Citations

The 6th edition of the WHO Classification of Breast Tumours introduces both major and minor changes based on recent advances in our understanding of breast biology, developments in diagnostic modalities, identification of specific molecular targets and new treatment regimens necessitating modifications to pathology reporting and tumour biomarker categorisation. This review summarises the main changes that strive towards a classification of global relevance. In invasive carcinoma, predictive factors increasingly inform modern breast cancer treatment. The 6th edition provides an update on HER2 reporting categories following the DESTINY‐Breast 04 and 06 trials. Terminologies used to classify invasive tumours are clarified, with the term ‘variant’ now reserved for molecular/genetic alterations. Invasive lobular carcinoma (ILC) with extracellular mucin is recognised as a new diagnostic entity with prognostic implications. The diagnosis of mucinous carcinoma (MC) is reserved for mucin secreting carcinomas with grade 1 or 2 morphology and a favourable biomarker profile. The diagnosis of malignant phyllodes tumours requires only four of the original five adverse histological criteria. Classification of neuroendocrine tumours (NETs) is revised, recognising that the unified model, promoted in the 5th edition, is difficult to apply to the breast. New approaches to the classification of adenomyoepithelioma are discussed but the 5th edition system is broadly retained. A new section on ‘Small Diagnostic Samples’ outlines the merits of non‐operative biopsy diagnosis, the B coding system and the importance of multidisciplinary review. Changes to diagnostic practice and the emerging role of artificial intelligence, with advantages and challenges, are discussed in a new section on ‘Digital Pathology’.

Background: Stable osteochondritis dissecans (OCD) lesions are primarily treated nonoperatively. Nonoperative treatment includes several recommendations, including the use of an unloader brace. However, little is known about the clinical effectiveness of unloader bracing and its influence on OCD healing, return to sports, and patient-reported outcomes (PROs). The purpose of this investigation was to evaluate the impact of unloader bracing on patients with stable medial femoral condyle (MFC) OCD lesions treated nonoperatively. Purpose: To investigate the influence of valgus unloader bracing on the success of treating stable MFC OCD with nonoperative treatment strategies. Study Design: Cohort study; Level of evidence, 2. Methods: The authors used a prospective cohort of patients receiving nonoperative care for stable MFC knee OCD lesions. The primary variable of interest was the efficacy of bracing. The primary outcomes were transition from nonoperative care to surgical intervention, return-to-play (RTP) clearance, and PROs. Bivariate testing was used to determine if there were differences between groups. Chi-square testing was used to determine if there were differences in rates of transition to surgery by group. The timing of the transition by each group was assessed using a Wilcoxon rank-sum test, given the nonparametric nature of the data. Kaplan-Meier survival analysis was used to calculate time at risk, incidence rate, and survival times for each group. Results: A total of 185 knees (bracing group: 123 [66.5%] knees; no-bracing group: 62 [33.5%] knees) were analyzed. Overall, 142 (76.8%) knees were successfully treated nonoperatively. Transition to surgery occurred in 43 (23.2%) knees. There were no differences in transition to surgery by groups, with no differences seen by group. Of the knees that did not transition to surgical care, 65 (71.4%) in the bracing group and 38 (74.5%) in the no-bracing group received RTP clearance ( P = .693). PRO scores were similar between the 2 groups at the time of RTP clearance. Conclusion: The inclusion of an unloader brace in the nonoperative treatment for stable MFC OCD lesions did not decrease the likelihood of patients undergoing surgical intervention or improve their PRO scores at the time of RTP clearance. Registration: NCT02771496 (ClinicalTrials.gov identifier).

