Citations

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs.

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd.

Abstract Background To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS). Methods A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities. Results Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and 59 were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (P = .16). Like LF rates, there was no benefit in dose escalation for OS (P = .28) and CSS (P = .22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (P = .069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (P = .13). Conclusions This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation. Clinical Trial Information NCT00592748.

BACKGROUND: Increasing interest in neurosurgery residency has led to a growing number of unmatched applicants, who often struggle to find appropriate guidance for their next steps. The authors examined trends, opinions, and options available to unmatched neurosurgery residency reapplicants. STUDY DESIGN: Demographic data of US applicants from MD programs obtained from the National Resident Matching Program (2009 to 2024) were analyzed using 1-way ANOVA analysis of time-interval averages. Opinions about reapplicants were assessed via an online survey of national neurosurgery leaders, including residency program directors and chairpersons (N = 356). RESULTS: All application trends showed greater change over time; however, the rate of accepted reapplicants showed no significant change among early (2009 to 2013: 4.8 ± 1.8), mid (2014 to 2018: 7.6 ± 4.8), and recent periods (2019 to 2024: 9.8 ± 2.5; p = 0.068). The survey had a 23.0% response rate (82 of 356). Commonly indicated reasons for failure to match included poor interview skills, weak recommendation letters, and personality issues. Although most survey respondents supported candidates reapplying, dual applications (applying to more than 1 specialty) were not widely encouraged. For those reapplying, pursuing a preliminary general surgery or research fellowship, obtaining new letters of recommendation from new subinternships, and publishing higher-quality research were the most endorsed uses of time before reapplying. However, most programs reported interviewing reapplicants sometimes to rarely and matching a reapplicant rarely to never. CONCLUSIONS: The number of reapplicants successfully matching into neurosurgery has not changed significantly during the past 15 years. Surveys indicate that leaders view reapplicants unfavorably, despite reapplicants’ efforts to improve their applications. These results suggest that neurosurgery mentors may do a disservice to potential reapplicants based on how residency program leadership considers reapplications. Candid guidance is needed for reapplicants in the residency matching process.

Abstract Objectives There are striking differences among caregivers of people with dementia in their health and well-being during active caregiving and after caregiving has ended. A key factor influencing caregiver health is the emotional quality of the caregiver–care recipient relationship, which may be reflected in the emotional language caregivers use when describing this relationship. The present study assessed whether caregivers’ positive and negative language is associated with their current and future depression trajectories. Methods Active caregivers responded to an open-ended question about a recent time they felt connected to the care recipient. We summed the number of positive and negative emotion words and divided them by the total words in the response. We evaluated whether caregivers’ emotional language (a proxy for the emotional quality of the caregiver–care recipient relationship) was associated with their depression assessed both concurrently (N = 347 active caregivers) and longitudinally (N = 224 former caregivers). Results Neither positive nor negative emotional language significantly correlated with caregiver depression during active caregiving. Structural equation modeling revealed caregivers’ greater positive emotional language (accounting for baseline depression) was associated with less steep increases in depression after the care recipient’s death. Results were robust when accounting for negative emotional language and covariates. Negative emotional language was not significantly associated with changes in caregiver depression. Discussion Caregivers who use more positive words when describing their connection with the care recipient may be more resilient, underscoring the potential role of positive emotional qualities of the caregiving relationship in preserving caregivers’ mental health after caregiving ends.

Background The hemodynamic profile and remodeling patterns of paradoxical low‐flow, low‐gradient aortic stenosis are well understood. However, some patients with severe aortic stenosis exhibit eccentric remodeling with enlarged left ventricular cavities, enabling a normal flow, low ejection fraction ( NF ‐ LEF ) phenotype. We assessed the prevalence, hemodynamic characteristics, and post‐transcatheter aortic valve implantation outcomes of NF ‐ LEF . Methods In this substudy of the COMPARE‐TAVI 1 trial, 979 patients undergoing transfemoral transcatheter aortic valve implantation were stratified by left ventricular ejection fraction (LVEF) (< or ≥50%) and stroke volume index (< or ≥35 mL/m 2 ) into 4 groups: normal flow, normal LVEF, NF‐LEF, low flow, normal ejection fraction, and low flow, low ejection fraction. Results NF‐LEF was observed in 10.7% of patients. Reduced LVEF was associated with previous myocardial infarction, pacemakers, New York Heart Association class >2, atrial fibrillation, moderate or worse mitral regurgitation, and larger left ventricular cavities ( P <0.001) with eccentric hypertrophy ( P =0.004). Compared with low‐flow, low‐ejection fraction, patients with NF‐LEF more frequently had moderate or worse aortic regurgitation ( P =0.007), whereas low flow, low ejection fraction showed poorer diastolic indices, suggesting diastolic dysfunction with high left ventricular filling pressures. Patients with low flow, normal ejection fraction were the most symptomatic and showed less improvement in 6‐minute walk distance at 1 year compared with normal flow, normal ejection fraction. During follow‐up, both low‐flow groups demonstrated significant increases in stroke volume index ( P <0.001), whereas LVEF also improved among patients with reduced LVEF ( P <0.001). Conclusions NF‐LEF is a prevalent aortic stenosis phenotype characterized by preserved flow despite reduced LVEF, likely driven by eccentric remodeling with moderate or worse aortic regurgitation and more favorable diastolic properties, with similar survival and time‐to‐event outcomes across phenotypes after transcatheter aortic valve implantation at long‐term follow‐up. Despite higher comorbidity burdens, patients with NF‐LEF showed functional and clinical improvements comparable with normal flow, normal ejection fraction, indicating a severe aortic stenosis phenotype.

