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Wellcome Open Research 2023Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given...
BACKGROUND
Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response.
METHODS
We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed both by using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines, and for studies included in meta-analysis, also by the QUIPS tool.We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome.
RESULTS
Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3‒6) 90 days after ICH was associated with higher levels of fibrinogen (SMD 0.32; 95%CI [0.04, 0.61]; p=0.025), and high mobility group box protein 1 (HMGB1) (SMD 1.67; 95%CI [0.05, 3.30]; p=0.04). Higher WBC was associated with death or dependency at 90 days (pooled SMD 0.27; 95% CI [0.11, 0.44]; p=0.001; but the association was no longer significant when the analysis was restricted to studies with a low risk of bias (pooled SMD 0.22; 95% CI -0.04-0.48). Higher CRP seemed to be associated with death or dependency at 90 days (pooled SMD 0.80; 95% CI [0.44, 1.17]; p<0.0001) but this association was no longer significant when adjusted OR were pooled (OR 0.99 (95% CI 0.98-1.01)).
CONCLUSIONS
Higher circulating levels of, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets.
REGISTRATION
PROSPERO ( CRD42019132628; 28/05/2019).
PubMed: 38037559
DOI: 10.12688/wellcomeopenres.19187.2 -
Chemotherapy 2022Crizotinib and alectinib are the 2 most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Crizotinib and alectinib are the 2 most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA, and J-ALEX clinical trials.
METHODS
Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses, and adverse effects (AEs).
RESULTS
Seven articles on 3 randomized controlled clinical trials (ALEX, ALESIA, and J-ALEX) that included 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35 [0.25-0.49], p < 0.00001), OS (HR: 0.66 [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17 [0.11-0.24], p < 0.00001), duration of response (HR: 0.31 [0.23-0.42], p < 0.00001), objective response rate (risk ratio [RR]: 0.87 [0.80-0.94], p = 0.0003), partial response (RR: 0.88 [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43 [1.09-1.87], p = 0.009). Additionally, compared with crizotinib, alectinib exhibited a survival advantage that increased with its prolongation of survival time. The disease control rate, complete response, and total AEs were comparable between the 2 groups. The crizotinib group reported higher rates of constipation, nausea, diarrhea, vomiting, peripheral edema, dysgeusia, visual impairment, and levels of alanine aminotransferase and aspartate aminotransferase as well as greater decreases in appetite and neutrophil count.
CONCLUSIONS
In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.
Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 34915469
DOI: 10.1159/000521452 -
Diagnostics (Basel, Switzerland) Aug 2023This study evaluates the role of high-intensity focused ultrasound (HIFU) ablative therapy in treating primary breast cancer. (Review)
Review
BACKGROUND
This study evaluates the role of high-intensity focused ultrasound (HIFU) ablative therapy in treating primary breast cancer.
METHODS
PubMed and Scopus databases were searched according to the PRISMA guidelines to identify studies from 2002 to November 2022. Eligible studies were selected based on criteria such as experimental study type, the use of HIFU therapy as a treatment for localised breast cancer with objective clinical evaluation, i.e., clinical, radiological, and pathological outcomes. Nine studies were included in this study.
RESULTS
Two randomised controlled trials and seven non-randomised clinical trials fulfilled the inclusion criteria. The percentage of patients who achieved complete (100%) coagulation necrosis varied from 17% to 100% across all studies. Eight of the nine studies followed the treat-and-resect protocol in which HIFU-ablated tumours were surgically resected for pathological evaluation. Most breast cancers were single, solitary, and palpable breast tumours. Haematoxylin and eosin stains used for histopathological evaluation showed evidence of coagulation necrosis. Radiological evaluation by MRI showed an absence of contrast enhancement in the HIFU-treated tumour and 1.5 to 2 cm of normal breast tissue, with a thin peripheral rim of enhancement indicative of coagulation necrosis. All studies did not report severe complications, i.e., haemorrhage and infection. Common complications related to HIFU ablation were local mammary oedema, pain, tenderness, and mild to moderate burns. Only one third-degree burn was reported. Generally, the cosmetic outcome was good. The five-year disease-free survival rate was 95%, as reported in two RCTs.