ABSTRACT Background Quality of life and symptom burden of patients with myelofibrosis are well recognized and compounded in those with anemia; however, the effects of transfusion burden or anemia severity on quality of life have not been comprehensively characterized. This post hoc descriptive analysis explored the association between transfusion status or hemoglobin improvement and patient‐reported outcomes (PROs). Methods The analysis used pooled populations across treatment arms from 3 clinical trials (SIMPLIFY‐1, SIMPLIFY‐2, MOMENTUM); sample sizes for each PRO measure were dependent on the trials in which they were administered. Results At both baseline and week 24, transfusion independence was associated with umerically greater mean SF ‐36v2 and EORTC QLQ ‐ C30 scores than transfusion dependence; in the subgroup that was transfusion dependent at baseline, those who achieved transfusion independence at week 24 had greater PRO improvements than those who remained reliant on transfusions. Regardless of transfusion status, patients who achieved a hemoglobin improvement ≥ 1, ≥ 1.5, or ≥ 2 g/ dL from baseline also had clinically meaningful improvements in quality of life (assessed via mean EQ ‐ 5D ‐ 5L or SF ‐36v2 scores) and symptoms (assessed via PGIC or MPN ‐ SAF / MFSAF Total Symptom Score) at week 24 compared with those who did not. Conclusions Collectively, these results provide preliminary insights into the associations of transfusion status and anemia severity with quality of life in myelofibrosis; as current PRO measures do not directly evaluate the relationship between symptoms such as fatigue and anemia, development of new measures to more comprehensively capture the patient experience for those with anemia in myelofibrosis may be warranted. Trial Registration NCT01969838, NCT02101268, NCT04173494

Importance Left atrial appendage occlusion (LAAO) is used in patients with contraindications to oral anticoagulation, who are at increased risk for major bleeding (MB). Objective To evaluate the incidence, predictors, management, and clinical outcomes of MB after LAAO in the Amulet IDE trial. Design, Setting, and Participants The randomized clinical Amulet IDE trial enrolled patients from 2016 through 2019 with 5-year follow-up. Procedures were performed at specialized LAAO centers. Of 1878 randomized patients (1:1 Amulet vs Watchman), 1833 underwent attempted LAAO implantation. These data were analyzed from May 2025 through November 2025. Main Outcomes and Measures Pooled (Amulet and Watchman) patients with vs without MB (Bleeding Academic Research Consortium [BARC] score ≥3: overt bleeding with transfusion and ≥3 g/dL hemoglobin drop) were compared. Results This study included a total of 1833 patients (57.7% male and 42.3% female; mean [SD] age, 75.8 [7.5] years). MB occurred in 331 patients (18.1%) over 5 years (annualized rate 5.9% per year). Patients with MB were older (76.8 vs 74.7 years) and had higher CHA 2 DS 2 -VASc (4.8 vs 4.6) and HAS-BLED (3.4 vs 3.2) scores, as well as greater prevalence of diabetes (38.7% vs 34.1%), prior MB (45.3% vs 28.0%), and kidney disease (9.4% vs 4.5%). MB risk was highest in the first 6 months after LAAO (20.5% per year), then decreased to 3.9% per year through 5 years. Most MB events were nonprocedural (88.8%) with gastrointestinal bleeding accounting for 252 of 438 events. Independent predictors of MB included increasing age (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06), female sex (HR, 1.25; 95% CI, 1.01-1.56), diabetes (HR, 1.26; 95% CI, 1.01-1.58), prior MB (HR, 1.93; 95% CI, 1.55-2.40), and kidney disease (HR, 2.15; 95% CI, 1.48, 3.12). At first MB event, 47.1% of patients were not receiving antithrombotic therapy and 92 patients had recurrent events. Patients with MB had significantly higher rates of the composite of stroke, systemic embolism, or cardiovascular death (32.5% vs 18.0%; P < .001), driven by higher stroke (14.7% vs 6.6%) and cardiovascular death (24.4% vs 12.9%) rates. All-cause mortality was also higher (49.2% vs 25.4%; P < .001). MB was fatal (BARC score of 5) in 25 patients (1.4%). Conclusions and Relevance In this study, MB was common in this high-risk population and largely related to underlying patient factors. Early MB risk was highest 6 months post-LAAO, then dropped considerably. Most events were gastrointestinal and occurred even in patients on minimal or no antithrombotic therapy. MB after LAAO was strongly associated with increased stroke and mortality. Trial Registration ClinicalTrials.gov Identifier: NCT02879448

