Citations

Background: Acute myeloid leukemia (AML) with CBFB::MYH11 fusion and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are genetically defined and typically mutually exclusive entities. Case Presentation: We report a unique case of de novo AML harboring two clonal, transcriptionally active class-defining fusions: CBFB::MYH11 and GOLGA4::PDGFRB. A 61-year-old woman presented with leukocytosis with neutrophilia, eosinophilia, and monocytosis; circulating blasts; and a markedly hypercellular marrow. Cytogenetic analysis revealed inv(16)(p13.1q22) and t(3;5)(p21;q32) in all 20 metaphases, and RNA sequencing confirmed expression of both CBFB::MYH11 and GOLGA4::PDGFRB fusions. In addition, an oncogenic WT1 frameshift variant was identified. Hematopathologic findings were largely consistent with AML with CBFB::MYH11 fusion but exhibited features reminiscent of PDGFRB-rearranged MLN-TK. The patient achieved complete remission following the standard 7 + 3 induction chemotherapy regimen for AML with gemtuzumab ozogamicin. Conclusions: This case illustrates the diagnostic challenges posed by concomitant class-defining alterations in hematologic neoplasms and underscores the importance of integrated genomic assessment.

The intensive care unit (ICU) is a highly disease-focused environment where patients are often perceived primarily through their diagnoses rather than as individuals. The Get-To-Know-Me Board (GTKMB) was introduced as a humanizing tool to highlight patients’ personal attributes and foster person-centered care. Despite being found valuable in supporting humanized caring and fostering communication, completion rates at our institution remained low. Through a stakeholder-driven quality improvement initiative, we tested sequential interventions including reminders and checklists, visual magnets, and educational pamphlets to improve and increase the use of the GTKMB. These measures produced modest gains, with reminders and checklists yielding the most notable improvement. Barriers to using the GKTMB included unclear ownership, timing, and inconsistent integration into workflow. Our experience underscores both the promise and limitations of humanizing interventions in critical care. Sustainable implementation requires multidisciplinary buy-in and integration into daily routines. Whereas humanizing tools such as the GTKMB should be evaluated for their impact on meaningful patient outcomes, such outcomes are not clearly established; therefore, we embark on the necessary first step of a method of implementation.

Abstract Objective To estimate the incidence of de novo chronic rhinosinusitis and identify associated risk factors in kidney and liver transplant recipients without pre‐existing sinonasal complaints. Study design Retrospective cohort study. Setting Multisite study across Mayo Clinic Enterprise locations in Arizona, Florida, Minnesota, and Wisconsin. Methods Records of all patients who underwent kidney or liver transplantation between November 1, 2021, and November 1, 2022 were reviewed. Patients with documented sinonasal complaints prior to transplantation were excluded. Diagnoses were based on ICD‐10 codes assigned by board‐certified otolaryngologists, with follow‐up extending through November 2024. Demographic and clinical variables were collected, and multivariable logistic regression was used to identify predictors of de novo chronic rhinosinusitis. Results Among 1459 transplant recipients (mean age 55.1 years, 59.8% male), the cumulative 2‐year incidence of de novo chronic rhinosinusitis was 2.4% (24/986) in kidney and 2.3% (11/473) in liver transplant recipients ( P = .89). The overall incidence rate was 12.0 cases per 1000 person‐years, exceeding general population estimates. Transplant rejection (OR 3.2, 95% CI 2.5‐3.9, P < .001) and additional organ transplantation (OR 5.0, 95% CI 3.4‐6.5, P = .041) were independently associated with chronic rhinosinusitis development. Conclusion Kidney and liver transplant recipients experience a higher incidence of de novo chronic rhinosinusitis compared to the general population. Transplant rejection and additional organ transplantation significantly increase this risk. Early recognition and management of chronic rhinosinusitis in this population may support improved postoperative outcomes.

Abstract Rationale Neurodevelopmental disorders (NDDs) are characterised by significant challenges in communication, social interaction, and adaptive function, often impacting quality of life. Previous studies support genetic influences on the communication abilities of individuals with NDD, but were either limited to single genetic conditions or to small cohorts with a limited selection of communication measures. Methods We analysed caregiver-reported communication abilities in 79,518 individuals with NDD from the Simons Searchlight and SPARK registries: 4,439 with a CNV-based or monogenic NDD and 75,079 with autism spectrum disorder (ASD) without a known genetic cause (idiopathic ASD) as controls. For analysis, we a priori selected 10 communication-related measures based on their availability in the study cohorts, coverage of distinct communication aspects, and their frequent use in neurodevelopmental phenotyping, yielding 177,328 data points across all study cohorts. The individuals in the Searchlight registry were divided into a Discovery cohort (the 15 most prevalent genetic NDD conditions) and a Confirmation cohort (all other genetic NDD conditions). A second Confirmation cohort was generated using all individuals with genetic ASD forms from the SPARK registry. We then tested each of the three case cohorts and each genetic condition represented in the Discovery cohort against the ASD control cohort. Developmental trajectories were assessed through testing of participants grouped by age at evaluation. Results Measure-level analyses demonstrated significant associations between genetic status and communication abilities, differences in communication abilities between classes of genetic variants (monogenic vs. CNV-based NDDs), and variability between specific genetic NDD conditions. CNV-based NDDs showed milder communication impairment, outperforming idiopathic ASD controls in 9/10 communication measures, whereas monogenic NDD conditions had more pervasive impairments, especially in verbal communication. Although impaired in verbal communication, five monogenic NDD conditions showed at least suggestive strengths in nonverbal and social communication relative to idiopathic ASD controls ( CSNK2A1 , CTNNB1 , SETBP1 , MED13L , and PPP2R5D ), specifically in using gestures. Developmental trajectory analyses revealed STXBP1 as the gene group at highest risk of developmental stagnation in communication abilities. Conclusions These findings underscore the potential of precision speech-language pathology (SLP) approaches tailored to the specific verbal and nonverbal communication strengths and weaknesses of genetic groups. We also provide evidence for measurable improvements and declines in communication abilities with age at the group level, highlighting the need for developmentally informed care. By integrating genetic insights into clinical practice, precision SLP approaches may enhance communication outcomes and developmental progress and improve quality of life for individuals with genetic NDDs.