Background/Objective: Diabetic nephropathy (DN), a key microvascular complication of type 2 diabetes (T2DM), drives significant morbidity, mortality, and healthcare costs. Vitamin D deficiency has been linked to renal dysfunction, but its role in DN remains unclear. This study assessed the association between vitamin D status and DN versus T2DM without nephropathy. Methods: This cross-sectional hospital-based study included 399 participants (299 DN, 100 T2DM without nephropathy) at a tertiary endocrine clinic. Demographic, clinical, and biochemical data, including serum 25(OH)D, were collected. Chi-square and Mann–Whitney compared categorical and continuous variables, respectively, and multinomial logistic regression assessed the association between vitamin D status and DN (p < 0.05). Results: Patients with DN were older (58.2 ± 7.95 vs. 51.4 ± 9.94 years, p < 0.001), had more advanced CKD (stages 2–3b: 84.6% vs. 20.0%, p < 0.001), and higher albuminuria (moderate: 80.3% vs. 19.0%; severe: 18.4% vs. 0%, p < 0.001). They also showed poorer glycemic control, elevated urea and creatinine, lower serum albumin, dyslipidemia, elevated liver enzymes, and higher uric acid (all p < 0.05). Vitamin D deficiency was more prevalent in DN (37.7% vs. 8.0%, p < 0.001). Unadjusted multinomial regression indicated that T2DM patients without nephropathy had a 91% lower risk of vitamin D deficiency (RRR 0.09; 95% CI 0.04–0.19, p < 0.001) and an 87% lower risk of insufficiency (RRR 0.13; 95% CI 0.05–0.26, p < 0.001) compared with DN patients. After adjusting for age, HbA1c, creatinine, duration of diabetes and eGFR, the reduced risk of deficiency remained significant (RRR 0.04; 95% CI 0.01–0.16, p < 0.001), while the association with insufficiency was no longer significant (p = 0.310). Conclusions: This study shows a significant association between vitamin D deficiency and diabetic nephropathy, though its cross-sectional design precludes causal inference. Reverse causality and residual confounding cannot be excluded. Patients with DN had poorer glycemic control, dyslipidemia, and renal function, along with more frequent vitamin D deficiency. Routine vitamin D monitoring may support early detection and risk stratification in T2DM.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.

Coronary artery bypass grafting (CABG) remains a cornerstone of treatment for patients with advanced or complex coronary artery disease, yet long-term success is influenced by graft patency, progression of native disease, and ventricular remodeling. Optimizing the follow-up of these patients requires a structured approach in which multimodality cardiovascular imaging plays a central role. Echocardiography remains the first-line modality, providing readily available assessment of ventricular function, valvular competence, and wall motion, while advanced techniques, such as strain imaging and myocardial work, enhance sensitivity for subclinical dysfunction. Coronary computed tomography angiography (CCTA) offers excellent diagnostic accuracy for graft patency and native coronary anatomy, with emerging applications of CT perfusion and fractional flow reserve derived from CT (FFR-CT) expanding its ability to assess lesion-specific ischemia. Cardiovascular magnetic resonance (CMR) provides comprehensive tissue characterization, quantifying scar burden, viability, and inducible ischemia, and stress CMR protocols have demonstrated both safety and independent prognostic value in post-CABG cohorts. Nuclear imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains essential for quantifying perfusion, viability, and absolute myocardial blood flow, with hybrid PET/CT approaches offering further refinement in patients with recurrent symptoms. In patients after CABG, multimodality imaging is tailored to the patient’s characteristics, symptoms, and pre-test probability of disease progression. In asymptomatic patients, imaging focuses on surveillance, risk stratification, and the early detection of subclinical abnormalities, whereas in symptomatic individuals, it focuses on establishing the diagnosis, defining prognosis, and guiding therapeutic interventions. Therefore, the aim of our review is to propose updated and comprehensive guidance on the crucial role of multimodality cardiovascular imaging in the evaluation and management of post-CABG patients and to provide a practical, evidence-based framework for optimizing outcomes.