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BMJ Open Jun 2024Norepinephrine (NE) is the first-line recommended vasopressor for restoring mean arterial pressure (MAP) in vasoplegic syndrome (vs) following cardiac surgery with...
Norepinephrine weaning guided by the Hypotension Prediction Index in vasoplegic shock after cardiac surgery: protocol for a single-centre, open-label randomised controlled trial - the NORAHPI study.
INTRODUCTION
Norepinephrine (NE) is the first-line recommended vasopressor for restoring mean arterial pressure (MAP) in vasoplegic syndrome (vs) following cardiac surgery with cardiopulmonary bypass. However, solely focusing on target MAP values can lead to acute hypotension episodes during NE weaning. The Hypotension Prediction Index (HPI) is a machine learning algorithm embedded in the Acumen IQ device, capable of detecting hypotensive episodes before their clinical manifestation. This study evaluates the clinical benefits of an NE weaning strategy guided by the HPI.
MATERIAL AND ANALYSIS
The Norahpi trial is a prospective, open-label, single-centre study that randomises 142 patients. Inclusion criteria encompass adult patients scheduled for on-pump cardiac surgery with postsurgical NE administration for vs patient randomisation occurs once they achieve haemodynamic stability (MAP>65 mm Hg) for at least 4 hours on NE. Patients will be allocated to the intervention group (n=71) or the control group (n=71). In the intervention group, the NE weaning protocol is based on MAP>65 mmHg and HPI<80 and solely on MAP>65 mm Hg in the control group. Successful NE weaning is defined as achieving NE weaning within 72 hours of inclusion. An intention-to-treat analysis will be performed. The primary endpoint will compare the duration of NE administration between the two groups. The secondary endpoints will include the prevalence, frequency and time of arterial hypotensive events monitored by the Acumen IQ device. Additionally, we will assess cumulative diuresis, the total dose of NE, and the number of protocol weaning failures. We also aim to evaluate the occurrence of postoperative complications, the length of stay and all-cause mortality at 30 days.
ETHICS AND DISSEMINATION
Ethical approval has been secured from the Institutional Review Board (IRB) at the University Hospital of Amiens (IRB-ID:2023-A01058-37). The findings will be shared through peer-reviewed publications and presentations at national and international conferences.
TRIAL REGISTRATION NUMBER
NCT05922982.
Topics: Humans; Vasoplegia; Hypotension; Prospective Studies; Norepinephrine; Cardiac Surgical Procedures; Vasoconstrictor Agents; Randomized Controlled Trials as Topic; Postoperative Complications; Machine Learning
PubMed: 38926148
DOI: 10.1136/bmjopen-2024-084499 -
Discovery Medicine Jun 2024Atypical acinar cell foci (AACF) seen in pancreatic cancer are fatal and have been studied with some causative agents. However, for the first time, the effect of...
BACKGROUND
Atypical acinar cell foci (AACF) seen in pancreatic cancer are fatal and have been studied with some causative agents. However, for the first time, the effect of acetylsalicylic acid with nitric oxide (NO-ASA) on AACF was examined in this study. Although NO-ASA has very successful inhibitory effects against some types of cancer, it has not been investigated whether they can exert their inhibition effects on AACFs.
METHODS
For experimental purposes, 21 14-day-old male Wistar albino rats were used. Azaserine (30 mg/kg) was dissolved in 0.9% NaCl solution and injected intraperitoneally (i.p.) into 14 rats, except for the Control group (Cont) rats, for three weeks. Rats that were injected with azaserine once a week for three weeks and those that did not receive treatment were divided into experimental groups. 15 days after the end of the azaserine injection protocol, NO-ASA was applied to azaserine with NO-ASA (Az+NO-ASA) group rats three consecutive times with an interval of 15 days by gavage. At the end of the 5-month period, pancreatic tissue was dissected and weighed. Pancreas preparations prepared from histological sections were examined for AACF burden and analyzed via a video image analyzer. One-way analysis of variance (ANOVA) non-parametric statistical analyses were performed to test whether there was a difference between the averages of the experimental and Control groups.
