Citations

Adolescents and young adults (AYA; ages 15–39) with acute leukemia have significant unmet supportive care needs. This pilot study integrated same-day palliative care (PC) into an AYA leukemia clinic, measuring symptom burden (SB) with validated symptom assessment tools at baseline, 3, and 6 months. Among 31 patients, moderate-severe symptoms included tiredness, anxiety, and poor appetite. AYAs experienced high SB and psychological distress, regardless of care phase or sociodemographics. With PC integration, tiredness and depression improved significantly; no symptoms worsened. Half of the PC visits led to management changes. Early integration of symptom-focused PC was feasible, value-adding, and well-received by patients.

Background Antibiotic use may alter gut microbiota, which could be associated with various diseases, including cardiovascular disease (CVD). Accordingly, further epidemiological evidence is needed to clarify the potential risk of CVD associated with antibiotic exposure. We evaluated the association between long‐term antibiotic exposure and CVD risk in South Korea. Methods and Results This nationwide retrospective cohort study used data from the Korean National Health Insurance Service database. A total of 2 159 965 individuals aged 40 to 79 years who had no history of antibiotic prescriptions from 2004 to 2005 were included and followed through December 31, 2021. Antibiotic exposure was defined as the cumulative days of antibiotic prescriptions from 2006 to 2010. The primary end point was incident CVD with 2 or more days of hospitalization from 2011 to 2021. Adjusted hazard ratios (aHR) and 95% CIs for CVD according to antibiotic exposure were estimated using multivariable Cox proportional hazards models, adjusting for a range of covariates. Longer cumulative antibiotic prescription days were associated with an increased risk of CVD. The aHRs for CVD associated with 1 to 14, 15 to 90, 91 to 180, 181 to 364, and ≥365 days of antibiotic exposure were 0.98 (95% CI, 0.96–1.01), 1.01 (95% CI, 0.99–1.03), 1.05 (95% CI, 1.03–1.08), 1.06 (95% CI, 1.04–1.09), and 1.10 (95% CI, 1.07–1.13) compared with those with no antibiotic prescriptions. Conclusions In this large population‐based cohort study of Korean adults, long‐term antibiotic exposure may be associated with a higher risk of CVD. Further research is warranted to establish causality and elucidate the underlying mechanisms for this association.

Abstract Purpose: The role of tumor-infiltrating lymphocytes (TIL) remains unclear in hormone receptor (HR)–positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences. Experimental Design: Patients with stage I to III HR-positive/HER2-negative tumors were identified from a prospective cohort study of patients with breast cancer diagnosed at age ≤40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non–CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer–free survival, distant disease–free survival (DDFS), and overall survival, adjusted for clinicopathologic parameters. Results: Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histologic subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved invasive breast cancer–free survival. Higher intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T-cell infiltration and PDL1 expression were associated with improved overall survival. Conclusions: Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization. See related commentary by Salgado and Kok, p. 2133

