Long-term and short-term cardiovascular disease mortality among patients of 21 non-metastatic cancers.

INTRODUCTION: Previous studies on cardiovascular disease (CVD) death risk in cancer patients mostly focused on overall cancer, age subgroups and single cancers. OBJECTIVES: To assess the CVD death risk in non-metastatic cancer patients at 21 cancer sites. METHODS: A total of 1,672,561 non-metastatic cancer patients from Surveillance, Epidemiology, and End Results (SEER) datebase (1975-2018) were included in this population-based study, with a median follow-up of 12·7 years. The risk of CVD deaths was assessed using proportions, competing-risk regression, absolute excess risks (AERs), and standardized mortality ratios (SMRs). RESULTS: In patients with localized cancers, the proportion of CVD death and cumulative mortality from CVD in the high-competing risk group (14 of 21 unique cancers) surpassed that of primary neoplasm after cancer diagnosis. The SMRs and AERs of CVD were found higher in patients with non-metastatic cancer than the general US population (SMR 1·96 [95 %CI, 1·95-1·97]-19·85[95 %CI, 16·69-23·44]; AER 5·77-210·48), heart disease (SMR 1·94[95 %CI, 1·93-1·95]-19·25[95 %CI, 15·76-23·29]; AER 4·36-159·10) and cerebrovascular disease (SMR 2·05[95 %CI, 2·02-2·08]-24·71[95 %CI, 16·28-35·96]; AER 1·01-37·44) deaths. In the high-competing risk group, CVD-related SMR in patients with localized stage cancer increased with survival time but followed a reverse-dipper pattern in the low-competing risk group (7 of 21 cancers). The high-competing risk group had higher CVD-related death risks than the low-competing risk group. CONCLUSION: The CVD death risk in patients with non-metastatic cancer varied by cancer stage, site and survival time. The risk of CVD mortality is higher in 14 out of 21 localized cancers (high-competing cancers). Targeted strategies for CVD management in non-metastatic cancer patients are needed.

MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1 -weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

Long-term risks of cardiovascular death in a population-based cohort of 1,141,675 older patients with cancer.

BACKGROUND: previous studies have focused on the risk of cardiovascular disease (CVD)-related death in individual cancers, adolescents or all cancers. OBJECTIVE: to evaluate the risk of CVD-related death in older patients with cancer. METHODS: older patients with cancer (over 65 years) of 16 cancers diagnosed between 1975 and 2018 were screened out from the Surveillance, Epidemiology and End Results program. The proportion of deaths, competing risk regression models, standardized mortality ratios (SMRs) and absolute excess risks (AERs) were used to assess the risk of CVD-related death. RESULTS: this study included 1,141,675 older patients (median follow-up: 13.5 years). Of the 16 individual cancers, the risk of CVD death exceeded primary neoplasm death in older patients with cancers of the breast, endometrium, vulva, prostate gland, penis and melanoma of the skin over time (high competing risk group). Compared to the general older population, older patients with cancer had higher SMR and AER of CVD-related death (SMR: 1.58-4.23; AER: 21.16-365.89), heart disease-related death (SMR: 1.14-4.16; AER: 16.29-301.68) and cerebrovascular disease-related death (SMR: 1.11-4.66; AER: 3.02-72.43), with the SMR trend varying with CVD-related death competing risk classifications. The risk of CVD-related death in the high-competing risk group was higher than in the low-competing risk group. CONCLUSIONS: for older patients with cancer, six of 16 individual cancers, including breast, endometrium, vulva, prostate gland, penis and melanoma of the skin was at high risk of CVD-related death. Management for long-term cardiovascular risk in older patients with cancer is needed.

Association of KATP Variants With CMD and RAP in CAD Patients With Increased Serum Lipoprotein(a) Levels.

