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.

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.

Propranolol attenuates the establishment of conditioned context aversions: differential effects compared to MK-801 in an animal model of anticipatory nausea and vomiting.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Beta-blocker use and breast cancer outcomes: a meta-analysis.

PURPOSE: Beta blockers (BBs) are commonly used cardiovascular medications, and their association with breast cancer outcomes has been examined in several previous observational studies and meta-analyses. In this study, an updated meta-analysis was undertaken to ascertain the association between BBs and both breast cancer death (BCD) and breast cancer recurrence (BCR). METHODS: Articles were sourced from various databases up until the 14th of August 2023. Effect estimates were pooled using the random effects model, and the Higgins I2 statistic was computed to ascertain heterogeneity. Subgroup analyses were conducted by the potential for immortal time bias (ITB), the exposure period (prediagnosis vs postdiagnosis), and type of BB (selective vs non-selective). Publication bias was assessed using funnel plots and Egger's regression tests. RESULTS: Twenty-four studies were included. Pooled results showed that there was no statistically significant association between BB use and both BCD (19 studies, hazard ratio = 0.90, 95% CI 0.78-1.04) and BCR (16 studies, HR = 0.87, 95% CI 0.71-1.08). After removing studies with ITB, the associations were attenuated towards the null. There was no effect modification for either outcome when stratifying by the exposure period or type of BB. There was clear evidence of publication bias for both outcomes. CONCLUSION: In this meta-analysis, we found no evidence of an association between BB use and both BCD and BCR. Removing studies with ITB attenuated the associations towards the null, but there was no effect modification by the exposure period or type of BB.

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.

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.

Maintenance of beta-blockers and cardiac surgery-related outcomes: a prospective propensity-matched multicentre analysis.

BACKGROUND: We investigated the effects of maintaining beta-blockers on the day of surgery on the incidence of atrial fibrillation and postoperative acute kidney injury (AKI) in patients undergoing cardiac surgery. METHODS: We conducted a multicentre prospective observational study with propensity matching on patients treated with beta-blockers. We collected their baseline patient characteristics, comorbidities, and operative and postoperative outcomes. The endpoints were postoperative atrial fibrillation and AKI after cardiac surgery. RESULTS: Of the 1789 included patients, propensity matching led to 583 patients in each group. Maintenance of beta-blockers was not associated with a reduced risk of atrial fibrillation (odds ratio: 0.86 [95% confidence interval 0.66-1.14], P=0.335; 141 patients [24.2%] vs 126 patients [21.6%]). Sensitivity analysis did not demonstrate association between beta-blocker maintenance and atrial fibrillation after cardiac surgery (odds ratio: 0.93 [95% confidence interval: 0.72-1.22], P=0.625). Maintenance of beta-blockers was associated with a higher rate of norepinephrine use (415 [71.2%] vs 465 [79.8%], P=0.0001) and postoperative AKI (124 [21.3%] vs 159 [27.3%], P=0.0127). No statistically significant difference was observed in ICU length of stay. CONCLUSIONS: Maintenance of beta-blockers on the day of surgery was not associated with a reduced incidence of postoperative atrial fibrillation. However, maintenance of beta-blockers was associated with increased usage of vasopressors, potentially contributing to adverse postoperative renal events. CLINICAL TRIAL REGISTRATION: NCT04769752.

Ophthalmic complication of pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare dermatological condition which may present with ocular manifestations. We report a case of recurrent cicatricial ectropion (CE) with topical beta-blocker use in the rare dermatological condition PRP. The patient underwent release of scar tissue, lateral tarsal strip and full-thickness supraclavicular skin graft for CE following immunosuppression with methotrexate for 3 months. Postoperatively, CE recurred, with skin graft shrinkage and resumption of periocular disease activity, 8 weeks following the introduction of topical timolol. The patient was referred for further immunosuppression and substitution of timolol before consideration for further surgery. PRP has a variety of potential ocular complications. Surgery has a high risk of recurrence and should be performed when the overall disease is quiescent and drugs, which could trigger reactivation, have been discontinued and/or substituted. Skin grafts should be oversized to off-set shrinkage.

Association of preoperative beta-blocker use and cardiac complications after major noncardiac surgery: a prospective cohort study.

INTRODUCTION: Cardiac complications after major noncardiac surgery are common and associated with high morbidity and mortality. How preoperative use of beta-blockers may impact perioperative cardiac complications remains unclear. METHODS: In a multicentre prospective cohort study, preoperative beta-blocker use was ascertained in consecutive patients at elevated cardiovascular risk undergoing major noncardiac surgery. Cardiac complications were prospectively monitored and centrally adjudicated by two independent experts. The primary endpoint was perioperative myocardial infarction or injury attributable to a cardiac cause (cardiac PMI) within the first three postoperative days. The secondary endpoints were major adverse cardiac events (MACE), defined as a composite of myocardial infarction, acute heart failure, life-threatening arrhythmia, and cardiovascular death and all-cause death after 365 days. We used inverse probability of treatment weighting to account for differences between patients receiving beta-blockers and those who did not. RESULTS: A total of 3839/10 272 (37.4%) patients (mean age 74 yr; 44.8% female) received beta-blockers before surgery. Patients on beta-blockers were older, and more likely to be male with established cardiorespiratory and chronic kidney disease. Cardiac PMI occurred in 1077 patients, with a weighted odds ratio of 1.03 (95% confidence interval [CI] 0.94-1.12, P=0.55) for patients on beta-blockers. Within 365 days of surgery, 971/10 272 (9.5%) MACE had occurred, with a weighted hazard ratio of 0.99 (95% CI 0.83-1.18, P=0.90) for patients on beta-blockers. CONCLUSION: Preoperative use of beta-blockers was not associated with decreased cardiac complications including cardiac perioperative myocardial infarction or injury and major adverse cardiac event. Additionally, preoperative use of beta-blockers was not associated with increased all-cause death within 30 and 365 days. CLINICAL TRIAL REGISTRATION: NCT02573532.

