Citations

Background and Purpose Stroke is a frequent manifestation of non-bacterial thrombotic endocarditis (NBTE), yet current knowledge largely stems from case reports and small case series. This systematic review summarizes stroke presentation, imaging features, management, and outcomes in patients with NBTE-related stroke. Methods We conducted a patient-level systematic review of published case reports and case series. PubMed, MEDLINE, Embase, Web of Science, and PsycINFO were searched from inception through August 2025 for studies reporting individual patients with NBTE-related stroke. Extracted data included demographics, vascular risk factors, stroke presentation, imaging features, NBTE etiology, treatment (unfractionated heparin/low-molecular-weight heparin [UFH/LMWH], vitamin K antagonists [VKA], direct oral anticoagulants [DOACs], and/or valvular surgery), and outcomes. Multivariable regression was used to explore factors associated with recurrent stroke and mortality. Results We included 236 patients with NBTE and stroke from 218 studies (median age 56 years [IQR: 43–63], 63% female). Left hemispheric stroke syndromes predominated among clinical presentations (27%), and multi-vessel territory ischemic infarcts (>2 territories) were observed in 65%. Conventional vascular risk factors were infrequent (0%−21%), whereas deep vein thrombosis (43%) and systemic embolism (41%) frequently preceded or coincided with stroke onset. Malignancy (70%) and autoimmune disease (25%) were the main NBTE etiologies. Anticoagulation was initiated in 70%, and 21% underwent valvular surgery. Over a median follow-up of 2.0 months, stroke recurred in 43% and death occurred in 49% of patients. Malignant etiology (aOR 10.3, P < 0.001) and metastases (aOR 3.9, P < 0.001) were associated with increased mortality, while VKA use (aOR 0.08, P < 0.001) and autoimmune etiology (aOR 0.1, P < 0.001) were associated with lower mortality. Malignancy (aOR 2.8, P < 0.001) and DOAC use (aOR 5.2, P = 0.012) were associated with increased risk of recurrent stroke. Conclusion NBTE should be considered in stroke patients lacking conventional vascular risk factors, particularly those with malignancy or autoimmune disease. Malignancy and DOAC use were associated with higher recurrent stroke risk, while VKA use was associated with lower mortality; however, these anticoagulant-class findings should be considered hypothesis-generating and interpreted cautiously given the case-report evidence base, small treatment subgroups, potential confounding, and limited follow-up. What this study adds By synthesizing patient-level data from published case reports and case series, this review provides a stroke-focused characterization of NBTE, including clinical presentation, infarct topography, underlying etiologies, management strategies, recurrent cerebrovascular events, and mortality. The findings highlight multifocal infarction, malignancy-associated NBTE, and recurrent stroke despite anticoagulation as key clinical concerns, while emphasizing that observed associations with anticoagulant class should be viewed as hypothesis-generating rather than definitive treatment guidance

PURPOSE Incorporation of structured data elements within the electronic health record generates real-time data for many potential uses. However, this requires a change in documentation practices, which may increase documentation effort. The best strategies to support structured documentation interventions have not been thoroughly investigated. Herein, we report the results of extending a data capture tool across multiple disease sites and practice locations. METHODS A note-based data capture tool was developed to collect five data elements using minimum common oncology data elements language. Soft-stop close visit validation (CVV), offloading of data entry tasks to allied health staff, group education, individualized e-mails, and one-on-one assistance were used to support utilization. Baseline and follow-up surveys were collected. For each provider, we compared data capture in the 6 months before and after their CVV go-live. RESULTS Forty-five providers participated (31 physicians, 14 nurse pracationers and physician assistants [NPPAs]), resulting in 23,274 encounters pre-CVV go-live and 23,146 post-CVV go-live visits. Median percentage of all data elements captured increased from 69.5% to 82.6% across all providers. The effect of CVV was immediate and sustained. When surveyed, most respondents agreed with the value propositions of understanding practice population, outcomes, selecting trials to open, and identifying patients for trial enrollment. Most respondents (15/20, 75%) felt the soft stop was a helpful reminder. CONCLUSION Structured data can be successfully collected in provider notes with >80% data capture. Personalized assistance incorporating the structured data elements into users' preexisting templates and soft-stop CVV, along with monitoring the results of implementation and personalized follow-up, was used to support the structured data capture intervention.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Abstract In this systematic review, we aimed to assess the sensitivity of serum immunofixation (SIFE), urine immunofixation (UIFE), and serum free light chain (sFLC) in detecting plasma cell dyscrasia associated with light chain (AL) amyloidosis. We searched the literature using PubMed, Embase, and CENTRAL databases since inception through March 2024. We included studies reporting the diagnostic accuracy of immunofixation and/or sFLC in patients with AL amyloidosis. We used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of the evidence and QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) to assess the risk of bias. After deduplication, 29 237 records were screened, and 44 studies (n = 18 071) were included. For the meta-analysis, 28 studies reported sensitivity for SIFE (n = 3390), 24 studies for UIFE (n = 2830), 19 studies for SIFE and UIFE (n = 2819), 21 studies for sFLC ratio (n = 3678), 6 studies for SIFE and sFLC ratio (n = 372), 3 studies for UIFE and sFLC ratio (n = 242), and 10 studies for all 3 tests (n = 1430). Pooled sensitivities were as follows: SIFE, 0.68 (95% confidence interval [CI], 0.62-0.73); UIFE, 0.77 (95% CI, 0.72-0.81); SIFE and UIFE, 0.89 (95% CI, 0.84-0.93); and sFLC ratio, 0.82 (95% CI, 0.78-0.86). When SIFE, UIFE, and sFLC ratio were combined, the sensitivity reached 0.99 (95% CI, 0.96-1.00). The high sensitivity of combining SIFE, UIFE, and sFLC ratio supports their use as a reliable initial testing strategy to raise suspicion for AL amyloidosis and guide decisions regarding future diagnostic modalities.

