Citations

Objective: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Summary Background Data: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. Methods: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. Results: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Conclusions: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Abstract Background Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term—5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)—with the option to provide additional comments. Median score ≥4 and interquartile range ≤1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.

Pelvicalyceal invasion (PCI) is a relatively novel pT3a staging parameter for renal cell carcinoma (RCC) nephrectomies. While interobserver reproducibility staging studies of sinus/vascular invasion in RCC exist, a similar evaluation for PCI has not been performed. Moreover, in our experience, there is also diagnostic variability in how pathologists interpret PCI. Herein, we explore interobserver reproducibility among genitourinary (GU) pathologists. Twenty hematoxylin and eosin-stained digitized slides from RCCs (all grossly approaching the renal pelvis) were distributed to 31 GU pathologists to classify each as PCI or not PCI based on their respective clinical practices; slides with concomitant sinus/fat/vascular invasion were excluded. Slides were then evaluated for the following 4 morphologic features: tumor abutting renal pelvis, tumor pushing/indenting into the renal pelvis, polypoid configuration of tumor into the renal pelvis, and tumor eroding through renal pelvic urothelium. Interobserver reproducibility was assessed, and the morphologic features were correlated with PCI. Relationships between pathologists’ interpretations, morphologic features, and PCI were evaluated using hierarchical clustering. Although the diagnosis of PCI was relatively uniform with a majority agreement (>67%) reached in 16/20 slides, overall interobserver reproducibility was only moderate (kappa=0.601). While all 4 morphologic features were sensitive for PCI, polypoid configuration of the tumor into the renal pelvis and the tumor eroding through the renal pelvic urothelium were most specific (90%, 100%, respectively). Although we show general consensus among genitourinary pathologists on PCI assessment, clarifying the diagnostic guidelines with specific criteria should be included in pathologic staging systems.

Abstract In comparative effectiveness research (CER), ensuring internal, construct, and external validity is crucial. Internal validity determines whether observed outcomes are causally linked to an intervention; construct validity assesses whether a study measures what it intends to; and external validity relates to generalizability in routine practice. Double-blind randomized trials optimize internal validity by minimizing bias and confounding, while construct validity is strengthened through pre-specified protocols and standardized data collection. However, controlled conditions limit external validity. Pragmatic RCTs improve generalizability but may compromise internal validity due to open-label designs. Observational CER studies—including observational studies following the target trial emulation framework—offer broader external validity and feasibility in less time and at lower cost. However, due to lack of random assignment, these studies are susceptible to measured and unmeasured confounding. Several techniques help mitigate these concerns, including a detailed pre-specified protocol, tools such as propensity score matching to balance measured confounders, falsification endpoint testing for assessing the presence of unmeasured confounders, and quasi-experimental designs (including instrumental variable analysis), which may be able to address both. Pre-specified sensitivity analyses and triangulation with complementary data sources further enhance robustness. Construct validity in observational CER depends on accurate patient profiling and validated computational phenotypes for identifying patients, exposures, and outcomes. Thoughtful study design and analytic rigor are essential for balancing these validity considerations. This brief review highlights these issues with examples from thrombosis research.

ABSTRACTBackgroundWe aim to evaluate whether increased lymph node yield at prostatectomy (RP) is associated with improved outcomes in NRG/RTOG 9601, a randomized clinical trial of men who underwent either radiation (RT) alone or RT + bicalutamide for PSA elevation following RP for pT2/T3 prostate cancer.MethodsWe reviewed available pathology reports for patients in NRG/RTOG 9601 to determine the nodal count at RP. Cox proportional hazards models were used to assess effect of lymph nodes yield, arm (RT alone or RT + bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease‐specific survival.ResultsOf 760 patients, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range: 0–33, IQR: 3–9). There were no significant differences between arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm. There was no significant association between total lymph nodes and overall or disease‐specific survival with both arms combined and when adjusting for arm. Notably, interaction analysis revealed that in seminal vesicle invasion, there was a significant association between lymph node yield and OS and DSS (HR = 0.91, 95% CI: 0.83–0.99, p = 0.034; HR = 0.87, 95% CI: 0.77–0.99, p = 0.029, respectively).ConclusionsAlthough lymph node yield in NRG/RTOG 9601 did not show association with adverse outcomes in the entire cohort or either arm alone, there was significant association between lymph node yield and adverse outcomes when seminal vesicle invasion was present. The therapeutic benefit of extensive lymph node dissection remains uncertain but could be more relevant in higher risk patients.

