Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

ABSTRACT: In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

Depression among older adults with gastrointestinal malignancies.

BACKGROUND: Depression among older adults with cancer is under recognized and under treated. This study characterizes the burden of depression in older adults with gastrointestinal (GI) malignancies prior to chemotherapy and its relationship with geriatric assessment (GA) domains, health-related quality of life (HRQOL), and self-reported healthcare utilization. METHODS: Patients ≥60 years in GI oncology clinics at UAB were asked to complete a GA entitled the Cancer & Aging Resilience Evaluation (CARE). We examined depression using the Patient-Reported Outcomes Measurement Information System (PROMIS®) Depression four-item short form; moderate/severe depression was defined by a t-score ≥ 60. Multivariate analysis was used to examine associations between those with and without moderate/severe depression. RESULTS: Of 355 included patients, 46 had mild depression (13%) and an additional 46 patients had moderate/severe depression (13%). After adjustment for age, sex, education, cancer type, and cancer stage, those who reported moderate/severe depression had a significantly increased odds of reporting falls (adjusted odds ratio [aOR] 4.01, 95% confidence interval [CI] 1.94-8.26), dependence in IADLs (aOR 7.06,CI 2.91-17.1), dependence in ADLs (aOR 6.23, CI 2.89-13.4), malnutrition (aOR 5.86, CI 2.40-14.3), frailty (aOR 13.7, CI 5.80-32.1), and fatigue (aOR 11.2, CI 3.31-37.6). Moderate/severe depression was also significantly associated with worse physical (aOR 7.58, CI 3.30-17.4) and mental (aOR 26.3, CI 10.1-68.8) HRQOL sub-scores, without significant differences in healthcare utilization. CONCLUSIONS: More than one out of eight older adults with a GI malignancy reported moderate/severe depression prior to chemotherapy, which was associated with impairments in several GA domains and HRQOL.

Review of molecular and mechanical interactions in the aortic valve and aorta: implications for the shared pathogenesis of aortic valve disease and aortopathy.

Aortic valve disease (AVD) and aortopathy are associated with substantial morbidity and mortality, representing a significant cardiovascular healthcare burden worldwide. These mechanobiological structures are morphogenetically related and function in unison from embryonic development through mature adult tissue homeostasis, serving both coordinated and distinct roles. In addition to sharing common developmental origins, diseases of the aortic valve and proximal thoracic aorta often present together clinically. Current research efforts are focused on identifying etiologic factors and elucidating pathogenesis, including genetic predisposition, maladaptive cell-matrix remodeling processes, and hemodynamic and biomechanical perturbations. Here, we review the impact of these processes as they pertain to translational research efforts, emphasizing the overlapping relationship of these two disease processes. The successful application of new therapeutic strategies and novel tissue bioprostheses for AVD and/or aortopathy will require an understanding and integration of molecular and biomechanical processes for both diseases.

Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis.

Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF) and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs). An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs), whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN) and α-SMA (ACTA2). NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease.

Nonproteolytic properties of murine alternatively spliced tissue factor: implications for integrin-mediated signaling in murine models.

This study was performed to determine whether murine alternatively spliced tissue factor (masTF) acts analogously to human alternatively spliced tissue factor (hasTF) in promoting neovascularization via integrin ligation. Immunohistochemical evaluation of a spontaneous murine pancreatic ductal adenocarcinoma model revealed increased levels of masTF and murine full-length tissue factor (mflTF) in tumor lesions compared with benign pancreas; furthermore, masTF colocalized with mflTF in spontaneous aortic plaques of Ldlr(-/-) mice, indicating that masTF is likely involved in atherogenesis and tumorigenesis. Recombinant masTF was used to perform in vitro and ex vivo studies examining its integrin-mediated biologic activity. Murine endothelial cells (ECs) rapidly adhered to masTF in a ß3-dependent fashion. Using adult and embryonic murine ECs, masTF potentiated cell migration in transwell assays. Scratch assays were performed using murine and primary human ECs; the effects of masTF and hasTF were comparable in murine ECs, but in human ECs, the effects of hasTF were more pronounced. In aortic sprouting assays, the potency of masTF-triggered vessel growth was undistinguishable from that observed with hasTF. The proangiogenic effects of masTF were found to be Ccl2-mediated, yet independent of vascular endothelial growth factor. In murine ECs, masTF and hasTF upregulated genes involved in inflammatory responses; murine and human ECs stimulated with masTF and hasTF exhibited increased interaction with murine monocytic cells under orbital shear. We propose that masTF is a functional homolog of hasTF, exerting some of its key effects via ß3 integrins. Our findings have implications for the development of murine models to examine the interplay between blood coagulation, atherosclerosis and cancer.