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Subject terms | comorbidity, CML, Comorbidity | CHRONIC PHASE CML, ADVERSE EVENTS, PHILADELPHIA CHROMOSOME, CHRONIC MYELOID LEUKEMIA, CML | In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome–positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65–74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65–74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382. | PMC10776383 |
Introduction | CML, Comorbidity | CML | The development of The phase 4 BYOND study was designed to provide further information on the efficacy and safety of bosutinib in patients with CP CML who were resistant/intolerant to prior TKIs [In patients with CML, previous studies have reported an association between higher Charlson Comorbidity Index (CCI) score and reduced overall survival (OS) [ | PMC10776383 |
Methods | PMC10776383 |
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Study design and patients | BYOND (ClinicalTrials.gov, NCT02228382) was an open-label, nonrandomized, single-arm phase 4 study of bosutinib for which the methods have been previously published [The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before study procedures began, and the protocol was approved by institutional review boards at each study site. | PMC10776383 |
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Efficacy and safety assessments | Cancer | ADVERSE EVENT, EVENTS, CANCER | The primary endpoints of the BYOND study have been previously reported [Efficacy was evaluated by standard criteria [Treatment-emergent AEs (TEAEs), serious AEs, and laboratory evaluations were assessed up to 28 days after last dose. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.4.0. The frequency and characteristics of AEs of special interest were analyzed by selecting Medical Dictionary for Regulatory Activities (MedDRA) system organ class high-level group, high-level and preferred terms, and standardized MedDRA queries to generate TEAE clusters (Supplementary Methods).PROs were assessed using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) quality of life questionnaire at baseline, every 3 months for the first year, and every 6 months during years 2, 3, and 4 of treatment [ | PMC10776383 |
Statistical analysis | EVENT | Time-to-event endpoints (excluding OS) were estimated using cumulative incidence, adjusting for the competing risk of treatment discontinuation without the event. OS was estimated using the Kaplan–Meier method. Two-sided 95% confidence interval (CI) for response rate was determined using the exact binomial method. For Kaplan–Meier yearly probability estimates, two-sided 95% CI was based on Greenwood’s formula using a log(-log) transformation. All other data were summarized descriptively unless otherwise stated. All patients who received at least one dose of study drug (full analysis set) were included in the safety and PRO analyses.This analysis was based on the final database lock, ≥3 years after the last enrolled patient; 90% of patients with Ph+ CP CML had a follow-up of 4 years or had already permanently discontinued. | PMC10776383 |
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Results | PMC10776383 |
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Bosutinib dose over time in patients with Ph+ CP CML. | Patients grouped by (Bosutinib was permanently discontinued by 40.0%, 66.7%, and 75.0% of patients <65, 65–74, and ≥75 years of age, and 44.4%, 55.6%, and 73.3% of patients with mCCI 2, 3, and ≥4, respectively (Supplementary Table | PMC10776383 |
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Reasons for permanent treatment discontinuation over time in patients with Ph+ CP CML. | Patients grouped by ( | PMC10776383 |
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Safety | The incidence of any grade TEAEs was similar between the age groups and between the mCCI risk groups (Supplementary Table | PMC10776383 |
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Summary of grade 3–4 TEAEs in patients with Ph+ CP CML. | Patients grouped by (Medical history and incidences of TEAEs of special interest for the overall population are shown in Supplementary Table | PMC10776383 |
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Patient-reported outcomes | At baseline, mean (standard deviation) FACT-Leu leukemia-specific subscale scores were, respectively, 128.9 (24.7), 131.1 (20.8), and 125.7 (18.9) in patients <65, 65–74, and ≥75 years; and 129.7 (23.1), 123.9 (24.5), and 130.3 (20.6) in patients with mCCI 2, 3 and ≥4. Over the course of treatment, mean FACT-Leu leukemia-specific scores were maintained in patients aged <65 years and in patients with mCCI 2 (Fig. | PMC10776383 |
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Mean change from baseline on the FACT-Leu leukemia-specific subscale in patients with Ph+ CP CML. | Patients grouped by ( | PMC10776383 |
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Discussion | pleural effusion, comorbidity, gastrointestinal TEAEs, edema, toxicities, TEAEs, Comorbidity, myelosuppression, effusion | CHRONIC MYELOID LEUKEMIA, PLEURAL EFFUSION, EDEMA, EVENT, CML, EFFUSION, EVENTS | After ≥3 years of follow-up in the phase 4 BYOND study, a substantial proportion of patients across age and mCCI groups achieved/maintained cytogenetic and molecular responses. Cumulative CCyR and MMR rates were comparable in patients across age groups. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) had higher rates of grade 3/4 and serious TEAEs. There was a trend toward higher rates of treatment discontinuation due to AEs with increasing age and in those patients with a high comorbidity burden. Across age and mCCI groups, dose reductions and interruptions were frequently used to manage AEs. Dose reduction to 400, 300, or 200 mg QD to manage TEAEs did not have an impact on efficacy in any subgroup. This is consistent with a previous study of bosutinib in patients with CP CML resistant/intolerant to prior therapy, which demonstrated that dose reduction did not compromise efficacy while reducing the occurrence of some common TEAEs, such as gastrointestinal TEAEs, even at doses as low as bosutinib 200 mg QD [As expected in patients receiving TKIs, the estimated OS rate at 48 months was high (>68%) in each subgroup [Patients with a medical history of liver, myelosuppression, edema, renal, effusion, cardiac, and vascular cluster events were more likely to experience the corresponding TEAE event of interest than those patients without the relevant medical history. Therefore, proactive management and monitoring may be warranted in patients with these preexisting conditions. These results are generally consistent with what has previously been reported for bosutinib treatment [Health-related quality of life was maintained from baseline throughout treatment for patients aged <65 and 65–74 years and patients with mCCI 2. A meaningful reduction in health-related quality of life was seen at multiple timepoints on treatment in patients aged ≥75 years, and patients with mCCI 3 and 4. A potential reason for