The 2025 Voice AI Symposium represented a transition from conceptual research to clinical implementation in vocal biomarker science. Hosted by the NIH-funded Bridge2AI-Voice consortium, the meeting convened global experts to address the methodological, ethical, and translational challenges of integrating voice-based artificial intelligence (AI) into healthcare. This mini-review synthesizes symposium insights across six domains: multimodal integration, FAIR (Findable, Accessible, Interoperable, Reusable) and CARE (Collective Benefit, Authority to Control, Responsibility, Ethics) data governance, clinical translation, interdisciplinary training, and cross-sector innovation. Research presented demonstrated voice as a latent, multimodal biomarker reflecting neurological, cardiopulmonary, and psychological states, while discussions emphasized ethical data practices and human-centered design. The implementation-focused panels underscored the importance of workflow alignment and usability for adoption in real-world care. Collectively, the symposium reflects a field advancing toward translational readiness and ethical accountability, positioning voice AI as a scalable, inclusive tool for next-generation healthcare.

Abstract Background: Survivor plots permit adjustment by baseline demographics and clinical characteristics; log-normal survival analysis may be more robust than a Cox model under departures from model assumptions. We depicted distant disease-free survival (DDFS) for statistically standardized quantitated ER, PgR, and HER2. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER, PgR, and HER2 HSCORE were centrally assessed by machine image quantitation, and statistically standardized to mean of 0, standard deviation (SD) of 1 following Box-Cox variance stabilization transformations of square for ER, natural logarithm (ln) and square root for PgR, and ln for HER2. For the ln transformation, 0.1 was added to 0 HSCOREs for a stable transformation. The primary endpoint was DDFS at the longest trial follow-up of 4.1 years. For log-normal survival analysis, ln(time) is a linear function of covariates and had a normal distribution; the Cox models were log-linear for covariates. Survival was depicted with log-normal and Cox survivor plots adjusted at the means of age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics. We examined ER and PgR ASCO/CAP cut-points at (0; >0), HER2 cut-points at (IHC 0, 0 stain; IHC 0, (0,10%] stain; IHC 1+; IHC 2+; IHC 3+), and ER/PgR/HER2 standardized cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1). P was based on the likelihood ratio criterion (∼Χ2 (1)) for the addition of ER/PgR/HER2 to the model of baseline covariates, and had nominal significance if P<0.05. Log-normal and Cox multivariable regressions with unstandardized and standardized categorical, and continuous, ER, PgR, and HER2 were adjusted by baseline covariates; 2-sided Wald tests had nominal significance if P<0.05. Results: Of 7576 MA.27 patients, 2325 patients had quantitated image analysis assessments for ER, PgR, and HER2; 113 of 2325 (4.9%) patients experienced a DDFS event during follow-up. Multivariable log-normal survival analysis indicated DDFS was significantly longer for patients with T1 (p=0.01), N0 (p=.002), and grade 1/2 tumors (p=0.01); similar significance levels were found with a Cox model. Log-normal survivor plots were smooth, while Cox survivor plots were step-wise discontinuous at events. Adjusted log-normal survivor plots indicated similar 5-year DDFS for patients by standardized ER categories (p=0.43): 95.4% for those with ER <-1.0 (n=401); 95.8%, for (-1.0,0.0] (n=737); 96.1%, for (0.0,1.0] (n=737); and 96.4%, for >1.0 (n=450). The log-normal standardized PgR survivor plots indicated patients had significantly different 5-year DDFS (p<.001) by categories, with both ln and square root transformations of HSCORE: with a ln transformation, 93.7% for <-1.0 (n=607); 95.4%, for (-1.0,0.0] (n=390); 96.8%, for (0.0,1.0] (n=826); and 97.8%, for >1.0 (n=502). Patients had similar 5-year DDFS by standardized HER2 categories (p=0.71): 96.2% for <-1.0 (n=83); 96.0%, for (-1.0,0.0] (n=1201); 95.9%, for (0.0,1.0] (n=527); and 95.7%, for >1.0 (n=514). In full fit multivariable log-normal survival analyses, DDFS was not significantly different for ER (p=0.51-0.89) and HER2 (p=0.12-0.98); higher PgR was associated with significantly better DDFS (p=0.01 to <.001). Adjusted Cox survival analyses had similar results. Conclusions: Survivor plots adjusted for baseline demographic and clinical characteristics provided similar indications of significance for standardized ER, PgR, and HER2 as those seen in multivariable models with both log-normal and Cox survival analyses. Higher PgR was associated with significantly better DDFS. Citation Format: J. W. Chapman, J. Bayani, S. SenGupta, J. M. S. Bartlett, T. Piper, M. A. Quintayo, S. Virk, P. E. Goss, J. N. Ingle, M. J. Ellis, G. W. Sledge, G. T. Budd, M. Rabaglio, R. H. Ansari, R. Tozer, D. P. D'Souza, H. Chalchal, S. Spadafora, V. Stearns, E. A. Perez, K. A. Gelmon, T. J. Whelan, C. Elliott, L. E. Shepherd, B. E. Chen, K. J. Taylor. Survivor plots for quantitated adjunctive statistically standardized ER, PgR, and HER2 in adjuvant postmenopausal breast cancer: Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-23.