CONTEXT: Refractory angina pectoris (RAP) is a specific subtype of coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] and its induced coronary microvascular dysfunction (CMD) play an important role in pathogenesis of RAP, but its metabolism was mostly genetically determined. The adenosine triphosphate (ATP)-sensitive potassium channel (KATP) is involved in lipid metabolism and microvascular homeostasis and becomes a promising target for the management of Lp(a) and its related RAP. OBJECTIVE: To investigate associations of KATP variants with hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD. DESIGN, PATIENTS, SETTINGS: A total of 1148 newly diagnosed patients with CAD were prospectively selected and divided into control (Lp(a) < 180 mg/dL) and case (Lp(a) ≥ 180 mg/dL, hyperlipoprotein(a)emia) group. METHODS: 9 KATP variants were genotyped by MassARRAY system. The expression profile of exosome-derived microRNAs (exo-miRs) was identified by next-generation sequencing, and the expression levels of differentially expressed exo-miRs were evaluated by quantitative RT-PCR in verification cohort. RESULTS: Three KATP variants were associated with increased risk of hyperlipoprotein(a)emia in patients with CAD as follows: rs2285676 (AA + GA genotype, adjusted odds ratio [OR] = 1.44; 95% CI, 1.10-1.88; P = 0.008), rs1799858 (CC genotype, adjusted OR = 1.33; 95% CI, 1.03-1.73; P = 0.030), and rs141294036 (CC genotype, adjusted OR = 1.43; 95% CI, 1.10-1.87; P = 0.008). Only rs141294036 was associated with increased risk of CMD (CC genotype, adjusted OR = 1.62; 95% CI, 1.23-2.13; P = 0.001), and further with increased RAP risk (CC genotype, adjusted hazard ratio = 2.05; 95% CI, 1.22-3.43; P = 0.007) after median follow-up of 50.6 months. Between the 2 genotypes of rs141294036, 152 exo-miRs were significantly differentially expressed, but only 10 exo-miRs (miR-7110-3p, miR-548az-5p, miR-214-3p, let-7i-5p, miR-218-5p, miR-128-3p, miR-378i, miR-625-3p, miR-128-1-5p, and miR-3187-3p) were further confirmed in patients with RAP with hyperlipoprotein(a)emia and CMD. CONCLUSION: KATP rs141294036 may serve a potential genetic marker for hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD.

Metastatic patterns and prognosis of patients with primary malignant cardiac tumor.

Background: Distant metastases are independent negative prognostic factors for patients with primary malignant cardiac tumors (PMCT). This study aims to further investigate metastatic patterns and their prognostic effects in patients with PMCT. Materials and methods: This multicenter retrospective study included 218 patients with PMCT diagnosed between 2010 and 2017 from Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was utilized to identify metastatic risk factors. A Chi-square test was performed to assess the metastatic rate. Kaplan-Meier methods and Cox regression analysis were used to analyze the prognostic effects of metastatic patterns. Results: Sarcoma (p = 0.002) and tumor size¿4 cm (p = 0.006) were independent risk factors of distant metastases in patients with PMCT. Single lung metastasis (about 34%) was the most common of all metastatic patterns, and lung metastases occurred more frequently (17.9%) than bone, liver, and brain. Brain metastases had worst overall survival (OS) and cancer-specific survival (CSS) among other metastases, like lung, bone, liver, and brain (OS: HR = 3.20, 95% CI: 1.02-10.00, p = 0.046; CSS: HR = 3.53, 95% CI: 1.09-11.47, p = 0.036). Conclusion: Patients with PMCT who had sarcoma or a tumor larger than 4 cm had a higher risk of distant metastases. Lung was the most common metastatic site, and brain metastases had worst survival among others, such as lung, bone, liver, and brain. The results of this study provide insight for early detection, diagnosis, and treatment of distant metastases associated with PMCT.

Long-Term Cardiovascular Mortality among 80,042 Older Patients with Bladder Cancer.

BACKGROUND: To identify the risk of death from cardiovascular disease (CVD) in older patients with bladder cancer (BC). METHODS: This population-based study included 80,042 older BC patients (≥65 years) diagnosed between 1975 and 2018, with a mean follow-up of 17.2 years. The proportion of deaths, competing risk models, standardized mortality ratio (SMR), and absolute excess risk (AER) per 10,000 person-years were applied to identify the risk of CVD-related deaths among older BC patients. RESULTS: For older patients with BC, CVD-related death was the chief cause of death, and cumulative CVD-related mortality also exceeded primary BC as the leading cause of death mostly 5-10 years after BC diagnosis, especially in localized-stage and low-grade subgroups. The risk of short- and long-term CVD-related death in older BC patients was higher than in the general older adult population (SMR = 1.30, 95% CI 1.28-1.32; AER = 105.68). The risk of sex-specific CVD-related deaths also increased compared to the general population of older adults, including heart disease, cerebrovascular diseases, hypertension without heart disease, atherosclerosis, aortic aneurysm and dissection, and other diseases of the arteries, arterioles, and capillaries. CONCLUSIONS: CVD-related death is an important competing risk among older BC patients and has surpassed primary BC as the chief cause of death, mainly 5-10 years after BC diagnosis. The risk of CVD-related death in older patients with BC was greater than in the general population. The management of older patients with BC should focus not only on the primary cancer but also on CVD-related death.

Association of marital status with cardiovascular outcome in patients with breast cancer.