Spontaneous coronary artery dissection: A review of medical management approaches.

Spontaneous coronary artery dissection (SCAD) is an underdiagnosed cause of acute coronary syndrome (ACS) that usually presents in young female patients. Risk factors include female sex, physical and emotional stressors, and fibromuscular dysplasia, and diagnosis is usually made by coronary angiography aided by intravascular ultrasound (IVUS) or optical coherence tomography (OCT). While conservative treatment is usually preferred over percutaneous coronary intervention or surgery, medical management of SCAD has been under debate. This comprehensive review aims to summarize findings from recent studies exploring various medical treatment approaches for the management of SCAD. Antiplatelet therapy with aspirin is generally safe and beneficial for SCAD patients, with dual antiplatelet (DAPT) being recommended for patients undergoing PCI. In the absence of intervention, DAPT may be given for a short period followed by a longer single-antiplatelet (SAPT) therapy with aspirin. Beta-blockers appear to be safe and effective for SCAD patients. On the other hand, fibrinolytics, anticoagulants, and glycoprotein IIa/IIIb inhibitors are contraindicated. Cardiovascular medications such as renin-angiotensin-aldosterone system (RAAS) inhibitors, mineralocorticoid receptor antagonists, and statins are not recommended in the absence of left ventricular dysfunction. Hormonal therapy is contraindicated for patients who develop SCAD during pregnancy and future pregnancy is discouraged in that patient population.

Trends in Number and Appropriateness of Prescription Medication Utilization Among Community-Dwelling Older Adults in the United States: 2011-2020.

BACKGROUND: Contemporary data on the quantity and quality of medication use among older adults are lacking. This study examined recent trends in the number and appropriateness of prescription medication use among older adults in the United States. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) between 2011 and March 2020 were used, and 6 336 adult participants aged 65 and older were included. We examined the number of prescription medication, prevalence of polypharmacy (≥5 prescription drugs), use of potentially inappropriate medication (PIM), and use of recommended medications (angiotensin-converting enzyme inhibitor [ACEI]/angiotensin receptor blockers [ARBs] plus beta-blockers among patients with heart failure and ACEI/ARBs among patients with albuminuria). RESULTS: There has been a slight increase in the prevalence of polypharmacy (39.3% in 2011-2012 to 43.8% in 2017-2020, p for trend = .32). Antihypertensive, antihyperlipidemic, antidiabetic medications, and antidepressants are the most commonly used medications. There was no substantial change in the use of PIM (17.0% to 14.7%). Less than 50% of older adults with heart failure received ACEI/ARBs plus beta-blockers (44.3% in 2017-2020) and approximately 50% of patients with albuminuria received ACEI/ARBs (54.0% in 2017-2020), with no improvement over the study period. Polypharmacy, older age, female, and lower socioeconomic status were generally associated with greater use of PIM but lower use of recommended medications. CONCLUSIONS: The medication burden remained high among older adults in the United States and the appropriate utilization of medications did not improve in the recent decade. Our results underscore the need for greater attentions and interventions to the quality of medication use among older adults.

Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Incident Cancer.

BACKGROUND: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. METHODS: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. RESULTS: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. CONCLUSIONS: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up.

Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a ß-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.

The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. METHODS: A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. RESULT: The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). CONCLUSION: Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.

Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer.

AIM: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks. METHOD: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68-1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31-1.92). CONCLUSION: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.

Color Doppler Ultrasound Indices as Predictors of Propranolol Response in Infantile Hemangioma: A Prospective Study.

OBJECTIVE: To evaluate the utility of color Doppler ultrasonography in assessing infantile hemangioma response to treatment with oral propranolol. METHODS: A prospective study was conducted between January, 2016 and December, 2022, wherein children with symptomatic (ulceration, bleeding, pain and scarring) infantile hemangioma were given oral propranol (2 mg/kg per day in three divided doses) as outpatient therapy. The clinical response was assessed three months post-initiation of treatment (intermediate clinical response) and three months post-completion of treatment (final clinical response, FCR). The primary outcome measurement was a clinical and radiological response (resistivity index (RI), pulsatility index (PI) and peak systolic velocity) to treatment. The secondary outcomes assessed were the complications related to treatment. RESULTS: Out of 601 patients who were started on propranolol, 99 developed severe adverse effects and were excluded from analysis. At FCR assessment, out of 502 participants, 64.3% (n = 323) showed excellent response, 17.7% (n = 89) showed partial, and 17.9% (n = 90) were non-responders. A significant increase in RI and PI values was noted in all children following propranolol treatment for six months. An increase > 7.5% in RI could identify responders with 92% sensitivity, 91% specificity and area under the curve (AUC) of 0.963. An increase of > 11.5% in PI could identify responders with 86% sensitivity, 91% specificity and AUC of 0.896. Patients initially showing no response but later becoming excellent responders had significantly higher RI and PI values. CONCLUSIONS: Color Doppler ultrasonography is a valuable tool in predicting the treatment outcome of infantile hemangioma using propranolol.