this is that the increase in grade 3–4 and serious TEAEs observed in these subgroups of patients adversely affected health-related quality of life, as has been previously reported in patients receiving TKIs [Together these results suggest that while a substantial proportion of patients maintained/achieved cytogenetic and molecular responses with bosutinib across age groups and mCCI scores, both comorbidities and age are important factors to consider during bosutinib treatment. Older patients and those with a high comorbidity burden are more likely to experience more severe TEAEs, which can also impact health-related quality of life. Age, comorbidities, and risk factors, as well as the safety profile and schedule of administration of TKIs, should be considered when selecting the most appropriate TKI for the treatment of patients with previously treated CML. Patients should be monitored throughout treatment, not only for response but also for health conditions, whether they were preexisting or developed during therapy [The phase 2 Bosutinib in Elderly Chronic Myeloid Leukemia (BEST) and Bosutinib Dose Optimization (BODO) studies investigated dose optimization strategies to minimize the severity and incidence of AEs [Although comparisons between studies are difficult due to differences in methodologies and patient populations, the results reported here for bosutinib appear comparable to those with other second-generation TKIs. In a retrospective study of patients with resistance or intolerance to imatinib who received dasatinib, stratification by Charlson Comorbidity Index was able to identify patients at risk of major toxicities such as pleural effusion [In conclusion, the findings of this study further support bosutinib use for patients with Ph+ CP CML across age groups and mCCI scores. Age and mCCI stratification may enable the identification of patients who are at higher risk of developing TEAEs and may require more careful monitoring in clinical practice.Information about this study in a plain language format is available in the supplementary materials. | PMC10776383 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41375-023-02080-y. | PMC10776383 |
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Acknowledgements | The authors thank Ulla Olsson-Strömberg, MD, for her contributions to this manuscript. The study was sponsored by Pfizer Inc. Medical writing support was provided by Gemma Shay-Lowell, PhD, and Anne Marie McGonigal, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc. | PMC10776383 |
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Author contributions | All authors were involved in the trial conception/design, or the acquisition, analysis, or interpretation of data. All authors contributed to the drafting of the manuscript and approved the final version. | PMC10776383 |
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Data availability | Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See | PMC10776383 |
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Competing interests | Cancer | CANCER | GR received research support from Pfizer and served on the speaker bureau for Bristol Myers Squibb, Incyte, Novartis, and Pfizer. THB provides consultancy to Janssen, Merck, Novartis, Pfizer, and Takeda, and received research support from Novartis and Pfizer. BTG provides consultancy to BerGenBio, Novartis, Pfizer, and Sanofi, received research support from Pfizer, and has stock ownership in Alden Cancer Therapy AS and KinN Therapeutics AS. PG-C received research support from Bristol Myers Squibb and Pfizer. FC provides consultancy to and received honoraria from Bristol Myers Squibb, Incyte, Novartis, and Pfizer, and received research support from Pfizer. CG-P provides consultancy to Bristol Myers Squibb and received honoraria and research support from Pfizer. TE, no relationships to disclose. HZ, LK, and SP are employees of Pfizer. FJG provided consultancy to Actuate Therapeutics Inc, provided expert testimony to Novartis, and received research support from Pfizer. AH received research support from Bristol Myers Squibb, Incyte, Novartis, and Pfizer. | PMC10776383 |
References | PMC10776383 |
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Introduction | OA, pain | CHRONIC PAIN, MINOR | Endogenous pain modulation has been proposed and is discussed as a leading feature of the nociceptive system that can promote or protect the individual against the transition from acute to chronic pain [Offset analgesia can be defined as a disproportionally large pain decrease after a minor noxious stimulus intensity reduction [Interestingly, psychological interventions have never been used in the context of OA. It is of clinical interest, whether psychological processes influence endogenous pain modulation, especially since—amongst others- hypo- or hyperalgesic suggestion have been shown to effectively decrease [This experiment attempted to influence the magnitude of OA by manipulating participants’ expectations using suggestions. In this study, suggestions were used to modulate OA selectively, that is, by changing the pain response in the final temperature phase of the paradigm. Therefore, the á priori hypothesis implied that suggestion would influence the OA effect in a bidirectional manner, i.e., analgesia was expected to be increased or decreased, respectively, compared to a control group that was not exposed to any form of suggestion. | PMC9844857 |
Materials and methods | PMC9844857 |
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Study design | pain | HEAT | This experimental study was conducted as a randomized controlled trial in which healthy, pain-free participants were randomly divided (counterbalanced) into two intervention groups and one control group. Both intervention groups received either a hypoalgesic or a hyperalgesic suggestion related to the pattern of the subsequently applied heat pain within an OA paradigm. The control group received no suggestion. All participants received the identical information about the exact temperature course of the heat stimuli beforehand. In order to perform the suggestions as authentically as possible, a cover story was told to all participants at the beginning of the study. All participants were blinded to the true purpose of the study. The study was previously approved by the ethics committee of the University of Lübeck (file number: 21–028) and pre-registered in the Open Science Framework ( | PMC9844857 |
Study design. | hypoalgesia, hyperalgesia, pain | HEAT | Before randomization, participants were instructed and a cover story was provided. Participants were told that in this study, changes in electrodermal activity (EDA) would be assessed as a measure of the autonomic nervous system during experimental heat stimuli and used to predict the perception of pain (cover story). Participants were assigned to either i) the hypoalgesic group with suggestion towards profound hypoalgesia following the temperature reduction, ii) the hyperalgesic group with verbal suggestion towards hyperalgesia following the temperature reduction (see the example above), or iii) the control group with no intervention. Regardless of the group assignment participants were exposed to two offset and two constant trials provided in a counterbalanced manner. | PMC9844857 |
