Cancer Incidence After Diagnosis of Abdominal Aortic Aneurysm-Brief Report.

BACKGROUND: Epidemiological and mechanistic data support a potential causal link between cardiovascular disease (CVD) and cancer. Abdominal aortic aneurysms (AAAs) represent a common form of CVD with at least partially distinct genetic and biologic pathogenesis from other forms of CVD. The risk of cancer and how this risk differs compared with other forms of CVD, is unknown among AAA patients. We conducted a retrospective cohort study using the IBM MarketScan Research Database to test whether individuals with AAA have a higher cancer risk independent of traditional shared risk factors. METHODS: All individuals ≥18 years of age with ≥36 months of continuous coverage between 2008 and 2020 were enrolled. Those with potential Mendelian etiologies of AAA, aortic aneurysm with nonspecific anatomic location, or a cancer diagnosis before the start of follow-up were excluded. A subgroup analysis was performed of individuals having the Health Risk Assessment records including tobacco use and body mass index. The following groups of individuals were compared: (1) with AAA, (2) with non-AAA CVD, and (3) without any CVD. RESULTS: The propensity score-matched cohort included 58 993 individuals with AAA, 117 986 with non-AAA CVD, and 58 993 without CVD. The 5-year cumulative incidence of cancer was 13.1% (12.8%-13.5%) in participants with AAA, 10.1% (9.9%-10.3%) in participants with non-AAA CVD, and 9.6% (9.3%-9.9%) in participants without CVD. Multivariable-adjusted Cox proportional hazards regression models found that patients with AAA exhibited a higher cancer risk than either those with non-AAA CVD (hazard ratio, 1.28 [95% CI, 1.23-1.32]; P<0.001) or those without CVD (hazard ratio, 1.32 [95% CI, 1.26-1.38]; P<0.001). Results remained consistent after excluding common smoking-related cancers and when adjusting for tobacco use and body mass index. CONCLUSIONS: Patients with AAA may have a unique risk of cancer requiring further mechanistic study and investigation of the role of enhanced cancer screening.

Role of vascular smooth muscle cell clonality in atherosclerosis.

Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. While many cell types contribute to the growing atherosclerotic plaque, the vascular smooth muscle cell (SMC) is a major contributor due in part to its remarkable plasticity and ability to undergo phenotype switching in response to injury. SMCs can migrate into the fibrous cap, presumably stabilizing the plaque, or accumulate within the lesional core, possibly accelerating vascular inflammation. How SMCs expand and react to disease stimuli has been a controversial topic for many decades. While early studies relying on X-chromosome inactivation were inconclusive due to low resolution and sensitivity, recent advances in multi-color lineage tracing models have revitalized the concept that SMCs likely expand in an oligoclonal fashion during atherogenesis. Current efforts are focused on determining whether all SMCs have equal capacity for clonal expansion or if a "stem-like" progenitor cell may exist, and to understand how constituents of the clone decide which phenotype they will ultimately adopt as the disease progresses. Mechanistic studies are also beginning to dissect the processes which confer cells with their overall survival advantage, test whether these properties are attributable to intrinsic features of the expanding clone, and define the role of cross-talk between proliferating SMCs and other plaque constituents such as neighboring macrophages. In this review, we aim to summarize the historical perspectives on SMC clonality, highlight unanswered questions, and identify translational issues which may need to be considered as therapeutics directed against SMC clonality are developed as a novel approach to targeting atherosclerosis.

Combined near infrared photoacoustic imaging and ultrasound detects vulnerable atherosclerotic plaque.

Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Here, near-infrared auto-photoacoustic (NIRAPA) imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In an ex vivo study of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the NIRAPA signal, immunohistochemistry, spatial transcriptomics and spatial proteomics were co-registered with imaging and applied to adjacent plaque sections. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and with the cytoplasmic contents of inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque and a methodology for fusing molecular imaging with spatial transcriptomic and proteomic methods.

Identifying shared transcriptional risk patterns between atherosclerosis and cancer.

Cancer and cardiovascular disease (CVD) are the leading causes of death worldwide. Numerous overlapping pathophysiologic mechanisms have been hypothesized to drive the development of both diseases. Further investigation of these common pathways could allow for the identification of mutually detrimental processes and therapeutic targeting to derive mutual benefit. In this study, we intersect transcriptomic datasets correlated with disease severity or patient outcomes for both cancer and atherosclerotic CVD. These analyses confirmed numerous pathways known to underlie both diseases, such as inflammation and hypoxia, but also identified several novel shared pathways. We used these to explore common translational targets by applying the drug prediction software, OCTAD, to identify compounds that simultaneously reverse the gene expression signature for both diseases. These analyses suggest that certain tumor-specific therapeutic approaches may be implemented so that they avoid cardiovascular consequences, and in some cases may even be used to simultaneously target co-prevalent cancer and atherosclerosis.

Risk of Cancer After Diagnosis of Cardiovascular Disease.

