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AbstractBackgroundWomen with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer’s disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain’s functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).Material and MethodsTwenty‐seven women with suspected CMD [Age; median (range) = 54 (29‐76)], drawn from ongoing cohorts (3R01HL146158‐04S1,3U54AG065141‐04S1), underwent a 3T MRI protocol, including submillimeter T2* 3‐dimensional echo‐planar‐imaging for assessing iron deposition with high‐resolution quantitative susceptibility mapping (QSM) and resting‐state fMRI (rs‐fMRI). Iron content was quantified by total‐generalized‐variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.ResultsMost of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure‐1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p = 0.005, adjusted‐r2 = 0.19) (Figure‐1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient = 531.09) as well as language functions and crystalized abilities (p = 0.036, coefficient = 362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = ‐254.54 /‐ 213.06) (Figure‐1C).ConclusionsOur results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.

DNA methylation is an essential epigenetic modification that plays a crucial role in regulating gene expression and maintaining genomic stability. With the advancement in sequencing technology, methylation studies have provided valuable insights into the diagnosis of rare diseases through the various identification of episignatures, epivariation, epioutliers, and allele-specific methylation. However, current methylation studies are not without limitations. This mini-review explores the current understanding of DNA methylation in rare diseases, highlighting the key mechanisms and diagnostic potential, and emphasizing the need for advanced methodologies and integrative approaches to enhance the understanding of disease progression and design more personable treatment for patients, given the nature of rare diseases.

Education-level or socioeconomic background of patients may dictate their ability to understand medical jargon. Inability to understand primary findings from a radiology report may lead to unnecessary anxiety among patients or missed follow up. We aim to meet this challenge by developing a patient-sensitive summarization model for radiology reports. We selected computed tomography (CT) exams of chest as a use-case and collected 7,000 studies from Mayo Clinic. Summarization model was built on top of the T5 large language model (LLM) as our experiments indicated that its text-to-text transfer architecture was suited for abstractive text summarization, resulting in a model with 0.77B trainable parameters. Noisy ground truth for model training was collected by prompting LLaMA-13B model. We recruited experts (board-certified radiologists) and laymen to manually evaluate model-generated summaries generated by model. Our model rarely missed information as marked by majority opinion of radiologists. Laymen indicated 63% improvement in their understanding by reading model-generated layman summaries. Comparison with zero-shot performance of ChatGPT indicated that the proposed model reduced the rate of hallucination by half and rate of missing important information by fivefold. The proposed model can generate reliable summaries for radiology reports understandable by patients with vastly different levels of medical knowledge.

Atrial fibrillation (AF) and cancer are increasingly recognized as interrelated conditions, with cancer patients showing elevated incidences of AF, and there is evidence that AF may sometimes precede cancer diagnoses. This comprehensive review investigates the epidemiology, pathophysiology, and management challenges associated with AF in cancer patients. Epidemiologically, several cancers are more closely related to increased rates of AF, including lung, colorectal, gastrointestinal, and hematologic malignancies. Mechanistically, both AF and cancer share pathophysiological pathways centered on inflammation, oxidative stress, and common cardiovascular risk factors, such as hypertension, obesity, and diabetes. The inflammatory microenvironment in tumors, marked by increased cytokines and growth factors, promotes atrial remodeling and AF susceptibility. Elevated reactive oxygen species (ROS) levels, driven by the metabolic demands of cancer, further contribute to atrial fibrosis and structural changes. Moreover, many anticancer treatments exacerbate AF risk. Management of AF in cancer patients presents many unique challenges and requires a multidisciplinary approach. Rate and rhythm control strategies are complicated by potential drug–drug interactions and limited data surrounding early implementation of rhythm control strategies in cancer patients. Interventional approaches such as catheter ablation, though effective in maintaining sinus rhythm, carry significant perioperative risk in patients with malignancy. Stroke prevention with anticoagulants is essential but requires cautious administration to avoid heightened bleeding risks, particularly in patients undergoing chemotherapy. Further, the limited applicability of standard risk stratification tools like CHA2DS2-VASc in this population complicate decisions regarding anticoagulation. This review highlights the bidirectional relationship between AF and cancer, the difficulties in management, and the critical need for further research in this field.