Study population | muscle soreness, pain, psychiatric, headache, chronic pain, toothache | CHRONIC PAIN, NEUROLOGICAL DISEASE | Healthy, pain-free participants aged 18 to 65 years were recruited on the campus of the University of Lübeck. All participants had to subjectively confirm that they were healthy. Furthermore, participant had no cardiovascular, systemic, psychiatric or neurological disease. Furthermore, all participants were excluded if they had a history of chronic pain (> 3 months) within the last 2 years or had experienced pain (including headache, toothache, muscle soreness, etc.) within the last week prior to study participation. In addition, the use of medication, excluding contraceptives, in the last 48 hours was an exclusion criterion. Furthermore, participants were asked not to drink alcohol, exercise, or take pain medication for 24 hours prior to participation in the study and not to drink coffee or smoke cigarettes for 4 hours prior to study participation. | PMC9844857 |
Equipment | pain | HEAT | A Pathway CHEPS (Contact Heat -Evoked Potential Stimulator) with a contact area of 27mm diameter was used for the application of the heat stimuli (Medoc, Ramat Yishai, Israel). The thermode was attached to the non-dominant volar forearm approximately 10 cm below the elbow using a blood pressure cuff with a pressure of 25 mmHg. A computerized visual analog scale hardware device (COVAS; with the range 0 = "no pain" to 100 = "most tolerable pain") was used for continuous assessment of pain intensity (Medoc, Ramat Yishai, Israel). Furthermore, during heat stimuli, electrodermal activity (EDA; respiBAN Professional, Plux, Lisbon, Portugal) was measured using two Ag/AgCl hydrogel electrodes (Covidien / Kendall, Dublin, Ireland) at the medial phalanx of index and middle finger of the non-dominant arm (sampling rate of 1000 Hz, PLUX Wireless Biosignals, S.A., Portugal). Electrodermal activity depends on sweat secretion, which is closely related to autonomic nervous system activity [ | PMC9844857 |
Experimental heat stimulation | HEAT | Two constant trials (CT) and two offset trials (OT) were performed on the non-dominant volar forearm, so that the participants were presented with a total of four heat stimuli. The order in which trials were presented was randomized in a counterbalanced fashion. A two-minute pause was kept between each stimulus, during which the thermode was moved on the forearm by a few centimeters. The temperature’s rise and fall rate for all heat stimuli was 15°C/second. During CT, the temperature increased from a baseline level of 35°C to 46°C and remained constant for 40 seconds before returning to the baseline level. During OT, the temperature first increased to 46°C (T1) for 10 seconds, then increased to 47°C (T2) for 10 seconds, and finally decreased again to 46°C (T3) lasting 20 seconds. The temperature pattern of the two trials can be seen in | PMC9844857 |
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Suggestion | OA, pain | HEAT | The participants were provided with a cover story. It was explained that the aim of the study was to find out whether the subjective sensation of pain could be "read out" from the physiological reaction of the body (skin conductance) and thus be predicted. A cover story was necessary to also justify the introduction of suggestion as credibly as possible without participants becoming skeptical or biased.The hypoalgesic or hyperalgesic groups received suggestions about the expected pain pattern and the pain intensity of the applied heat stimuli. The hypoalgesic group received a suggestion to enhance the effect of OA and adaptation to CT, i.e., to reduce pain perception. The hyperalgesic group, on the other hand, received a suggestion, which was intended to reduce the effect of OA and adaptation to CT, i.e., to increase pain perception. The expected pain pattern was manipulated verbally ( | PMC9844857 |
Questionnaires | depression | HEAT | Before starting the heat application, participants were asked to complete several questionnaires: The Patient Health Questionnaire (PHQ-9) includes nine questions about depression [ | PMC9844857 |
Manipulation check | pain | HEAT | To assess the effect of suggestion on pain perception during the OA paradigm, a manipulation check was performed immediately after pain assessment. The following was asked separately for OT and CT: “Please try to recall the moment immediately after receiving heat stimuli. Did you perceive the pain as in the previously displayed figures?” Participants provided a binary (yes vs. no) response. | PMC9844857 |
Statistical analysis | OA, pain | HEAT, SECONDARY | In the absence of studies investigating OA and verbal suggestion, a meta-analysis examining the effect of verbal suggestion on general pain perception was used to calculate the sample size [COVAS data from the Medoc software and the EDA signals were synchronized. The time-series data were down-sampled to a frequency of 1 Hz by using the “resample” function of the python package “Pandas” (Python 3.9.7, pandas 1.4.2). Here, multiple data points are aggregated and replaced by their average. No further preprocessing steps were performed. All other statistical analyses were performed using the IBM Statistical Package for Social Science (SPSS version 26, Armonk, NY). The three groups were tested for group differences using age, BMI, sex, dominant hand, and questionnaire data. One-way analysis of variance (ANOVA), Kruskal-Wallis tests, or chi-square tests were used accordingly.Differences between the groups in their initial pain response at the beginning of the heat stimuli were examined. For this purpose, pain ratings were averaged from the last 5 seconds of the T1 and T2 interval. Separately for OTs and CTs (mean value of the two CTs and two OTs) one-way ANOVAs were used to analyze differences between the groups. The primary outcome in this study was the magnitude of the pain response to the T3 interval (OT). To ensure that the magnitude of the OA effect was not under- or overestimated, the mean of 10 seconds centered in the T3 interval (secs. 25–34) were extracted. The 5 seconds at the beginning of the interval were not included, because the pain may still decrease during this time, and the 5 seconds at the end of the interval were not included, because the analgesic effect of OA usually decreases after approximately 15 seconds [The EDA data were analyzed according to identical principles as the pain response. As part of a secondary analysis of the EDA data in the control group, an ANOVA was performed with the within factor “interval” (T1, T2, T3) and the within factor “trial” (OT, CT). Furthermore, a dependent t-test was used to examine whether the magnitude of the EDA magnitude differed within the temperature increase/decrease (i.e. comparing the EDA magnitude from the difference of T2 and T1 with the difference of T2 and T3).If statistically significant main or interaction effects were detected, Bonferroni corrected post-hoc t tests were conducted. The correlations between the pain response of the T3 (OT) and the previously described questionnaires were calculated using the Spearman coefficient. No data were missing at the time of analysis. A | PMC9844857 |