Introduction: Optimizing patient selection and time-to-intervention will be crucial to the success of future clinical trials seeking to implement therapies and improve intracerebral hemorrhage (ICH) patient outcomes. Automated and accurate ICH and perihematomal edema (PHE) volumetry carries significant potential to strengthen trials targeting ICH and PHE expansion. Aims: The Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage (QUANTUM) trial was designed with aims of (1) validating a fully automated artificial intelligence (AI) method for supratentorial, spontaneous ICH and PHE volumetry against the manual and semiautomated quantification methods and (2) establishing a model framework for the translation of AI technology through conduct of a clinical trial under the equivalence hypothesis paradigm. Methods: This trial was a prospective, randomized, clinical study with blinded outcome assessment. Six independent raters were randomized in a 1:1 ratio to ICH and PHE volumetry from non-contrast CT scans in the Virtual International Stroke Trials Archive with either the semiautomated or manual quantification method. The primary outcomes were equivalence between (1)ICH volume measurements on admission (<24h from symptom onset) for the manual versus the fully automated or the sem-automated quantification methods, and (2)PHE volume measurements on day 3 (72±12h from symptom onset) for the manual versus the fully automated or the semiautomated quantification methods. The required sample size was 126 ICH and 126 PHE measurements, based upon a significance level of 0.025 to account for the two equivalence tests. Results: The geometric mean relative discrepancies between the fully automated and the manual ICH and PHE volume measurements did not cross the pre-specified 10% equivalence margin. The geometric mean relative discrepancies between the semiautomated and the manual ICH and PHE volume measurements did cross the pre-specified 10% equivalence margin. The fully automated method (mean 10.0±2.7s/scan) was significantly faster than the manual (mean 189±199 s/scan; P <0.001) and semiautomated (mean 79±68s/scan; P <0.001) methods. Conclusions: ICH and PHE volumes quantified by AI could replace clinician measurements within a 10% error margin and with substantially greater efficiency. The semiautomated method could not replace manual measurements. This trial demonstrated feasibility of the equivalence hypothesis framework for AI validation studies.

Ameloblastomas are locally aggressive odontogenic tumors that most commonly arise in the mandible and maxilla and often harbor BRAF V600E mutations. While rare extragnathic ameloblastomas have been reported, primary pulmonary cases have not been documented. We identified 3 pulmonary neoplasms with features of ameloblastoma that were submitted for consultation between 2022 and 2025 at 3 academic institutions and performed detailed clinicopathologic and molecular analysis. The tumors presented as 5.4 to 7.3 cm peribronchial solitary lung masses. All resected tumors exhibited a predominant stellate reticulum-like component composed of loosely arranged p40-reactive bland squamoid-to-spindled cells with long intercellular bridges, and streaming and swirling architecture, surrounded by palisaded columnar cells with focal reverse nuclear polarity at the interface with myxoid stroma. All tumors were immunoreactive for BRAF V600E IHC, and BRAF V600E mutations were confirmed by molecular assays, including broad next-generation sequencing on 2 cases. Florid hyperplasia of entrapped pneumocytes initially suggested a biphasic neoplasm, but the absence of BRAF V600E IHC labeling confirmed pneumocyte entrapment. Occult gnathic primary tumors were excluded by subsequent clinical examination, including negative panoramic dental x-rays. No recurrences or metastases have been observed to date. This first series of primary pulmonary ameloblastomas highlights a distinctive tumor with histologic and molecular features identical to gnathic counterparts. We discuss the potential histogenesis of these unusual tumors.

Background A substantial proportion of patients with chronic rhinosinusitis (CRS) remain partly controlled or uncontrolled despite endoscopic sinus surgery (ESS) and maximal medical therapy. For these difficult-to-treat cases, topical antibiotic irrigations have been proposed as an adjunctive therapy, particularly when delivered via large-volume, low-pressure systems that enhance sinus penetration post-ESS. Evidence on their efficacy and prescribing patterns in this population remains limited. Objective This study aims to evaluate the use and outcomes of topical antibiotic irrigations in patients with difficult-to-treat CRS. Methods A retrospective, multi-site cohort study was conducted across tertiary academic medical centers. Adult patients with persistent CRS symptoms despite bilateral full-house ESS and conventional postoperative medical management were included. Patients with cystic fibrosis or granulomatosis with polyangiitis were excluded. Demographic, clinical, and treatment data were collected. Primary outcomes were infection resolution at 8 weeks and changes in Sino-Nasal Outcome Test-22 (SNOT-22) scores. Results Sixty-seven patients met inclusion criteria. Mupirocin (41.8%), tobramycin (23.9%), and gentamicin (17.9%) were the most commonly prescribed agents. After 8 weeks, 62.7% of patients achieved infection clearance. Among 44 patients with SNOT-22 data, scores improved significantly from 34.8 ± 20.2 to 21.8 ± 14.7 ( P < .001). Improvement in SNOT-22 scores was more pronounced in patients who cleared the infection compared to those who did not. Conclusion Large-volume topical antibiotic irrigations were associated with high infection resolution rates and clinically meaningful SNOT-22 improvements in patients with difficult-to-treat CRS. These findings support their potential utility as an adjunctive therapy in select postsurgical patients and warrant further prospective investigation.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.