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Author contributions | G.H. and F.J. collected data, analysed results, interpreted findings and drafted the manuscript. BB provided statistical support and developed the analysis plan. BH conceptualised the idea. All authors reviewed the manuscript | PMC10475034 |
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Funding | This project received no funding. | PMC10475034 |
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Data availability | The datasets generated during used and/or analysed during the current study available from the corresponding author on reasonable request. | PMC10475034 |
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Competing interests | BH has a clinical partnership with Fourier Intelligence and a paid consultancy role with RecoveryVR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10475034 |
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References | PMC10475034 |
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1. Introduction | inflammation, MOF, organ dysfunction, septic shock, sepsis | MULTIPLE ORGAN FAILURE, PCT, INFLAMMATION, MOF, DYSFUNCTION, SEPTIC SHOCK, SEPSIS | These authors share first authorship.Background and aim: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems. Methods: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy. Results: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NOSepsis and septic shock cause a high mortality in Intensive Care Units (ICU) throughout the world and 80% of patients with this condition are admitted with multiple organ failure (MOF) [These conditions generate high costs to the public health system worldwide and to the families of the patients. Therefore, different strategies have been evaluated to predict the prognosis and reduce costs [However, there are other mechanisms involved during sepsis including deregulation of hemodynamic and oxidative stresses (OS), which exert a synergistic effect with inflammation and lead to dysfunction in various organs. Therefore, the use of antioxidants is currently being investigated [The systemic response that triggers sepsis leads to dysfunction in the heart through compensatory reaction of the sympathetic nervous system, leading to micro vascular dysfunction with activation of the immune system. The activation of the immune system damages tissues through a cascade that involves damage-associated molecular patterns, pathogen-associated molecular patterns [On the other hand, antioxidant therapy in septic shock has been proposed since Hippocrates, who used myrrh (Therefore, the aim of this study was to evaluate the use of antioxidants concomitantly with standard therapy in patients with septic shock with MOF, through a randomized clinical trial (RCT). We also evaluate the effect on various biomarkers of the enzymatic and non-enzymatic antioxidant system, before and after therapeutic intervention. | PMC10177152 |
2. Materials and Methods | PMC10177152 |
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2.1. Population Study | septic shock | SEPTIC SHOCK | This was a randomized and blinded longitudinal prospective clinical trial in a cohort of patients that was run between April 2018 and January 2022. The population studied included patients older than 18 years of any gender who were admitted to the intensive care unit of the ABC Medical Center, Observatory and Santa Fe campus with a diagnosis of septic shock [ | PMC10177152 |
2.2. Sample Size | The sample size was calculated considering the difference in the means of low ascorbic acid levels and improvement with the treatment using antioxidants. It suggested the inclusion of 11 patients in each group for a desired 80% power and an alpha error of | PMC10177152 |
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2.3. Ethical Aspects | A signed informed consent form was obtained from each participant as recommended in the Declaration of Helsinki, modified in the Tokyo Congress, Japan. The research was approved by the Ethical, Biosecurity and Investigation Committees of the National Institute of Cardiology (registration number INCICh: PT 10-0-76) and Centro Medico ABC Campus Observatory number ABC-18-19, Trial Registration: ClinicalTrials.gov Identifier: NCT 03557229. | PMC10177152 |
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2.4. Randomization | Electronic selection by computer was used to divide patients into blocks with a total of 5 groups with around 25 patients in each one. Group 1 received Vit C, group 2 Vit E, group 3 NAC and group 4 MT; group 5 patients remained without treatment (Tx) and formed the control group. Personnel unrelated to the study participated in the blinding and placed the indicated therapy in identical opaque envelopes numbered from 1 to 125 and these were applied consecutively. The randomized process is shown in | PMC10177152 |
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2.5. Data Collection | A medical examination and a complete clinical history were performed on each patient upon admission to the ICU, and the prognostic scales of APACHE II [ | PMC10177152 |
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2.6. Description of the Intervention | In addition to the standard therapy, each group of patients received an antioxidant orally or by nasoenteral tube for 5 days. In the NAC group, 600 mg effervescent tablets were administered every 12 h; in the MT group, extended-release capsules of 50 mg in a daily dose were administered; in the Vit C group, 1 g tablets every 6 h and in the Vit E group, capsules α-tocopherol of 400 IU were given every 8 h. | PMC10177152 |
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2.7. Sample Collection and Storage | A quantity of 20 mL of blood was obtained upon admission and 48 h after treatment. Samples were identified as pre (0 h) or post sample (48 h). They were centrifuged at 3000 rpm for 20 min at 4 °C. Serum was stored in 3 or 4 Eppendorff aliquots of 1.5 mL and stored at <70° until processed. | PMC10177152 |
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2.8. Evaluation of the Antioxidant Enzymes | PMC10177152 |
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2.8.1. GPx Activity | A quantity of 100 μL of serum was suspended in 1.6 mL of 50 mM phosphate buffer (KH | PMC10177152 |
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2.8.2. GST Activity | A quantity of 100 μL serum was added to 700 μL phosphate buffer (KH | PMC10177152 |
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2.8.3. TrxR Activity | TrxR activity was assessed as previously described [ | PMC10177152 |
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2.8.4. Extracellular Super Oxide Dismutase (ecSOD) Activity | ecSOD activity was determined by electrophoresis in native 10% polyacrylamide gels. Electrophoresis was carried out at 120 V for 4 h, as previously described by Pérez-Torres et al. [ | PMC10177152 |
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2.8.5. Peroxidase Activity | Measurement of peroxidase activity was carried out by electrophoresis in native 10% polyacrylamide gels as previously described by Pérez-Torres et al. [ | PMC10177152 |
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2.8.6. GR Activity | For GR activity, 100 μL of serum were utilized according to the previously described method [ | PMC10177152 |
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2.9. Oxidative Stress Markers | PMC10177152 |