Results | A total of 97 participants (hypoalgesic n = 32, hyperalgesic n = 33, control group n = 32) were included in this study. No significant differences were found between groups regarding baseline characteristics ( | PMC9844857 |
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Discussion | OA, pain | In summary, it can be concluded that OA was provoked in all groups, independent of the suggestion manipulation. However, the pain response but not the EDA response during an OA paradigm was influenced by visually reinforced verbal suggestion in healthy participants via hyperalgesic suggestion, but not via hypoalgesic suggestion. | PMC9844857 |
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Expectancy mechanism | hypoalgesia, OA, Pain, pain | To the best of our knowledge, this is the first study that has attempted to influence OA using suggestion. However, similar results have already been reported for studies that attempted to influence outcomes using other paradigms to quantify endogenous pain modulation by using suggestion. For example, a similar conclusion was reported by Vaegter et al. (2020) which attempted to influence exercise-induced hypoalgesia (EIH) using suggestion [In general, it can be assumed that suggestion influences OA, since brain activity during OA overlaps with the activity during placebo analgesia [Interestingly, no significant effect of the suggestion was found on CT in this study. Pain perception in the T3 interval of the CT was neither increased nor decreased. This result is in contrasts with other reports because, in principle, both hypo- or hyperalgesic suggestion have been found in previous studies to influence a wide variety of noxious stimuli [As a limitation, suggestions might not have been fully successful, as shown by the results of the manipulation check. Although the majority (70.1%) of the subjects reported that they perceived a pain response during OT according to the prior given suggestion. However, in contrast to the hypoalgesic group (90.6%), only 21.2% in the hyperalgesic group confirmed a pain response as suggested. Thus, it can be assumed that one reason for this may be the exceptionally robust analgesia during the OA paradigm. Thus, these results show that OA can be influenced only unidirectionally, being more likely to be enhanced but more difficult to be inhibited. | PMC9844857 |
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Physiological mechanisms | descending pain, hyperalgesia, pain | So far, physiological measurements taken during OA included functional magnetic resonance imaging [Interestingly, results of this study showed that, contrary to our prediction, EDA responses to OT were not decreased alongside pain perception. In turn, the increase of the temperature during a T2 interval significantly elevated the EDA level which persisted during the T3 interval, whereas the pain response was reduced. Indeed, a lowered pain intensity overlapped with higher EDA level in offset compared to constant trial. It can be suggested that the higher stimulus in T2 of the OT activates the descending pain inhibition pathways and therefore inhibits pain. In fact, the EDA level during CT gradually decreased over-time which was, in general, associated with higher pain compared to OTs. During OA, endogenous modulatory mechanisms have been shown to be activated [However, whether this EDA response represents a physiological correlate of the OA via pain response is not clear. Indeed, no differences were found for the EDA data within the OT (as is usual for the pain response) when the time intervals T1 and T3 were considered. One can therefore assume that the increased EDA response within T3, may related to an (still) ongoing EDA response caused by a higher stimulation during the T2 interval. Thus, it should be further investigated whether the EDA within an OA paradigm may also reflect the pain predictions that may involve perception of both temperature decreases (OA) and temperature increases (onset hyperalgesia) as shown by Alter et al. 2020 [Our psychological manipulation did not influence the EDA signal. Although EDA has been used extensively to capture reported pain intensity and has been shown to be a potent biomarker in pain prediction [ | PMC9844857 |
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Psychological mechanisms | OA | CHRONIC PAIN | The results of this study could serve as an explanatory approach to describe why OA is reduced in chronic pain patients. Various studies showed that a large proportion of chronic pain patients have dysfunctional beliefs about their condition and dysfunctional coping strategies in dealing with their condition [ | PMC9844857 |
Conclusion | OA, pain | In this study, suggestion manipulations have been shown to effectively reduce, but not increase, the pain response during OA in healthy participants. Using EDA, this pattern of responses was not observed. | PMC9844857 |
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Supporting information | PMC9844857 |
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Schematic representation of the heat stimuli and the suggestion figures of the expected pain perception. | pain | Heat stimuli within the Offset Trial (A): T1 interval (0–9 sec) at 46°C, T2 interval (10–19 sec) at 47°C, T3 interval (20–40 sec) at 46°C. Heat stimuli within the Constant Trial (B): constant at 46°C; suggestion figures of the hypoalgesic group during the Offset Trial (C), pain perception first increases to a level of 50/100, then to 70/100 and drops sharply in the last seconds to an almost non-painful level (approx. 5/100); during the Constant Trial (D), pain perception starts at a level of 50/100 and then slowly and constantly decreases; suggestion images of the hyperalgesic group: during the Offset Trial (E), pain perception first increases to a level of 50/100, then to 70/100 and finally to 50/100 again; during the Constant Trial (F), pain perception remains constant at a level of 50/100.(PDF)Click here for additional data file. | PMC9844857 |
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Standardized verbal suggestions. | (DOCX)Click here for additional data file. | PMC9844857 |
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Additional method of analysis for offset analgesia. | (DOCX)Click here for additional data file. | PMC9844857 |
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Data set for the analysis. | (XLSX)Click here for additional data file. | PMC9844857 |
