The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

NON-SELECTIVE BETA-BLOCKERS IN CIRRHOTIC PATIENTS WITH REFRACTORY ASCITES: WHERE ARE WE?

BACKGROUND: The established use of non-selective beta-blockers (NSBB) in the primary and secondary prevention of esophageal varices has recently been questioned in the subgroup of patients with diuretic-refractory ascites. OBJECTIVE: Critically analyze the body of evidence on the topic in order to assist clinical decisions. METHODS: A literature review was carried out in the Pubmed® and Scielo® databases. In total, 20 articles between 2010 and 2023 were read by independent researchers. CONCLUSION: It remains doubtful whether the use of NSBB is deleterious in cirrhotic patients with refractory ascites, however our literature review allows us to conclude that these drugs should not be proscribed in these patients. On the contrary, a doctor-patient decision based on tolerability and hemodynamic parameters certainly seems to be a safe conduct.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention - part 4: propranolol.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing propranolol for migraine prophylaxis. METHODS: We report methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared propranolol with placebo for migraine prophylaxis in adults. The outcomes of interest were informed by the Core outcome set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in monthly migraine days, the reduction of monthly migraine days, and the number of adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB (risk of bias) 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded twenty trials (n = 1291 patients) eligible for data synthesis and analysis. The analysis revealed a moderate certainty evidence that propranolol leads to a reduction in monthly migraine days versus placebo (-1.27; 95% CI: -2.25 to -0.3). We found moderate certainty evidence that propranolol increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo with a relative risk of 1.65 (95% CI 1.41 to 1.93); absolute risk difference: 179 more per 1,000 (95% CI 113 to 256). We found high certainty evidence that propranolol increases the proportion of patients who discontinue due to adverse events compared to placebo with a risk difference of 0.02 (95% CI 0.00 to 0.03); absolute risk difference: 20 more per 1,000 (95% CI 0 to 30). CONCLUSIONS: The present meta-analysis shows that propranolol has a prophylactic role in migraine, with an overall acceptable tolerability profile. Combining these results with its long-standing use and its global availability at a low cost confirms its role as a first line agent in the prophylaxis of migraine.

Consumer wearable devices for evaluation of heart rate control using digoxin versus beta-blockers: the RATE-AF randomized trial.

Consumer-grade wearable technology has the potential to support clinical research and patient management. Here, we report results from the RATE-AF trial wearables study, which was designed to compare heart rate in older, multimorbid patients with permanent atrial fibrillation and heart failure who were randomized to treatment with either digoxin or beta-blockers. Heart rate (n = 143,379,796) and physical activity (n = 23,704,307) intervals were obtained from 53 participants (mean age 75.6 years (s.d. 8.4), 40% women) using a wrist-worn wearable linked to a smartphone for 20 weeks. Heart rates in participants treated with digoxin versus beta-blockers were not significantly different (regression coefficient 1.22 (95% confidence interval (CI) -2.82 to 5.27; P = 0.55); adjusted 0.66 (95% CI -3.45 to 4.77; P = 0.75)). No difference in heart rate was observed between the two groups of patients after accounting for physical activity (P = 0.74) or patients with high activity levels (≥30,000 steps per week; P = 0.97). Using a convolutional neural network designed to account for missing data, we found that wearable device data could predict New York Heart Association functional class 5 months after baseline assessment similarly to standard clinical measures of electrocardiographic heart rate and 6-minute walk test (F1 score 0.56 (95% CI 0.41 to 0.70) versus 0.55 (95% CI 0.41 to 0.68); P = 0.88 for comparison). The results of this study indicate that digoxin and beta-blockers have equivalent effects on heart rate in atrial fibrillation at rest and on exertion, and suggest that dynamic monitoring of individuals with arrhythmia using wearable technology could be an alternative to in-person assessment. ClinicalTrials.gov identifier: NCT02391337 .

Prescribing trends of glaucoma medication in Korea from 2007 to 2020: A nationwide population-based study.