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2.9.1. Determination of Selenium (Se) | Selenium (Se) determination was performed using 200 µL of serum according to the method described by Soto et al. and the absorbance was read at 600 nm [ | PMC10177152 |
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2.9.2. Thiols | For the measurement of thiols, to 25 mL of serum 100 μL KBH | PMC10177152 |
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2.9.3. Total Antioxidant Capacity (TAC) | A quantity of 100 μL of serum was used for the TAC determination. The absorbance was measured at 593 nm, according to the method described by Benzie and Strain [ | PMC10177152 |
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2.9.4. Lipid Peroxidation (LPO) | A quantity of 100 μL of serum was used to determine LPO products, making them react with thiobarbituric acid as previously reported and measuring the absorbance at 532 nm [ | PMC10177152 |
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2.9.5. NO | The method reported by Griess was used for the determination of NO | PMC10177152 |
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2.9.6. Carbonylation | A quantity of 100 μL of serum was used and protein carbonylation was detected spectrophotometrically as previously described [ | PMC10177152 |
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2.10. Statistical Analysis | Continuous variables were expressed as mean ± standard deviation or median with minimum and maximum ranges. Categorical variables such as frequencies and percentages were also reported. Normality distribution was evaluated by Shapiro–France. For the graphic analysis of the distribution of the variables, histograms and/or stems of leaves graphics were employed. To test the significance of the results, we used nonparametric (Mann–Whitney) or Student’s t tests for independent measurements. Paired t with Friedman, Wilcoxon signed rank test or Kruskal–Wallis t test were used according to the number of comparisons in groups of two or multiples and according to Gaussian distribution. In some variables, standardization was made and in multiple comparisons, adjustment was made by Bonferroni correction. For the paired analysis (before-after), we used the Friedman or Wilcoxon tests with signed rank test according to the distribution of the data. For the comparison of proportions for two groups, Pearson’s Chi-square χ | PMC10177152 |
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4. Discussion | critically ill, non-septic, hypoxia, MOF, organ damage, septic shock, sepsis, septic | PCT, SARS-COV-2 INFECTION, CRITICALLY ILL, HYPOXIA, MOF, DYSFUNCTION, SEPTIC SHOCK, SEPSIS, PATHOGENESIS, INFLAMMATORY RESPONSE | The participation of OS in septic shock and MOF has been previously reported [In this study, we found that patients with septic shock had a high SOFA score on admission to the ICU. They had high PCT and CRP levels, elevated LPO and carbonylation, and decreased TAC. These variables were compensated by the treatment with antioxidants.The patients who received treatment with vitamin C and vitamin E had a decrease in LPO levels and although the difference did not reach a statistical significance, we can interpret that there is a tendency of six to seven times greater decrease with the use of this therapy. Our findings resemble those previously reported in an animal model where Vit C decreased LPO [Vit C is an enzymatic cofactor with an antioxidant function derived from its ability to act as an electron donor. It reduces LPO and carbonylation, OIn addition, LPO was blocked by Vit E treatment in our series of patients. This vitamin binds to the cell membrane and decreases the polyunsaturated fatty acid oxidation due to its lipophilic characteristics. The oxidation of these fatty acids is increased in proinflammatory states. Therefore, supplementation with this vitamin in patients with sepsis may modulate the excessive inflammatory response coordinated by macrophages [Protein oxidation can be estimated by carbonylation, which results from the direct oxidation of amino acid side chains and from oxidative cleavage of protein. Carbonyls are difficult to induce and therefore may indicate a more severe state of OS [At present, there are still controversies regarding the complementary use of Vit C in the general therapy of patients with septic shock. In a systematic review with a meta-analysis that included 16 randomized clinical trials, it was concluded that Vit C does not help improve clinical outcomes in patients [In the group treated with Vit C, the levels of ecSOD were decreased. This effect may be due to the fact that this enzyme regulates the ORegarding the findings associated with the clinical part, the use of Vit C did not decrease the number of days of hospital stay, but its use was related to a lower percentage of the employment of inotropes and invasive mechanical ventilation, which was observed in all patients that received antioxidant therapy. In the treated groups, the percentage of inotropic use was 15.6% and mechanical ventilation was necessary in 11%, while in the untreated groups, it was of 31% and 19%, respectively. However, the difference did not reach a statistical significance.A more recent meta-analysis reported that Vit C showed no evident clinical improvement and therefore effectiveness of the therapy was not recommended [One of the main objectives to be evaluated in this study was whether the use of antioxidants decreased organ damage. We found that with the early use of Vit C, patients had a decrease in organ damage measured through the SOFA score and that this occurred since the beginning (first day of therapy with this antioxidant), showing a 37.5% reduction. On the fifth day, the decrease reached 63%. This finding confirmed the effects seen in a previous study, in which a decrease in the SOFA score in patients who received MT and Vit C was observed in a smaller number of patients [In this study, this same effect was achieved with the use of NAC, which also reduces mortality [Other antioxidants such as MT could also be useful in patients with septic shock. We have found that it reduces the SOFA score and the LPO in SARS-CoV-2 infection. The reproducibility of the findings reinforces what was recently published in a pilot group, where evidence of its effect on reducing organ damage was found [In in vitro and in vivo studies, MT scavenges ROS, thus protecting cell membrane lipids, cytosol proteins, and nuclear and mitochondrial DNA. It preserves the permeability of the membrane, increasing its fluidity [In this study, we found that in patients treated with MT, the Se levels were maintained, ecSOD was decreased, and TAC and GPx were increased. Therefore, it is feasible that the therapeutic effect on other enzymes such as the one observed in the decrease in ecSOD may be beneficial to control the OS in sepsis.On the other hand, Se is used by GPx as cofactor and is decreased in septic shock [The possible benefits of therapy with trace elements such as Se, Cu, Zn and Mn in critically ill patients have been investigated without clear results. With the results obtained in this study, Se levels are maintained, which supports the role of this metal in the regulation of OS. Multiple studies have evaluated the effect of Se supplementation in critically ill patients. However, there are still controversies regarding the path of administration (enteral vs. parenteral), the dose (high vs. low), the use of loading doses, the selection of patients (septic vs. non-septic) and the supplementation of other antioxidants (mono therapy vs. cocktails), [On the other hand, the study of thiols in this series of