Abstract Background: While there are abundant data on the surgical management of BC after neoadjuvant chemotherapy (NAC), there is less guidance regarding surgical management of BC after NET, particularly with respect to lymph node (LN) surgery. While pathologic complete response (pCR) is common with NAC, it is a rare event with NET. In this analysis we assess the surgeons’ approach in the context of NET. Methods: The ALTERNATE trial is a phase III study that randomized postmenopausal patients (pts) with clinical stage II/III ER+ HER2- BC to receive neoadjuvant anastrozole (A), fulvestrant (F), or both for 6 mos. before surgery. The primary objective was to determine if neoadjuvant F or A+F increases the rate of pCR or ypT1-2N0/N1mic/Ki67 <2.7% residual disease over A alone. Breast surgery was per standard of care. Sentinel lymph node biopsy (SLNB) with or without axillary lymph node dissection (ALND) was required to determine preoperative endocrine prognostic index PEPI score and residual cancer burden (RCB). Surgeons were required to indicate if the patient would be eligible for breast- conserving surgery (BCS) prior to NET. Patient accrual occurred from 2014-2018. The surgical outcomes are reported for the entire group. Results: Among the 3 treatment arms, 933 patients completed 6 cycles of NET. The clinical T stage at diagnosis was 73.6% T2, 22.6% T3and 3.8% T4. Initial tumor size was assessed by mammogram and ultrasound. Primary tumor histology was ductal in 64.8% and lobular in 25.4%.568 pts (60.9%) were clinically node negative (cN0), 36.2% cN1, 2.6% cN2 with 0.3% cN3. LNs were palpable in 25.2%. 383 had LN needle biopsy pre NET, of which 80.9% were positive. The surgeons’ initial impression of the patient’s eligibility for BCS was 74% while 0.6% were considered inoperable.75.5% of pts had post-NET imaging performed. Of those with tumor size recorded, 52.9% were T1 or not visible. Overall, 69.9% of the 933 patients had BCS. Of those 330 pts without post-NET imaging or who had post-NET imaging without a size noted, 64.8% underwent BCS. For pts undergoing BCS, 80.2% required only one surgery for margin clearance. Of the 690 pts deemed eligible for BCS pre NET, 79% had BCS. Of the 240 pts deemed ineligible for BCS pre-NET, 43.8% had BCS. Of the pre-NET cT2 tumors, 79% had BCS while only 45.5% of T3 tumors and 37.1% of T4 tumors had BCS. On surgical pathology, 474 (50.8%) pts were LN+ compared to pre-NET cN+ 39.1% and needle biopsy-proven 33.2%. For pts with pN0, 93.3% had SLNB alone. 6.7 % of pN0 had ALND alone or SLNB+ALND. For those with pN1-3 , 36.3% had SLN only; 37.3% SLN+ ALND; 26.4% ALND alone. Only 0.8% of the patients had no ALND or SLNB performed. Pts undergoing BCS were more likely to have SLNB alone for a +SLN compared to mastectomy pts (62.9% vs. 37.6%; chi-square p<0.0001). For pts with pre-NET +LN on needle biopsy, only 26.8% underwent SLNB alone, while 37.4% underwent ALND alone. Of the 204 LN-positive pts having SLNB alone, 55.9% had only 1 + LN and 27% had only 2+ LNs. For pN+ pts who underwent SLNB +ALND, 42.1% had 1-2 + LNs. Conclusion: With NET, 69.9% of pts achieved BCS, including 43.8% deemed ineligible pre-NET. Given the low rate of pCR to NET, there should not be the expectation of pCR in +LNs. Based on the procedures performed in pts with +SLNs, it appears that surgeons were applying ACOSOG Z0011 criteria for pts having BCS, but were less likely to omit ALND for +LN in pts having mastectomy. The finding of only 1-2 +LNs in many of the LN+ pts suggests that omission of ALND may be a reasonable approach post-NET. Longer follow-up is required to assess local-regional recurrence. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: A. M. Leitch, T. Dockter, V. suman, A. Weiss, G. W. Unzeitig, J. Guenther, S. Sanati, K. Vij, J. Hoog, A. Caudle, A. Tiersten, M. Mita, W. Razaq, T. J. Hieken, Y. Wang, M. Rimawi, M. J. Ellis, E. Winer, K. K. Hunt, A. H. Partridge, L. A. Carey. Surgical outcomes in the ALTERNATE trial (Alliance A011106) -a randomized phase 3 neoadjuvant endocrine therapy (NET) trial in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF1-02.

