Flow diagram of selection of the study patients. BB, beta blocker; ICD-10, International Classification of Disease, 10th Revision; NSBB, non-selective beta blocker; SBB, selective beta blocker.

Flow diagram of selection of the study patients. BB, beta blocker; ICD-10, International Classification of Disease, 10th Revision; NSBB, non-selective beta blocker; SBB, selective beta blocker.

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Objective: The impact of beta blockers (BBs) on survival outcomes in ovarian cancer was investigated. Methods: By using Korean National Health Insurance Service Data, Cox proportional hazards regression was performed to analyze hazard ratios (HRs) with 95% confidence intervals (CIs) adjusting for confounding factors. Results: Among 866 eligibl...

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Context 1
... with ovarian cancer (C56) and had a record of hospital admission due to ovarian cancer. Only patients who were older than 20 years of age at the time of diagnosis were included. Further, only patients who had a medical record of ≥1 year & follow up of ≥3 years before & after the diagnosis were included for better data accuracy and analysis (Fig. ...
Context 2
... the 866 ovarian cancer patients, 206 (23.8%) were BB users and 660 (76.2%) were non-users. Among the 206 BB users, 151 (73.3%) were NSBB users and 105 (51.0%) were SBB users. Fifty (24.3%) patients were taking both NSBB and SBB (Fig. ...

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Citations

... The effect of beta-blockers on the incidence and prognosis has been extensively reported in several cancers, including lung, breast, ovary and prostate cancers. [8,[20][21][22][23][24][25] A retrospective study of non-small-cell lung cancer patients who received definitive radiotherapy showed that betablocker use was associated with improved distant metastasisfree survival (HR = 0.67), disease-free survival (HR = 0.74) and OS (HR = 0.78). [20] The meta-analysis of breast cancer suggested that the use of beta-blockers significantly reduced the risk of cancer death among women with breast cancer (HR = 0.50). ...
... [21] A cohort study of ovarian cancer reported that a long duration of beta-blocker use was associated with better OS (HR = 0.26) and disease-specific survival (HR = 0.25). [22] Lu et al. suggested that beta-blocker use was an independent favorable prognostic factor for CSS in a meta-analysis of prostate cancer (HR = 0.85). [23] Preclinical studies have suggested that beta-adrenergic signaling plays a role in cancer development, including that of HCC. ...
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Introduction Preclinical data have revealed that beta-adrenergic stimulation can affect the growth and progression of different types of malignancies. Beta-adrenergic receptor blockers have been associated with improved survival in patients with many types of cancer. We performed a meta-analysis to investigate the association between beta-blocker use and hepatocellular carcinoma (HCC) prognosis. Methods In this meta-analysis, a full search was conducted using PubMed, the Cochrane library and Embase to identify all relevant studies published up to May 2021. Available hazard ratios (HRs) were extracted for overall survival (OS), cancer-specific survival (CSS) and pooled using a random-effects meta-analysis. Results Four studies involving 7252 patients with HCC met the inclusion criteria and were included in the systemic review. Three studies that reported OS data of 5148 patients were included in the meta-analysis. The random-effects model showed that beta-blocker use was associated with significantly improved OS in HCC (HR = 0.69, 95% CI = 0.54–0.88, P = 0.0031), without significant heterogeneity (I² = 41%; Q = 6.42, P = 0.18). Conclusion This meta-analysis suggested that beta-blocker use can be associated with prolonged OS of patients with HCC.
... By blocking the effects of excess catecholamine stimulation these drugs have found widespread use in the treatment of a variety of cardiovascular diseases. Interestingly, epidemiological studies have shown that β-blocker use correlates with improved ovarian cancer patient survival 31,32 although the precise underlying mechanisms have not been defined and the specific effect of carvedilol is unknown. Carvedilol is a non-selective inhibitor of β1-AR, β2-AR and also the α1-AR. ...
... In one study, 344 HGSC patients receiving a range of β-blockers had a better overall survival of 90 compared to 38.2 months 32 . In another study of ovarian cancer patients over the age of 60, the use of non-selective β-blockers (151 patients) was again associated with better survival (hazard ratio = 0.579) 31 . It has been postulated that this could be due to the known anti-proliferative effects of these drugs 39-41 but both studies group multiple different β-blocking drugs in their analysis and provide no detail on the specific effect of carvedilol. ...