patients was included since thiols are molecules that contain a hydrogen sulfide group in the side chain (SH) which may act as an antioxidant by stabilizing and reducing the bridge between proteins caused by free radicals by accepting an unpaired electron. This process is also regulated by TxrR, another selenoenzyme which was decreased in these patients. However, the antioxidant therapy increased the activity of this enzyme. Our results suggest that the increase in thiols can participate with a synergic effect with the Vit E and decrease the OS damage mechanism on protein carbonylation in patients with septic shock. Vit E and thiols may act together preventing and blocking LPO, carbonylation and increasing TAC [This study confirms the effect of antioxidants on the reduction of MOF measured by the SOFA score, which occurs from the second day of treatment on. Studies to follow should consider an adequate evaluation of the nutritional status and the participation of OS, and its consequences such as cytopathic hypoxia. This condition could explain the failure of different strategies used in the clinical management of septic shock, since when the mitochondrial machinery is blocked, many therapies result in unsuccessful efforts aimed at improving tissue oxygenation by increasing systemic oxygen supply and/or optimizing cardiovascular function.Specific pharmacological treatments to modulate or block components of the inflammatory process have not achieved the expected success. The participation of OS in the pathways of damage in patients with septic shock constitutes a solid foundation to propose an adjuvant antioxidant therapy for sepsis and septic shock. This therapy may improve these conditions by regulating enzymatic and non-enzymatic pathways as previously observed in animal models. Studies are needed to substantiate the interaction and participation of nitrosative stress, OS and the interaction of cytokines in the pathogenesis of sepsis. Nevertheless, the antioxidant therapy modulates the over-synthesis of NO and nitrosative stress, reducing organic dysfunction.These results raise new expectations for antioxidant treatment in MOF caused by sepsis. There are still gaps that need to be solved and these constitute areas of opportunity to explore in the future. The exact doses, the time of use and synergistic effects of combined use of several simultaneous antioxidants still remain unexplored. | PMC10177152 |
5. Conclusions | MOF, septic shock | MOF, PCT, SEPTIC SHOCK | The addition of antioxidant therapy to standard therapy in patients with septic shock decreases MOF and regulates the inflammatory state and the OS. Vit C therapy increases its serum levels and decreases CRP, PCT and NO | PMC10177152 |
Author Contributions | A.A.-Á., M.E.S. Acquisition, statistical and data analysis or interpretation of data. M.E.S. Had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. A.A.-Á., I.P.-T. and M.E.S. Conceptualization and methodology. I.P.-T., R.C.-S., L.M.-P., S.C.-A., R.M.-V., J.F.-G. and M.E.N.-M. Methodology, patient care and sample handling. Acquisition, data analysis, or interpretation of data. L.M.-P. Graphical abstract. V.G.-L. Revised and structured the manuscript. All authors have read and agreed to the published version of the manuscript. | PMC10177152 |
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Institutional Review Board Statement | Biosecurity and Investigation Committees of the National Institute of Cardiology (registration number INCICh: PT 10-0-76) and Centro Medico ABC Campus Observatory number ABC-18-19, Trial Registration: ClinicalTrials.gov Identifier: NCT 03557229. | PMC10177152 |
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Informed Consent Statement | A written informed consent for enrollment or consent to continue and use patient data was obtained from each patient or their legal surrogate. | PMC10177152 |
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Data Availability Statement | The data in our study are available from the corresponding author upon reasonable request. | PMC10177152 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10177152 |
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References | cerebral vascular disease, sepsis, Sequential organ failure, COPD, RTT | ACUTE MYOCARDIAL INFARCTION, PCT, CVD, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, OXIDATIVE STRESS, AMI, SEPSIS, PVC | Electronic selection by computer was used to divide patients into blocks with a total of 5 groups of 131 patients in total. In the group Vit C (n = 27) patients were studied, in the group with Vit E (n = 24), NAC (n = 24), MT (n = 26) and (n = 29) patients remained without treatment.PCR = C-reactive protein; Vit C = vitamin C; Vit E = vitamin E; NAC = n-acetylcysteine; MT = melatonin; Tx = treatment, Values median. Test statistician: Kruskal-Wallis. PCT = procalcitonin; Vit C = vitamin C; Vit E = vitamin E; NAC = n-acetylcysteine; MT = melatonin; Values are expressed as mean ± SD. Test Statistic: One-Way Kruskall Wallis between groups NAC = N-acetylcysteine, MT = Melatonin, Tx = without treatment, SOFA = Sequential organ failure assessment. Values are expressed as median (p25–p75 quartiles), Test statistic: One-way Kruskall Wallis Showed oxidative stress markers in plasma of patients with sepsis before and after of antioxidant therapy.Enzymatic pathway that comprised the activity of the glutathione-S-transferase, glutathione reductase, glutathione peroxidase, Thioredoxin, superoxide dismutase, peroxidases and glutathione before and after antioxidant therapy. Abbreviations: Vit C = Vitamin C, Vit E = Vitamin E, NAC = n-acetyl cisteine, MT = Melatonin.Showed some markers of the non-enzymatic pathway such as Vitamin C, Thiols and selenium levels before and after antioxidant therapy.Demographic characteristics and comorbidities by treatment group at admission in ICU.Abbreviations: Vit C = vitamin C, Vit E = vitamin E, NAC = N-acetylcysteine, MT = melatonin, Tx = without treatment, COPD = chronic obstructive pulmonary disease, CVD = cerebral vascular disease, AMI = acute myocardial infarction, CNS = central nervous system, SAPS II = Simplified Acute Physiology Score, APACHE II = Acute Physiology and Chronic Health Evaluation, SOFA = sequential organ failure assessment, NUTRIC: Nutrition Risk in the Critical III.Condition of the patients at the time of admission, according to the assigned antioxidant therapeutic management and the type of standard management and ventilatory assistance.Abbreviations: Vit C = vitamin C, Vit E = vitamin E, NAC = N-acetylcysteine, MT = melatonin, Tx = COPD = chronic obstructive pulmonary disease, CVD = cerebral vascular disease, PVC = peripheral venous catheters, AMI = acute myocardial infarction, CNS = central nervous system, IMV = intermittent mandatory ventilation, SAPS II = Simplified Acute Physiology Score, APACHE II = acute physiology and chronic health evaluation, SOFA = sequential organ failure assessment, MAP = mean arterial pressure, RTT = referral to treatment. Treatment statistics, Kruskal–Wallis and Fisher. The values are expressed as median (Min-Max). | PMC10177152 |
Objective | post-stroke non-fluent aphasia | To explore an extension speech training program that takes Chinese idioms as context and expands them into characters, words, sentences and paragraphs and evaluate the effects of this program in patients with post-stroke non-fluent aphasia. | PMC9907817 |
