Citations

Chimeric antigen receptor (CAR) T cell therapy faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous T cell receptor (TCR) using an oncolytic virus enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to non–TCR-primed CAR T cells. Single-cell RNA sequencing showed clonal expansion of anti-VSV CAR T cells and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in the development of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of systemic oncolytic virotherapy and for directly exploiting the CAR T cell TCR to fine tune the CAR T cell phenotype and function.

Abstract High-risk breast lesions (HRLs) encompass a heterogeneous group of pathologies that coexist with an adjacent or synchronous malignancy, confer an increased risk of future breast cancer, or warrant surgical consideration because of upgrade potential or local behavior. Despite their clinical importance, management of HRLs remains variable. The American Society of Breast Surgeons (ASBrS) and the Society of Breast Imaging are collaborating to establish unified, evidence-based guidelines for managing these lesions. While these recommendations are currently in development, this review summarizes the existing literature and current guidance, including ASBrS recommendations, to provide context for multidisciplinary management. The article reviews the histopathologic features, imaging appearance, and management strategies for HRLs, including atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), flat epithelial atypia (FEA), papillomas with and without atypia, radial scar/complex sclerosing lesion (RS/CSL), mucocele-like lesion (MLL), desmoid tumor, and pseudoangiomatous stromal hyperplasia (PASH). Recent literature supports nonoperative management for specific radiologic-pathologic concordant lesions, particularly limited ADH, pure FEA, and pure RS, highlighting the important role of multidisciplinary discussion for personalized care. Lesions such as LCIS subtypes, papilloma with atypia, and MLL with atypia continue to warrant excision due to higher reported upgrade rates to malignancy. Beyond short-term management, HRLs such as ADH, ALH, and LCIS serve as biomarkers of long-term breast cancer risk, informing recommendations for surveillance, risk assessment, and chemoprevention counseling. Achieving a consensus among radiology, pathology, and surgical disciplines is essential to ensure oncologic safety while minimizing overtreatment in the era of precision breast care.

Background Invasive micropapillary carcinoma (IMPC) of the breast is associated with a high propensity for lymphovascular invasion and lymph node metastasis. However, whether chemotherapy is associated with improved survival outcomes in these patients remains unclear. Methods This retrospective study analyzed IMPC patients from the SEER database (2010–2018) (n=1,150) and an external validation cohort from Nanjing Drum Tower Hospital (n=199). Propensity score matching assessed chemotherapy’s impact on overall survival (OS) and breast cancer-specific survival (BCSS) in the SEER cohort. A risk stratification model was developed and validated using the external cohort. Results In the SEER cohort, chemotherapy was associated with significantly improved OS (HR = 0.517, 95% CI 0.293-0.910, P = 0.020) but not BCSS. A risk model incorporating marital status, tumor size, subtype, and radiotherapy history identified high- and low-risk groups. Chemotherapy was associated with significantly better OS only for high-risk patients (internal training cohort: HR = 0.577, 95% CI 0.349-0.952, P = 0.029; internal validation cohort: HR = 0.213, 95% CI 0.070-0.647, P = 0.003). External validation consistently confirmed poorer prognosis for high-risk patients (HR = 2.969, 95% CI 1.028-8.571, P = 0.035) and verified the model’s ability to identify patients with differential OS associations with chemotherapy: chemotherapy was associated with better OS in high-risk patients (HR = 0.163, 95% CI 0.031-0.868, P = 0.016), but not in low-risk patients (HR = 0.793, 95% CI 0.153-4.103, P = 0.782). Conclusions Chemotherapy was associated with improved prognosis particularly in high-risk patients with IMPC. However, chemotherapy decisions should be made cautiously for low-risk patients, taking into account a comprehensive assessment of clinical and pathological factors.

Abstract Background Preterm premature rupture of membranes (PPROM) and preterm labor (PTL) are adverse obstetrical outcomes that are strongly associated with cervical high-risk human papilloma virus (cHPV) infection at the time of pregnancy. Persistent cHPV may lead to oncogenic changes in the cervico-vaginal tract and can cause inflammation in gestational tissues, but it is unknown how persistent cHPV infection may affect obstetrical outcomes. The aim of this study is to evaluate whether persistent cHPV infection is associated with recurrent PPROM or PTL among patients with a prior spontaneous preterm birth due to PPROM/PTL, and to examine clinical and pathologic characteristics of cHPV infection in this population. Methods We conducted a retrospective cohort study of patients delivering at Mayo Clinic Rochester or Mayo Clinic Health System (5/1/2018–12/31/2023). Eligible patients had ≥ 1 spontaneous preterm birth due to PPROM/PTL and positive cHPV testing. Demographics and pregnancy outcomes from index and subsequent pregnancies were abstracted. Persistent cHPV was defined as > 1 pregnancy with positive cHPV testing. Results Of 191 index pregnancies, 90 (47.1%) and 30 (33.3%) had one and two subsequent pregnancies, respectively. Patients were predominantly White (91.3%), non‑Hispanic (94.2%), non-smokers (72.0%), and 34.8% were unvaccinated for HPV. Approximately one‑third (31%) experienced recurrent PPROM/PTL in the second pregnancy, with recurrence in 40.7% of those with persistent cHPV and 27.4% without (p = 0.69). Excisional procedures occurred before 12.0% of index pregnancies and 20–24% of subsequent pregnancies; recurrence of PTL/PPROM remained high regardless of procedure history. HPV strain data were available for 132 index pregnancies, and types 16 and 18 were more likely to persist into a subsequent pregnancy (p = 0.0043). CIN persistence occurred at similar rates in patients with and without persistent cHPV infection. Placental inflammation rates were high in both patients with persistent and non-persistent cHPV. Conclusion Recurrent PPROM/PTL, CIN persistence, and placental inflammation were common; a finding independent of persistent cHPV infection, excisional procedure history, or HPV vaccination status. These findings suggest that factors other than cHPV persistence may play a larger role in recurrent preterm birth. Larger studies with higher cHPV prevalence and subsequent pregnancies are needed to provide clarity.