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Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment.
... Previous findings have suggested that β-blockers have a potentially favorable prognostic role for several tumors (22,23). Due to the small sample size of the hypertension group in this study, we did not classify antihypertensive drugs or analyze the effects of different antihypertensive drugs on the prognosis of NPC. ...
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Background: The prognostic value of hypertension remains unknown in nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). In this study, we aimed to develop hypertension as a prognostic signature for improving the clinical outcome of non-metastatic NPC patients treated with IMRT. Methods: A clinical cohort, comprising 1,057 patients with non-metastatic, histologically proven, NPC who were treated with IMRT were retrospectively reviewed. Associations between hypertension and overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were estimated by Cox regression. A subgroup analysis of the relationship between hypertension grade and NPC prognosis was also conducted. Results: Among the 1057 patients, 94 (8.9%) had hypertension. Significant differences were observed between patients with hypertension and patients without hypertension in relation to OS (66.6% vs. 85.4%; P<0.0001), PFS (60.8% vs. 76.3%; P=0.001), LRRFS (85.3% vs. 90.5%; P=0.024), and DMFS (77.4% vs. 85.1%; P=0.048), and patients without hypertension had greater treatment success rates. The Cox analysis showed that hypertension was an independent unfavorable prognostic factor for OS [hazards ratio (HR), 2.056; P=0.001], PFS (HR, 1.716; P=0.005), and DMFS (HR, 1.658; P=0.049). The patients with more severe levels of hypertension had worse OS and LRRFS. Specifically, the 5-year OS and LRRFS for grades 1, 2, and 3 were 70.6%, 64.3%, and 62.4% (P=0.712), and 89.5%, 86.4%, and 76.1% (P=0.376), respectively. Conclusions: Hypertension is an independent adverse prognostic factor in NPC patients treated with IMRT. The question of whether the severity of hypertension affects prognosis needs to be further verified by large sample data.
... All of the included literatures were published between 2012 and 2020, with a scope of 123 to 6,626 OC cases each study. Five of the studies were performed in the United States (17,18,20,22,24), three of the studies were performed in Europe (16,25,38), two studies were performed in Korea (23,37), and one study was conducted (19) across Belgium, Canada, and Germany. All of the cohort studies were retrospectively designed, with a median follow-up duration between 17 and 91 months. ...
... For "selection" classification, three studies (16,17,20) were not assigned to full stars. For the item of "control for important factor or additional factor", two studies (19,37) were not awarded two stars since these studies had adjusted for less than two important confounder factors. For classification of "outcome", one study (19) was not assigned to full stars because of insufficient duration of follow-up. ...
... OC patients with hypertension were more likely to take beta blocker as prescription drugs, whereas OC patients without hypertension may also use beta blocker for perioperative treatment. Baek et al. (37) described a increasement in survival with post-diagnostic beta blocker use among OC patients with hypertension (HR = 0.65, 95% CI = 0.45-0.93); however, no statistically correlated was found for OC patients and normal blood pressure levels (HR = 0.60, 95% CI = 0.34-1.07). ...
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Objectives Previous experimental studies have indicated that exposure to beta blocker provides protective effects against ovarian cancer (OC). However, findings from epidemiologic studies have still been controversial. Therefore, we carried out a meta-analysis to update and quantify the correlation between post-diagnostic beta blocker usage and OC prognosis. Methods The meta-analysis had been registered at PROSPEPO. The number of registration is CRD42020188806. A comprehensive search of available literatures in English prior to April 16, 2020, was conducted in PubMed, EMBASE, and the Web of Science databases. Random-effects models were used to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Publication bias assessments, and subgroup, sensitivity, and meta-regression analyses were also performed. Results Of the 637 initially identified articles, 11 retrospective cohort studies with 20,274 OC patients were included. The summary HRs did not reveal any statistically significant associations between post-diagnostic beta blocker use and OC prognosis characteristics, such as total mortality (HR = 1.08, 95% CI = 0.92–1.27, I ² = 76.5%, n = 9), cancer-specific mortality (HR = 1.22, 95% CI = 0.89–1.67, I ² = 88.1%, n=3), and progression-free survival (HR = 0.88, 95% CI = 0.75–1.05, I ² = 0, n = 4). No evidence of publication bias was observed in current analysis. In our subgroup analyses, the majority of results were consistent with the main findings. However, several positive correlations were detected in studies with ≥800 cases (HR = 1.20, 95% CI = 1.05–1.37), no immortal time bias (HR = 1.28, 95% CI = 1.10–1.49), and adjustment for comorbidity (HR = 1.20, 95% CI = 1.05–1.37). In the meta-regression analysis, no evidence of heterogeneity was detected in the subgroups according to study characteristics and confounding factors. Conclusions Post-diagnostic beta blocker use has no statistical correlation with OC prognosis. More prospective cohort studies are necessary to further verify our results. Systematic Review Registration Identifier (CRD42020188806).
