Citations

ABSTRACT Beta‐lactam antibiotics (beta‐lactams) are first‐line treatments for most major infectious syndromes in acutely ill patients, with in vitro activity against common pathogens, demonstrated efficacy in trials, and a perceived low risk of adverse effects. The current dosing approach, informed by population‐level data, tends to be simplistically reduced to a “one size fits all” dosing method which only accounts for body weight (i.e., in pediatrics) and end organ function to estimate drug clearance (e.g., estimated glomerular filtration rate); this approach results in substantial variability in observed serum concentrations in acutely ill patients, which can compromise real‐world effectiveness and safety. Beta‐lactam dose individualization, therefore, defined as a dosing regimen for one patient informed by measured concentrations from that patient, has been recommended in international clinical guidelines. Comprehensive guidance on best practices for beta‐lactam dose individualization is lacking. To address this knowledge gap and develop guidance, a multidisciplinary panel of international experts was assembled from the disciplines of infectious diseases, critical care, pharmacometrics, and laboratory medicine, representing both adults and pediatrics. The panel systematically evaluated the literature, using the GRADE approach where feasible, to address broad thematic questions pertaining to whether beta‐lactam dose individualization should be pursued, for what indications beta‐lactam dose individualization is warranted, and the most critical considerations and best practices for implementation of beta‐lactam individualization. The resultant consensus recommendations will equip healthcare professionals caring for acutely ill patients treated with beta‐lactam therapy with the evidence and tools necessary to guide optimal use of beta‐lactam dose individualization.

Background: Greater trochanteric (GT) fractures after total hip arthroplasty (THA) are typically managed nonoperatively. However, outcome data for patient counseling remain limited. We evaluated the nonoperative results, focusing on fracture union rates and the presence of persistent limp in relation with fracture location, displacement magnitude, and direction. Methods: We retrospectively reviewed 82 postoperative GT fractures not associated with trochanteric osteolysis following primary THA performed between 1984 and 2020. The mean follow-up was 9 years. Fracture location was classified relative to the contralateral lesser trochanter as tip, waist, or base. Initial displacement, migration, final displacement, and bony union were assessed radiographically. Clinical outcomes included the presence of a persistent limp and Harris Hip Score. Multivariable analyses were performed to identify factors associated with nonunion and limp. Results: Fractures were classified as tip (n = 32), waist (n = 29), or base (n = 21). The mean initial displacement was 8.9 mm, with 43% displaced >10 mm. Initial displacement was significantly lower in base fractures (4.8 mm) compared with tip (10.1 mm) or waist (10.8 mm) fractures (p < 0.05). The mean final displacement was 14.6 mm. 45% of fractures achieved complete bony union, and 38% of patients demonstrated a persistent limp. In multivariable analysis, greater final displacement (>12 mm), and tip and waist fractures were independently associated with nonunion. Posterior fracture displacement was significantly associated with persistent limp. Conclusions: Outcomes following nonoperative management of GT fractures after THA depend on fracture morphology and displacement characteristics. Tip and waist fractures and fractures with final displacement >12 mm have a higher risk of nonunion, whereas posterior and superior displacement is associated with persistent limp. Greater than 20 mm of displacement is associated with both limp and nonunion. These findings may assist surgeons in counseling patients and in identifying fracture patterns at higher risk for adverse outcomes of nonoperative management. Level of Evidence: Level III (Prognostic Study). See Instructions for Authors for a complete description of levels of evidence.

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Accurate assessment of renal function is fundamental to dosing renally eliminated drugs. For decades, serum creatinine–based estimating equations have been used to approximate glomerular filtration rate (GFR) for this purpose. While these equations perform reasonably well at the population level, they exhibit substantial individual‐level imprecision and inaccuracy. Simultaneously, recent efforts to remove race from estimating equations addressed important ethical concerns but did not resolve the core limitation of population‐based estimation for individual drug dosing. In this perspective, we argue that personalized dosing requires a shift away from demographic surrogates toward direct measurement of renal clearance and clarify when incremental therapeutic complexity is warranted. We review the limitations of endogenous biomarkers, discuss the role of cystatin C, and propose exogenously measured GFR using iohexol integrated within a Bayesian pharmacometric framework as a clinically actionable approach to individualized drug dosing. Practically, this framework can be implemented by administering a small iohexol dose, collecting sparse timed samples, estimating absolute mGFR and its uncertainty with Bayesian software, and using that posterior estimate to refine renal dose selection.

Background: The current guidelines recommend that women at elevated risk for breast cancer (BC), defined as lifetime BC risk ≥ 20%, undergo annual screening with breast magnetic resonance imaging (MRI) and mammogram. However, limited evidence exists in the literature to guide the optimal timing of the MRI relative to the mammogram. Our study evaluated women undergoing high-risk BC screenings to determine the impact of timing for supplemental MRI on BC detection. Methods: Patients who completed high-risk screening MRI at a single institution from January 2019 through June 2022 were included. Baseline characteristics and clinical outcomes were collected through retrospective chart review. MRI exams were divided into two groups based on timing of MRI: concurrent (<90 days from mammogram) and staggered (≥90 days from mammogram). Results: Of 1115 patients initially identified, 770 met inclusion criteria, with a total of 3707 screening exams performed (2073 mammograms and 1634 MRIs). The final analysis included 1355 MRI exams for 712 patients, where a prior mammogram and MRI were available. Of the MRIs included, 784 (57.9%) were concurrent and 571 (42.1%) were staggered. Additional imaging was performed for 12.5% (98/784) of concurrent MRIs and 9.6% (55/571) of staggered MRIs. Biopsy rates were 9.8% (77/784) for concurrent and 7.0% (40/571) for staggered MRIs. In this high-risk population, there were surprisingly low BC detection rates, with a BC incremental detection rate of 0.5% in both the concurrent and staggered groups (p = 1.0), with the median size of detected invasive BCs equaling 5 mm in the concurrent group and 4 mm in the staggered group (p = 0.72). Conclusions: When comparing concurrent and staggered MRI regimens, there were no significant differences in incremental cancer detection rate, tumor size, rates of additional imaging, or negative biopsies. Further investigation with prospective analysis is needed to validate these findings.