Background: The influences of marital status on cardiovascular death risk in patients with breast cancer remained unclear. This study aimed to evaluate the associations of different marital status with cardiovascular death risk in patients with breast cancer. Methods: A total of 182,666 female breast cancer patients were enrolled in this study from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2014, and was divided into two groups: married (N=107,043) and unmarried (N=75,623). A 1:1 propensity score matching (PSM) was applied to reduce inter-group bias between the two groups. Competing-risks model was used to assess the associations between different marital status and cardiovascular death risk in patients with breast cancer. Results: After PSM, marital status was an independent predictor for cardiovascular death in patients with breast cancer. Unmarried condition was associated with increased cardiovascular death risk than married condition among breast cancer patients [unadjusted model: hazard ratio (HR) =2.012, 95% confidence interval (CI): 1.835-2.208, P<0.001; Model 1: HR =1.958, 95% CI: 1.785-2.148, P<0.001; Model 2: HR =1.954, 95% CI: 1.781-2.144, P<0.001; Model 3: HR =1.920, 95% CI: 1.748-2.107, P<0.001]. With the exception of separated condition (adjusted HR =0.886, 95% CI: 0.474-1.658, P=0.705), further unmarried subgroups analysis showed that the other three unmarried status were associated with increased cardiovascular death risk as follows: single (adjusted HR =1.623, 95% CI: 1.421-1.853, P<0.001), divorced (adjusted HR =1.394, 95% CI: 1.209-1.608, P<0.001), and widowed (adjusted HR =2.460, 95% CI: 2.227-2.717, P<0.001). In particularly, widowed condition showed the highest cardiovascular death risk in all 4 unmarried subgroups. Conclusions: Unmarried condition (e.g., single, divorced and widowed) was associated with elevated cardiovascular death risk compared with their married counterparts in patients with breast cancer, suggesting that more attention and humanistic care should be paid to unmarried breast cancer patients (especially the widowed patients) in the management of female breast cancer patients.

Cardiovascular and Other Competing Causes of Death in Male Breast Cancer Patients: A Population-Based Epidemiologic Study.

PURPOSE: Male breast cancer (MBC) is a rare disease that tends to occur in elderly men. Little is known about the causes of death in MBC because of the small sample size of most studies. This study aimed to investigate the causes of death in MBC patients. PATIENTS AND METHODS: MBC patient data were obtained from the Surveillance, Epidemiology, and End Results database (1975-2016). Time trends of MBC mortality in the US population were analyzed using Joinpoint software. We calculated the proportion of each cause of death in the overall cohort and in different patient subgroups. Competing risk models were used to calculate cumulative mortality at different follow-up times. The risk of cardiovascular death (CVD) in MBC patients was compared to that of the age-matched general population by calculating standardized mortality ratio (SMR). RESULTS: In total, 6426 patients were included in the analysis. MBC mortality rate increased between 2004 and 2019 (annual percentage change=1.16, 95% confidence interval [CI]: 0.50, 1.80). There were 1757 patients (27.3%) who died of non-breast cancer causes. CVD was the leading cause of death in patients who were elderly or had localized disease. MBC patients had a 6.58-fold higher risk of CVD than the general population (SMR=6.58, 95% CI: 6.14, 7.05). CONCLUSION: Non-breast cancer death accounts for the majority of deaths in MBC patients who are elderly or have localized cancer. Compared to the general population, MBC patients have an increased risk of CVD. These results highlight the importance of monitoring cardiovascular comorbidities in MBC patients.

Cardiovascular Death Risk in Primary Central Nervous System Lymphoma Patients Treated With Chemotherapy: A Registry-Based Cohort Study.

PURPOSE: To study the cardiovascular death (CVD) risk in primary central nervous system lymphoma (PCNSL) patients with chemotherapy. METHODS: We obtained 2,020 PCNSL participants and 88,613 non-central nervous system lymphoma (NCNSL) participants with chemotherapy from Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. A 1:3 propensity score matching (PSM) was used to reduce the imbalance between PCNSL participants with and without chemotherapy, as well as the imbalance between PCNSL and NCNSL participants with chemotherapy. Competing risks regressions were conducted to evaluate the independent influence of chemotherapy on CVD. RESULTS: After 1:3 PSM, the CVD risk in PCNSL patients with chemotherapy was lower than those without chemotherapy [decreased 53%, adjusted HR, 0.469 (95% CI, 0.255-0.862; P = 0.015)] as well as NCNSL patients with chemotherapy [decreased 36%, adjusted HR in model 1, 0.636 (95% CI, 0.439-0.923; P = 0.017)]. The CVD risk of chemotherapy decreased in PCNSL patients with age at diagnosis >60 years old [adjusted HR, 0.390 (95% CI, 0.200-0.760; P = 0.006)], and those patients diagnosed at 2010 to 2015 [adjusted HR, 0.339 (95% CI, 0.118-0.970; P = 0.044)]. CONCLUSION: PCNSL patients with chemotherapy are associated with lower CVD risk. Our findings may provide new foundations for that chemotherapy is the first-line treatment for PCNSL patients, according to a cardiovascular risk perspective.