PURPOSE: Investigating long-term trends in glaucoma medication. METHODS: All patients diagnosed with glaucoma and prescribed glaucoma eye drops between 2007 and 2020 in Korea's Health Insurance Review and Assessment Service database participated in this study. A weight was assigned to each prescription using the reciprocal of the total number of prescriptions received by the individual in that year. The number of patients who received each type of glaucoma eye drop prescription was calculated by summing the weights for each year. RESULTS: During the study period, prostaglandin analog eye drop monotherapy was the most frequently given type of glaucoma eye drop prescription. Until 2008, the second most frequently given type of glaucoma eye drop prescription was beta blocker eye drop monotherapy; thereafter, it changed to carbonic anhydrase inhibitor/beta blocker fixed-combination eye drop monotherapy. The prescription proportion of single-ingredient glaucoma eye drops decreased (-1.290%/year, P < 0.001), whereas that of fixed-combination glaucoma eye drops increased (1.291%/year, P < 0.001). The number of glaucoma eye drops prescribed per patient remained constant (-0.00030/year, P = 0.167) with an average of 1.302, while the number of active ingredients prescribed per patient increased (0.01737/year, P < 0.001) from 1.659 in 2007 to 1.896 in 2020. CONCLUSION: Over 14 years, there was no change in the number of glaucoma eye drops prescribed to individual patients in Korea. However, the number of active ingredients prescribed increased owing to the increased prescription of fixed-combination eye drops. The current trends in glaucoma medication are expected to help establish future treatment strategies.

Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Comparison of allergy prevalence using brinzolamide 1.0% / brimonidine 0.2% fixed combination with and without ß-blocker in glaucoma patients: a retrospective cohort study.

BACKGROUND: Glaucoma treatment often involves multi-drug regimens, which can lead to poor adherence and side effects. Fixed-dose combinations aim to improve adherence and reduce side effects compared to traditional therapies. This study aimed to compare the prevalence and clinical characteristics of ocular allergy in glaucoma patients using brinzolamide 1.0%/brimonidine 0.2% fixed combination (BBFC), with and without concurrent ß-blocker. METHODS: Of these, 176 patients used a ß-blocker concurrently, whereas 96 patients did not. Allergy prevalence, allergy type, and allergy occurrence time were compared between the concurrent and non-concurrent ß-blocker-usage groups. Ocular allergies were classified and evaluated using Kaplan-Meier survival analysis. RESULTS: Allergy prevalence was 10.23% and 15.63% (p = 0.193), whereas allergy occurrence time was 15.92 ± 13.80 months and 6.26 ± 6.20 months (p = 0.04) in the concurrent and non-concurrent ß-blocker-usage groups, respectively. Kaplan-Meier survival analysis indicated that half of the allergies in the concurrent ß-blocker-usage group occurred within 12.5 months, with the BBFC discontinuation rate gradually increasing up to 36 months. Contrarily, half of the allergies in the non-concurrent ß-blocker-usage group occurred within 3.3 months, with a rapid increase in BBFC discontinuation rate the first 6 months. Intergroup differences in allergy types were significant (p = 0.015). Among all patients with allergy, the average allergy occurrence time of blepharoconjunctivitis, papillary conjunctivitis, and follicular conjunctivitis was 12.52, 9.53, and 13.23 months, respectively. Follicular conjunctivitis tended to occur later than papillary conjunctivitis (p = 0.042). In the concurrent ß-blocker-usage group, follicular conjunctivitis was the most prevalent allergy type (61.1%), whereas papillary conjunctivitis was the most common (66.7%) in in the non-concurrent ß-blocker-usage group. CONCLUSIONS: Concurrent use of ß-blocker with BBFC decreases allergy prevalence, delays allergy onset, and predominantly results in follicular conjunctivitis, thereby facilitating longer treatment duration. Understanding these characteristics of allergy in BBFC users is useful to manage patients and improve treatment adherence. This study provides insights into the role of ß-blockers in modulating ocular allergy in BBFC-treated glaucoma patients, highlighting implications for clinical practice and patient education.

Who Can Receive Clinical Benefit from Mid-Term Vericiguat Add-on Therapy Among Patients with Systolic Heart Failure Receiving Quadruple Medical Therapy?

Vericiguat, a soluble guanylate cyclase stimulator known for augmenting cyclic guanosine monophosphate production, has garnered substantial clinical attention in patients with systolic heart failure. Despite its proven efficacy, discerning the specific subset of individuals who can enjoy clinical advantages from vericiguat therapy in contemporary real-world clinical practice, particularly among the individuals undergoing "quadruple medical therapy" comprising administration of a beta-blocker, angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter 2 inhibitor, remains an unresolved query. This study involved patients undergoing 3-month vericiguat therapy alongside complete quadruple medical therapy in a contemporary real-world clinical practice. Baseline characteristics associated with the primary outcome, defined as a reduction in serum NT pro-B-type natriuretic peptide (BNP) levels over the 3-month therapeutic duration, were scrutinized. A cohort of 24 patients (median age: 66 years; 20 males) were included. All participants diligently adhered to the 3-month vericiguat therapy in conjunction with the quadruple medical regimen. A higher baseline systolic blood pressure emerged as an independent factor linked to the primary outcome, yielding an adjusted odds ratio of 1.31 (95% confidence interval: 1.03-1.65, P = 0.026) at a threshold of 105 mmHg. This threshold notably stratified the trajectories of serum NT pro-BNP levels during the 3-month vericiguat therapy. In conclusion, preservation of baseline systolic blood pressure emerged as a pivotal determinant for reaping the clinical benefits from mid-term vericiguat therapy among patients with systolic heart failure receiving quadruple medical therapy.