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Correlation analysis of pain scores within the third time interval (T3) and included questionnaires. | Pain | SENSITIVITY | PHQ9: Patient Health Questionnaire; PVAQ: Pain Vigilance and Awareness Questionnaire; PSQ: Pain Sensitivity Questionnaire; STAIT-SKD: State-Trait-Anxiety-Inventory-SKD; SDS-17: Social Desirability Scale-17; MAAS: Mindful Attention and Awareness Scale, LOT-R: Life-Orientation-Test, r: spearman-correlation coefficient, p: p-value, significant correlations are marked in bold.(DOCX)Click here for additional data file.The authors thank the Institute of Medical Informatics, University of Lübeck, kindly for providing the research facilities and equipment. | PMC9844857 |
Abstract | PMC10766003 |
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Introduction | RA, T2DM, angina | TYPE 2 DIABETES MELLITUS | Sodium–glucose cotransporter 2 (SGLT2) inhibitors are emerging antidiabetic agents with various potential cardiovascular benefits. The EMPT‐ANGINA trial examined the effect of empagliflozin on the angina burden in those with concurrent type 2 diabetes mellitus (T2DM) and refractory angina (RA). | PMC10766003 |
Method | RA, T2DM | In this 8‐week, double‐blind, randomized, placebo‐controlled trial, 75 patients with T2DM and RA were randomly assigned to one of two groups: empagliflozin ( | PMC10766003 |
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Results | The mean age of individuals in the empagliflozin and placebo groups was 67.46 ± 9.4 and 65.47 ± 7.0 years, respectively ( | PMC10766003 |
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Conclusion | angina symptoms, RA, T2DM, angina | TYPE 2 DIABETES MELLITUS | Empagliflozin can be safely added as a metabolic modulator agent to existing antianginal medications in individuals with concurrent T2DM and RA to reduce angina symptoms and enhance exercise capacity with minimal side effects.The EMPT‐ANGINA randomized trial evaluated the effect of empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on angina symptoms and exercise capacity in patients with both type 2 diabetes mellitus (T2DM) and refractory angina (RA). Patients were divided into two groups: one received empagliflozin (
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INTRODUCTION | angina, ASCVD, myocardial ischemia, T2DM, RA, type 2 diabetes mellitus | ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, ASCVD, STABLE ANGINA, MYOCARDIAL ISCHEMIA, TYPE 2 DIABETES MELLITUS | Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM).The term “refractory angina” (RA) refers to the chronicity of symptoms (≥3 months in duration) and failure of symptom control with a combination of optimal medical therapy and revascularization methods.Traditional treatments for angina and myocardial ischemia are based on increasing coronary blood flow, increasing blood oxygen‐carrying capacity, and decreasing oxygen consumption; however, more recent treatments compromise agents that alter the metabolism of myocytes (Trimetazidine and Perhexiline), inhibition channels (Ranolazine), and use invasive (percutaneous myocardial laser revascularization) and noninvasive (enhanced external counterpulsation [EECP]) techniques.The effectiveness of antianginal drugs in patients who have both stable angina and T2DM is not well studied.Large randomized controlled trials on SGLT2 inhibitors in T2DM have shown remarkable benefits on cardiovascular and renal outcomes in individuals with established ASCVDs.Due to the possible antianginal effect of SGLT2 inhibitors, we conducted a double‐blind, placebo‐controlled, randomized trial to evaluate the potential impact of empagliflozin on angina burden and exercise capacity in patients with both RA and T2DM, regardless of its glucose‐lowering effects. | PMC10766003 |
MATERIALS AND METHODS | PMC10766003 |
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Study design | In the EMP‐ANGIN study (URL: | PMC10766003 |
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Study population | angina, stroke, heart failure symptoms, hepatic or renal impairment, acute coronary syndrome, rhythm abnormalities, depression, RA, T2DM | BRUCE, UNCONTROLLED HYPERTENSION, TRANSIENT ISCHEMIC ATTACK, STROKE, STD, ACUTE CORONARY SYNDROME, HEART, LEFT BRANCH BUNDLE BLOCK | Participants were included if they were aged over 18 with concurrent T2DM and CADs. Moreover, key inclusion criteria were as follows: (1) baseline AF score of ≤90 on SAQ, (2) treatment with at least three antianginal medications for more than 3 months, (3) unsuitable candidates for revascularization procedures (either percutaneous coronary intervention or coronary artery bypass grafting), (4) reproducible angina with concomitant ischemic ST‐segment depression of at least 1 mm on the electrocardiogram (ECG), (5) restricted treadmill testing exercise capacity (3–9 min on a modified Bruce protocol) at baseline.Key exclusion criteria initially included: (1) New York Heart Association (NYHA) functional class of III–IV, (2) presence of heart failure symptoms, (3) an acute coronary syndrome in the past 2 months, (4) any coronary revascularization during the study period, (5) the occurrence of stroke or transient ischemic attack within 6 months of screening, (6) uncontrolled hypertension, (7) clinically significant hepatic or renal impairment, (8) prior treatment with empagliflozin, (9) recent use of invasive treatments for RA (including the EECP), extracorporeal shockwave therapy, coronary sinus reducer implantation, spinal cord stimulation, or sympathectomy), (10) any relative or absolute contraindications for the exercise test, (11) specific conditions that may preclude the accurate interpretation of ECG (such as left bundle branch block, resting ST depression (STD) more than 1 mm, pre‐excitation rhythm abnormalities or usage of Digoxin). | PMC10766003 |
Interventions, clinical measurements, and data collection | Angina, diabetic care and cardiology clinics | BRUCE | Patients who met our inclusion criteria were recruited from outpatient visits at comprehensive diabetic care and cardiology clinics. An informed consent form was signed by each person before the patient was enrolled. All Patients had baseline ECG, heart rate (HR), and blood pressure (BP) measurements recorded, as well as height and weight. Also, patients completed the Seattle Angina Questionnaire (SAQ). Patients were assessed at study visits for major outcomes, including BP, HR, and exercise stress test with a modified Bruce protocol at the time of enrollment and 8 weeks later.After enrollment, the study consisted of two consecutive phases. The first was a 4‐week run‐in period for extended screening. Cases with SAQ <90 were kept under remote observation for about four consecutive weeks. If SAQ remained less than 90, the participant entered the randomization process. Eligible subjects were randomized to receive either a placebo or empagliflozin (25 mg/day) for 8 weeks. Prior prescribed antianginal drugs were continued for participants in both arms during the study period. Both investigators and participants remained blinded to the treatment arms until the completion of the trial, and data collection was performed by a physician. Participants were followed each week with telephone calls for assurance of proper daily pill consumption and to report possible side effects. | PMC10766003 |
