Citations

Importance Observational studies have associated use of aspirin and selective cyclooxygenase inhibitors with decreased recurrence and improved survival in patients with colon cancer. While randomized clinical trials have not shown benefit across all patients, these findings suggest that select subgroups may benefit from their use. Despite the well-established prognostic value of circulating tumor DNA (ctDNA), its role in guiding treatment remains unclear. Objective To investigate the predictive value of postoperative ctDNA for survival outcomes with adjuvant celecoxib alongside conventional chemotherapy in patients with stage III colon cancer. Design, Setting, and Participants This was a post hoc analysis of the phase 3 Cancer and Leukemia Group B (now Alliance)/Southwest Oncology Group 80702 randomized clinical trial (2010-2015) assessing adjuvant celecoxib vs placebo and 3 vs 6 months of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin for stage III colon cancer. Patients consented to biospecimen collection and had ctDNA analysis performed. Data analysis was performed from September 2024 to June 2025. Exposures Postoperative ctDNA positivity was determined using a clinically validated, tumor-informed 16-plex-polymerase chain reaction-next-generation sequencing assay (Signatera; Natera Inc) performed between surgery and initiation of adjuvant therapy. Main Outcomes and Measures Disease-free survival (DFS) and overall survival (OS). Survival by ctDNA status and adjuvant celecoxib use were assessed as part of a post hoc companion study with prespecified statistical analysis plan. Results Among 940 patients (mean [SD] age, 60.9 [10.8] years; 426 female [45.3%] and 515 male [54.7%] individuals; 222 [23.6%] with prior low-dose aspirin use; and median follow-up of 6.0 [95% CI, 6.0-6.0] years), 767 (81.6%) were ctDNA negative and 173 (18.4%) were ctDNA positive. ctDNA positivity was highly prognostic of worse DFS (reference, ctDNA negativity; adjusted hazard ratio [aHR], 6.12; 95% CI, 4.66-8.03) and OS (aHR, 5.86; 95% CI, 4.19-8.19). In patients with ctDNA positivity, celecoxib was associated with improved DFS (aHR, 0.61; 95% CI, 0.42-0.89) and OS (aHR, 0.62; 95% CI, 0.40-0.96) compared to placebo. Among patients with ctDNA negativity, celecoxib did not provide survival benefit (DFS: aHR, 0.76; 95% CI, 0.53-1.09; OS: aHR, 0.85; 95% CI, 0.54-1.36), although the interaction was not significant ( P for interaction, .41 and .33 for DFS and OS, respectively). These findings persisted when stratifying patients by microsatellite instability status and PIK3CA mutational status. Conclusion and Relevance The findings of this post hoc analysis suggest that ctDNA status has the potential to inform clinical decision-making among patients with stage III colon cancer who should consider adjuvant celecoxib in addition to conventional chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT01150045

Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

Background: Discovering risk biomarkers in small benign breast disease (BBD) biopsies is constrained by scarce tissue and microanatomic heterogeneity of terminal duct lobular units (TDLUs). We tested whether tissue-sparing tissue microarray (TMA)–based Digital Spatial Profiling (DSP) can deliver reproducible, biologically coherent protein measurements across benign lobules and breast cancers (BCs), and how well DSP aligns with standard immunoassays. Methods: We performed a pilot using tissues from the Mayo Clinic BBD cohort using TMAs representing four contexts: terminal duct lobular units (TDLUs) from BBD biopsies preceding BC and matched BBD-controls, subsequent BCs, and BC-associated TDLUs. We profiled 79 proteins by DSP (37 retained after QC) and benchmarked against chromogenic IHC and OPAL immunofluorescence. Reproducibility was evaluated using intraclass correlation coefficients (ICCs), cross-platform agreement (weighted kappa), marker correlations, and mixed-effects models with false-discovery-rate (FDR) control. Results: We analyzed 368 BBD-TDLU cores (88 cases; 88 controls), 204 BC cores and 110 BC-associated TDLU cores. ICCs were highest in BC tissues, and lower in BC-associated TDLUs and BBD-TDLUs. Agreement was slight–to-fair in TDLUs but moderate (ER/PR) to substantial (BCL2) in BC. DSP recapitulated expected immunologic correlations (CD45 with T-cell, B-cell, and macrophage markers) and tissue-type gradients (BC > BC-associated TDLUs > BBD-TDLUs). Exploratory case–control differences in BBD-TDLUs did not persist after FDR control. Conclusions: TMA-based DSP is feasible in archival breast tissues and yields biologically coherent, cross-platform-benchmarked profiles that are particularly robust in BC, while conserving scarce TDLUS and clarifying current limits of single-marker risk stratification from benign lobules. These data provide a foundation for refined sampling and expanded panels in future TDLU-focused studies.