Background: Cardiovascular disease (CVD) and cancer share several risk factors. Although preclinical models show that various types of CVD can accelerate cancer progression, clinical studies have not determined the impact of atherosclerosis on cancer risk. Objectives: The objective of this study was to determine whether CVD, especially atherosclerotic CVD, is independently associated with incident cancer. Methods: Using IBM MarketScan claims data from over 130 million individuals, 27 million cancer-free subjects with a minimum of 36 months of follow-up data were identified. Individuals were stratified by presence or absence of CVD, time-varying analysis with multivariable adjustment for cardiovascular risk factors was performed, and cumulative risk of cancer was calculated. Additional analyses were performed according to CVD type (atherosclerotic vs nonatherosclerotic) and cancer subtype. Results: Among 27,195,088 individuals, those with CVD were 13% more likely to develop cancer than those without CVD (HR: 1.13; 95% CI: 1.12-1.13). Results were more pronounced for individuals with atherosclerotic CVD (aCVD), who had a higher risk of cancer than those without CVD (HR: 1.20; 95% CI: 1.19-1.21). aCVD also conferred a higher risk of cancer compared with those with nonatherosclerotic CVD (HR: 1.11; 95% CI: 1.11-1.12). Cancer subtype analyses showed specific associations of aCVD with several malignancies, including lung, bladder, liver, colon, and other hematologic cancers. Conclusions: Individuals with CVD have an increased risk of developing cancer compared with those without CVD. This association may be driven in part by the relationship of atherosclerosis with specific cancer subtypes, which persists after controlling for conventional risk factors.

Combined near infrared photoacoustic imaging and ultrasound detects vulnerable atherosclerotic plaque.

Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Photoacoustic imaging has sufficient penetration and sensitivity to map and characterize human atherosclerotic plaque. Here, near infrared photoacoustic imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In an ex vivo study of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the near-infrared auto-photoacoustic (NIRAPA) signal, immunohistochemistry, spatial transcriptomics and proteomics were applied to adjacent sections of the plaque. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque.

Constrictive Pericarditis Revealing Rare Case of ALH Amyloidosis With Underlying Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia).

We present a case of pericardial amyloidosis with associated lymphoplasmacytic lymphoma in a patient with chronic worsening shortness of breath and cough. This case highlights the wide variation in the presentation of cardiac amyloidosis, and the rare occurrence of clinically significant light-chain and heavy-chain amyloidosis in the pericardium. (Level of Difficulty: Advanced.).

Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma.

Melanomas originating from mucosal surfaces have low mutation burden, genomic instability, and poor prognosis. To identify potential driver genes, we sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloging point mutations, amplifications, and deletions. The SPRED1 gene, which encodes a negative regulator of mitogen-activated protein kinase (MAPK) signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT mutations. SPRED1 knockdown caused MAPK activation, increased cell proliferation, and conferred resistance to drugs inhibiting KIT tyrosine kinase activity. These findings provide a rationale for MAPK inhibition in SPRED1-deficient melanomas and introduce a zebrafish modeling approach that can be used more generally to dissect genetic interactions in cancer.

Neurocognitive performance profile postparathyroidectomy: a pilot study of computerized assessment.

BACKGROUND: Neurocognitive symptoms attributable to primary hyperparathyroidism are important diagnostic criteria, yet the basic characterization and assessment of neurocognitive deficits in primary hyperparathyroidism are not defined fully. METHODS: In this prospective pilot study, patients with unequivocal biochemical diagnosis of primary hyperparathyroidism were evaluated for neurocognitive performance preoperatively and postparathyroidectomy (2 weeks, 6 months) using a battery of computerized modular tests designed by LUMOSITY. The individual test scores and aggregate scores representing a subject's total neurocognitive performance profile were calculated. Statistical comparisons between groups were performed using univariate analysis and repeated measures of analysis of variance. RESULTS: In the study, 34 participants were assessed preoperatively; 18 completed all 3 assessments, 2 completed pretest and 6-month assessments, and 30 completed preoperative and 2-week postparathyroidectomy assessments. Primary hyperparathyroidism patients demonstrated significant deficits in memory, attention, mental flexibility, and speed of processing when compared with controls. Total neurocognitive performance profile score was significantly lower at the preoperative (P = .0001) and 2-week postparathyroidectomy (P = .0004) time points when compared with controls; this difference was bridged by 6 months postparathyroidectomy. CONCLUSION: Computerized neurocognitive performance profile assessment validated the neurocognitive benefits of parathyroidectomy. Additional study is needed to determine if this novel method provides long-term, objective, quantifiable, and accessible neurocognitive performance profile assessment in primary hyperparathyroidism patients and can serve as a valuable diagnostic and prognostic tool.

The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.

Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase. Shelterin includes the heterodimeric POT1-TPP1 protein, which binds the telomeric single-stranded DNA tail. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event). Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP1 (refs 15-17). Here we identify separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anticancer drug development.