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1105 Background: Approximately 2-5% of breast cancers harbor HER2 mutations, often occurring in hormone receptor-positive (HR+) disease. There are currently no approved treatment options for patients (pts) with HER2-mutated metastatic breast cancer (HER2-mut MBC). Tucatinib (TUC) is a tyrosine kinase inhibitor highly selective for HER2 and is approved for previously treated HER2+ MBC with or without brain metastases in combination with trastuzumab (Tras) and capecitabine. Here, we report the efficacy and safety results of TUC combined with Tras in pts with previously treated HER2-mut MBC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with metastatic HER2-altered solid tumors. Pts in the HER2-mut MBC cohort must have HER2 mutations determined locally by tissue- or blood-based next-generation sequencing, not be HER2+ per local testing, been previously treated with ≥1 systemic therapy in the locally advanced, unresectable, or metastatic setting, and if HR+, have received a CDK4/6 inhibitor. Pts were treated in 21-day cycles with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Pts with HR+ disease also received fulvestrant (F; 500 mg IM once every 4 wks starting from cycle 1 day 1, and cycle 1 day 15). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is cORR per investigator assessment. Secondary endpoints include OS, DCR, DOR, PFS, and safety. Results: As of Nov 1, 2023, 31 pts were enrolled in the HER2-mut MBC cohort. The median duration of follow-up for OS was 15.0 months. Twenty-seven (87%) pts had HR+ disease and 18 (58%) had lobular histology. The pts received a median of 4 prior lines of systemic therapy in any setting. cORR was 41.9% (90% CI, 26.9-58.2) with 13 responses including 2 complete responses. Median DOR was 12.6 months (90% CI, 4.7, not estimable), DCR was 80.6% (n=25; 90% CI, 65.3-91.2), median PFS was 9.5 months (90% CI, 5.4-13.8), and median OS was 20.1 months (90% CI, 15.9 to not estimable). The most common treatment-emergent adverse events (TEAEs) reported were diarrhea (64.5%) and nausea (35.5%). The most common grade ≥3 TEAEs reported were diarrhea (13%), alanine aminotransferase increase (10%), and hypertension (10%). Two (6.5%) pts discontinued TUC due to TEAEs, but these pts continued Tras. No deaths were due to TEAEs. Additional biomarker analyses will be included in the presentation. Conclusions: The investigational combination of TUC and Tras, plus F in pts with HR+ disease, was well tolerated and had clinical activity in pts with previously treated HER2-mut MBC. The results support further evaluation of the combination of TUC and Tras as a potential treatment option for this pt population. Clinical trial information: NCT04579380 .

Abstract Objectives Precise literature recommendation and summarization are crucial for biomedical professionals. While the latest iteration of generative pretrained transformer (GPT) incorporates 2 distinct modes—real-time search and pretrained model utilization—it encounters challenges in dealing with these tasks. Specifically, the real-time search can pinpoint some relevant articles but occasionally provides fabricated papers, whereas the pretrained model excels in generating well-structured summaries but struggles to cite specific sources. In response, this study introduces RefAI, an innovative retrieval-augmented generative tool designed to synergize the strengths of large language models (LLMs) while overcoming their limitations. Materials and Methods RefAI utilized PubMed for systematic literature retrieval, employed a novel multivariable algorithm for article recommendation, and leveraged GPT-4 turbo for summarization. Ten queries under 2 prevalent topics (“cancer immunotherapy and target therapy” and “LLMs in medicine”) were chosen as use cases and 3 established counterparts (ChatGPT-4, ScholarAI, and Gemini) as our baselines. The evaluation was conducted by 10 domain experts through standard statistical analyses for performance comparison. Results The overall performance of RefAI surpassed that of the baselines across 5 evaluated dimensions—relevance and quality for literature recommendation, accuracy, comprehensiveness, and reference integration for summarization, with the majority exhibiting statistically significant improvements (P-values <.05). Discussion RefAI demonstrated substantial improvements in literature recommendation and summarization over existing tools, addressing issues like fabricated papers, metadata inaccuracies, restricted recommendations, and poor reference integration. Conclusion By augmenting LLM with external resources and a novel ranking algorithm, RefAI is uniquely capable of recommending high-quality literature and generating well-structured summaries, holding the potential to meet the critical needs of biomedical professionals in navigating and synthesizing vast amounts of scientific literature.

Abstract The fourth Society for Academic Emergency Medicine (SAEM) Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE‐4) is on the topic of the emergency department (ED) management of nonopioid use disorders and focuses on alcohol withdrawal syndrome (AWS), alcohol use disorder (AUD), and cannabinoid hyperemesis syndrome (CHS). The SAEM GRACE‐4 Writing Team, composed of emergency physicians and experts in addiction medicine and patients with lived experience, applied the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding six priority questions for adult ED patients with AWS, AUD, and CHS. The SAEM GRACE‐4 Writing Team reached the following recommendations: (1) in adult ED patients (over the age of 18) with moderate to severe AWS who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone [ low to very low certainty of evidence ]; (2) in adult ED patients (over the age of 18) with AUD who desire alcohol cessation, we suggest a prescription for one anticraving medication [ very low certainty of evidence ]; (2a) in adult ED patients (over the age of 18) with AUD, we suggest naltrexone (compared to no prescription) to prevent return to heavy drinking [ low certainty of evidence ]; (2b) in adult ED patients (over the age of 18) with AUD and contraindications to naltrexone, we suggest acamprosate (compared to no prescription) to prevent return to heavy drinking and/or to reduce heavy drinking [ low certainty of evidence ]; (2c) in adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms [ very low certainty of evidence ]; (3a) in adult ED patients (over the age of 18) presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [ very low certainty of evidence ]; and (3b) in adult ED patients (over the age of 18) presenting to the ED with CHS, we also suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [ very low certainty of evidence ].