Since the dawn of humanity, human beings have inherently sought a state of security, trying to make their existence as comfortable as possible. Accordingly, among the many factors affecting human health, comfort and well-being, the quality of the micro-environment and ecology, as well as the health care system and health-saving resources, are important. In this regard, environmental security, with its systemic nature, brings a significant contribution to the PPM model by optimizing the state of balance in the interrelationship of natural, anthropogenic, physiological and social processes. Accordingly, individualized nutrition and pharmacointervention for preventive and prophylactic purposes, being important tools for health preservation, represent an integrative approach aimed at understanding the interaction between nutrition and the environment within the formed or formed lifestyle. This review will consider the main components of human health protection, as well as their impact on the preservation of ecobiocenosis stability.

Everyone has the right to the highest attainable standard of health, and modern preventive, preventive and rehabilitative manipulations promote health and well-being. Thanks to a number of fundamental projects on the study of human health at various levels (genomic, proteomic, and metabolomic), and molecular mechanisms of the development of pathological conditions, there has been a great leap in the field of applied sectors of industrial biotechnology, including segments of the pharmaceutical and food industries, significantly replenished health-saving resources and improved the quality of life of the population. This article will review the advanced achievements of fundamental and applied research, as well as promising areas of the bioindustry.

PURPOSE SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). METHODS Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m 2 , cisplatin 25 mg/m 2 , and nab-paclitaxel 100 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle). RESULTS Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). CONCLUSION The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.

Objective To evaluate cochlear implant speech perception among patients with sporadic inner ear schwannoma who underwent ipsilateral implantation. Study Design Retrospective multi-institutional cohort study. Setting Eleven tertiary academic medical centers across Germany, Denmark, and the United States. Patients One hundred six patients with sporadic inner ear schwannoma who received an ipsilateral cochlear implant from 2011 to 2022. Interventions Ipsilateral cochlear implantation with observation, stereotactic radiosurgery, or microsurgery for tumor management. Main Outcome Measures Monosyllabic speech perception testing scores and rates of open-set speech perception. Results Among 106 patients studied, 101 (95%) achieved open-set speech perception with a median of 24 months (interquartile range [IQR] 12–42 mo) of audiometric follow-up. Median ipsilateral monosyllabic speech perception testing achieved was 72% (IQR 54–85%), and median ipsilateral AzBio in quiet was 75% (IQR 46–90%). Most (91 of 106 [86%]) underwent microsurgery for tumor control, with cochlear implantation performed simultaneously in 98% (89 of 91) of these patients. The ability to achieve gross total resection significantly differed by tumor complexity, with 97% of low-complexity tumors, 100% of intermediate complexity, and 0% of high-complexity tumors undergoing gross total resection (p < 0.001). However, among patients managed with microsurgery, there was not a statistically significant difference in post-cochlear implantation monosyllabic speech perception scores across complexity groupings, with median scores of 75 and 70% for patients with tumors of low or intermediate complexity and those with tumors of high complexity, respectively (p = 0.5). Eight of 102 patients (8%) assessed experienced deterioration in cochlear implant performance over time. Among the subset of 39 patients with available MRI to review, the region of surveillance interest could be visualized postoperatively on MRI in all cases. Conclusions Open-set speech perception is achieved in most patients with inner ear schwannoma undergoing ipsilateral cochlear implantation. Although cochlear implantation in high-complexity inner ear schwannomas is only possible with incomplete tumor resection, long-term open-set speech perception outcomes are similar to lower-complexity tumors.