RESULTS
AACF burden in both groups injected with azaserine was found to be statistically significant in all categories compared to that of the Control group ( < 0.05). The average Calculated Estimated average AACF volume (mm) values, the Calculated estimated average AACF diameter (μm), the Estimated average number of AACF per unit volume, AACF rate as a % of Calculated Organ Volume were higher in the AzCont group rats than in the Az+NO-ASA group, when compared, and there was an important level statistical difference between the groups ( < 0.05). It was determined that for all parameters AACFs load in Az+NO-ASA group rats were significantly reduced compared to that of AzCont group rats ( < 0.05).
CONCLUSIONS
We observed that, as a result of the NO-ASA application, the experimental AACF focus ratio created by azaserine injection was significantly inhibited. The inhibitory effect of AACFs in Az+NO-ASA group rats may have resulted from the significant and independent chemopreventive and/or chemotherapeutic activity of NO-ASA against exocrine pancreatic AACF foci.
Topics: Animals; Male; Aspirin; Rats, Wistar; Nitric Oxide; Rats; Pancreatic Neoplasms; Acinar Cells; Pancreas, Exocrine
PubMed: 38926102
DOI: 10.24976/Discov.Med.202436185.106 -
Heart (British Cardiac Society) Jun 2024Despite restoration of epicardial blood flow in acute ST-elevation myocardial infarction (STEMI), inadequate microcirculatory perfusion is common and portends a poor...
BACKGROUND
Despite restoration of epicardial blood flow in acute ST-elevation myocardial infarction (STEMI), inadequate microcirculatory perfusion is common and portends a poor prognosis. Intracoronary (IC) thrombolytic therapy can reduce microvascular thrombotic burden; however, contemporary studies have produced conflicting outcomes.
OBJECTIVES
This meta-analysis aims to evaluate the efficacy and safety of adjunctive IC thrombolytic therapy at the time of primary percutaneous coronary intervention (PCI) among patients with STEMI.
METHODS
Comprehensive literature search of six electronic databases identified relevant randomised controlled trials. The primary outcome was major adverse cardiac events (MACE). The pooled risk ratio (RR) and weighted mean difference (WMD) with a 95% CI were calculated.
RESULTS
12 studies with 1915 patients were included. IC thrombolysis was associated with a significantly lower incidence of MACE (RR=0.65, 95% CI 0.51 to 0.82, I=0%, p<0.0004) and improved left ventricular ejection fraction (WMD=1.87; 95% CI 1.07 to 2.67; I=25%; p<0.0001). Subgroup analysis demonstrated a significant reduction in MACE for trials using non-fibrin (RR=0.39, 95% CI 0.20 to 0.78, I=0%, p=0.007) and moderately fibrin-specific thrombolytic agents (RR=0.62, 95% CI 0.47 to 0.83, I=0%, p=0.001). No significant reduction was observed in studies using highly fibrin-specific thrombolytic agents (RR=1.10, 95% CI 0.62 to 1.96, I=0%, p=0.75). Furthermore, there were no significant differences in mortality (RR=0.91; 95% CI 0.48 to 1.71; I=0%; p=0.77) or bleeding events (major bleeding, RR=1.24; 95% CI 0.47 to 3.28; I=0%; p=0.67; minor bleeding, RR=1.47; 95% CI 0.90 to 2.40; I=0%; p=0.12).
CONCLUSION
Adjunctive IC thrombolysis at the time of primary PCI in patients with STEMI improves clinical and myocardial perfusion parameters without an increased rate of bleeding. Further research is needed to optimise the selection of thrombolytic agents and treatment protocols.
PubMed: 38925881
DOI: 10.1136/heartjnl-2024-324078 -
Anticancer Research Jul 2024Sorafenib and lenvatinib have long been used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Along with the development of systemic chemotherapy...
BACKGROUND/AIM
Sorafenib and lenvatinib have long been used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Along with the development of systemic chemotherapy for HCC, the concept of conversion hepatectomy has recently become widespread. The present study aimed to assess the clinical outcomes of sorafenib and lenvatinib for HCC regarding the possibility of conversion hepatectomy in clinical practice.