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

Background Supination-external rotation (SER) variant ankle fractures can have unstable injury patterns indicating surgical treatment. Medial clear space (MCS) on 2-dimensional radiographs is often variable, and validity of this measurement is argued. Recently, lateral talar subluxation (LTS) has been posed to be a more specific measurement than MCS likely because the pattern of injury is an external rotation pivoting displacement mechanism. However, there have been no studies using computed tomography (CT) scans to investigate the 3-dimensional talar displacement with this novel measurement. This axial rotation measurement of the talus may be a better measure than current standards, as the rotational component of these ankle fractures is underestimated. Methods This study is a retrospective review that initially identified 158 patients with unstable (SER IV) bi- or trimalleolar ankle fracture variants with injury radiographs and CT scans over a consecutive 10-year period from 2013 to 2023. Standardized measurements of radiographic MCS and LTS were acquired as well as CT scan measurements of the axial MCS, axial LTS, and a novel measurement of axial rotation angle, which is the amount of talar rotatory fracture deformity relative to the tibia. Coronal MCS and coronal LTS were also measured (Figure 1). Ultimately, 20 patients fit our inclusion criteria. The primary outcome measure investigated was the degree of external rotation of the talus in SER IV patterns. Secondary outcomes were other measurement surrogates and their correlations. Regression analysis was performed to predict the amount of rotational displacement by MCS or LTS abnormalities. Post hoc power analysis was subsequently performed. Results The mean axial rotation angle was noted to be 6.20 ± 3.79 degrees in external rotation. Axial MCS and axial LTS were 3.64 mm ± 1.10 mm and 2.20 mm ± 1.41 mm, respectively. Coronal MCS and coronal LTS were 3.15 mm ± 1.28 mm and 1.08 mm ± 1.61 mm, respectively. There were significant correlations between both MCS and LTS with respect to talar external rotation on axial CT (r = 0.85 and 0.78, respectively). Regression analysis predicted that for each 1 mm of MCS increase, there are 1.5 degrees of increased talar external rotational displacement. Similarly, for every 1 mm LTS increase, there are 2 degrees of talar external rotational displacement. Conclusion Lateral talar subluxation has previously been described as a useful measurement tool in identifying ankle instability and the potential need for surgical intervention. However, plain radiographs have limitations as the talus undergoes displacement in 3-dimensional positional planes. Using CT imaging, we found that both increased MCS and increased LTS positively correlated with increased talar external rotational as well as other displacement surrogates. There may be unrecognized rotational displacement that persists after SER ankle fracture injury, and careful consideration should be given by the surgeon for this phenomenon. Level of Evidence: Level III, retrospective cohort study

