0.2 were considered trivial, whereas > 0.5 were considered moderately large. RESULTS A total of 24,800 arthrodesis procedures were identified in the ASR for the period between January 1, 2017, and December 31, 2019. During the same time period, 1,305,360 cases were recorded in the NIS. Cervical fusions comprised 35.9% of the ASR cohort (8911 cases) and 36.0% of the NIS cohort (469,287 cases). The two databases presented trivial differences in terms of patient age and sex for all years of interest across both cervical and lumbar arthrodeses (SMD < 0.2). Trivial differences were also noted in the distribution of open versus percutaneous procedures of the cervical and lumbar spine (SMD < 0.2). Among lumbar cases, anterior approaches were more common in the ASR than in the NIS (32.1% vs 22.3%, SMD = 0.22), but the discrepancy among cervical cases in the two databases was trivial (SMD = 0.03). Small differences were illustrated in terms of race, with SMDs < 0.5, and a more significant discrepancy was identified in the geographic distribution of participating sites (SMDs of 0.7 and 0.74 for cervical and lumbar cases, respectively). For both of these measures, SMDs in 2019 were smaller than those in 2018 and 2017. CONCLUSIONS The ASR and NIS databases presented a very high similarity in proportions of cervical and lumbar spine surgeries, as well as similar distributions of age and sex, and distribution of open versus endoscopic approach. Slight discrepancies in anterior versus posterior approach among lumbar cases and patient race, and more significant discrepancies in geographic representation were also identified, yet decreasing trends in differences suggested the improving representativeness of the ASR over the course of time and its progressive growth. These conclusions are important to underline the external validity of quality investigations and research conclusions to be drawn from analyses in which the ASR is used.

Abstract Objective Antibiotic prophylaxis is recommended before invasive dental procedures to prevent endocarditis in those at high risk, but supporting data are sparse. We therefore investigated any association between invasive dental procedures and endocarditis, and any antibiotic prophylaxis effect on endocarditis incidence. Subjects and Methods Cohort and case‐crossover studies were performed on 1,678,190 Medicaid patients with linked medical, dental, and prescription data. Results The cohort study identified increased endocarditis incidence within 30 days of invasive dental procedures in those at high risk, particularly after extractions (OR 14.17, 95% CI 5.40–52.11, p < 0.0001) or oral surgery (OR 29.98, 95% CI 9.62–119.34, p < 0.0001). Furthermore, antibiotic prophylaxis significantly reduced endocarditis incidence following invasive dental procedures (OR 0.20, 95% CI 0.06–0.53, p < 0.0001). Case‐crossover analysis confirmed the association between invasive dental procedures and endocarditis in those at high risk, particularly following extractions (OR 3.74, 95% CI 2.65–5.27, p < 0.005) and oral surgery (OR 10.66, 95% CI 5.18–21.92, p < 0.0001). The number of invasive procedures, extractions, or surgical procedures needing antibiotic prophylaxis to prevent one endocarditis case was 244, 143 and 71, respectively. Conclusions Invasive dental procedures (particularly extractions and oral surgery) were significantly associated with endocarditis in high‐risk individuals, but AP significantly reduced endocarditis incidence following these procedures, thereby supporting current guideline recommendations.

The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (1) editing cultured cells; (2) cell cloning and selection of clones with and without intended edit, presumed to be isogenic. The application of CRISPR-Cas9 system may result in off-target edits, whereas cloning will reveal culture-acquired mutations. We analyzed the extent of the former and the latter by whole genome sequencing in three experiments involving separate genomic loci and conducted by three independent laboratories. In all experiments we hardly found any off-target edits, whereas detecting hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10–20 passages. Notably, clones also differed in copy number alterations (CNAs) that were several kb to several mb in size and represented the largest source of genomic divergence among clones. We suggest that screening of clones for mutations and CNAs acquired in culture is a necessary step to allow correct interpretation of DNA editing experiments. Furthermore, since culture associated mutations are inevitable, we propose that experiments involving derivation of clonal lines should compare a mix of multiple unedited lines and a mix of multiple edited lines.

Abstract Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, counteracted the oncogenic effects of TP63 fusions in multiple preclinical models in vivo. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2. Citation Format: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla Heavican-Foral, Huiyun Liu, Geoffrey Nelson, Lu Yang, Renee Chen, Katherine Donovan, Marcus Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit Nirmal, Salvia Jain, Catharine Leahy, Kristen Jones, Kristen Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing Chan Chan, Shannan Ho Sui Ho Sui, Samuel Ng, Andrew Feldman, Steven M. Horwitz, Mathew Meyerson, Karen Adelman, Eric Fischer, Chun-Wei Chen, David Weinstock, Myles Brown. TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5755.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