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Methods | post-stroke non-fluent aphasia | This was a randomized controlled trial. We recruited patients with post-stroke non-fluent aphasia from the Renmin Hospital of Wuhan University from January 2021 to January 2022. Participants were randomly assigned to group I and group II. Patients in group I had treatment with extension speech training based on Chinese idioms, and those in group II had treatment with conventional speech rehabilitation training. The training period in both groups was 40 min daily for 2 weeks. | PMC9907817 |
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Results | A total of 70 patients (group I, n = 34; and group II, n = 36) completed the trial and were analyzed according to protocol. There were no significant differences in baseline values between both groups. After intervention, the scores of oral expression, comprehension, and reading in the Aphasia Battery Of Chinese scale and the scores of the Comprehensive Activities of Daily Living questionnaire significantly improved in both groups (P <0.05), with group I benefiting more (P <0.05). | PMC9907817 |
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Conclusion | post-stroke non-fluent aphasia | This extension speech training program based on Chinese idioms can improve the language function and daily communication ability of the patients with post-stroke non-fluent aphasia. | PMC9907817 |
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Trial registration | Chinese Clinical Trial Registry | PMC9907817 |
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Data Availability | The data are available at the following link: DOI: | PMC9907817 |
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Introduction | communication disorder, stroke, Post-stroke aphasia, aphasia, cerebrovascular disease | STROKE, CEREBROVASCULAR DISEASE | Post-stroke aphasia (PSA) is an acquired communication disorder caused by cerebrovascular disease damaging the language center of the dominant hemisphere of the brain. Patients with PSA usually have difficulty remembering words or lose the ability to speak, comprehend, read, or write. PSA is one of the most common and devastating symptoms of stroke, being present in 23%–40% of survivors [Patients with non-fluent PSA usually have impaired language expression but retain their listening comprehension ability [An important feature of Chinese idioms is that they have a complete and vivid story background. For example, “Yu Gong YI Shan,” it tells the story of an old man named Yu Gong who finally moved a mountain through his constant efforts. This Chinese idiom teaches people that success is acquired only through enough efforts. Therefore, in the context of one idiom, relevant words, sentences, and paragraphs can be expanded, meaning that patients with aphasia can train in the same story background with different degrees of difficulty. This expandable rehabilitation material may be applicable to the whole cycle of rehabilitation for such patients.Accordingly, this study aimed to explore an extension speech training program that takes Chinese idioms as context and expands them into characters, words, sentences and paragraphs and evaluate the feasibility and effectiveness of this extension speech training program based on Chinese idioms through randomized controlled trials. We hypothesize that the this program will be more effective at improving language function, as demonstrated by increased scores on the Aphasia Battery Of Chinese scale and the Comprehensive Activities of Daily Living questionnaire, than the conventional speech training program. | PMC9907817 |
Methods | PMC9907817 |
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Design | We conducted a randomized controlled trial in the Renmin Hospital of Wuhan University from January 2021 to January 2022 to evaluate the effectiveness of speech training through Chinese idioms. This study was reviewed and approved by the ethics committee of the Renmin Hospital of Wuhan University (approval number: WDRY2020-K229), and the trial was registered in the Chinese Clinical Trial Registry in April 2020 (registration number: ChiCTR2000031825).All data presented in the studies were deposited in an appropriate public repository (DOI: 10.6084/m9.figshare.20766493). | PMC9907817 |
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Patients | We recruited patients with non-fluent PSA in the Department of Neurology, Neurosurgery and Rehabilitation of the Renmin Hospital of Wuhan University from January 2021 to January 2022. Patients who met the inclusion and exclusion criteria, agreed to participate in the study, and signed an informed consent form were included in the study. The following criteria were used: | PMC9907817 |
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Inclusion criteria | stroke, aphasia, Non-fluent aphasia, cognitive impairment | STROKE | First stroke patients with a definite clinical diagnosis by brain CT scan or MRI examination.Non-fluent aphasia diagnosed by the aphasia screening scale.Stable condition, clear consciousness, and no cognitive impairment.Native language is Chinese.Age >18 years.An education level of primary school and above. | PMC9907817 |
Exclusion criteria | dysarthria, hearing comprehension impairment, transcortical sensory, wernicke aphasia, Visual defect, aphasia | HEARING IMPAIRMENT, SPEECH APRAXIA, DISEASES | Suffering from other serious diseases or intolerable examination.Complete aphasia, wernicke aphasia, transcortical sensory aphasia, and transcortical mixed aphasia with severe hearing comprehension impairment.Visual defect, hearing impairment, dysarthria, and speech apraxia.Previous mental history. | PMC9907817 |
Sample size | The software Gpower (HHU, Germany, Dusseldorf)was used to calculate the sample size [ | PMC9907817 |
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Study groups | BLIND | After the participants signed the consent form, we randomly assigned them into group I (Chinese idioms training) and group II (routine rehabilitation training) in a 1:1 manner. We used the random envelope method for grouping concealment. After preparing the randomization plan, the sequentially-coded, opaque, and sealed envelope was used. Each grouping plan was put into an opaque envelope, the code was written outside of it, and the envelope was sealed and given to the researcher. After each participant entered the study, the researcher will determine the eligibility of the subject, subsequently open the envelope with the corresponding number, and intervene accordingly. As this study involved changes in the content and form of rehabilitation training, it was impossible to blind participants and research intervention personnel, yet blinding will be used on data collection and analysis personnel to avoid bias to a great extent. | PMC9907817 |
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Intervention | PMC9907817 |
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Assessment of treatment outcomes | stroke, hemiplegia, aphasia | STROKE, SECONDARY | The Aphasia Battery of Chinese (ABC) scale is the main efficacy index to evaluate the language ability of participants. The ABC scale is compiled by combining the internationally recognized Boston Diagnostic Aphasia Examination (BDAE) and Western Aphasia Battery (WAB). It has good reliability and validity [The Comprehensive Activities of Daily Living (CADL) scale was used as the secondary index to evaluate the language ability of participants. The examination mainly includes 22 items, in addition to 34 sub-items, of daily life communication activities. It aims to obtain objective results by assessing the daily life communication ability of patients with aphasia and guide language training. The total score of the scale is 136. The higher the score, the better the communication ability [Baseline characteristics were collected for each patient, including age, sex, education, stroke type, aphasia type, and hemiplegia side. Prior to intervention, the therapists assessed participants using the ABC Scale and CADL questionnaires and continued follow-up at the end of the treatment period. Data were analyzed by a intent-to-treat analysis and the missing data were filled out using the last-observation-carried-forward. | PMC9907817 |