Definitions | symptomatic).Ischemia, depression, angina, angina pectoris | STD | The SAQ is a 19‐item, self‐administered questionnaire that has been validated for use in patients with CADs. The questionnaire is divided into several categories, including angina pectoris frequency, physical limitations (PL), angina stability (AS), treatment satisfaction (TS), and QOL. For each of these five categories, the scores range from 0 (most symptomatic) to 100 (least symptomatic).Ischemia in exercise‐induced ECG was defined as a newly developed horizontal or down‐sloping ST‐segment depression of ≥1 mm at 60–80 ms after J point. STD was defined as an additional ST‐segment depression of at least 1 mm below the resting value. | PMC10766003 |
Study endpoints | angina | ALTERNATION, SECONDARY, STD | The primary endpoint of the study was the improvement in angina symptoms, function, and patient's QOL assessed by the SAQ Summary Score (SS). The secondary outcome of this study was any alterations from the baseline of SAQ domains, including AF, PL, AS, TS, QOL, and also alternation in exercise test components, including treadmill exercise duration, STD, time to angina onset, and the mean HRR before study initiation and 8 weeks afterward. | PMC10766003 |
Statistical analysis | Quantitative and qualitative variables were reported as mean ± standard deviation (or mean ± standard error of the mean for adjusted means) and number (percentage), respectively. The normality assumption for continuous variables was checked using the skewness test and Q–Q plots. Baseline characteristics and measurements of the participants were compared using an independent samples | PMC10766003 |
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RESULTS | PMC10766003 |
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Trial population | angina, TED, CHF, TAO, depression | MYOCARDIAL INFARCTION, STD, CONGESTIVE HEART FAILURE, CHF, HEART, TAO | From November 2019 to January 2021, a total of 935 patients were screened and 86 patients were equally and randomly allocated to either empagliflozin or the placebo group. During the time of the study, 11 individuals (empagliflozin group: 6, placebo group: 5) were lost to follow‐up, and eventually, a total of 75 patients were included in the analyses. A detailed explanation of screening, randomization, and follow‐up is shown in Figure Comparison of baseline characteristics between treatment groups.
Abbreviations: ACE, angiotensin‐converting enzyme; AF, angina frequency; ARB, angiotensin II receptor blockers; AS, angina stability; BB, beta blocker; BMI, body mass index; CABG, coronary artery bypass grafting; CCB, calcium channel blocker; CHF, congestive heart failure; HRR, heart rate recovery; MI, myocardial infarction; NYHA: New York Heart Association; PCI, percutaneous coronary intervention; PL, physical limitation; PPI, proton pump inhibitor; QOL, quality of life; STD, ST depression; TAO, time to angina onset; TED, treadmill exercise duration; TS, treatment satisfaction.Obtained from independent sample Obtained from Obtained from Mann–Whitney Obtained from Fisher exact test using Monte Carlo simulations. | PMC10766003 |
OUTCOMES AND ESTIMATIONS | angina, TED, TAO, SE, depression | SECONDARY, STD, TAO | As shown in Table Comparison means of endpoints before and after intervention within treatment groups.Abbreviations: AF, angina frequency; AS, angina stability; DBP, diastolic blood pressure; GEE, generalized estimation equation; HR, heart rate; HRR: heart rate recovery; PL, physical limitation; QOL, quality of life; SBP, systolic blood pressure; STD, ST depression; TAO, time to angina onset; TED, treadmill exercise duration; TS, treatment satisfaction.Follow‐up mean ± SE of endpoints and measurements after adjustment for baseline values.Obtained from paired sample Obtained from Wilcoxon signed‐rank test.Logarithmic transformation was performed to assess the normality assumption. Anti‐log of transformed values reported.Regarding secondary outcomes, there was no significant alteration in the placebo group except for QOL and AS, which were not significantly improved in comparison with the empagliflozin group after adjustment for baseline values. Adjusted models have also indicated the higher means of both primary and secondary endpoints in patients receiving Empagliflozin compared to the placebo group, except for PL. Figure Mean changes (95% confidence interval [CI]) of endpoints (follow‐up minus baseline) in the treatment group.A 10‐point change (clinically significant improvement) in SAQ domains.Abbreviations: AF, angina frequency; AS, angina stability; PL, physical limitation; QOL, quality of life; TS, treatment satisfaction.Obtained from Fisher's exact test using Monte Carlo simulations.Obtained from As shown in Table Comparison of adverse side effects between treatment groups.obtained from Fisher's exact test using Monte Carlo simulations. | PMC10766003 |
DISCUSSION | angina, hyperglycemia, PH, diabetic, T2DM, chronic stable angina, glucotoxicity, RA, cardiovascular complications, lipotoxicity | EVENTS, HYPERGLYCEMIA, CHRONIC STABLE ANGINA, MYOCARDIAL ISCHEMIA, HEART FAILURE, CARDIOVASCULAR COMPLICATIONS | The EMPT‐ANGINA trial demonstrated that in individuals with concurrent T2DM and RA, adding empagliflozin to routine anti‐hyperglycemic therapies was linked to a substantial reduction in angina symptoms and improvement in exercise capacity compared to placebo.Given the increased risk of cardiovascular complications in patients with T2DM, the cautious selection of antianginal treatment appears to be a crucial concern.Antianginal therapy for diabetic patients with chronic stable angina appears to be a complex issue, partly because some of the pharmacological agents that alleviate angina may impair glucose regulation. In addition, unfavorable hemodynamic effects may make the patient less compliant.SGLT2 inhibitors are novel, approved oral antidiabetic agents that block sodium and glucose cotransporters on the luminal surface of the proximal convoluted renal tubules.Myocardial ischemia is no longer considered a mere imbalance between myocardial oxygen demands and/or coronary blood flow to the ischemic myocardium but might be an issue related to energy metabolism.Increased FA oxidation and hyperglycemia cause an accumulation of glucose and FA intermediate metabolites in the cells, resulting in lipotoxicity and glucotoxicity, respectively.Empagliflozin switches energy substrate preference from FA to glucose, resulting in the inhibition of cardiac FA oxidation and increasing the oxidation of pyruvate, leading to lower lactate production and less fall in myocytes' PH, which would be beneficial for the ischemic heart.Large‐scale studies have shown that SGLT2 inhibitors enhance cardiorenal function and lower cardiovascular events, particularly heart failure.Our data demonstrated a substantial decrease in HRR following empagliflozin, indicating that SGLT2 inhibitors may have antisympatholytic effects that might relieve angina symptoms by lowering resting HR and cardiac demand. | PMC10766003 |