CONCLUSIONS
HIFU ablation can induce tumour coagulation necrosis in localised breast cancer, with a favourable safety profile and cosmetic outcome. However, there is variable evidence of complete coagulation necrosis in the HIFU-treated tumour. Histopathological evidence of coagulation necrosis has been inconsistent, and there is no reliable radiological modality to assess coagulation necrosis confidently. Further exploration is needed to establish the accurate ablation margin with a reliable radiological modality for treatment and follow-up. HIFU therapy is currently limited to single, palpable breast tumours. More extensive and randomised clinical trials are needed to evaluate HIFU therapy for breast cancer, especially where the tumour is left in situ.
PubMed: 37568958
DOI: 10.3390/diagnostics13152595 -
Archives of Cardiovascular Diseases 2020The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK)... (Meta-Analysis)
Meta-Analysis
Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.
BACKGROUND
The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized.
AIM
To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting.
METHODS
We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data.
RESULTS
MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach.
CONCLUSIONS
In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.
Topics: Adverse Drug Reaction Reporting Systems; Aged; Antineoplastic Agents; Cardiovascular Diseases; Databases, Factual; Female; Fibrosarcoma; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Patient Safety; Pharmacovigilance; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 32418884
DOI: 10.1016/j.acvd.2020.03.014 -
Frontiers in Pharmacology 2019Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials...
Appraisal of Non-Cardiovascular Safety for Sodium-Glucose Co-Transporter 2 Inhibitors: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials.
Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials regarding the non-cardiovascular safety. This was the focus of our study. We systematically searched MEDLINE, EMBASE, and Cochrane Library (5 Sep 2018) for randomized controlled trials (RCTs) that reported safety data for SGLT2 inhibitors and placebo. Relative risks (RRs) and their 95% confidence intervals (CIs) were pooled using random-effects models. Seventy RCTs (83 studies enrolling 36,958 patients in 78 publications) were identified. SGLT2 inhibitors were associated with a lower risk of serious adverse events (RR 0.90, 95% CI 0.86 to 0.94, < 0.001), death (RR 0.78, 95% CI 0.64 to 0.94, < 0.05), gastroenteritis (RR 0.38, 95% CI 0.20 to 0.72, < 0.05), arthralgia (RR 0.72, 95% CI 0.54 to 0.96, < 0.05), hypertension (RR 0.61, 95% CI 0.50 to 0.75, < 0.001), and edema/peripheral edema (RR 0.49, 95% CI 0.33 to 0.72, < 0.001) compared to placebo. SGLT2 inhibitors were associated with higher risk of infections compared to placebo (RR 1.27, 95% CI 1.17 to 1.37, < 0.001), especially for genital mycotic infection (GMI) (RR 3.71, 95% CI 3.19 to 4.32, < 0.001). Other significant effects were observed for osmotic diuresis-related AEs (RR 2.73, 95% CI 2.20 to 3.40, < 0.001), volume-related AEs (RR 1.26, 95% CI 1.08 to 1.46, < 0.05), renal-related AEs (RR 1.36, 95% CI 1.02 to 1.80, < 0.05), hypoglycemia (RR 1.18, 95% CI 1.10 to 1.26, < 0.001), and increased blood ketone bodies (RR 2.00, 95% CI 1.01 to 3.97, < 0.05). Subgroup and sensitivity analyses strengthened the robustness of primary results. Results from RCTs confirmed lower risk of death, serious adverse events, hypertension, and edema associated with type 2 diabetes mellitus (T2DM) patients treated with SGLT2 inhibitors when compared with placebo. The use of SGLT2 inhibitors were associated with higher risk of infection, osmotic diuresis, volume depletion effects, renal related AEs, and higher blood ketone bodies when compared with placebo.
PubMed: 31616297
DOI: 10.3389/fphar.2019.01066 -
PloS One 2022Trastuzumab is a valuable therapy option for women with ERBB2(HER2)+ breast cancer tumours, often used in combination with chemotherapy and alongside other therapies. It... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Trastuzumab is a valuable therapy option for women with ERBB2(HER2)+ breast cancer tumours, often used in combination with chemotherapy and alongside other therapies. It is known to have adverse effects, but these have proved difficult to separate from the effects of other concurrent therapies patients are usually taking. This study aims to assess the adverse effects specifically attributable to trastuzumab, and whether they vary by patient subgroup or concurrent therapies.