Importance Prostate-specific membrane antigen positron emission tomography (PSMA-PET), a form of molecular imaging, increases detection of advanced and metastatic prostate cancer, but its potential to increase treatment costs due to increased detection is poorly defined. Objective To estimate lifetime health and cost outcomes and evaluate the cost-effectiveness associated with implementing PSMA-PET in the clinical evaluation of a patient with a biochemical recurrence (BCR) of prostate cancer, with evaluation of sources of uncertainty in the underlying evidence and assessment of the need and focus of additional data collection. Design, Setting, and Participants This economic evaluation developed a decision-analytic model consisting of a decision tree and a Markov model informed by published literature and a study of patients with BCR prostate cancer undergoing PSMA-PET after definitive surgery or radiation therapy at 2 high-volume US academic centers. The analysis was performed between August 1, 2024, and May 1, 2025. Interventions Patients underwent (1) PSMA-PET, (2) PSMA-PET imaging as a reflex test if computed tomography plus bone scan (CTBS) was negative or equivocal (CTBS + PSMA-PET), and (3) CTBS alone. Main Outcomes and Measures Lifetime quality-adjusted life-years (QALYs) and costs, incremental cost-effectiveness ratio (ICER), and value of information estimates were assessed, with 95% uncertainty intervals (UIs). We assumed a willingness-to-pay threshold of $150 000 per QALY. Results The model simulated 1000 patients with BCR (median age, 66 years) and estimated that up-front PSMA-PET is expected to have the highest mean QALYs (7.12 QALYs [95% UI, 6.71-7.51 QALYs]) compared with 6.55 QALYs (95% UI, 6.08-7.03 QALYs) for CTBS; it was also estimated to have higher mean costs ($451 000 [95% UI, $336 000-$577 000]) compared with $351 000 (95% UI, $263 000-$455 000]) for CTBS; consequently, PSMA-PET had mean increments of $99 000 (95% UI, $55 000-153,000) in costs and 0.58 QALYs (95% UI, 0.35-0.82 QALYs) compared with CTBS, leading to an ICER of $172 000 per QALY, which exceeded the assumed $150 000/QALY willingness-to-pay threshold. In patients with lower prostate-specific antigen levels (<2 ng/mL), PSMA had mean increments of $61 000 (95% UI, $21 000-$104 000) in costs and 0.54 QALYs (95% UI, 0.34-0.77 QALYs) compared with CTBS, leading to an ICER of $113 000/QALY, suggesting it had the potential to be cost-effective. Because of high decisional uncertainty, additional information regarding outcomes and diagnostic characteristics may be associated with reduced uncertainty and a gain of 15 747 QALYs. Conclusions and Relevance This study found that PSMA-PET may be associated with improved disease detection but may not be cost-effective due to high treatment costs offsetting moderate improvements in QALYs. Further research is needed to identify patient subsets and clinical scenarios in which molecular imaging provides the greatest value.

Abstract The diagnosis of T‐cell neoplasms remains one of the most challenging areas in hematopathology due to the immunophenotypic heterogeneity and subtle aberrancies often present in these entities. This “Best Practice” manuscript provides a practical framework for laboratories to design, validate, and interpret immunophenotyping studies of immature and mature T‐cell neoplasms. We outline the utility of key antigens in the screening and classification of T‐cell lymphomas/leukemia including TRBC1 and TRBC2. Analytical strategies using the “difference from normal” method and template‐based gating are discussed, along with validation considerations aligned with CLSI H62 guidelines. By integrating these principles into laboratory workflows, this manuscript aims to standardize and improve the assessment of T‐cell neoplasms across diverse clinical settings.

Abstract Background Sickle cell disease (SCD) is a hemoglobinopathy with limited treatment options. Genetic modification of the patient's own hematopoietic stem cells (HSCs) offers an avenue to curative therapy using the patient's own cells. Many challenges exist in collecting sufficient numbers of starting material for manufacturing, beginning with the pre‐mobilization optimization of the patient to the mobilization, collection, and post‐collection phases. Study Design and Methods A working group within the Cellular Therapy Subcommittee of the American Society for Apheresis Clinical Applications Committee describes the challenges associated with apheresis collection of the starting material for gene therapy (GT) product manufacturing for patients with SCD and discusses potential strategies for overcoming these challenges. Results and Discussion Patients must undergo automated red blood cell exchange (RCE) to lower hemoglobin S in a relatively short window of time before apheresis collection of HSCs. The risks and benefits of transfusion as well as the logistics of providing adequate and appropriate blood products must be considered. Limited agents are available for mobilization of HSCs into the peripheral blood for collection and the timing of administration is short. Each collection cycle consists of RCE followed by at least three mobilization and apheresis collection events in addition to collecting backup cells. More than one cycle is typically needed to collect enough cells for GT drug product manufacturing. Optimization of patient factors and apheresis instrument parameters leads to better collection yields. Early and frequent ongoing coordination with all stakeholders involved is critical to developing personalized treatment plans for patients.