Statistical analyses | SPSS version 26.0 (IBM, Armonk, NY) was used to process and analyze the data. Normally distributed data are expressed by mean (SD) and non-normally distributed data are expressed by Median(interquartile range, IQR). For the comparison of paired measurement data, the paired sample t-test was used for normally distributed data, and the Wilcoxon signed rank test was used for non-normally distributed data. As for the comparison of two-sample measurement data, the two independent sample t-test was used for normally distributed data, whereas the two independent sample Wilcoxon signed rank test was used for non-normally distributed data. The Chi-square test was used to classify data. A p-value <0.05 was considered statistically significant. | PMC9907817 |
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Results | From January 2021 to January 2022, a total of 124 patients were recruited, and 70 patients(group I, n = 34; and group II, n = 36) met the criteria and agreed to participate in this study. Three participants (group I, n = 1; and group II, n = 2) withdrew halfway during the intervention process, and all participants were finally analyzed. | PMC9907817 |
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Flow diagram. | left hemiplegia, right hemiplegia, stroke, Transcortical motor aphasia, ischemic stroke, Broca’s aphasia, hemiplegia | STROKE, ISCHEMIC STROKE | A total of 20 women (29%) and 50 men (71%) were included in this study, with an average of 65.0 (11.3) years. The educational background mainly comprised junior middle school (n = 29, 41.4%) and senior high school (n = 22, 31.4%). The main types of stroke were ischemic stroke (n = 56, 80.0%), Broca’s aphasia (n = 41; 57.1%), and Transcortical motor aphasia (n = 29; 41.4%). Most patients had right hemiplegia (n = 39, 55.7%), and the median of intervention period was 15(1) days. All patients participated in the expression, comprehension, and reading of ABC and scoring of all CADL items. Moreover, 17 patients without hemiplegia and 11 patients with left hemiplegia participated in the scoring of ABC writing items (group I, n = 13; and group II, n = 15). Baseline data are shown in | PMC9907817 |
Comparison of the two groups’ general clinical data. | stroke, hemiplegia, aphasia | STROKE | Differences between groups in classify data(gender, education level, stroke type, aphasia type and hemiplegia side), age and intervention time were analysed by Chi-square test, two independent sample t-test and Wilcoxon signed rank test respectively. | PMC9907817 |
Language function evaluation | All participants who completed intervention were evaluated for oral expression, comprehension and reading through the ABC scale. Moreover, 28 patients (group I, n = 13; and group II, n = 15) participated in the writing evaluation. There is no significant difference between the intervention and control groups in initial ABC score(all P > 0.05).The scores of oral expression, comprehension, reading were significantly higher following intervention than before intervention in both groups (all P <0.05), and group I underwent a better effect (all P <0.05). Nevertheless there was no significant difference in the scores of writing before and after the intervention in both groups(both P > 0.05) ( | PMC9907817 |
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Comparison of the ABC scores before and after the intervention in both groups. | Analysed by the two independent sample t-test between groups and paired sample t-test within groups.*P <0.05 | PMC9907817 |
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Daily communication skills | aphasia | The daily communication ability of patients with aphasia was evaluated using the CADL scale. There is no significant difference between the intervention and control groups in initial CADL scores (P > 0.05). The CADL scores of both groups significantly improved following intervention compared to values before intervention (both P <0.05), with group I demonstrating more of an improvement than group II (P <0.05) ( | PMC9907817 |
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Comparison of the CADL scores before and after the intervention in both groups. | Analysed by the two independent sample t-test between groups and paired sample t-test within groups.*P <0.05 | PMC9907817 |
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Discussion | aphasia | In the present study, we found that after a 2-week intervention, both group I (Chinese idioms training) and group II (routine rehabilitation training) showed significant improvement in the scores of oral expression, comprehension and reading sections in ABC and the scores of CADL, and the improvement in group I was significantly better than that in group II(The average improvement rates of oral expression, comprehension, reading and CADL were 48%, 13%, 45.2% and 55.9% in group I and 36.4%, 6.3%, 18.1% and 33.3% in group II, respectively).This indicates that the rehabilitation training based on Chinese idioms can effectively improve the language function and daily communication ability of patients, and its effect is better than that of conventional rehabilitation methods. Simultaneously, we also found that patients can benefit from the rehabilitation training of Chinese idioms in listening comprehension, even if they retain better in this ability.The benefit of the patient’s language function in this program may be related to the characteristics of the training material. Chinese idioms are harmonious, with level and oblique deployment and a strong sense of rhythm [The coherence of training material context may be the influencing factor of oral expression in aphasia. Studies have shown that providing contextual sentences helps patients with aphasia better understand [We recruited patients with non-fluent PSA, who are the main population of clinical rehabilitation training due to their retention of understanding ability, correct semantic expression, and high degree of cooperation [In conclusion, this randomized controlled trial shows that idiom rehabilitation training can improve the language function and daily communication ability of patients with non-fluent PSA, which is feasible and effective. | PMC9907817 |
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Supporting information | PMC9907817 |
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CONSORT 2010 checklist. | (DOC)Click here for additional data file. | PMC9907817 |
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PLOSOne clinical studies checklist. | (DOC)Click here for additional data file. | PMC9907817 |
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Study protocol. | (PDF)Click here for additional data file. | PMC9907817 |
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Translation of study protocol. | (PDF)Click here for additional data file. | PMC9907817 |