... It was found that β-blockers that bind to β 2 -adrenergic receptors (e.g. propranolol) exert beneficial effects, including the reduction of cancer incidence, attenuation of cancer progression and prolongation of survival [4][5][6][7][8][9][10][11]. These studies indicate that β-blockers might also be utilized in preventing cancer development in individuals with an increased risk of cancer. ...
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... There are several reasons that propranolol is the most often used β blocker in the investigation of neurobiology of cancer: (a) it was the first β blocker effectively used in the treatment of coronary artery disease and hypertension and therefore has been used in clinical practice for a long time [41]; (b) its pharmacological properties have been described in detail [42]; (c) there have been several retrospective studies involving patients treated with propranolol that have investigated the effect of β blockers on cancer incidence and progression [43][44][45][46][47][48][49][50][51]; (d) propranolol is readily available, inexpensive, and easily applicable in animal experiments; (e) as a clinically approved drug, off-label propranolol use by cancer patients in clinical trials is highly likely to be considered acceptable by the approving authorities of these studies. ...
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... Antihypertensive (anti-HT) drugs may be beneficial in OC either via the systemic control of hypertension or other cardiovascular diseases or by some unknown beneficial mechanism of action directly against cancer cells. Beta-blockers and especially non-selective beta-blockers have been associated with better OC specific and overall survival [10][11][12][13], though not all investigators have been able to confirm this association [14][15][16]. According to one report, angiotensin-converting enzyme (ACE)-inhibitors, another anti-HT drug group with a different mechanism of action, might improve OC survival [16]. ...
... One previous study has reported a decreased risk of OC death among post-diagnostic ACE-inhibitor users [12]. Previous investigators have also reported better OC survival among beta-blocker users [10][11][12][13]. The follow-up times in these studies have varied between 6 and 15 years with no restrictions for follow-up time or separate analyses for 5-year mortality being applied. ...
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Ovarian cancer (OC) has a poor prognosis. Hypertension may be a prognostic factor for OC, but it is unclear whether antihypertensive (anti-HT) drug use of modifies OC prognosis. We performed a population-based analysis assessing the effect of anti-HT drug use on OC mortality. A cohort of 12,122 women identified from the Finnish Cancer Registry with OC in 1995–2013 was combined with information on their anti-HT drug use during the same time period. Use of each anti-HT drug was analysed as a time-dependent variable. Analyses were run for five, ten and full follow-up (19-year) mortality with cardiovascular morbidity risk evaluated in competing risk analysis. No anti-HT drug group was associated with OC survival within five years after OC diagnosis. At ten years, a dose-dependent association was observed between pre-diagnostic ACE-inhibitor use and improved OC survival. With full follow-up, post-diagnostic high-intensity use associated with reduced OC death risk for multiple anti-HT drug groups. In competing risk analysis, only the post-diagnostic use of ACE-inhibitors associated with increased OC survival. Anti-HT drugs were not associated with survival benefits within five years after OC diagnosis. ACE-inhibitors may confer survival benefits in women with OC, but further confirmatory studies are needed.
... Several recent studies demonstrated a connection between the activation of ADRB2/PKA pathway and therapy resistance in preclinical models of prostate cancer. Additionally, retrospective studies show that the use of beta-blockers is associated with the increased survival of patients with melanomas [203,204] and ovarian cancer [205], as well as prevention of metastasis and improvement of relapse-free survival of breast cancer patients [206]. In PCa the use of beta-blockers use has been linked with decreased metastasis, [207] decreased mortality in patients with high-risk or metastatic disease, [208] and improved survival in ADT-treated patients [209]. ...