Context.— Title 45, section 164.524 of the Code of Federal Regulations states that health care systems must provide patient health records upon that patient’s request. For complex testing, such as next-generation sequencing (NGS), this raises questions related to what data should be released and the laboratory considerations regarding the release of this data. Objective.— To describe the laboratory implications of releasing different NGS data files and the limitations for the clinical use of different NGS data files. Design.— The College of American Pathologists workgroup, composed of laboratorians with expertise regarding NGS testing, reviewed pertinent literature, including title 45, section 164.524, and the Health and Human Services “Guidance on Individuals’ Right to Access Health Information.” Results.— From an accreditation standpoint, validation of NGS includes both the wet bench and data processing (bioinformatics) portions, and appropriately validated laboratory testing is required to ensure quality patient results. NGS testing generates intermediate data files that have not completed the fully validated process but are often kept by the laboratory. These files may be requested by patients, but most patients will not be aware of the test validation process and the limitations of data that have not gone through a fully validated process. Conclusions.— Laboratories should encourage patients to receive their health data and to help individuals understand the content, uses, and limitations of laboratory data they have requested or received. NGS data used in a nonvalidated manner should not be used for clinical purposes without confirmation by a clinically validated method.

Background: Metaphyseal cones with cemented stems can be successfully utilized in most revision total knee arthroplasties (TKAs). However, if the diaphysis has been previously violated, fixation of the cemented stem, which is important for cone ingrowth and construct survival, can be compromised. The initial results of our novel technique combining diaphyseal impaction bone-grafting with a metaphyseal cone were promising but required additional study. The purpose of the present study was to assess results of this technique in a larger cohort. Methods: A metaphyseal cone combined with diaphyseal impaction grafting and a cemented stem was utilized in 88 revision TKAs at our institution, including 35 from our prior study. The mean age at the time of revision was 67 years, and 67% of patients were male. Patients had had a mean of 4 prior knee arthroplasty procedures. The 2 most common reasons for revision were aseptic loosening (78%) and 2-stage reimplantation for periprosthetic joint infection (PJI) (19%). The mean follow-up was 4 years. Results: At the time of the latest follow-up, no cone-impaction grafting constructs required re-revision for aseptic loosening. Five-year survivorship free from any revision of the cone-impaction grafting construct and free from any reoperation was 95% and 65%, respectively. A total of 25 knees (28%) underwent reoperation, with the 2 most common indications being PJI and periprosthetic fracture. All cones were osseointegrated, and all bone graft appeared stable or incorporated. One patient had radiographic evidence of tibial component loosening despite a well-fixed cone; however, this patient was asymptomatic and had not undergone revision at 9 years. Conclusions: When presented with a sclerotic, polished diaphyseal canal with deficient cancellous bone and concomitant metaphyseal bone loss, our technique of combining diaphyseal impaction grafting with a metaphyseal cone proved extremely durable in this larger series of patients. No cone-impaction grafting constructs required re-revision for aseptic loosening. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND COVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined. METHODS This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization–equivalent anti–Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis. RESULTS SARS-CoV-2 anti–S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01). CONCLUSION In unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors’ antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use. TRIAL REGISTRATION ClinicalTrials.gov NCT04373460. FUNDING Department of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)–positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

ABSTRACT The use of ceftriaxone, a highly protein-bound drug, in the setting of hypoalbuminemia may result in suboptimal drug exposure. Patients with obesity also exhibit higher absolute drug clearance. We aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone. This retrospective review included adult inpatients with weight >100 kg or body mass index >40 kg/m 2 who received ceftriaxone 2 g intravenously every 12 hours for at least 72 hours. The primary outcome was clinical success, a composite of clinical cure and microbiologic cure. Secondary outcomes included clinical cure, microbiologic cure, length of stay, ICU length of stay, mortality, 30-day readmission, and adverse events. In all, 137 patients were included, 34 of whom had a serum albumin of ≤2.5 g/dL. In a propensity-score-weighted analysis, clinical success was significantly more common among those without hypoalbuminemia (91.2%) as compared to those with hypoalbuminemia (77.8%) ( P = 0.038). Death within 30 days (13.7% vs 0%, P < 0.001) and 30-day readmission (31.6% vs 12.0%, P = 0.008) were more common in the hypoalbuminemia group. In a univariate analysis, serum albumin and indication for ceftriaxone use were found to be predictors of clinical success. Hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 g every 12 hours.