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Ethics approval. | (PDF)Click here for additional data file. | PMC9907817 |
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Translation of ethics approval. | (PDF)Click here for additional data file. | PMC9907817 |
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Examples of idiom materials. | post-stroke aphasia | (PDF)Click here for additional data file.We thank the Department of Neurology, Neurosurgery and Rehabilitation of the Renmin Hospital of Wuhan University for providing a platform for the development of this study. We would like to thank the speech therapist Ms. Yang HM for providing relevant training for this study. We would like to thank the neurologist Professor Li T and the rehabilitation doctor Professor Zhu SS for their technical support. Finally, we would like to sincerely thank the patients with post-stroke aphasia who participated in this study. | PMC9907817 |
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Supplementary Information | toxicities, high-grade gliomas, mucositis, Hypertension, hypertension, gliomas, HGGs | COLORECTAL CANCER, DISEASE, SOLID TUMORS, ADVERSE EVENT, MUCOSITIS, HYPERTENSION, HYPERTENSION, GLIOMAS | SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (The online version contains supplementary material available at 10.1007/s10637-022-01325-4. | PMC10140125 |
Keywords | PMC10140125 |
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Introduction | tumor, HGG, high-grade glioma, Malignant tumors, gliomas | TUMOR, SOLID TUMORS, MALIGNANT TUMOR, INFILTRATING, NEOVASCULARIZATION, GLIOMAS, TUMOR ANGIOGENESIS | Despite advances in treating recurrent high-grade glioma (HGG, WHO grade III and IV gliomas), the prognosis remains poor, and much work still needs to be done for improvement. Malignant tumors require neovascularization for growth, invasion, and metastasis[Tumor-associated macrophages (TAMs), defined as macrophages infiltrating the tumor microenvironment (TME), comprise 30–40% of the tumor mass in HGG and play a major role in promoting tumor angiogenesis and progression[SYHA1813 is a selective TKI that inhibits VEGFR-1 (half maximal inhibitory concentration [ICThe present study is a dose-escalation phase I clinical trial to evaluate the safety, pharmacokinetics (PK), maximum tolerated dose (MTD), efficacy, and potential biomarkers of SYHA1813 in patients with recurrent HGG or advanced solid tumors. | PMC10140125 |
Methods | PMC10140125 |
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Patient eligibility | myocardial infarction, unstable angina pectoris, arrhythmia, impaired cardiac function, Tumors, glioma, cardiovascular and cerebrovascular diseases, hypertension | MYOCARDIAL INFARCTION, UNSTABLE ANGINA PECTORIS, ARRHYTHMIA, TRANSIENT ISCHEMIC ATTACK, BRAIN METASTASES, CENTRAL NERVOUS SYSTEM TUMORS, SOLID TUMORS, TUMORS, CEREBROVASCULAR ACCIDENT, GLIOMA, CONGESTIVE HEART FAILURE, ONCOLOGY, HYPERTENSION, LACUNAR INFARCTION | Eligible patients were ≥ 18 years of age with recurrent or advanced solid tumors confirmed by histology or cytology refractory to standard therapy or for which no effective therapy was available. Patients had at least one measurable lesion during the baseline period (primary central nervous system tumors were assessed as per the Response Assessment in Neuro-Oncology [RANO] criteria; other solid tumors were assessed as per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). The time interval between the end of the last antitumor treatment and the first administration of SYHA1813 was ≥ four weeks for cytotoxic drugs, immunotherapy, macromolecular targeted drugs, and biological therapy; ≥ two weeks or five half-lives (whichever is longer) for oral small-molecule targeted drug therapy, anticancer traditional Chinese medicines or proprietary Chinese medicines; and ≥ four weeks for radiotherapy (≥ two weeks for palliative local radiotherapy for symptom relief). Other inclusion criteria included a Karnofsky Performance Status (KPS) of 60 or more for patients with central nervous system tumors, an Eastern Cooperative Oncology Group (ECOG) physical performance status of 0 to 2 for patients with other solid tumors, and a life expectancy of 12 weeks.Exclusion criteria included participation in other interventional clinical studies within four weeks, major surgery within four weeks, use of glucocorticoids at a dose equivalent to more than 5 mg dexamethasone within five days for glioma or brain metastases, and use of bevacizumab, ramucirumab, and other anti-VEGF/VEGFR antibodies within three months for glioma or brain metastases. Patients were also excluded if they had impaired cardiac function or clinically significant cardiovascular and cerebrovascular diseases, including but not limited to a history of myocardial infarction, congestive heart failure, and unstable angina pectoris within six months; cerebrovascular accident within six months (patients with transient ischemic attack or lacunar infarction with no clinical significance could be enrolled); hypertension uncontrollable after medication (repeated blood pressure measurement at least 1 h apart, and blood pressure 150/90 mmHg at two consecutive tests); uncontrolled arrhythmia requiring medical treatment; QTc interval > 470 ms on electrocardiogram (ECG) examination; or left ventricular ejection fraction < 50%. | PMC10140125 |
Study design and drug administration | toxicities, DLTs | DISEASE | This was a phase Ia, multicenter, open-label, dose-escalation study of SYHA1813. The overall study design is presented in Supplementary Fig. S1. The primary endpoints were the safety and tolerability of SYHA1813, including the occurrence of dose-limiting toxicities (DLTs) and the establishment of the maximum tolerated dose (MTD). Secondary endpoints included determination of the PK profile and preliminary antitumor activity based on the objective response rate (ORR), and disease control rate (DCR), as well as exploration of potential biomarkers related to SYHA1813 therapy. The study was approved by the National Medical Products Administration (NMPA) for clinical trials. We conducted the study according to the ethical principles of the Declaration of Helsinki and Good Clinical Practices guidelines. The study was approved by an institutional review board at each participating site. All patients provided written informed consent. The study was registered at chictr.org.cn (trial registration ID: ChiCTR2100045380).The maximum recommended starting dose (based body weight 60 kg) of 11 mg was estimated based on 1/6 of the highest non-severely toxic dose in the beagle dog study. Based on further safety considerations, 5 mg was selected as the starting dose in human subjects. In the dose-escalation study, patients were enrolled sequentially to receive a single oral dose of SYHA1813 (5, 15, 30, 60, 100, 150, and 200 mg) followed by a 3-day observation period with safety and PK assessments, subsequent once-daily treatment at the same dose level during 21-day multiple-dose period followed by a 4-day observation period with safety, PK and efficacy assessments. From the second cycle onwards, the study drug was given every day (3 weeks/cycle) if the treatment was well tolerated and beneficial. | PMC10140125 |