LIMITATIONS AND SUGGESTIONS | RA, T2DM | ADVERSE EVENTS | To the best of our knowledge, this study was the first to assess the effect of empagliflozin on ischemic symptoms in patients with T2DM and RA. Although we tried our best to enhance the quality of this study, several limitations exist. Our sample size was relatively small, which might affect the generalization of our findings. We followed the patients for 8 weeks, which might be relatively short for an accurate assessment of the effectiveness of our intervention or the probable occurrence of adverse events. Furthermore, we did not measure the serum level of empagliflozin in the treatment group for further assurance of proper medication consumption. | PMC10766003 |
CONCLUSION | RA, T2DM | The EMPT‐ANGINA trial showed that in people with concurrent T2DM and RA, adding empagliflozin to regular anti‐hyperglycemic treatments was linked to a significant decrease in angina symptoms and an increase in exercise capacity compared to placebo. These findings justify the use of empagliflozin in patients with DM and RA for clinical cardiologists. | PMC10766003 |
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CONFLICT OF INTEREST STATEMENT | The author declares no conflict of interest. | PMC10766003 |
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Supporting information | Supplementary Figure 1. Flow diagram of study.Click here for additional data file.Supplementary Figure 2. Probable mechanism of cardiovascular benefits of SGLT2 inhibitors. Hb, hemoglobin, HCT, hematocrit, BP, blood pressure.Click here for additional data file.Supplementary Figure 3. Probable anti‐anginal effect of empagliflozin, hemodynamic effect (A) metabolic effect (B).Click here for additional data file. | PMC10766003 |
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DATA AVAILABILITY STATEMENT | Derived data supporting the findings of this study are available from the corresponding author on request. | PMC10766003 |
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REFERENCES | PMC10766003 |
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Background | There is the ongoing debate over the effect of inspired oxygen fraction (FiO | PMC10408131 |
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Methods | We performed a randomized controlled trial with 120 patients. Subjects were randomly assigned to receive 30% or 60% FiO | PMC10408131 |
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Results | In total, 113 subjects completed the trial, including 55 and 58 subjects in the 30% and 60% FiO | PMC10408131 |
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Conclusions | Compared with 60% FiO | PMC10408131 |
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Trial registration | Chinese Clinical Trial Registry ( | PMC10408131 |
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Keywords | PMC10408131 |
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Background | POSTOPERATIVE ATELECTASIS |
Postoperative atelectasis diagnosed by CT occurs in 60–90% of patients with mechanical ventilation under general anesthesia [
Mechanical ventilation provides the necessary oxygen supply for patients under general anesthesia during surgery, however, the optimal inspired oxygen fraction (FiO
Previous studies have provided conflicting results; thus the effect of FiO
Therefore, we conducted a randomised controlled study to investigate the effects of 30% versus 60% FiO | PMC10408131 |
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Methods | PMC10408131 |
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Ethics |
This prospective, randomized study was conducted from April 2019 to September 2020 at the Huadong Hospital affiliated to Fudan University, Shanghai, China. The study was appoved on 6 March 2019 by the Ethics Commission of Huadong Hospital affiliated to Fudan University under the approval number 20,190,030. All patients were informed about the research purposes along with the practical aspects and gave written informed consent prior to inclusion. The trial was registered prior to patient enrollment at Chinese Clinical Trial Registry ( | PMC10408131 |
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Study population |
Patients were included if they met all the following criteria: (1) scheduled to undergo neurosurgery with an expected duration ≥ 2 h (the reason for choosing neurosurgery is that postoperative chest CT scans could be performed at the same time as routine brain CT scans in patients undergoing neurosurgery); (2) supine position during surgery; (3) age ≥ 18-years-old; (4) American Society of Anesthesiologists (ASA) of I-III; (5) oxygen saturation (SpO | PMC10408131 |
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Randomization and blinding |
A stratified block randomization method was conducted, dividing patients into 30% and 60% FiO
An anesthesiologist, who was not involved in recruiting patients or collecting outcome data, opened the sealed envelope before the start of anesthesia and provided the designated FiO | PMC10408131 |
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Anesthesia | Neuromuscular blockage |
The participants in the trial followed the standard anesthesia protocol. An arterial catheter was placed into the dorsal artery of the foot under local anesthesia for repeated blood gas sampling and continuous blood pressure monitoring. Propofol, sufentanil, and rocuronium were used for induction of general anesthesia. After tracheal intubation, both groups were ventilated in volume-control mode with a tidal volume of 6–8 ml·kg
Neuromuscular blockage was reversed before emergence using neostigmine/anticholinergic agent based on train-of-four ratio stimulation (TOF) monitoring [ | PMC10408131 |
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FiO |
All patients received standard FiO
The perioperative management of FiO | PMC10408131 |
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Primary outcome | atelectasis | POSTOPERATIVE ATELECTASIS, ATELECTASIS |
Within 30 min of extubation, the chest CT was performed by a trained and experienced technician who was unaware of the group assignment. All CT images were assessed by an experienced radiologist. The primary outcome was the postoperative atelectasis volume, expressed as a percentage of the total lung volume. The calculation of the percentage of atelectasis volume consisted of three steps. The first step was to measure the total lung area by accurately depicting the contour of the lung image on each CT image with a thickness of 5 mm. The pulmonary hilus vessels were manually excluded from the lung region of interest. The second step was to delineate the volume of the atelectasis region in each CT image. When drawing the atelectasis area, it should be outlined as close to the pleura as possible, and vascular structures with diameters larger than 3 mm should be manually excluded. Lastly, we used the histogram functional view using ITK-SNAP software (version 3.6.0) to identify the atelectasis region (Fig.