Characteristics of the phenotypes in prevalent and incident cases of heart failure in primary care: IBERICAN study.

BACKGROUND: The management in primary care (PC) of the patients with Heart Failure (HF) is different from the management hospital, in a special way compared to cardiology departments. OBJECTIVE: To define the characteristics in both phenotypes of HF in prevalent and incident cases of HF in patients recruited in a large PC sample. METHODS: We proposed a and longitudinal analyses, in patients of the IBERICAN cohort, that recruited 8,066 patients in the Spanish primary care system, with 15,488 patients-years of follow-up. Of them, 252 patients (3.1%) had diagnoses of HF. HF was classified according to the 2014 guidelines in two groups: HF with a reduced eject fraction or HFrEF (LVEF < 50%) and HF with preserved eject fraction or HFpEF (LVEF ≥ 50%). Recommended treatment was defined as the patient receiving drug treatment with Renin-Angiotensin-System (RAS) blockers with beta-blockers and, optionally, spironolactone. The incidence of new cases of HF was calculated in the 7,814 patients without HF in the inclusion visit. Finally, we analysed which variables associated the onset new cases and get the hazard ratio (HR) with the confidence interval at 95% ([95%CI]). Clinical trials register: NCT02261441 (02/05/2017). RESULTS: The HFpEF was the most frequent phenotype in prevalent cases (61.1%) and incident cases (73.9%). Patients with HFrEF had a higher prevalence of coronary heart disease (p = 0.008) and PAD (p = 0.028), and no statistically significant differences was observed in the therapeutic groups used between both groups. The incidence of HF was 12.8 cases/1000 inhabitants/year, 35.6% of them was diagnosed in PC. The renin-angiotensin system blockers were more used in PC (60%) and beta-blockers (100%) and spironolactone (60%) in hospital. The female sex showed a protective effect for incident cases (0.51 [0.28-0.92]); and AF (HR [95%CI]: 2.90 [1.51-5.54]), coronary heart disease (HR [95%CI]: 2.18 [1.19-4.00]) and hypertension (HR [95%CI]: 1.91 [1.00-3.64]) increased the risk of developing HF. CONCLUSIONS: HF phenotype more frequent and incident in PC was the HFpEF, but only one third of them are diagnosed in PC level. The female sex showed a protective effect and atrial fibrillation, ischaemic heart disease and hypertension increased the risk of develop HF.

Effect of low blood pressure on prognosis of acute heart failure.

Low blood pressure (BP) is associated with poor outcomes in patients with heart failure (HF). We investigated the influence of initial BP on the prognosis of HF patients at admission, and prescribing patterns of HF medications, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and beta-blockers (BB). Data were sourced from a multicentre cohort of patients admitted for acute HF. Patients were grouped into heart failure reduced ejection fraction (HFrEF) and HF mildly reduced/preserved ejection fraction (HFmrEF/HFpEF) groups. Initial systolic and diastolic BPs were categorized into specific ranges. Among 2778 patients, those with HFrEF were prescribed ACEi, ARB, or BB at discharge, regardless of their initial BP. However, medication use in HFmrEF/HFpEF patients tended to decrease as BP decreased. Lower initial BP in HFrEF patients correlated with an increased incidence of all-cause death and composite clinical events, including HF readmission or all-cause death. However, no significant differences in clinical outcomes were observed in HFmrEF/HFpEF patients according to BP. Initial systolic (< 120 mmHg) and diastolic (< 80 mmHg) BPs were independently associated with a 1.81-fold (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.349-2.417, p < 0.001) and 2.24-fold (OR 2.24, 95% CI 1.645-3.053, p < 0.001) increased risk of long-term mortality in HFrEF patients, respectively. In conclusion, low initial BP in HFrEF patients correlated with adverse clinical outcomes, and BP < 120/80 mmHg independently increased mortality. However, this relationship was not observed in HFmrEF/HFpEF patients.