Prognostic Impacts of Tumour Size on Patients With Primary Cardiac Sarcoma.

BACKGROUND: Primary cardiac sarcoma (PCS) is a deadly disease. The impacts of tumour size on prognosis and surgical outcomes in PCS patients remains unclear. Here, we evaluate the impact of tumour size on overall survival (OS) and cancer-specific survival (CSS) of PCS patients to provide a reference for the surgical treatment. METHODS: A total of 261 PCS participants enrolled from 1983 to 2016 were identified from the Surveillance, Epidemiology, and End Results database. Using the X-tile program, we classified the tumour size into 2 subgroups: ≤ 4.0 cm and > 4.0 cm. The Kaplan-Meier method was used to determine OS and CSS. Univariate and multivariate Cox regression analyses were used to identify the independent prognostic impacts of tumour size and surgery in the 2 subgroups (≤ 4.0 cm vs > 4.0 cm). RESULTS: With the use of 4.0 cm as a cutoff value, tumour size seemed to be an independent prognostic factor for OS (P = 0.009) and CSS (P = 0.014) of PCS patients. Surgery improved the OS (P = 0.017) and CSS (P = 0.040) in PCS patients with tumour size > 4.0 cm but not in with tumour size ≤ 4.0 cm (both P > 0.05). CONCLUSIONS: Tumour size of > 4.0 cm is an independent predictor of poor prognosis and is associated with the surgical outcomes in PCS patients. Surgery significantly improves the prognosis in PCS patients with tumour size > 4.0 cm. Our findings have the potential to assist clinicians to better evaluate the prognosis of PCS patients and develop optimal therapeutic strategies.

Increased Risk of Cardiovascular Death in Breast Cancer Patients Without Chemotherapy or (and) Radiotherapy: A Large Population-Based Study.

BACKGROUND: Cardiovascular death (CVD) in breast cancer patients without chemotherapy (CT) or (and) radiotherapy (RT) has not been studied yet. This study evaluates the correlation between breast cancer and CVD risk independent of chemotherapy or (and) radiotherapy. METHODS: Data of female breast cancer patients without receiving CT or RT were retrieved from the Surveillance, Epidemiology, and End Result (SEER) database (2004-2015). Data were divided into two cohorts: tumor resection cohort and no resection cohort. The CVD risk in patients was expressed as standardized mortality ratios (SMRs). A 1:1 propensity score matching (PSM) was applied to balance inter-group bias, and competing risk regressions were utilized to evaluate the impact of tumor resection on CVD. RESULTS: The CVD risk was significantly higher (SMR = 2.196, 95% CI: 2.148-2.245, P<0.001) in breast cancer patients who did not receive CT or RT compared to the general population. Breast cancer patients without tumor resection showed higher CVD risk than patients who underwent tumour resection (tumor resection SMR = 2.031, 95% CI: 1.983-2.079, P<0.001; no resection SMR = 5.425, 95% CI: 5.087-5.781, P<0.001). After PSM, the CVD risk among patients without tumor resection indicated an increase of 1.165-fold compared to patients with tumor resection (HR=1.165, 95% CI: 1.039-1.306, P=0.009). CONCLUSIONS: Female breast cancer patients are at higher risk of CVD despite unexposure to cardio-toxic CT or RT. However, female breast cancer patients subjected to tumor resection have decreased CVD risk. These results indicated that monitoring female breast cancer patients not receiving RT or CT might serve as a preventative measure against CVD.

Nomograms and risk classification systems predicting overall and cancer-specific survival in primary malignant cardiac tumor.