Introduction: Teclistamab (Tec) is the first approved BCMA x CD3 bispecific antibody for the treatment of triple-class-exposed patients with relapsed/refractory multiple myeloma (RRMM) based on the pivotal MajesTEC-1 study. Tec was associated with high overall response rate (ORR) of 63% in heavily pretreated patients. After a longer follow-up of 30.4 months, CR rate was 46.1%, median duration of response (DOR) was 24 months (95% CI, 17.0 - not estimable), and median progression-free survival (PFS) was 11.4 months (95% CI, 8.8 - 16.4). Herein, we present updated analysis of real-world outcomes and safety with tec in RRMM with extended follow-up of more than 12 months. Methods: This is an international multicenter retrospective study of patients with RRMM treated with tec on-label at 9 academic centers from 5 countries (United States, United Kingdom, Greece, Spain, and Canada) through the International Myeloma Working Group (IMWG) Immunotherapy Committee. Patients with RRMM treated with commercial tec at the respective institutions between May 24, 2022 to January 4, 2024 were included. Median follow-up was 14 months with data collected until July 15, 2024. High-risk cytogenetic abnormalities (HRCA) was defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using the IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (interquartile range [IQR] or range). PFS, overall survival (OS), DOR were evaluated using the Kaplan-Meier method. Results: There were 223 patients included in this analysis with the following characteristics: median age of 67 (range 33-91) with 24% ≥75 years; 45% female; 74% White, 10% Black, 9% Asian, and 7% other/unknown; 86 of 176 (49%) with high risk cytogenetics, including del(17p), t(4;14), t(14;16), t(14;20), and gain/amp 1q; 29.4% (37/126) with known extramedullary disease; 14% with creatinine clearance ≤30 ml/min. Patients received a median of 6 (IQR, 4-8) prior lines of therapy with 52% (107/206) being penta-drug refractory. Among 212 patients with available data, 161 (75.9%) patients would have been ineligible for MajesTEC-1. There were 94 (42%) patients who received prior BCMA-directed therapy (29.8% antibody-drug conjugate [ADC] alone; 45.7% CART alone; 6.3% bispecific antibody alone; 17.0% ADC and CART). Median time from diagnosis to tec initiation was 6.1 (range 0.6-29.2) years. For the 206 response-evaluable patients, ORR was 66%, including 25.2% ≥CR, 33.5% VGPR, and 7.3% PR. ORR for the 90 response-evaluable patients with prior BCMA-directed therapy was 54.5% (21.1% ≥CR, 26.7% VGPR, 6.7% PR). After a median follow-up of 14 (95%CI, 13-14) months, median PFS and OS were 8.8 (95% CI, 5.5-14) and 20 (95% CI, 18-not reached [NR]) months, respectively. 12-month PFS estimate was 46% (95% CI, 40%-54%), and 12-month OS rate was 65% (95% CI, 59%-72%). Median DOR was 17 (95% CI, 17-NR) months with 12-month estimate of 68% (95% CI, 60%-77%). Tec step-up dosing occurred in the outpatient setting for 57 (25.6%) patients. CRS occurred in 119 out of 222 (53.6%) patients with almost all being grade 1-2, except for 1 grade 4 event. ICANS occurred in 18 out of 216 (8.3%) patients (grade 1-2: 5.1%; grade 3-4: 2.8%). Any grade infection occurred in 130 (58.3%) patients; 25.1% of patients had grade ≥3 infection, including 10 patients with grade 5 infection. While receiving teclistamab, 79 (35.4%) patients had ≥2 infections. IVIG was given in 114 out of 164 (69.5%) patients. Conclusion: In this multicenter international real-world analysis of outcomes and safety associated with tec, ORR was high at 66% with 25.2% of patients achieving ≥CR. CR rates may be underestimated due to infrequent bone marrow confirmation in the real-world datasets. Encouragingly, ORR was 54.5% in BCMA exposed RRMM patients, including 21.1% with ≥CR. After a median follow-up of 14 months, heavily pretreated patients including patients with prior BCMA therapy had durable responses with median PFS of 8.8 months and median DOR of 17 months. There were no new safety signals noted in this real-world study. This is the largest real-world study to date of teclistamab with long-term follow-up of more than 12 months. Additional data including more patients, longer follow-up and results from difficult to treat subgroups will be presented at the meeting.