Objectives: To analyze the association between primary infertility and infertility type with the age of natural menopause. Methods: This is a retrospective cohort study reviewing a subset of women from the Mayo Primary Infertility Cohort (MPIC). The MPIC is a cohort of 1,001 women diagnosed with primary infertility and 1,001 age-matched referent women. In this study, we included all women at risk for natural menopause and further evaluated those who had reported natural menopause in the medical record. We compared the risk of natural menopause using Cox proportional hazard models with infertility status and infertility type as covariates. In those with documented menopause during the study period, the association between primary infertility and early and premature menopause was analyzed with χ 2 testing. We evaluated the association between age at natural menopause, primary infertility status, and infertility type in this group using linear regression. Results: In all, 461 women with primary infertility, with 530 referent individuals, were at risk of natural menopause, and of these, 340 women with infertility and 346 referent women underwent documented natural menopause on review of medical records. Women with primary infertility had an increased risk of natural menopause (hazard ratio: 1.25, 95% CI: 1.06-1.46) and underwent menopause 1 year earlier than referent individuals (β=−1.17, 95% CI: −1.82 to −0.52) after adjustment for body mass index, tobacco use, race, menstrual cycle regularity, and previous contraception use. Women with primary infertility were more likely to undergo early menopause (age 40-45) than referent women (7.6% vs. 3.0%, P =0.01). Compared with referent women, women with endometriosis underwent menopause 2.75 years earlier (95% CI: −4.38 to −1.13, P =0.0009), and women with unexplained infertility underwent menopause 1.45 years earlier (95% CI: −2.26 to −0.64, P =0.0005). Conclusions: Women with primary infertility had an increased risk of early menopause and collectively underwent menopause 1 year earlier than women without a history of primary infertility.

Abstract Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

Background: Colorectal cancer (CRC) remains one of the common causes of cancer-related morbidity and mortality in the United States. Emerging increases in early-onset CRC and persistent disparities remain major public health concerns. Objective: To characterize long-term CRC incidence and mortality trends in the United States, with particular emphasis on identifying demographic groups experiencing rising or plateauing disease burden. Methods: We conducted a population-based ecological study using CRC incidence data from the United States Cancer Statistics database (1999–2022) and mortality data from CDC WONDER (1999–2023). Temporal trends were evaluated using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC), stratified by age, sex, race/ethnicity, and urbanization level. Results: Overall CRC incidence and mortality declined during the study period (both AAPC approximately −2.08%). However, incidence increased significantly among adults younger than 55 years, particularly those aged 20–24 years. Mortality also increased among younger adults aged 25–44 years and remained elevated among individuals aged 45–54 years. Non-Hispanic Black individuals consistently experienced the highest incidence and mortality rates. Mortality declines plateaued in several older age groups after 2018–2020. Conclusions: Despite overall improvements in CRC burden, increasing incidence and mortality among younger adults and persistent disparities highlight the need for risk-stratified prevention, earlier detection strategies, and tailored therapeutic approaches.

Background/objectives: To develop expert consensus on peripheral venous access devices (PVAD) and associated care practices, and to formulate guidance recommendations aimed at improving peripheral venous access and management, including the integration of vein visualization technology. This is particularly important for patient populations with peripheral venous depletion, who often present with compromised vasculature that complicates successful PVAD access and increases the risk of complications. Preserving vascular integrity in these patients is essential for maintaining treatment pathways and preventing long-term vascular damage. Methods: A multi-phase approach to consensus development was used consisting of the following: (1) a literature review, (2) a survey and consultation with a vascular access expert panel ( n = 9), and (3) a consultation meeting with patient and public representatives ( n = 2). Results: Survey results and consultation findings from the expert panel demonstrated consensus for 14 of 24 statements. Further analysis resulted in a total of four key problem statements on peripheral venous access and care, and 11 recommendations for future development. Following review by patient and public representatives, three additional recommendations were added, and three existing recommendations were refined. The final consensus statement reflects four problem statements with 14 recommendations. Conclusion: This expert consensus presents 14 evidence-informed statements designed to strengthen practice, improve patient safety, and enhance clinician confidence and competence. Central to these recommendations is the adoption of routine structured pre-insertion vessel assessment using vein visualization technology where appropriate to minimize vessel trauma, and promote more consistent, high-quality vascular access care.