Abstract Up to half of patients with HER2+ metastatic breast cancer (MBC) develop brain metastases (BM), leading to significant morbidity and reduced survival. Yet, genomic characterization of BM remains limited. Plasma-ctDNA has low sensitivity for brain disease. CSF-ctDNA may better reflect the genomic landscape of central nervous system (CNS) tumors, potentially serving as a better biomarker. Here, we analyzed ctDNA from CSF and plasma samples collected in a phase II trial (NCT03765983) evaluating paxalisib, a brain-penetrant PI3K/mTOR inhibitor, plus trastuzumab in patients with active/progressive HER2+ BCBM. Patients with LMD were excluded. Ultra-low-pass whole-genome sequencing (ULP-WGS) and whole-exome sequencing (WES) were performed. Among 5 patients with WES (10 samples: 7 CSF, 3 plasma), genomic alterations were consistent with HER2+ MBC, including ERBB2 amplification (4/5), TP53 (3/5), PIK3CA (2/5) and PTEN (1/5) mutations. MYC and proliferation-related copy number alterations were frequent (3/5). The only patient with clinical benefit (RANO-BM SD>24 weeks) lacked PIK3CA pathway mutations. ULP-WGS was performed at baseline and cycle 2 day 1 in 8 patients with paired plasma and 5 patients with paired CSF samples. Baseline tumor fraction (TF) was consistently higher in CSF than plasma (median TF 0.56 vs 0.03). CSF TF dynamics correlated with CNS target lesion changes: 3/5 patients with declining TF had tumor shrinkage (though none met RANO-BM criteria for PR), while 2 with increasing TF had increase or were unevaluable. The patient with clinical benefit had the most pronounced TF decline (0.58 to 0.08). CSF clonal evolution (|△CCF|>0.20) was observed in two patients, including the clinical benefit patient, who exhibited the strongest dynamics. Phylogenetic analysis in one patient showed shared truncal mutations in plasma and CSF, with a CSF subclone of low clonality in plasma. These findings suggest that CSF-ctDNA may better capture tumor genomics and treatment response than plasma-ctDNA in HER2+ BCBM.

Hispanic/Latinx males and those who are non-English proficient are significantly less likely to receive germline genetic evaluation for prostate cancer. Undertesting can impact downstream outcomes, including reduced access to approved targeted therapies, barriers to precision medicine trials, and hereditary cancer assessment for patients and family members. The goal of our study was to explore the knowledge and perceptions of genetic testing among U.S. Hispanic males, with the ultimate goal to identify potentially actionable targets to increase guideline-concordant genetic evaluation. We conducted a nationwide online survey including U.S. Hispanic males aged ≥ 40 in English and Spanish using the 9-item Knowledge of Hereditary Prostate Cancer Scale and adapted questions about desire for more information from the Behavioral Beliefs about BRCA Genetic Counseling scale. Among 807 participants, the mean score for genetic knowledge was 5.8 out of 9, with gaps in understanding of incomplete penetrance of genes and maternal genetic inheritance. Medical mistrust and lower health literacy were associated with significantly lower knowledge of prostate cancer genetics. Overall, attitudes toward genetic counseling were favorable, with the majority of participants endorsing that it would help with decision-making, is concordant with cultural beliefs, and that they were interested in more information. Concerns about genetic evaluation included cost and impact for insurance. Despite generally favorable attitudes toward genetic evaluation among Hispanic males, there are important knowledge gaps, including the importance of both maternal and paternal family history, as well as logistical concerns. Addressing these gaps through culturally targeted outreach may help to promote equitable uptake of germline genetic evaluation.

This cohort study evaluates the incidence rate of lymphomas of the breast after implant-based breast reconstruction after cancer-directed mastectomy.