PATIENTS AND METHODS
A total of 295 patients with advanced HCC receiving sorafenib and lenvatinib, accounting for 306 treatments (sorafenib, n=157; lenvatinib, n=149, 11 patients received lenvatinib after sorafenib treatment) at five different institutions were enrolled. Patients were assessed for their clinical characteristics and therapeutic response using both Response Evaluation Criteria in Solid Tumors criteria (RECIST) and modified RECIST (mRECIST) criteria. Additionally, an indication of surgery after tyrosine kinase inhibitor administration was determined based on the tumor status of patients.
RESULTS
The median survival times of patients treated with sorafenib and lenvatinib were 12.8 and 16.4 months, respectively, without significant difference (p=0.1645). The objective response rates (ORR) of sorafenib based on mRECIST and RECIST were 10.1% and 5.9%, respectively, and those of lenvatinib were 38.1% and 19.0%, respectively. Among the 306 treatments, two cases (sorafenib and lenvatinib, one each) underwent hepatectomy after systemic chemotherapy.
CONCLUSION
Few cases with unresectable HCC were amenable to conversion hepatectomy after sorafenib and lenvatinib treatments due to the limited ORR by RECIST. Cautious approach must be taken when administering neoadjuvant chemotherapy aimed at conversion hepatectomy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Quinolines; Phenylurea Compounds; Sorafenib; Male; Female; Hepatectomy; Middle Aged; Aged; Adult; Aged, 80 and over; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 38925835
DOI: 10.21873/anticanres.17123 -
Anticancer Research Jul 2024The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the introduction of several novel agents. However,...
BACKGROUND/AIM
The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the introduction of several novel agents. However, limited data are available to determine whether the introduction of novel agents affected patient characteristics, treatment patterns, and outcomes compared with the period when these agents were not available. The objective of this study was to evaluate the impact of the introduction of novel mCRPC agents on patient characteristics, treatment patterns, and outcomes.
PATIENTS AND METHODS
Two cohorts of Japanese patients diagnosed with mCRPC between 2009 and 2014 (Epoch 1) and 2015 and 2019 (Epoch 2) were retrospectively analyzed.
RESULTS
A total of 125 treatment-naïve mCRPC patients, consisting of 42 patients in Epoch 1 and 83 patients in Epoch 2, were evaluated. We obtained the following results: (i) a dramatic shift in the first-line treatment from docetaxel to androgen receptor axis-targeted agents (ARATs), (ii) an age range expansion for first-line treatment, and (iii) an overall survival (OS) advantage in Eopch 2 compared to Epoch 1. Multivariate analysis in the overall population showed that Epoch 2 and low prostate-specific antigen (PSA) levels at the start of first-line treatment were independent prognostic factors for OS.
CONCLUSION
In real-world mCRPC practice, the introduction of novel agents has improved the prognosis of mCRPC while allowing more patients to receive mCRPC treatment across a broad age range. In addition, low PSA levels at the start of first-line treatment were associated with improved OS, indicating the importance of starting mCRPC treatment while PSA levels are low.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Aged, 80 and over; Retrospective Studies; Middle Aged; Treatment Outcome; Docetaxel; Prostate-Specific Antigen; Neoplasm Metastasis; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 38925833
DOI: 10.21873/anticanres.17130 -
Anticancer Research Jul 2024Randomized trials have shown the benefit of combining tyrosine kinase inhibitors (TKI) and chemotherapy in the treatment of epidermal growth factor receptor-mutant...
BACKGROUND/AIM
Randomized trials have shown the benefit of combining tyrosine kinase inhibitors (TKI) and chemotherapy in the treatment of epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). For anaplastic lymphoma kinase-rearranged (ALK) NSCLC, prospective trial results of the combination are not available and have not even been thoroughly investigated in vitro. In this study, we investigated combinations of TKI and chemotherapy using in vitro models of ALK NSCLC.
MATERIALS AND METHODS
ALK cell line models H3122, H2228, and DFCI032 with differing primary resistance to ALK receptor TKIs were used. We investigated short-(viability assay) and long-term (colony-formation assay) cytotoxicity, apoptosis, and cell signaling in response to the combinations of agents. We selected the most commonly used agents, alectinib, cisplatin, and pemetrexed, to investigate the combination effects.