Safety assessments and definition of DLT | non-DLTs, Cancer | ADVERSE EVENTS, ADVERSE EVENT, CANCER | DLT was defined as the occurrence of adverse events (AEs) that the investigator judged to be related to SYHA1813 within 28 days of the first dose during the dose-escalation period (Supplementary Table S1). The MTD was defined as the maximum dose for which the probability of a DLT was ≤ 33%.An accelerated titration design with one patient enrolled was utilized for the first two dose levels (5 and 15 mg). Then, a 3 + 3 dose-escalation design was employed starting from the third dose level (30 mg). If grade 3 or above adverse events (AEs, non-DLTs) occurred in one patient at the first two doses, two more patients were enrolled for further observation. If DLT was observed in one of the 3 patients, up to 3 more patients were enrolled at the same level. If 2 or more out of 3 to 6 patients experienced DLT at a dose level, the dose was decreased to the previous dose group. When decreasing to the previous dose group, if there were only 3 patients in the dose group, 3 more patients were added; if there were already 6 patients, the dose escalation ended, and the dose was defined as the MTD. Any patient who withdrew from the study before the completion of the DLT observation period due to a reason other than DLT was replaced. Dose de-escalation or reduction was permitted if safety re-evaluation was deemed necessary.Safety analyses were conducted for all patients who received at least one dose of SYHA1813. AEs were assessed throughout the study using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The health status assessment of the patients included a physical examination (vital signs, weight, PS score, etc.), hematologic and biochemical profiling, routine urine and stool tests, and electrocardiogram assessment performed at screening and throughout the study. | PMC10140125 |
PK evaluation | BLOOD | Blood samples for the assessment of PK parameters were collected at predefined time points during the DLT observation period as follows: Cycle 0 Day 1 (predose; 0.5, 1, 2, 4, 8, and 12 h postdose), Day 2 (24 h postdose), and Day 3 (48 h postdose); Cycle 1 Day 1 (predose), Day 8 (predose), Day 15 (predose), Day 21 (predose; 0.5, 1, 2, 4, 8, and 12 h postdose), Day 22 (24 h postdose), Day 23 (48 h postdose), and Day 24 (72 h postdose). Plasma SYHA1813 levels were measured using a validated high-performance liquid chromatography‒mass spectrometry method.Single- and multiple-dose PK parameters of SYHA1813 were estimated using noncompartmental analysis, including maximum observed plasma concentration (C | PMC10140125 |
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Efficacy assessment | toxicity, PD, SD | DISEASE PROGRESSION, DISEASE, CENTRAL NERVOUS SYSTEM TUMORS, SOLID TUMORS | Radiographic assessments were conducted at screening and at the end of the DLT observation period and repeated every six weeks during the extended treatment period until disease progression, intolerable toxicity, or withdrawal of consent (whichever came first). The patients with central nervous system tumors were evaluated for responses according to the RANO criteria by enhanced magnetic resonance imaging (MRI) scan. Patients with other solid tumors were assessed by computed tomography (CT) or MRI scan according to RECIST version 1.1. The categories used for the evaluation of the response to treatment included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ORR and DCR were defined as CR + PR and CR + PR + SD, respectively. | PMC10140125 |
Exploratory biomarker analysis | Samples for biomarker analyses were collected on Cycle 1 Day 1 (predose), Cycle 1 Day 24 (72 h post-dose), and 14 days after the end of treatment. Soluble VEGFR2, VEGF, and CSF1 levels were measured using multiplex enzyme-link immunosorbent assay (ELISA) plates from R&D Systems (Minneapolis, MN), and placental growth factor (PlGF) levels were measured using an electrochemiluminescence immunoassay (ECLIA) kit from Roche Diagnostics (Mannheim, Germany). | PMC10140125 |
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Statistical analysis | All statistical analyses were performed using SAS® 9.4 (SAS Institute, Inc., Cary, NC, USA) except for the calculation of PK parameters using Phoenix® WinNonlin 8.1 (Pharsight Corp., Certara, Princeton, NJ, USA). Exploratory biomarker analyses were performed by a two-tailed paired t test using GraphPad Prism 9.3 (GraphPad Software, Inc., CA, USA). | PMC10140125 |
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Results | PMC10140125 |
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DLTs and MTD | anaplastic astrocytoma, bradycardia, DLTs, non-DLT, mucositis, glioblastoma, hypertension | GLIOBLASTOMA, ANAPLASTIC ASTROCYTOMA, HYPERTENSION, MUCOSITIS | According to the accelerated titration design, two patients successively completed the DLT observation period (28 days) of treatment at 5 and 15 mg. However, the patient treated with 15 mg experienced grade 3 hypertension (non-DLT), and another two patients were enrolled at 15 mg based on the study design. Of those patients, one patient discontinued the treatment due to grade 2 bradycardia, which the investigator considered not related to the treatment. As a result, one more patient was enrolled at 15 mg for safety evaluation, and no more than grade 3 AEs were reported. In the 30 mg group, two out of five patients experienced DLTs (grade 3 mucositis oral and grade 4 hypertension), and the drug administration to the sixth patient in the 30 mg group was stopped according to the investigator’s decision to protect the safety and welfare of patients. Hence, for safety re-evaluation, four additional patients were enrolled in the lower dose level of 15 mg (one patient withdrew consent and was replaced), and no DLTs occurred. The dose-escalation process is shown in Supplementary Fig. S3.Two patients in the dose escalation had DLTs. The first patient with WHO grade III anaplastic astrocytoma in the 30-mg group had a DLT (grade 3 mucositis oral) on Cycle 1 Day 18, which lasted 5 days. The second patient with WHO grade IV glioblastoma in the 30-mg group had a DLT (grade 4 hypertension) on Cycle 1 Day 15, which lasted 8 days. No DLT was observed at doses of 15 mg and lower. Based on protocol-defined criteria, the MTD for SYHA1813 was determined to be 15 mg once daily. | PMC10140125 |
Safety and tolerability | toxicities, hypertension, mucositis, Treatment-emergent adverse | SINUS BRADYCARDIA, HYPERTENSION, MUCOSITIS, ADVERSE EVENTS | All 14 patients were evaluated for safety. Overall, 13 (92.9%) patients had treatment-emergent AEs (TEAEs) during the study (Table
Treatment-emergent adverse events (affecting ≥ 10% of patients in either treatment group)Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase; α-HBDH, alpha-hydroxybutyrate-dehydrogenase.Four patients experienced treatment interruptions and dose reductions due to SYHA1813-related toxicities, which were grade 2 sinus bradycardia, grade 2 platelet count decreased, grade 3 mucositis oral, and grade 4 hypertension. Serious adverse events considered to be related to SYHA1813 treatment were reported for one (7.1%) patient with grade 4 hypertension in the 30-mg group. No grade 5 AEs occurred. | PMC10140125 |
Efficacy | tumor, colorectal cancer, HGG, RECIST, S3).For glioma, glioma, PD | GLIOMA, TUMOR, COLORECTAL CANCER, SOLID TUMOR | Ten patients were assessable for tumor response per investigator assessment, 9 with glioma (RANO criteria) and 1 with colorectal cancer (RECIST version 1.1); the other four enrolled patients withdrew from the study before the first tumor assessment. In the efficacy-evaluable population, the ORR was 20% (2/10), with all responses being PRs (Supplementary Table S3).For glioma, the best percent change in tumor size from baseline and the best response and time on therapy for patients with HGG are shown in Fig.