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Prostate cancer is the second most common malignancy and the fifth leading cancer-caused death in men worldwide. Therapies that target the androgen receptor axis induce apoptosis in normal prostates and provide temporary relief for advanced disease, yet prostate cancer that acquired androgen independence (so called castration-resistant prostate cancer, CRPC) invariably progresses to lethal disease. There is accumulating evidence that androgen receptor signaling do not regulate apoptosis and proliferation in prostate epithelial cells in a cell-autonomous fashion. Instead, androgen receptor activation in stroma compartments induces expression of unknown paracrine factors that maintain homeostasis of the prostate epithelium. This paradigm calls for new studies to identify paracrine factors and signaling pathways that control the survival of normal epithelial cells and to determine which apoptosis regulatory molecules are targeted by these pathways. This review summarizes the recent progress in understanding the mechanism of apoptosis induced by androgen ablation in prostate epithelial cells with emphasis on the roles of BCL-2 family proteins and “druggable” signaling pathways that control these proteins. A summary of the clinical trials of inhibitors of anti-apoptotic signaling pathways is also provided. Evidently, better knowledge of the apoptosis regulation in prostate epithelial cells is needed to understand mechanisms of androgen-independence and implement life-extending therapies for CRPC.
... This is consistent with clinical observations that patients with lung cancer who used -blockers showed extended lung cancer survival (60). It has been reported that patients with cancer undergoing -blocker therapy for associated pathology showed reduced breast cancer recurrence (61) and better survival from ovarian cancer (62). In a meta-analysis over 300,000 patients, -blocker use was associated with improved survival among patients with ovarian cancer, pancreatic cancer, and melanoma (63). ...
Article
Tumor recurrence years after seemingly successful treatment of primary tumors is one of the major causes of mortality in patients with cancer. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using dormancy models of lung and ovarian cancer, we found a specific mechanism, mediated by stress and neutrophils, that may govern this process. Stress hormones cause rapid release of proinflammatory S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase, resulting in accumulation of oxidized lipids in these cells. Upon release from neutrophils, these lipids up-regulate the fibroblast growth factor pathway in tumor cells, causing tumor cell exit from the dormancy and formation of new tumor lesions. Higher serum concentrations of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2-adrenergic receptors abrogated stress-induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress and specific neutrophil activation with early recurrence in cancer.
... Our results did not explicitly support a bene t of antihypertensive medications for the prognosis of NPC patients treated with IMRT. Previous study results suggested a potential favourable prognostic role of β-blockers for several tumours [25][26]. Moreover, a meta-analyse found that bevacizumab-induced hypertension may represent a prognostic factor in patients with metastatic colorectal cancer [27]. ...
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Purpose To investigate the prognostic value of hypertension in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Methods and Materials A total of 1057 patients with nonmetastatic, histologically proven NPC who were treated with IMRT were retrospectively reviewed. Associations between hypertension and overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were estimated by Cox regression. Results Among 1057 patients, 94 (8.9%) had hypertension. Compared to normotensive patients, the hypertensive patients were generally older, had higher body fat, were more likely to be alcohol consumers, were more often in the early stage and usually received radiotherapy alone. Compared to normotension, hypertension was significantly associated with worse OS (hazard ratio (HR), 2.20; 95% confidence interval (CI), 1.41–3.42; P = 0.000), LRRFS (HR, 2.13; 95% CI, 1.12–4.03; P = 0.021) and DMFS (HR, 1.82; 95% CI, 1.09–3.05; P = 0.023) after adjusting for covariates. Moreover, the association with OS remained unchanged regardless of smoking, body mass index (BMI), N stage and chemotherapy, whereas it was limited in the subgroup of patients who were older than 50 years, male, not alcohol consumers, in advanced T stage and in advanced clinical stage. Compared with treated hypertension, untreated hypertension was associated with increased risks for death (P = 0.221; HR, 1.88; 95% CI, 0.69–5.15), locoregional recurrence (P = 0.073; HR, 3.29; 95% CI, 0.89–12.09) and distant metastasis (P = 0.640; HR, 1.30; 95% CI, 0.44–3.83). The patients with more severe levels of hypertension had worse survival and locoregional control, although there was no statistically significant difference (P > 0.05). Conclusions Hypertension is an independent adverse prognostic factor in NPC patients treated with IMRT. The NPC patients with untreated hypertension had similar survival as those with treated hypertension. The severity of hypertension did not influence the prognosis.