RESULTS
In the combination experiments with short-term exposure, synergism between TKI and pemetrexed was observed, while cisplatin had antagonistic effects. In the long-term experiments, the combination of cisplatin and TKI was synergistic in all lines, while no synergism was observed with pemetrexed. Among the chemotherapy and TKI sequences, cisplatin followed by TKI was more cytotoxic than the opposite in two out of the three models. In the TKI-sensitive H3122 cell line, the combination of chemotherapy and TKI combination increased apoptosis. Interestingly, pemetrexed treatment resulted in the activation of ALK, which was abolished with TKI.
CONCLUSION
Combining TKI and chemotherapy in ALK models has some synergistic effects that overcome primary TKI resistance. However, the synergy varies depending on the chemotherapeutic agent, cytotoxic assay, and the cell line used. Prospective clinical trials are warranted to fully characterize the potential of combination chemotherapy with TKIs in ALK NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Anaplastic Lymphoma Kinase; Lung Neoplasms; Protein Kinase Inhibitors; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Pemetrexed; Apoptosis; Drug Synergism; Drug Resistance, Neoplasm; Receptor Protein-Tyrosine Kinases; Piperidines; Carbazoles
PubMed: 38925827
DOI: 10.21873/anticanres.17092 -
European Respiratory Review : An... Apr 2024Lower respiratory tract infections (LRTIs) present a significant global health burden, exacerbated by the rise in antimicrobial resistance (AMR). The persistence and... (Review)
Review
Lower respiratory tract infections (LRTIs) present a significant global health burden, exacerbated by the rise in antimicrobial resistance (AMR). The persistence and evolution of multidrug-resistant bacteria intensifies the urgency for alternative treatments. This review explores bacteriophage (phage) therapy as an innovative solution to combat bacterial LRTIs. Phages, abundant in nature, demonstrate specificity towards bacteria, minimal eukaryotic toxicity, and the ability to penetrate and disrupt bacterial biofilms, offering a targeted approach to infection control. The article synthesises evidence from systematic literature reviews spanning 2000-2023, and studies, case reports and ongoing clinical trials. It highlights the synergistic potential of phage therapy with antibiotics, the immunophage synergy in animal models, and the pharmacodynamics and pharmacokinetics critical for clinical application. Despite promising results, the article acknowledges that phage therapy is at a nascent stage in clinical settings, the challenges of phage-resistant bacteria, and the lack of comprehensive cost-effectiveness studies. It stresses the need for further research to optimise phage therapy protocols and navigate the complexities of phage-host interactions, particularly in vulnerable populations such as the elderly and immunocompromised. We call for regulatory adjustments to facilitate the exploration of the long-term effects of phage therapy, aiming to incorporate this old-yet-new therapy into mainstream clinical practice to tackle the looming AMR crisis.
Topics: Humans; Phage Therapy; Respiratory Tract Infections; Animals; Anti-Bacterial Agents; Bacteriophages; Treatment Outcome; Bacterial Infections; Bacteria; Host-Pathogen Interactions
PubMed: 38925791
DOI: 10.1183/16000617.0029-2024 -
BMJ Open Jun 2024Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage heart failure. Compared with the best medical therapy,...
BACKGROUND
Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage heart failure. Compared with the best medical therapy, LVADs improve survival and enhance functional capacity and quality of life. However, two major complications compromise this patient population's outcomes: thrombosis and bleeding. Despite technological innovations and better hemocompatibility, these devices alter the rheology, triggering the coagulation cascade and, therefore, require antithrombotic therapy. Anticoagulation and antiplatelet therapies represent the current standard of care. Still, inconsistency in the literature exists, especially whether antiplatelet therapy is required, whether direct oral anticoagulants can replace vitamin K antagonists and even whether phosphodiesterase type 5 inhibitors with their antithrombotic effects could be added to the regimen of anticoagulation.
METHODS AND ANALYSIS
We will perform a living systematic review with network meta-analysis and indirect comparison between current antithrombotic therapies, which have and have not been directly compared within clinical trials and observational studies. We will systematically search the following electronic sources: Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica Database (EMBASE). We will exclusively examine studies published in English from 2016 to the present. Studies conducted before 2016 will be omitted since our primary focus is evaluating continuous flow devices. Two independent reviewers will assess the articles by title, abstract and full text; any disagreement will be resolved through discussion, and a third reviewer will be involved if necessary. The Cochrane Risk of Bias tool will be used to assess the risk of bias. We will then conduct a pairwise meta-analysis; if the assumption of transitivity is satisfied, we will proceed with network meta-analysis using Bayesian methodology.