Purpose To assess how comfortable patients with cancer are in responding to intimate questions on sexual orientation and gender identity (SOGI) and to examine whether question sequencing alters patient-reported comfort. Patients and Methods Patients with cancer were asked to respond to one of two surveys that were provided to patients in a randomized manner and that included seven identical SOGI questions but differed in sequence of responses (upfront vs later debated terms, e.g. “genderqueer”). Using a Likert scale (1 = very uncomfortable to 5 = very comfortable), patients rated comfort. The primary endpoint was the percentage of patients comfortable with the question, “Do you consider yourself to be… [12 response options, including genderqueer]”. Secondary endpoints included differences in comfort based on question sequence or demographics. Write-in comments were captured. Results 74% of patients (95% CI: 70%, 78%) were comfortable when reviewing the primary endpoint SOGI question. Similar comfort levels were reported for the other questions. No significant differences in comfort were observed based on question sequence or demographics. Four themes emerged from write in comments 1) emotional reactions to the questions (“uncomfortable because this question is essentially gender binary”) 2) emotional reactions toward SOGI (“bending over backwards to be politically correct”); 3) concern for privacy and relevance to cancer care (“not sure why this information is needed/necessary”); and 4) constructive remarks (“didn’t know what cisgender was - please define”). Conclusions Most patients with cancer are comfortable in answering SOGI questions. However, their comfort might be enhanced with slight question/response modifications.

Abstract As a group of diverse co-authors working in the fields of clinical radiology and oncology, we have first-hand experience of the systems that impact medical careers. Women remain underrepresented in most spaces and often face a complex set of obstacles exacerbated by additional protected characteristics such as race, disability and sexual orientation. The impact of flexible working and care giving responsibilities on career development as well as leadership opportunities further widens the gap between under- and overrepresented groups. In this commentary we describe the intersectional challenges faced by women in our specialties and the challenge of navigating these spaces to achieve career success. We explore the various forms of discrimination and its impact on representation in medicine. Potential strategies and solutions aimed at promoting a more equitable specialty are also highlighted.

PURPOSE This national study was undertaken to determine screening mammography rates among transgender and gender diverse (TGD) individuals. METHODS TGD individuals and cisgender women who qualified to receive screening mammography based on American College of Radiology guidelines were identified in the longitudinal OptumLabs Data Warehouse. The primary end point was the percentage of patients who had high rates of screening (>75% recommended screenings). Multivariable analyses were conducted in a matched population of transgender men to cisgender women to identify and adjust for factors associated with high adherence. Individuals were matched at a 1:4 ratio (transgender men: cisgender women) on age, race/ethnicity, year of enrollment in their health care plan, and duration of follow-up. RESULTS This study focused on 10,478 TGD individuals (3,778 transgender men; 1,294 transgender women; 5,406 with gender dysphoria not meeting other TGD criteria, NMOT) and 6,218,369 cisgender women. For transgender men, transgender women, individuals with gender dysphoria NMOT, and cisgender women, high mammography rates were observed in 41.1% (95% CI, 39.5 to 42.6), 7.4% (95% CI, 6.0 to 8.8), 11.9% (95% CI, 11.0 to 12.7), and 38.3% (95% CI, 38.3 to 38.4), respectively ( P < .0001). When transgender men were compared with 15,112 matched cisgender women, an age-based differential association was observed between sex and high mammography rates (interaction P = .0003); compared with cisgender women, transgender men appeared more likely to manifest high rates of screening at age 40-49 years (odds ratios [ORs], 1.38 [95% CI, 1.28 to 1.50]; P < .0001) and 50-59 years (OR, 1.57 [95% CI, 1.35 to 1.81]; P < .0001) but not in the older age groups. CONCLUSION The relatively high rates of screening mammography in cisgender women and transgender men suggest clinicians are offering mammography to individuals who are at average or high breast cancer risk, as compared with cisgender women, and not to transgender women at low risk.