Abstract We report the serendipitous discovery of an absorption feature at 4.8 keV in the NuSTAR spectra of ESP 39607, a Seyfert 2 galaxy at z = 0.201, observed in 2023 May and 2024 August. The feature is detected in both observations with individual significance levels between 2σ and 3σ, computed with multiple statistical methods. The combined probability of detecting it in both observations is ≳4σ. The absorption feature is consistent with an ultrafast inflow (UFI) potentially associated with Fe xxv or Fe xxvi Kα transitions. The inferred inflow velocity is ∼0.15–0.20c, with an estimated launching radius of 22–89R g , depending on the assumed iron transition and whether radiation pressure is accounted for. Photoionization modeling associates the UFI primarily with Fe xxv Kα absorption, blended with a minor contribution from Fe xxvi Kα. Alternative explanations, including associations with the warm-hot intergalactic medium or outflows of lighter elements, are investigated but found unlikely. If confirmed, this detection represents a rare example of a UFI, providing valuable evidence into extreme and/or nonstandard accretion processes near supermassive black holes. Follow-up observations with higher-resolution X-ray spectroscopy, such as with XMM-Newton or XRISM, will be essential to confirm the nature of this feature and better constrain the physical mechanisms driving it.

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases that are prognostically stratified into lower-risk (LR-MDS) and higher-risk MDS on the basis of the International Prognostic Scoring System (eg, IPSS, revised IPSS, and molecular IPSS). Anemia is a hallmark of MDS and can lead to worsening of preexisting comorbidities, long-term RBC transfusion dependence, and profound fatigue. Although RBC transfusion support provides rapid relief of anemia-associated symptoms, it also carries a risk of iron overload and alloimmunization, and is associated with a decreased quality of life. Thus, many clinical trials and treatment strategies for LR-MDS focus on RBC transfusion independence (RBC-TI) as a primary end point. In this review, we discuss the updated treatment paradigm for anemia in LR-MDS. Novel insights in the pathogenesis of MDS and results from positive phase III clinical trials in LR-MDS have led to a growing number of therapeutic options (eg, luspatercept and imetelstat). Imetelstat was recently added as a new agent for patients who are refractory/resistant or ineligible for erythropoiesis-stimulating agent treatment on the basis of the randomized phase III IMerge trial, showing that imetelstat led to the primary end point of RBC-TI for ≥8 weeks in 40% of patients compared with 15% in patients receiving placebo. However, future clinical trials are needed to investigate the optimal sequencing of different agents and the potential of improving efficacy using combination of therapeutic strategies in LR-MDS.

T cell repertoires of different individuals occasionally converge on the same T cell receptor (TCR) sequence as a solution to target immunodominant epitopes. A complete mapping of these “public” TCR specificities may enable a global understanding of population-level immune histories. Here, we sought to determine the antigen specificities of public TCRs with unknown target identity. We developed a functional screening workflow in which we screen panels of TCRs for reactivity to individual viral genomes or to approximately 1,000 viral reference strains, and then sort out the immunogenic peptides by labeling antigen-presenting cells that are in proximity to activated T cells. Using this workflow, we identified the target specificities of T cells that are circulating in up to 14% of individuals, including a pre-COVID-19 seasonal coronavirus-reactive TCR that cross-reacts with peptides within pandemic coronaviruses; an influenza B-reactive TCR that targets a highly conserved epitope; and TCRs targeting Herpesviridae family viruses that cause long-term latent infections. Our results demonstrate an efficient strategy to reveal public T cell memories de novo, offering a window into shared immune exposures.

RAF inhibitor “paradoxical activation” (PA) is a phenomenon where RAF kinase inhibitors increase RAF kinase signaling. Through mathematical modeling and experimental data analysis, we recently demonstrated that the combination of conformational autoinhibition (CA) with the disruption of CA by RAF inhibitors plays an important role in PA. 14-3-3 proteins are known to modulate RAF CA and RAF dimerization. We here extend our mathematical model to include both roles of 14-3-3 proteins, and we derive rigorous analytical expressions of RAF signal regulation as modulated by 14-3-3 proteins. We then use the model to investigate how 14-3-3 proteins may modulate PA. We mathematically show 14-3-3 protein stabilization of the autoinhibited form of RAF should potentiate PA, while 14-3-3 protein stabilization of the active RAF dimer should reduce PA. Our analysis suggests that the net-effect will often be a potentiation of PA, and that 14-3-3 proteins may be capable of inducing PA for RAF inhibitors that normally show little to no PA. We test model-based insights experimentally with two different approaches: forced increases in 14-3-3 expression (which we find amplifies PA) and evolved resistance assays (which suggest increased 14-3-3 expression may contribute to resistance to RAF inhibitors). Overall, this work supports a role for 14-3-3 in modulating RAF-inhibitor mediated paradoxical activation.