Nineteen-Year-Old Woman with Symptomatic Intramuscular Thigh Hemangioma-Radiographic Changes and Management: A Case Report.

CASE: We report a case of an intramuscular thigh hemangioma in a 19-year-old woman with a several year history of atraumatic thigh pain. Radiographs obtained by her primary care physician demonstrated periosteal bone reaction, prompting referral to Orthopaedic Oncology department. The patient had successful symptomatic management with propranolol. CONCLUSION: The case highlights the diagnosis and potential treatments. In a stepwise approach to care for symptomatic benign vascular lesions, propranolol has been a proven therapeutic option and may be a useful first-line therapy for symptomatic hemangiomas.

Investigating the Relationship Between Acne and Vasodilatory Medications in a Hospital-Wide Adult Population.

Acne vulgaris is a common chronic dermatological condition characterized by obstruction and inflammation of pilosebaceous units. Recent research on a different dermatologic condition has demonstrated that the use of vasodilatory medications is associated with a decreased relative risk of rosacea. This finding is significant due to the overlapping inflammatory pathways involved in rosacea and acne. Herein, a retrospective cohort study was designed to determine the correlation between vasodilator usage and the risk of developing acne within 5 years, contrasting it with thiazide diuretics, chosen as a control due to its non-vasodilatory antihypertensive mechanism and availability of data. Angiotensin-converting enzyme (ACE) inhibitors (RR, 0.775; 95% CI, 0.727-0.826; P<0.05), angiotensin receptor blockers (ARBs) (RR, 0.739; 95% CI, 0.685-0.797; P<0.05), beta-blockers (BB) (RR, 0.829; 95% CI, 0.777-0.885; P<0.05), and calcium channel blockers (CCB) usage (RR, 0.821, 95% CI, 0.773-0.873; P<0.05) were associated with a significantly lower risk of developing acne within 5 years of initiating therapy compared to thiazide diuretics. It is unclear if thiazide diuretics are more likely to cause acne within the adult population or if vasodilators are protective against the development of acne. Finding mechanisms and therapeutics that lower the risk of developing acne is of significant public health interest, and this study provides a step toward this endeavor. Further research is required to uncover the underlying mechanisms for this reduction in the development of acne.  J Drugs Dermatol. 2024;23(6):446-449.     doi:10.36849/JDD.8362.

The heart rate response to the 6-min walk test in atrial fibrillation patients with or without beta-blockers: Referring to patients with sinus rhythm.

BACKGROUND: The aim was to evaluate the effect of beta-blockers (BB) on the response of heart rate (HR) to 6-min walk test (6MWT) in atrial fibrillation (AF) and whether the AF patients treated with BB have a similar HR response to 6MWT as the AF and sinus rhythm (SR) patients without BB treatment at the same resting HR level. METHODS: The before-after study involving 74 AF patients was to evaluate the effect of BB treatment (pre-BB and with BB). The comparison study included 74 BB-treated AF patients (with BB), 74 matched AF patients without BB (no BB), and 74 SR patients. The percentage increase amplitude of HR (HR-PIA) in 6MWT was calculated: [(the exercise HR - the resting HR)/(the resting HR)] × 100%. RESULTS: The before-after study showed that BB treatment decreased the resting and mean exercise HR (98.6 ± 15.2 vs. 85.5 ± 11.2 bpm and 121.3 ± 17.3 vs. 109.0 ± 16.7 bpm) during 6MWT. The comparison study demonstrated that against the SR, the AF with BB and no BB groups have higher mean exercise HR-PIA (28.2 ± 17.1% and 22.0 ± 9.6%, vs. 6.9 ± 3.7%) when their resting HR is similar. Moreover, the mean exercise HR-PIA was also significantly higher in the with BB group than in the no BB group. CONCLUSION: In AF patients with relatively higher resting HR, BB treatment could decrease the resting and exercise HR during 6MWT. However, BB treatment could not effectively attenuate the exercise HR rise as compared with AF without BB treatment, even with similar resting HR levels.

Therapies for Cirrhotic Cardiomyopathy: Current Perspectives and Future Possibilities.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.

Role of transforming growth factor-ß1 pathway in angiogenesis induced by chronic stress in colorectal cancer.

BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or ß-adrenergic receptor (ß-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-ß (TGF-ß) receptor Type I kinase (Ly2157299) in vitro. TGF-ß1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-ß1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-ß1 signaling during this process. In addition, ß-AR/TGF-ß1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.