Objectives: The aim of this study was to investigate differences in utilization of diagnostic imaging between the adult and pediatric trauma teams when caring for adolescent trauma patients. Methods: This was a retrospective observational study from 2015 to 2019 comparing pediatric trauma team activations for patients ages 12 to 14 and adult trauma team activations for patients ages 15 to 17 at a single institution verified as both a level I adult and a level I pediatric trauma center. Data were collected from a prospective trauma registry and manual chart review of the electronic medical records. The primary outcome was the frequency of whole body computed tomography (WBCT) and computed tomography (CT) imaging of individual body regions. Results: We identified 191 adult and 100 pediatric trauma team cases, with similar proportions transferred from outside hospitals (40% vs. 43%). Among patients presenting directly from the scene, WBCT use was significantly higher in the adult trauma team group (64% vs. 12%; RR: 5.21; 95% CI: 2.57-10.58), as was CT of all individual body regions. For transferred patients, the adult trauma team more often performed WBCT and individual CT scans, excluding head CT. CT imaging rates before transfer did not differ between groups. No significant differences were observed in injury severity scores, altered mental status, length of stay, or missed injuries. Conclusions: Among adolescents with similar injury severity, the adult trauma team more frequently utilizes WBCT and regional CT than the pediatric team. However, CT use before transfer from outside hospitals without dedicated pediatric trauma teams was similar across age groups.

Background: Institutions that participate in PCORnet ® transform their local electronic health record (EHR) data into the PCORnet ® Common Data Model (CDM), which is then used to generate data extracts for PCORnet ® Studies. PCORnet ® Studies can also include institutions that do not participate in PCORnet, and for these organizations, the cost of instantiating a PCORnet ® CDM can be prohibitive. Fast Health care Interoperability Resources (FHIR) provides an alternative method of obtaining EHR data. Objective: To determine whether data obtained through FHIR might be a viable study solution for those sites that do not participate in PCORnet. ® This mixed-methods project had 2 objectives: (1) survey sites participating in PCORnet on the availability of FHIR (FHIR survey); (2) compare the coverage of a FHIR-based data extract using REDCap with one from the PCORnet ® CDM across 3 sites (FHIR extract). Methods: (1) FHIR survey: A series of questions were asked about the use of FHIR in a production capacity. (2) FHIR extract: REDCap FHIR and PCORnet ® CDM extracts were created based on study variables from 2 prior PCORnet ® Studies. Data were extracted for 40 patients and concordance measures were computed between the 2 sources. Results: (1) FHIR survey: Of responding organizations, 73% (n=49) reported that FHIR was deployed in a production capacity. (2) FHIR extract: Results were highly variable. Cohen kappa ranged from 0.01 to 0.76 for certain diagnoses, 0.24 to 0.84 for laboratory results, and 0.1 to 0.87 for medications. Conclusions: Despite differences in data, certain studies may be well-suited for FHIR-based extracts.