BACKGROUND: Primary malignant cardiac tumors (PMCTs) are fatal, but up to now, there is still a lack of survival prediction model for prognosis evaluation. We developed nomograms to predict overall survival (OS) and cancer-specific survival (CSS) for PMCTs by the Surveillance, Epidemiology, and End Result (SEER) database. METHODS: A total of 506 PMCTs participants were identified in the SEER database from 1973 to 2014 and were randomly assigned into the training cohort (N = 354) and the validation cohort (N = 152). The prognostic factors for PMCTs were identified by Kaplan-Meier and multivariate Cox analysis and further incorporated to build OS and CSS nomograms. The nomograms were internally and externally validated via concordance indexes (C-index) and calibration curves. RESULTS: The independent prognostic factors for OS and CSS in PMCTs were associated with age at diagnosis, histopathology, tumor stage, cancer-directed surgery, and chemotherapy (all P < .05). In the internal validation, the C-index values were 0.71 (95% confidence interval [CI]: 0.68-0.75) for OS nomogram, and 0.70 (95% CI: 0.67-0.74) for CSS nomogram. In the external validation, the C-index values were 0.71 (95% CI: 0.66-0.77) for OS nomogram, and 0.71 (95% CI: 0.65-0.77) for CSS nomogram. The calibration curves of internal and external validation showed consistency between the nomograms and the actual observation. The risk stratification of PMCTs was significant distinction (P < .05). CONCLUSION: We developed and validated credible nomograms to predict OS and CSS in PMCTs. These nomograms can be offered to clinicians to more precisely estimate the survival and identify risk stratification of PMCTs.

Application of nomograms to predict overall and cancer-specific survival in patients with chordoma.

BACKGROUND: The survival prediction of patients with chordoma is difficult to make due to the rarity of this oncologic disease. Our objective was to apply a nomogram to predict survival outcomes in individuals with chordoma of the skull base, vertebral column, and pelvis. METHODS: A total of 558 patients with chordoma between 1973 and 2014 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors in patients with chordoma were identified via univariate and multivariate Cox analysis. Then these prognostic factors were incorporated into a nomogram to predict 3- and 5-year overall survival and cancer-specific survival rates. Internal and external data were used to validate the nomograms. Concordance indices (C-indices) were used to estimate the accuracy of this nomogram system. RESULTS: A total of 558 patients were randomly assigned into a training cohort (n = 372) and a validation cohort (n = 186). Age, surgical stage, tumor size, histology, primary site, and use of surgery were identified as independent prognostic factors via univariate and multivariate Cox analysis (all p < 0.05) and further included to establish the nomogram. The C-indices for overall survival and cancer-specific survival prediction of the training cohort were 0.775 (95% confidence interval, 0.770-0.779) and 0.756 (95% confidence interval, 0.749 -0.762). The calibration plots both showed an excellent consistency between actual survival and nomogram prediction. CONCLUSION: Nomograms were constructed to predict overall survival and cancer-specific survival for patients with chordoma of the skull base, vertebral column, and pelvis. The nomogram could help surgeons to identify high risk of mortality and evaluate prognosis in patients with chordoma.

Simvastatin attenuated rat thoracic aorta remodeling by decreasing ROCK2­mediated CyPA secretion and CD147­ERK1/2­cyclin pathway.

Reactive oxygen species­induced cyclophilin A (CyPA) release from vascular smooth muscle cells (VSMCs) may be inhibited by simvastatin in vitro. The present study aimed to further examine the effect of simvastatin on serum CyPA levels and the basigin (CD147)­extracellular signal­regulated kinase (ERK) 1/2­cyclin pathway during thoracic aorta remodeling. The mechanisms through which simvastatin may inhibit CyPA secretion from VSMCs were further investigated. Serum CyPA levels and the expression kinetics of CyPA­associated signaling pathways were examined following simvastatin treatment in rat thoracic aortas during hypertension. Cell lysates were prepared from middle layer of thoracic aortas at 1, 4, 8 and 12 weeks subsequent to surgery. ELISA analysis revealed that serum CyPA levels were gradually increased with the progression of thoracic aorta remodeling. Western blotting demonstrated that the expression of CD147, phosphorylated­ERK1/2, cyclin D1, cyclin A, and cyclin E were increased with the progression of thoracic aorta remodeling. Simvastatin administration for 4, 8 and 12 weeks diminished all these changes, as observed in the hypertensive group. VSMCs from simvastatin­treated rats secreted a decreased amount of CyPA compared with VSMCs from hypertensive rats. In addition, pretreatment with geranylgeraniol partly reversed the inhibitory effect of simvastatin on LY83583­induced CyPA secretion in cultured VSMCs, whereas GGTI­298 and KD025 [a selective Rho­associated protein kinase 2 (ROCK2) inhibitor] mimicked the inhibitory effect of simvastatin. The present study demonstrated that simvastatin alleviated thoracic aorta remodeling by reducing CyPA secretion and expression of the CD147­ERK1/2­cyclin signaling pathway. In addition, the results of the present study demonstrated that the Rho­ROCK2 pathway mediated CyPA secretion from VSMCs.