Abstract Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma, NOS (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin classification, 59% were germinal center B-cell–like (GCB), and 25% were activated B-cell–like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC rearrangement (47% vs 6%); dark zone signature (DZsig) expression (45% vs 7%); and more frequent mutation of ID3, MYC, CCND3, and TP53, all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, and those classified as DLBCL-like were frequently BCL2-rearranged. Among DZsig− GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.

Objective Mechanical thrombectomy (MT) is well-established for the treatment of acute ischemic stroke (AIS) from large vessel occlusion (LVO), with growing data supporting the expansion to distal and medium vessel occlusions (DMVO). Despite successful recanalization in DMVO, certain patients still experience poor long-term clinical outcomes, prompting our study to comprehensively explore pre-MT factors influencing outcome despite excellent recanalization (final modified Thrombolysis in Cerebral Infarction [mTICI] score ≥2c). Methods We retrospectively examined data from patients who consecutively underwent MT for a primary middle cerebral artery (MCA) DMVO across 37 centers in North America, Asia, and Europe. We identified baseline clinical and imaging factors associated with poor clinical outcome (defined as a modified Rankin Scale [mRS] score of 3–6) at 3 months, despite excellent recanalization using a multivariable model. Results Between September 2017 and July 2021, 623 patients achieved mTICI > 2b and they were included in our study. Among them, 198 (32%) experienced a poor clinical outcome (mRS 3–6). Predictors of poor clinical outcome included higher age (OR 1.05 [1.03–1.07], p < 0.001), higher NIHSS at admission (OR 1.12 [1.08–1.15], p < 0.001), higher baseline mRS (OR 1.77 [0.96–3.26], p = 0.067), and diabetes (OR 1.59 [1.01–2.48], p = 0.044). Higher ASPECTS was associated with a decreased risk of poor clinical outcome (OR 0.82 [0.71–0.94], p = 0.006). Conclusion Older age, diabetes, higher baseline mRS, and NIHSS were associated with poor clinical outcome in MCA DMVO despite excellent recanalization. Conversely, a higher ASPECTS decreased the probability of such an outcome.

Abstract Introduction While randomized clinical trials (RCT) confirmed superiority of Mepitel film (MF) in reducing acute radiation dermatitis (ARD) compared to standard-of-care (SoC), the incremental cost difference has limited its use. A cost-effectiveness analysis (CEA) was conducted from a Canadian healthcare payer’s perspective to guide policy decisions. Methods: A decision model was constructed to perform a CEA for MF compared to SoC (moisturisers) for prevention of grade 2 or higher ARD following adjuvant hypo-fractionated whole-breast radiotherapy (RT) based on a Canadian multicentre RCT. Direct and indirect cost data were collected from two oncology centres in Canada. Quality-of-life (QoL) utility values were derived from mapping Dermatology Life Quality Index (DLQI) scores for patients with grade 2 or higher ARD at week 6 of RT to EQ-5D. A willingness-to-pay (WTF) threshold of CAD 50,000 per quality-adjusted life years (QALY) gained was used. One-way sensitivity analysis was performed to account for uncertainty in decision model assumptions. Results: Base case analysis demonstrated that MF is cost-effective in preventing grade 2 or higher ARD as compared with SoC with an incremental cost-effectiveness ratio (ICER) of CAD 3,366 per QALY gained. When nursing costs were included, MF resulted in an ICER of CAD 2,823 per QALY gained. One-way sensitivity analysis showed that the results were most sensitive to the QoL utility value for ARD. All sensitivity variations remained well below the WTP threshold. Conclusions: MF is a cost-effective intervention for preventing high-grade ARD and should be recommended for patients with breast cancer undergoing adjuvant RT.