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Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

ABSTRACT Cutaneous manifestations of chronic lymphocytic leukemia (CLL) are heterogeneous and may result from leukemic infiltration, secondary malignancies, infectious complications, or reactive inflammatory processes. Reactive angioendotheliomatosis (RAE) is a rare vascular proliferation that has only infrequently been reported in association with hematologic malignancies. We describe a 58‐year‐old man with high‐risk relapsed/refractory CLL harboring TP53 mutation and del(17p) who developed rapidly enlarging, fungating cutaneous lesions involving the right thumb, upper arm, and additional sites despite multiple prior therapies, including fludarabine, cyclophosphamide, rituximab, ibrutinib, and venetoclax. Histopathologic evaluation demonstrated dermal vascular proliferation with endothelial marker positivity (CD31, CD34, ERG, and vimentin), consistent with RAE and without evidence of leukemic infiltration. The lesions were refractory to local supportive measures but showed marked regression following treatment with CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy using lisocabtagene maraleucel. Notably, cutaneous remission despite persistent measurable residual disease and eventual systemic relapse requiring allogeneic hematopoietic cell transplantation. This discordance suggests that regression of RAE may be mediated through immune modulation and alteration of inflammatory or angiogenic pathways rather than direct elimination of cutaneous leukemia. To our knowledge, this is among the first reports describing resolution of paraneoplastic RAE following CAR T‐cell therapy in CLL, and it highlights the broader immunomodulatory effects of cellular immunotherapy beyond direct antitumor activity. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

Background Odontogenic sinusitis (ODS) is a common cause of unilateral infectious maxillary sinusitis but is frequently underdiagnosed due to nonspecific symptoms, subtle dental findings on imaging, and limitations of traditional bacterial cultures—particularly for anaerobic organisms. Next-generation DNA sequencing (NGS) may enhance detection of odontogenic bacteria. Objective This study compared bacterial detection between standard cultures versus NGS in patients with confirmed ODS. Methods Twenty consecutive adults with confirmed ODS were enrolled. Maxillary sinus purulence was collected endoscopically and submitted for routine aerobic and anaerobic bacterial cultures and for NGS-based microbial profiling using 16S rRNA gene sequencing. Detected organisms were categorized by aerotolerance and ODS relationship, and likely nasal colonizers were excluded from analyses. Alpha diversity, beta diversity, and compositional differences between methods were analyzed statistically. Results NGS detected significantly more bacterial species per specimen than culture (mean 4.9 vs 2.7; P = .0015). Compared to cultures, NGS identified more anaerobic bacteria (4.2 vs 0.9; P = .00004) and more ODS-related species (4.4 vs 1.0; P = .0001), while detection of aerobic species was similar between methods. Cultures also often yielded nonspeciated results, whereas NGS consistently revealed polymicrobial communities dominated by oral anaerobes. Microbial composition differed significantly between detection methods. Conclusion In confirmed ODS, NGS detected significantly more anaerobic and ODS-related species than culture from the same specimens. These findings suggest that culture alone may underestimate odontogenic contributions to purulent sinusitis. Future studies should explore he utility of NGS as an adjunctive tool to facilitate diagnosis and treatment in the setting of possible ODS.

ABSTRACT Objectives Dravet syndrome (DS) is a severe, drug‐resistant developmental and epileptic encephalopathy (DEE) that requires polytherapy for adequate seizure control. The need to combine multiple antiseizure medications (ASMs), together with variability in seizure types, safety considerations, and evolving patient needs, makes treatment optimization particularly complex for clinicians. As the United States (US) has one of the largest populations of DS patients and pediatric neurologists/epileptologists worldwide, this study aimed to develop US‐focused consensus guidance to guide clinicians in managing treatment combinations in DS. Methods A modified Delphi consensus methodology was applied. 35 statements tailored to the US clinical context were developed, covering six key themes: general treatment principles; strategies to support and empower caregivers; stiripentol (STP) as an add‐on to DS‐specific and nonspecific ASMs; use of fenfluramine (FFA) in STP‐containing regimens; use of cannabidiol (CBD) in STP‐containing regimens; and patient follow‐up during treatment initiation. Statements were submitted for online voting to 52 US clinicians with expertise in DS and experience with all approved DS‐specific ASMs. Agreement was rated using a 9‐point Likert scale, with predefined criteria used to determine strong, good, or absent consensus. Results 26 experts participated in the voting process. Of the 35 statements evaluated, 23 (66%) reached strong consensus, 6 (17%) reached good consensus, and 6 (17%) did not reach consensus. Strong agreement was observed for general principles of DS management, caregiver involvement, structured follow‐up, and several practical aspects of initiating and managing STP‐ and FFA‐containing regimens. Areas without consensus primarily concerned CBD efficacy expectations, dosing strategies, and pharmacokinetic interactions in complex polytherapy regimens. Significance This US‐focused consensus provides structured guidance to support clinical decision‐making in the management of polytherapy for DS. Plain language summary Dravet syndrome is a rare and severe form of epilepsy that begins in early childhood and causes seizures that are difficult to control and often persist throughout life. Because most patients require treatment with multiple medications, managing Dravet syndrome is complex and must adapt as patients grow and their needs change. This US‐focused consensus brings together published evidence and expert clinical experience to provide practical guidance on the management of polytherapy in Dravet syndrome, supporting clinicians in optimizing patient care.