ETHICS AND DISSEMINATION
Formal ethical approval is not required as no primary data are collected. This systematic review and network meta-analysis will delineate the risks of stroke, thromboembolic events, pump thrombosis, gastrointestinal bleeding and mortality in patients equipped with LVADs who are subjected to various antithrombotic regimens. The findings will be disseminated via a peer-reviewed publication and presented at conference meetings. This will enhance clinical practice and guide future research on anticoagulation strategies within this distinct patient cohort.
PROSPERO REGISTRATION NUMBER
CRD42023465288.
Topics: Humans; Heart-Assist Devices; Systematic Reviews as Topic; Network Meta-Analysis; Fibrinolytic Agents; Anticoagulants; Thrombosis; Heart Failure; Platelet Aggregation Inhibitors; Research Design; Hemorrhage
PubMed: 38925683
DOI: 10.1136/bmjopen-2023-080110 -
Cancer Reports (Hoboken, N.J.) Jun 2024Reduced ovarian reserve is among the crucial long-term side effects of using chemotherapy agents in breast cancer, yielding early ovarian failure. On the other hand,... (Randomized Controlled Trial)
Randomized Controlled Trial
The protective effect of vitamin D on ovarian reserve and anti-mullerian hormone in patients undergoing chemotherapy for breast cancer, a randomized phase ΙΙ clinical trial.
BACKGROUND
Reduced ovarian reserve is among the crucial long-term side effects of using chemotherapy agents in breast cancer, yielding early ovarian failure. On the other hand, vitamin D is an essential factor in protecting the follicles and an important predictive factor for successful IVF therapy.
AIM
The aim of this study is evaluation of vitamin D as a agent that can reduce fertility complications of chemotherapy specially in young women.
METHODS
Breast cancer patients undergoing chemotherapy at two cancer institutes were enrolled in this study. The case group received 1000 IU of calcitriol, and the AMH level was measured at the baseline, after chemotherapy, and six months after chemotherapy. The primary end point was improvement in the AMH level after six months of chemotherapy. the secondary endpoint was to evaluate the predictive factors of AMH level decline during chemotherapy.
RESULTS
Between 2018 and 2019, 18 and 15 patients were enrolled in the case and control groups, respectively. The mean AMH level (ngr/ml) of the patients in the case and control group were 3.16 and 2.37 ng/mL, respectively (p-value = .16). These levels were 0.387 and 0.19 after six months (p-value = .38). The AMH rise immediately after chemotherapy cycles to six months after chemotherapy, in the case and control groups were 0.86 and 0.44 ng/mL, respectively, which was slightly higher in the case group but not statistically significant between two groups (p-value = .054).
CONCLUSION
Despite a minimal rise in the AMH level after six months of chemotherapy, the study could not demonstrate any protective effect of vitamin D on patients' ovarian reserve undergoing chemotherapy for breast cancer. Further larger studies are needed to evaluate the effect of vitamin D supplements on ovarian reserve beside optimal dose and duration.
Topics: Humans; Female; Anti-Mullerian Hormone; Ovarian Reserve; Breast Neoplasms; Adult; Vitamin D; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38925607
DOI: 10.1002/cnr2.2104 -
Cancer Medicine Jun 2024Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore,...
AIM
Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs.
METHODS
This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed.
RESULTS
The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039).
CONCLUSIONS
DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs.
Topics: Humans; Carcinoma, Hepatocellular; Male; Liver Neoplasms; Female; Antibodies, Monoclonal, Humanized; Retrospective Studies; Lung Neoplasms; Aged; Middle Aged; Feasibility Studies; Hemorrhage; Bevacizumab; Antineoplastic Combined Chemotherapy Protocols; Anticoagulants; Administration, Oral; Aged, 80 and over
PubMed: 38924675
DOI: 10.1002/cam4.7430