Importance The effect of cornea donor diabetes on endothelial cell density (ECD) and morphometry after Descemet membrane endothelial keratoplasty (DMEK) is not known. Objective To determine whether endothelial cell loss (ECL) and morphometric changes 1 year after successful DMEK are related to cornea donor’s diabetes status. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2024 at 28 US clinical sites (46 surgeons) and 13 eye banks. Included in the trial were the eyes of recipients (some of whom received tissue from donors without diabetes and others who received tissue from donors with diabetes) who underwent successful DMEK, primarily for Fuchs endothelial corneal dystrophy, and had at least 1 analyzable postoperative endothelial image. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure to achieve an approximate 2:1 distribution. Main Outcomes and Measures ECD, ECL, coefficient of variation in cell area (CV), and percentage of hexagonal cells (HEX) at 1 year from eye bank and postoperative specular central endothelial images. Results A total 1274 eyes of 982 recipients (mean [SD] age, 70 [8] years; 569 female [57.9%]; 816 [64.1%] with tissue from donors without diabetes and 458 [35.9%] with tissue from donors with diabetes) were included in the study. Preoperatively, mean (SD) central ECD in tissue from donors without diabetes and with diabetes were 2676 (290) cells/mm 2 and 2671 (286) cells/mm 2 , respectively. At 1 year, mean (SD) ECL was 28.3% (16.1%) and 28.0% (17.0%), in the donor groups without and with diabetes, respectively (adjusted mean difference = −0.4%; 95% CI, −2.3% to 1.4%), resulting in a mean (SD) 1-year ECD of 1927 (498) cells/mm 2 and 1920 (496) cells/mm 2 , respectively (adjusted mean difference = 10 cells/mm 2 ; 95% CI, −36 to 56; P = .95). No difference in ECD at 1 year associated with diabetes severity was noted ( P = .97). Mean (SD) CV did not differ at 1 year between the 2 groups of eyes (31.5% [4.1%] vs 31.4% [4.1%]; adjusted mean difference = −0.4%; 95% CI, −0.9% to 0.1%; P = .51), and mean (SD) HEX did not differ at 1 year between the 2 groups of eyes (57.7% [5.8%] vs 57.2% [5.8%]; adjusted mean difference = 0.1%, 95% CI, −0.8% to 0.9%; P = .33). Conclusions and Relevance This randomized clinical trial found that ECL and morphometry 1 year after DMEK were not affected by cornea donor diabetes status. With comparable 1-year graft success with tissue from donors with and without diabetes demonstrated in this trial, these findings support the use of corneas from donors with diabetes for endothelial keratoplasty procedures. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Importance If the success of Descemet membrane endothelial keratoplasty (DMEK) is not affected by whether the donor has diabetes, then the donor pool should expand. Objective To determine whether the 1-year DMEK success rate is affected by the presence of diabetes in the donor. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2025 at 28 clinical sites (46 surgeons), with donor corneas provided by 13 eye banks in the US. Included in the study were individuals undergoing low to moderate risk DMEK (95% for Fuchs endothelial corneal dystrophy). Study data were analyzed from April to September 2025. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure (comparable with randomization) to achieve an approximate 2:1 distribution, respectively. Main Outcomes and Measures Graft success at 1 year Results A total of 1097 individuals (1421 study eyes; median [IQR] age, 71 [66-76] years; 631 female [57.5%]) were included in the study. The 1-year cumulative probability of graft success was 96.3% (95% CI, 95.0%-97.5%) among 912 study eyes (64.2%) receiving tissue from donors without diabetes and 97.1% (95% CI, 95.5%-98.4%) among 509 study eyes (35.8%) receiving tissue from donors with diabetes (difference between groups = 0.7 percentage points; 95% CI, −1.2 to 2.6; P = .63). The 1-year cumulative probability of graft success was 96.5% (95% CI, 93.6%-98.9%) in the mild donor diabetes severity subgroup (n = 173) and 97.3% (95% CI, 95.4%-98.8%) in the moderate to severe donor diabetes severity subgroup (n = 336), using a diabetes severity rating scale based on medical history. The rates of primary donor failure, early failure related to surgical complications, and subsequent failure were as follows: 2.5% (23 of 912), 0.7% (6 of 912), and 0.3% (3 of 912), respectively, in recipients of tissue from a donor without diabetes, and 2.6% (13 of 509), 0.4% (2 of 509), and 0%, respectively, among recipients of tissue from a donor with diabetes. There were no failures due to graft rejection. Conclusions and Relevance The 1-year success rate in eyes undergoing DMEK with successfully prepared tissue was very high regardless of donor diabetes status. These results, supported by the separately reported finding that endothelial cell loss and cornea morphometry after 1 year were not affected by donor diabetes status, provide strong support for having no restrictions on the use of tissue from donors with diabetes for DMEK. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Vascular surgery has evolved from durable yet invasive open reconstructions to less traumatic endovascular techniques. While endovascular repair reduces perioperative morbidity, it introduces durability challenges and the need for lifelong surveillance. Laparoscopic surgery bridged some gaps but was hindered by steep learning curves and technical limitations. Robotic-assisted surgery represents a “third revolution”, combining the durability of open repair with the recovery and ergonomic benefits of minimally invasive approaches through enhanced 3D visualization, wristed instrumentation, and tremor filtration. This review synthesizes current evidence on robotic applications in vascular surgery, including aortic, visceral, venous, and endovascular interventions. Feasibility of robotic vascular surgery has been demonstrated in over 1500 patients across aortic, visceral, venous, and decompression procedures. Reported outcomes include pooled conversion rates of ~5%, 30-day mortality of 1–3%, and long-term patency rates exceeding 90% in aortoiliac occlusive disease. Similarly favorable outcomes have been observed in AAA repair, visceral artery aneurysm repair, IVC reconstructions, renal vein transpositions, and minimally invasive decompression procedures such as median arcuate ligament and thoracic outlet syndromes. Endovascular robotics enhances catheter navigation precision and reduces operator radiation exposure by 85–95%, with multiple series demonstrating consistent benefit compared to manual techniques. Despite these advantages, adoption is limited by high costs, lack of dedicated vascular instruments, absent haptic feedback on most platforms, and the need for standardized training. Most available evidence is observational and from high-volume centers, highlighting the need for multicenter randomized trials. Future directions include AI-enabled planning and augmented-reality navigation, which are the most feasible near-term technologies since they rely largely on software integration with existing systems. Other advances such as microsurgical robotics, soft-robotic platforms, and telesurgery remain longer-term developments requiring new hardware and regulatory pathways. Overcoming barriers through collaborative innovation, structured training, and robust evidence generation is essential for robotics to become a new standard in vascular care.