Abstract Background: Fatty Acid Synthase (FASN) is a key lipogenic enzyme co-regulated with HER2 and highly expressed in ER+ and HER2+ BC. Its targeting downregulates HER2 expression. Our preclinical studies revealed that FASN inhibition can sensitize or restore sensitivity to trastuzumab, paclitaxel and ET in HER2+ BC models. Denifanstat (deni, formerly TVB-2640) is a novel FASN inhibitor that demonstrated promising clinical activity and safety in a prior phase I trial as either monotherapy or in combination with paclitaxel. The primary objective of this study was to evaluate the objective tumor response rate (ORR) of deni plus trastuzumab (H) in combination with paclitaxel (T) or ET. Methods: Two independent, phase II clinical trials were initiated to assess the efficacy and safety of deni plus H in combination with T (Cohort A) or ET (Cohort B). Key inclusion criteria included HER2+ MBC resistant to HER2-directed therapy, measurable disease, unlimited ET, ≤6 prior chemotherapy or antibody drug conjugate regimens, and confirmation of HER2+ MBC on a pre-registration biopsy. Deni was administered 100 mg/m2 orally once daily. HP or H plus ET (fulvestrant or aromatase inhibitor) was administered at standard dose and schedule. Blood was collected on Cycle 1 Day 1 (C1D1), C1D8 and C2D1 for serum FASN analysis. An additional MBC tumor biopsy was collected on C2D1 for correlative studies. A 2-stage Simon design with a safety-run in was used to test the null hypothesis that the true ORR is at most 5% against the alternative it is at least 20%. With a sample size of 32 patients (pts) per cohort, if ≥4 responses are seen, this design has a 90% chance of rejecting the true ORR is &lt;5% when the true ORR is ≥20% at a 0.10 level of significance. The decision to close both trials to enrollment early was multifactorial. Results: From August 2017 - February 2024, 33 pts with HER2+ MBC pre-registered, among which 17 were eligible and 16 were evaluable (15 pts in Cohort A and 1 pt in Cohort B). The most common reason for ineligibility was HER2-negative status on central review of the pre-registration biopsy. Median age was 57 years (range 35-80). All pts were non-Hispanic and 13 (81.3%) were White. Median prior lines of therapy was 5 (range 0 - 11). In Cohort A, there were 5 partial responses; thus, the primary endpoint was met with the ORR estimated to be 33.3% (90% CI: 14.2-57.7%). The median PFS time was 7.0 months (95 %CI: 3.7 - 11.3), and median OS was 25.7 months (95%CI: 10.2 - NE). No dose limiting toxicities were observed during the C1 safety run-in (6 pts). In Cohort A, 7 (46.7%) developed a grade 3 or 4 adverse event (AE) attributed to combination therapy. Grade ≥2 AEs regardless of attribution occurring in ≥20% of all pts included anemia, fatigue, neutropenia, palmar plantar erythrodysesthesia (PPE), and peripheral neuropathy. Treatment was discontinued due to progression (12; 80%) or AE (3; 20% - pneumonitis; neuropathy; PPE). In Cohort B, the pt maintained stable disease through 8 cycles with grade 3 ALT increase, and she remained alive 31.2 months post-registration. Median C1D1 FASN level was 32.7 ng/mL (IQR: 18.7 - 49.6 ng/mL). There was minimal association between C1D8 and C2D1 FASN levels and time to disease progression (C1D8 n=9, Spearman rank correlation coefficient (r s) = 0.040; C2D1 n=13, r s = -0.019). Analyses of changes in MBC tumor expression of FASN, phospho-AKT, and phospho-S6 are in progress. Conclusion: Deni combined with HP provided clinical antitumor activity in pts with HER2+ MBC resistant to trastuzumab. Expected paclitaxel-associated AEs were observed. Nearly half of pts experienced a grade 3 or 4 AE attributed to the combination therapy, and 20% stopped treatment due to AE. Further study of deni, H plus ET is necessary to draw safety and efficacy conclusions. Citation Format: T. C. Haddad, V. J. Suman, R. R. Roa, B. J. Ernst, R. Lupu, T. Vander Steen, M. H. Solanki, M. Keeney, D. W. Northfelt, K. S. Anderson, T. J. Hobday, S. Chumsri, J. E. Hoppenworth, J. L. Carroll, K. V. Giridhar, C. C. O’Sullivan, R. A. Leon-Ferre, M. P. Goetz. Phase II Trial of the FASN Inhibitor, Denifanstat (TVB-2640), Plus Trastuzumab in Combination with Paclitaxel or Endocrine Therapy (ET) in Patients with HER2+ Metastatic Breast Cancer (MBC) Resistant to Trastuzumab [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 PS5-01-16.