Abstract Objectives This study used both researcher and patient perspectives to identify high-priority research questions related to clinical reasoning. Methods This study integrates findings from two previously published research prioritization exercises aimed at advancing the science of diagnostic safety, focusing on questions relevant to clinical reasoning. In Study 1 (April 2019), 97 researchers submitted 177 unique research questions that could be useful “to reduce patient harm in the diagnosis process”. In Study 2 (November 2019), 41 patients/caregivers/advocates submitted 84 unique research questions on the same topic. In an in-person meeting, a subset of these participants identified 81 of these questions as high-priority (51 from Study 1; 30 from Study 2). For the current study, five investigators identified questions that focused on clinical reasoning, first independently and then by consensus. They then categorized the clinical reasoning questions into inductively identified themes. Results Twenty-nine of the 81 high-priority research questions addressed clinical reasoning and were categorized into 5 themes: understanding clinical reasoning and cognition (12 questions), decision support/technology (6 questions), team-based decision making (5 questions), how to learn from cases/scenarios (3 questions), and patient engagement (3 questions). Questions addressed a range of basic/foundational science and clinical applications, and involved individuals, teams, and/or systems. Conclusions Identification of high-priority clinical reasoning research questions can help medical educators, clinicians, researchers, and funders catalyze research and discovery of interventions to improve clinical reasoning and ultimately improve patient outcomes.

Abstract Concerns about declining gray fox (Urocyon cinereoargenteus) populations in the Midwest, United States, prompted a petition to list the prairie gray fox subspecies (Urocyon cinereoargenteus ocythous) under the US Endangered Species Act. Although previous studies identified a deep phylogenetic break between eastern and western lineages of the gray fox at the Great Plains Suture Zone, population structure within the Midwest remains poorly understood, complicating subspecies classification. To address this, we genotyped 339 individuals from the eastern lineage of the gray fox using single nucleotide polymorphisms (SNPs) generated from 2bRAD genomic sequencing to assess genetic diversity and structure. Bayesian clustering and principal component analysis supported three genetic clusters (K = 3), revealing a cryptic break within Missouri that subdivides the morphologically defined range of U. c. ocythous and a secondary break coinciding with the Mississippi River and the currently accepted subspecies boundary. However, low pairwise FST values and admixture indicate weak overall genetic differentiation with ongoing gene flow, whereas declining genetic diversity at northern latitudes is reflective of founder effects from post-glacial population expansion. Consistent with prior mitochondrial DNA (mtDNA) results, nuclear SNP data suggest that U. c. ocythous and Urocyon cinereoargenteus cinereoargenteus are unlikely to represent distinct evolutionary units. However, because 2bRAD detects primarily neutral variation, whole-genome sequencing will be needed to test for adaptive divergence that might persist despite gene flow. Our findings provide an important step toward a comprehensive understanding of population structure and refining subspecies boundaries within the eastern lineage of the gray fox.

Abstract Sepsis is a multi-system physiological syndrome defined as a dysregulated host response to infection. Despite recent advances clinicians continue to depend on clinically or physiologically defined syndromes as poor classifiers and therefore fail to accurately predict outcome or responses to treatment. Recent studies suggest that advances in screening, diagnosis, prognosis, and treatment of sepsis can be used to tailor immunomodulatory therapies. In the present narrative review, we critically analyze important academic literature published between January 2025 and June 2026 with a focus on epidemiology, screening, diagnosis, prognosis and personalized management. We believe that sepsis care will soon be defined by the convergence of rapid diagnostics, multi-omics profiling, and artificial intelligence, enabling a shift from generalized treatment approaches toward truly personalized, dynamic patient management. While the scientific and technological foundation for this transformation is emerging rapidly, clinical validation using innovative (adaptive) clinical trial design is required. Successful implementation within routine care will require multidisciplinary collaboration, robust infrastructure, clinician and patient engagement, and healthcare systems capable of integrating innovation into practice. The coming years may see a paradigm shift in sepsis management comparable to advances observed in personalized management of malignancies.

Abstract Background Molecular underpinnings and clinical characteristics of ERBB2/HER2-mutated colorectal cancers (CRCs) remain poorly understood. We aimed to comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated CRC and to compare them with those of ERBB2/HER2-amplified CRC. Patients and methods We analyzed cBioPortal data from 4348 CRC patients with available ERBB2/HER2 profiling. Clinicodemographic features, microsatellite instability (MSI), tumor mutational burden, and alterations in 94 cancer-associated genes were evaluated using chi-square/Fisher’s exact test, Kruskal–Wallis test, and hierarchical clustering. Results ERBB2/HER2 putative driver mutations were identified in 95 patients (2.2%), amplifications in 87 (2.0%), and wild-type status in 4166 (95.8%). In the overall cohort, ERBB2/HER2-mutated tumors demonstrated significant KRAS enrichment (50.5%) compared to wild-type (37.7%; P = .014) and amplified tumors (18.4%; P < .001), alongside MSI enrichment (37.2% vs 1.6%; P < .001), elevated tumor mutational burden, and right-sided predominance. ERBB2/HER2-mutated tumors also showed broad driver co-alterations largely reflecting their MSI background. In contrast, ERBB2/HER2-amplified tumors exhibited left-sided predominance, with microsatellite stable (MSS)-restricted analyses revealing selective mutual exclusivity with KRAS (Log2 OR = −1.58; q = 0.019) and TP53 co-occurrence (Log2 OR = 2.04; q = 0.019). Hierarchical clustering confirmed that mutated and amplified tumors consistently occupy separate clusters across anatomical sites. Conclusion ERBB2/HER2 mutations and amplifications represent molecularly and clinically distinct subgroups. ERBB2/HER2-mutated tumors are characterized by an MSI-enriched, hypermutated background with frequent concurrent KRAS alterations, whereas amplified tumors exhibit selective KRAS mutual exclusivity and TP53 co-occurrence. These exploratory findings support alteration-specific therapeutic strategies in CRC.