Abstract Transcription factors and their cofactors are major and selective nononcogene dependencies in multiple myeloma cells. By performing a gain-of-function perturbation screen in human multiple myeloma cell lines, we identified the inhibitor of DNA binding (ID) genes as putative suppressors of multiple myeloma cell fitness. Among them, ID2 was found to be downregulated in multiple myeloma patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix-loop-helix factor TCF3, also known as E2A. Lower ID2 expression in multiple myeloma cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in multiple myeloma cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL6, revealing a mechanism by which the tumor microenvironment affects multiple myeloma cell behavior. Significance: Multiple myeloma cells exploit the oncogenic and proliferative potential of TCF3 by downregulating the transcriptional regulator ID2, a process facilitated by the bone marrow microenvironment.

Abstract Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation and plays multiple roles in RNA splicing, DNA damage-response, cell cycle, and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA sequencing, ChIP sequencing, and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease. Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression was significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.

Abstract Background Few studies have assessed the burden of chronic medical conditions in adolescent and young adult (AYA) cancer survivors. This study estimated the risk of these conditions among AYA survivors compared to a matched cohort without cancer. Methods This retrospective cohort study included 2‐year survivors ( n = 14,917) of 11 common AYA (15–39 years) cancers diagnosed at the integrated health care organizations of Kaiser Permanente (KP) Southern and Northern California during 2006–2020. A comparison cohort ( n = 149,164) without cancer (matched 10:1 by age, sex, calendar year, and KP site) was included. Cumulative incidence (CMI) accounting for death as a competing risk was calculated. Poisson regression estimated the incidence rate ratio (IRR) of each condition in cancer survivors versus the matched cohort, adjusting for age, sex, and race/ethnicity. Results The 5‐year CMI was highest for thyroid (17.4%), respiratory (6.6%), cardiovascular (5.0%), and liver (4.8%) diseases. At 10 years, the CMI of any condition was 39% in survivors versus 26% in the matched cohort. Survivors had a 2‐fold increased risk of being diagnosed with any medical condition (IRR, 2.0; 95% confidence interval [CI], 1.9–2.0) as well as two or more conditions (IRR, 2.3; 95% CI, 2.2–2.5). Risk was highest among survivors of hematologic cancers and those diagnosed with distant stage disease. Elevated risks were observed within all sociodemographic groups of this insured population. Conclusion AYAs with cancer had a higher risk of chronic medical conditions compared to those without cancer. Long‐term surveillance, risk mitigation through lifestyle modifications and effective disease management are crucial to reduce premature mortality.