3525 Background: Tumor microenvironment (TME) features of colorectal cancer (CRC) may influence detection of circulating tumor DNA (ctDNA) and further refine prognosis. We applied a deep learning histopathologic algorithm to quantify TME features in stage III colon cancers and evaluated their association with postoperative ctDNA status among participants in a phase III FOLFOX-based adjuvant trial (NCCTG N0147). Methods: QuantCRC (Aiforia Technologies) was applied to digitized hematoxylin and eosin-stained whole-slide images of stage III colon adenocarcinomas to extract quantitative histopathologic features. Among cases where data met quality control (N=1817), associations between 15 distinct pathologist-defined features and clinical outcomes—time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS)—were evaluated, stratified by postoperative ctDNA status assessed by a tissue-free assay (Guardant Reveal). Relationships were analyzed using univariate and multivariable Cox proportional hazards models that were adjusted for clinicopathologic and molecular features ( KRAS , BRAF V600E , MMR status). Interaction testing was performed. Results: We found statistically significant quantitative differences for histopathological features by ctDNA status. Features associated with ctDNA positivity(+) included lymphovascular invasion (LVI), and increased %high grade, %tumor budding, %necrosis, and %stroma. ctDNA+ cases had lower %inflammatory stroma and fewer %signet ring cells (all p< 0.006). Multivariable analyses, irrespective of ctDNA status, identified %tumor budding, %mucin, %signet ring cells, %inflammatory tumor bed, and %inflammatory stroma as significantly associated with adverse outcomes (TTR, DFS, OS). Within ctDNA+ cases, higher %immature tumor bed was associated with adverse outcome for all 3 variables. Among ctDNA-negative cases, significantly poorer outcomes (TTR, DFS, OS) were observed for tumors with lower tumor infiltrating lymphocyte (TIL) density and reduced %necrosis. After adjustment, significant interactions with ctDNA status were observed for LVI (p< 0.006) and %signet ring cells (p< 0.035) across all outcome variables, for %necrosis with DFS, OS (p<0.040), and for TILs with TTR (p<0.015). Analysis is ongoing for ctDNA tumor fraction as well as tumor genotyping data (739 genes; Guardant360). Conclusions: QuantCRC identifies TME features associated with postoperative ctDNA status that enable risk-stratification within ctDNA groups. Among ctDNA-negative patients, reduced intratumoral TIL density and reduced tumor necrosis identify high-risk subgroups with inferior clinical outcomes, and may have clinical utility.

3052 Background: Minimal residual disease (MRD) detected using circulating tumor DNA (ctDNA) is associated with increased breast cancer (BC) relapse risk in patients (pts) with early BC after curative-intent surgery. However, the clinical utility of ctDNA-based MRD testing for post-surgical surveillance and risk stratification remains incompletely defined. We used real-world data to evaluate the performance of Guardant Reveal, a tissue-free epigenomic assay for MRD detection, and the clinical significance of a positive MRD test (+MRD) in pts with resected early BC. Methods: Data of pts with resected stage I-IIIA BC in the Guardant InfinityAI Data Library who underwent Guardant Reveal testing between February 2023 and September 2025 was analyzed. Pts with ≥1 post-surgical MRD were included if they had either no distant metastatic BC recurrence with ≥1 year of follow up after the last MRD test or a documented distant metastatic BC postoperatively; pts with a new non-breast primary malignancy were excluded. Sensitivity was assessed by site of distant metastasis and interval from MRD test to recurrence; nodal recurrences were excluded due to claims data limitations. Specificity was assessed using all tests from pts without recurrence and ≥1 year of follow up after the last post-treatment MRD test. Claims data were used to infer treatment changes following +MRD. Results: A total of 822 pts was analyzed. 114 pts with real-world clinico-genomics data were evaluable for sensitivity and 708 for specificity. One-year sensitivity for distant metastatic recurrence was 71%, and was highest for bone-only (97%, 35/36 cases) or lung (89%, 8/9 cases) recurrences and lowest for brain-only recurrences (33%, 1/4 cases). Sensitivity within 12 months of recurrence was higher in hormone receptor-positive (HR+)/HER2-negative BC (79%) and stage IIIA BC (81%) and for multiple-organ versus single-organ metastasis (83% versus 69%). Sample-level specificity was 94%. Following +MRD, 41 pts did not initiate or switch systemic therapy; 29 had distant BC recurrence, including 24 within 90 days after +MRD. Twenty pts switched therapy within 90 days of +MRD; 19 recurred, including 17 within 90 days after +MRD. Among 10 pts with post-recurrence MRD testing, only 3 had +MRD. Conclusions: In a real-world cohort of pts with resected early-stage BC, a tissue-free epigenomic ctDNA MRD assay demonstrated high specificity and clinically meaningful sensitivity for distant metastatic recurrence, particularly for bone-only and lung metastases and in pts with HR+ BC. These findings support ctDNA-based MRD testing as a noninvasive tool for postsurgical surveillance and risk stratification in early BC.

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.