METHODS
As registered on PROSPERO (CRD42019146541), we used previous systematic reviews as well as the clinicaltrials.gov registry to identify randomised controlled trials in breast cancer which compared treatment regimes with and without trastuzumab. Neoadjuvant, adjuvant and metastatic settings were examined. Data was extracted from those which had, as of July 2022, reported adverse events. Risk of bias was assessed using ROB2. Primary outcomes were adverse events of any type or severity (excluding death). A standard random-effects meta-analysis was performed for each outcome independently. In order to ascertain whether adverse effects differed by individual factors such as age or tumour characteristics, or by use of trastuzumab concurrently with hormone therapy, we examined individual-level patient data for one large trial, HERA.
RESULTS
79 relevant trials were found, of which 20 contained comparable arms of trastuzumab-containing therapy and corresponding matched therapy without trastuzumab. This allowed a comparison of 8669 patients receiving trastuzumab versus 9556 receiving no trastuzumab, which gave a list of 25 statistically and clinically significant adverse effects related to trastuzumab alone: unspecified pain, asthenia, nasopharyngitis, skin disorders (mainly rash), dyspepsia, paraesthesia, infections (often respiratory), increased lacrimation, diarrhoea, myalgia, oedema (limb/peripheral), fever, nose bleeds, cardiac events, insomnia, cough, back pain, dyspnoea, chills, dizziness or vertigo, hypertension, congestive heart failure, increased levels of aspartate aminotransferase, gastrointestinal issues and dehydration. Analysis of individual patient-level data from 5102 patients suggested that nausea is slightly more likely for women taking trastuzumab who are ER+ /also taking hormone therapy than for those who are ER-/not taking hormone therapy; no other potential treatment-subgroup interactions were detected. We found no evidence for significantly increased rates of neutropenia, anaemia or lymphopenia in patients on trastuzumab-containing regimes compared to those on comparable regimes without trastuzumab.
CONCLUSIONS
This meta-analysis should allow clinicians and patients to better identify and quantify the potential adverse effects of adding trastuzumab to their treatment regime for breast cancer, and hence inform their decision-making. However, limitations include serious risk of bias due to heterogeneity in reporting of the outcomes and the open-label nature of the trials.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Neutropenia; Hormones
PubMed: 36454979
DOI: 10.1371/journal.pone.0275321 -
International Journal of Cardiology.... Jun 2024Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this...
Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this medication has a significant cardiovascular side effect profile, such as high-grade hypertension. We performed this updated meta-analysis of RCTs to compile cardiovascular adverse events, such as all-grade and high-grade (>3) hypertension, the risk for thrombosis (DVT and PE), and peripheral edema. A systematic search was performed on PubMed, Cochrane, and Embase from inception until October 2023 for studies using axitinib to treat various cancers. Trials with patients randomly allocated for VEGFRi drug therapy with axitinib and reported all-grade hypertension as an outcome were included. Statistical analysis was performed using Cochrane Review Manager to calculate pooled proportions of odds ratios (OR) with a 95 % confidence interval (CI) using the random-effects model, Mantel-Haenszel method. A total of 8 RCTs and 2502 patients were included in the review. Compared with the placebo group, the VEGFRi (Axitinib) therapy group was associated with a higher risk of all-grade and high-grade hypertension, hand-foot syndrome, and fatigue. Furthermore, there was no increased risk of thromboembolism (DVT/PE) or hypothyroidism. However, a lower risk of peripheral edema was noted between the two groups. Screening for patients with preexisting hypertension, identifying risk factors for cardiovascular diseases before the initiation of VEGFRi therapy, and careful monitoring of high-risk patients during VEGFRi therapy, as well as prompt treatment with antihypertensive drugs, will help mitigate the adverse effects. Further evaluation using prospective designs is required to study the clinical significance and develop mitigation strategies.
PubMed: 38715853
DOI: 10.1016/j.ijcha.2024.101415