Antitumor activity for patients with HGG. The other advanced solid tumor patient, a 49-year-old male patient with stage IV colorectal cancer, received standard regimens and developed PD. He was then enrolled in the 15-mg SYHA1813 group and achieved SD assessed on Cycle 1 Day 25, which had lasted 2 weeks by the study cutoff date. | PMC10140125 |
Analysis of biomarkers | Five patients were excluded from the biomarker analysis set due to a lack of postdose measurements. After multiple-dose administration of SYHA1813, there were significant increases in the serum levels of PlGF ( | PMC10140125 |
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Discussion | tumor, DLTs, toxicities, HGG, Hypertension, hypertension | TUMOR, SINUS BRADYCARDIA, HYPERTENSION, HYPERTENSION, MALIGNANT GLIOMAS | This trial was the first to investigate the safety, PK profile, and preliminary antitumor activity of single and multiple doses of SYHA1813. The MTD of SYHA1813 was defined as 15 mg once daily.While most patients experienced at least one TRAE, most treatment-related toxicities were mild and included hypertension, platelet count decreased, and sinus bradycardia. Doses up to 15 mg per day were considered tolerable. Two patients in the 30-mg group experienced DLTs. Hypertension and platelet count decreased were the most frequently reported grade 3–4 AEs. The occurrence of hypertension was likely the result of effective inhibition of the VEGF signaling pathway, consistent with the observations of increased incidence of hypertension in other clinical studies with small-molecule VEGF TKIs[When administered as a single dose, the exposure (CSYHA1813 administration resulted in a significant decrease in the level of sVEGFR2 from baseline, consistent with previous clinical findings with other VEGFR inhibitors, such as cediranib and pazopanib. Previous preclinical studies suggested that changes in the level of sVEGFR2 could be a pharmacodynamic marker of systemic exposure to drug, not a predictive marker of tumor response or clinical benefit. Similar to a previous study of the CSF1R inhibitor pexidartinib, we also observed an increased plasma concentration of CSF1 following multiple-dose administration [SYHA1813 has promising antitumor activity in recurrent HGG. A sustained tumor response was observed in HGG. Similar to the results of the phase II studies of cediranib (ORR of 56.7%) and pazopanib (ORR of 5.9%) in patients with recurrent malignant gliomas, SYHA1813 monotherapy showed encouraging antitumor activity (ORR of 20%) [In conclusion, oral administration of SYHA1813 at 15 mg daily demonstrated acceptable tolerability and preliminary antitumor activity in recurrent HGG. The subsequent dose-expansion cohort and phase Ib clinical trials of SYHA1813 should include HGG as a focus. | PMC10140125 |
Acknowledgements | We would like to thank all the patients, their families, and all the investigators involved in this study. | PMC10140125 |
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Author contributions | WL | RECRUITMENT | ZK developed the study protocol, conducted the clinical study, and coordinated with the participating hospitals. SL, YL, YL, YM, JZ, and TL were the principal researchers in each hospital and helped to contribute to participant recruitment and provide feedback about the study procedure. HW, YS, YY, and JQ performed the statistical analysis, analyzed and interpreted the results, and provided comments. WL designed the research and supervised the report. All authors contributed to the article and approved the submitted version. | PMC10140125 |
Funding | The study was funded by Shanghai Runshi Medical Technology Co., Ltd, China. | PMC10140125 |
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Statements and declarations | PMC10140125 |
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Conflict of interest | HW, YS, YY, and JQ are employed by CSPC Pharmaceutical Group Limited. The other authors have no conflicts of interest. | PMC10140125 |
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Ethics approval | The studies involving human participants were reviewed and approved by an institutional review board at each participating site. This study is registered at chictr.org.cn (trial registration ID: ChiCTR2100045380). | PMC10140125 |
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Consent to participate | All patients provided written informed consent prior to the initiation of any study-related procedures. | PMC10140125 |
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Consent to publish | The authors affirm that human research participants provided informed consent for the publication of the images in Supplementary Figures S4 and S5. | PMC10140125 |
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References | PMC10140125 |
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Purpose | To analyze serum estradiol (E2) and estrone (E1) during letrozole treatment and their association to Quality of Life (QoL) and side-effects. | PMC10460747 |
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Methods | breast cancer | BREAST CANCER | Postmenopausal breast cancer patients starting adjuvant letrozole were eligible. Serum samples were taken at baseline, three, and 12 months. E2 and FSH were measured with routine chemiluminescent immunoassays. E2 and E1 were analyzed after trial completion with a highly sensitive liquid chromatography-tandem mass spectrometry method (LC–MS/MS) with lower limits of quantification (LLOQ) of 5 pmol/L. QoL was measured at baseline and at 12 months with the EORTC QLQ-C30 and QLQ-BR23 and the Women’s Health questionnaires, and menopause-related symptoms with the modified Kupperman Index. | PMC10460747 |
Results | aching joints, muscle aches, vaginal dryness, Pain | Of 100 screened patients 90 completed the trial. Baseline mean LC–MS/MS E2 and E1 were 12 pmol/L (range < 5–57) and 66 pmol/L (< 5–226), respectively. E2 levels measured by immunoassay and LC–MS/MS showed no correlation. E2 and E1 were completely suppressed by letrozole except for one occasion (E1 11 pmol/L at 3 months). Pain, side effects of systemic therapy, vasomotor symptoms, joint and muscle aches, and vaginal dryness increased during letrozole treatment. A high baseline E2 was significantly associated with increased aching joints and muscles, but not with the other side effects. | PMC10460747 |
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Conclusions | muscle pain | Letrozole supresses E2 and E1 completely below the LLOQ of the LC–MS/MS in postmenopausal women. High pre-treatment E2 levels were associated with more joint and muscle pain during letrozole. Automated immunoassays are unsuitable for E2 monitoring during letrozole therapy due to poor sensitivity. | PMC10460747 |
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