144 Background: Kinase inhibitors have been ineffective in prostate cancer and have no known role in androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from non-gonadal precursor steroids and confers poor clinical outcomes in castration-resistant prostate cancer (CRPC). About half of all men with prostate cancer inherit the adrenal-permissive HSD3B1 allele. Multiple clinical studies demonstrate that adrenal-permissive HSD3B1 allele inheritance confers more rapid progression on ADT and others also suggest worse CRPC outcomes even after treatment with abiraterone or enzalutamide. However, there is no known method to clinically block 3βHSD1. Furthermore, 3βHSD1 is not known to be phosphorylated. Methods: Mass spectrometry was used to identify protein phosphorylation sites and steroid metabolites, genetic and pharmacologic methods were used to identify the kinase required for 3βHSD1 phosphorylation and mouse xenograft studies were performed with BMX inhibition. The identified mechanism was used to design and launch a multicenter phase 2 study of the BMX inhibitor abivertinib in combination with abiraterone in men with metastatic CRPC. Results: 3βHSD1 enzyme activity requires tyrosine phosphorylation at Y344 by the BMX kinase. Androgen biosynthesis is blocked by a phosphorylation-defective 3βHSD1 344F, or BMX genetic knockdown, or BMX pharmacologic inhibition. BMX inhibition using zanubrutinib suppresses CRPC growth in the C4-2 and VCaP xenograft models by blocking intratumoral androgen synthesis and tumor androgen receptor (AR) signaling. Discovery of this mechanism provides the rationale for the phase 2 Maverick trial of abivertinib, a BMX inhibitor, combined with abiraterone, in men with CRPC with adrenal-permissive HSD3B1 allele inheritance (NCT05361915). Eligibility includes 1) presence of metastatic CRPC, 2) measurable and/or non-measurable disease, and 3) confirmed positivity of adrenal-permissive HSD3B1(1245C) allele inheritance via central testing (cap heterozygosity at 50%). Patients will be enrolled in 2 arms: 1) abiraterone naïve (n=45) and 2) abiraterone progressing (n=55). All patients will receive treatment with abivertinib 200mg twice daily with abiraterone 1000mg daily and prednisone 5mg by mouth twice daily. The primary outcome is 6-month radiographic progression-free survival. On-treatment biopsies will be used to inform mechanisms of response and resistance in patients. Conclusions: BMX is required for 3βHSD1 phosphorylation, androgen biosynthesis and CRPC progression with the adrenal-permissive HSD3B1(1245C) allele. The Maverick trial will test clinical proof-of-concept of BMX inhibition in men with adrenal-permissive HSD3B1(1245C) inheritance. Clinical trial information: NCT05361915 .

ImportanceGlaucoma can develop following cataract removal in children.ObjectiveTo assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age.Design, Setting, and ParticipantsThis cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022.ExposuresUsual clinical care after lensectomy.Main Outcomes and MeasuresThe main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events.ResultsThe study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean [SD] age, 0.89 [1.97] years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean [SD] age, 5.65 [3.32] years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio [aHR], 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events.Conclusions and RelevanceIn this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.

397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

424 Background: Understanding the impact of anticancer therapies on immune system is critical to successful design and incorporation of immunotherapies. We developed a novel immune monitoring platform that measures the relative amount of circulating effector T cells and antitumor cytotoxicity of circulating immune cells. We previously showed that this assay can differentiate patients’ clinical response to anti-PD-1 therapy. Here, we applied this assay to patients with gastric or gastroesophageal junction adenocarcinoma (GGEA) who received chemoradiation or chemotherapy-based therapies. Methods: Patients underwent peripheral blood collection at baseline and during follow-up. Levels of circulating effector T cells (CX3CR1+NKG7+/CD3+CD8+) were quantified by flow cytometry using peripheral blood mononuclear cells (PBMCs). Antitumor cytotoxicity of circulating immune cells was evaluated by co-culturing CD3/CD28 activated PBMCs with calcein-AM labeled GGEA tumor cells (FLO-1). Antitumor cytotoxicity of individual patients’ PBMCs was calculated based on the amount of calcein released by dead tumor cells. Results: In a pilot study of 8 patients with mismatch repair-proficient (pMMR) GGEA, the changes in the frequency of effector T cells appeared to be associated with radiographic response to treatment based on RECIST (3 partial response [PR], 3 stable disease [SD], and 2 progressive disease [PD]). The median interval between sequential blood collections was 64 days and an increase in effector T cells was observed in patients with PD. Antitumor cytotoxicity was evaluated in 4 patients who did not receive targeted therapies or immune checkpoint inhibitors. Two of these patients (a, b) had blood collected at the time of diagnosis (treatment naïve) and after neoadjuvant therapy. One developed pulmonary metastases after chemoradiation while the other had significant tumor shrinkage after chemotherapy. The decrease in antitumor cytotoxicity of PBMCs was less in the patient with PD (-19.4%) than the one with PR (-48.5%). Two patients (c, d) had blood collected twice while receiving the same chemotherapy for metastatic disease (not treatment naïve). The decrease in antitumor cytotoxicity of PBMCs was less in the patient with SD (-0.3%) than the one with PR (-14.5%). Conclusions: We demonstrated the feasibility of using PBMCs to monitor immune response to anticancer therapies. Our data raise the possibility that the amount of circulating effector T cells and antitumor cytotoxicity of PBMCs may be associated with tumor burden in patients with pMMR solid tumors. [Table: see text]