Examples of CT scans. Original chest CT image: ( | PMC10408131 |
Secondary outcomes | SECONDARY |
The percentages of different aeration volumes were considered as secondary outcomes. Areas of different aeration were measured using a workstation software (Sinvo.gia, Siemens Healthcare GmbH) by setting the histogram parameters between − 1,000 and − 901, − 900 and − 501, and − 500 and − 101 Hounsfield Units for over-aeration, normal-aeration, and poor-aeration, respectively [ | PMC10408131 |
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Sample size |
Twenty patients were randomly assigned to the 30% or 60% FiO | PMC10408131 |
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Statistical analysis | postoperative atelectasis | POSTOPERATIVE ATELECTASIS |
According to the distribution of the data evaluated using the Kolmogorov-Smirnov test, continuous variables were analyzed using the two-sample t-test or Mann-Whitney U test and presented as mean ± standard deviation (SD) or median [interquartile range (IQR)]. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test and reported as numbers and percentages. The primary outcome (the percentage of postoperative atelectasis volume) was normalized using the square root transformation and then analyzed using the two-sample t-test. Moreover, the Mann-Whitney U test was performed to assess the differences in the unnormalized primary outcome data between the two groups. The differences in the oxygenation index at the end of surgery between the two groups were compared, with the oxygenation index before anesthesia as a covariate. A two-sided
We handled missing normalized primary outcome data using multiple imputation by chained equations (MICE), and the iterations were set to 5 [ | PMC10408131 |
Results | PMC10408131 |
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Subject characteristics |
In this study, 120 patients were randomly allocated to either the 30% FiO
Consolidated Standards of Reporting Trials (CONSORT) diagram. CT, computed tomography; FiO
Patient characteristics and perioperative dataValues are presented as mean ± SD, median (IQR), or n (%). | PMC10408131 |
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Primary outcome | postoperative atelectasis, atelectasis | POSTOPERATIVE ATELECTASIS, ATELECTASIS |
There was no significant difference in the percentage of postoperative atelectasis volume between the 30% FiO
The primary outcome was missing in seven patients among the patients in the randomization, thus we performed multiple imputation to handle missing normalized primary outcome data. Consistent with the results of the original data, none of the five imputations showed significant differences in the percentage of postoperative atelectasis volume between the two groups (Table
The percentage of atelectasis volume handled by multiple imputation (5 imputations datasets)CI, confidence interval; FiO
The normalized percentage of atelectasis volume (square root transformation) handled by multiple imputation and sensitivity analysisCI, confidence interval; FiO
The normalized primary outcome. The percentage of postoperative atelectasis volume is shown by (
The multiple imputation pattern. Grey square: no missing data; Red square: missing data imputed by multiple imputation | PMC10408131 |
Sensitivity analysis | REGRESSION |
KNN imputation, regression imputation, and mean imputation were performed as sensitivity analysis to handle missing normalized primary outcome data (Table | PMC10408131 |
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Secondary outcomes | atelectasis | ATELECTASIS |
There were no significant differences in the percentages of over-aeration, normal-aeration, or poor-aeration volumes between the two groups. The overall incidence of clinically significant atelectasis was 83.2%, but again, there was no significant intergroup difference. Additionally, after adjusting for blood gas indicators before anesthesia, the oxygenation index at the end of surgery in the 30% FiO
Secondary outcomesValues are presented as mean ± SD, median (IQR), or n (%). | PMC10408131 |
Discussion | postoperative atelectasis, atelectasis | POSTOPERATIVE ATELECTASIS, ATELECTASIS |
In this randomised study, we found no significant differences in the percentage of postoperative atelectasis volume in patients ventilated with 30% FiO
Recently, a large number of clinical trials have compared the effects of high FiO
In the present study, the areas of different aeration were automatically measured using a workstation software. It was found that there were no significant differences between the two groups regarding the percentages of over-aeration, normal-aeration, and poor-aeration volumes. These results were consistent with the volume of atelectasis. In addition, there was no significant difference in the oxygenation index at the end of surgery between the two groups. The oxygenation index is an index to evaluate the gas exchange in the lung, and it is correlated with atelectasis [
It should be noted that the study is not without limitations. Firstly, the effect of recovery of spontaneous breathing after extubation on atelectasis could not be completely excluded. Secondly, the generalizability of the study is slightly weakened by the mode of mechanical ventilation. In order to explore the effect of intraoperative FiO | PMC10408131 |
Conclusions |
These results suggest that 30% FiO | PMC10408131 |
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Acknowledgements | The authors would like to acknowledge Zhichao Jin (Department of Health Statistics, Second Military Medical University, Shanghai, China) for his assistance with statistical consultation. | PMC10408131 |
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Authors’ contributions | ZSJ | ZSJ and SBL: study design, data analysis, data interpretation, and drafting of manuscript; LW: data acquisition, data interpretation and critical revision of manuscript; WLL: data analysis and critical revision of manuscript; CL: data acquisition, data analysis, and critical revision of manuscript; FFL, RXL, YZ, and JJW: data acquisition and critical revision of manuscript; YXC: study design and critical revision of manuscript; WX and ZC: data acquisition and critical revision of manuscript; ZJB: study conception and critical revision of manuscript; ML and WDG: study conception, study design, and critical revision of manuscript. All authors read and approved the final manuscript. All authors agreed to be accountable for all aspects of the work. | PMC10408131 |
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Funding | This work was supported by the project of National Natural Science Foundation of China (82271286), the Science and Technology Commission of Shanghai Municipality (20Y11900200), Shanghai Municipal Health Commission (2020YJZX0119), Huadong Hospital Excellent Project (GZRPY016Y), National Key Research and Development Program of China (2018YFC2002000), Shanghai Municipal Key Clinical Specialty (shslczdzk02801), and High-level Local University Construction Project of Shanghai Medical College (FNDGJ202212). | PMC10408131 |
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Data Availability | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10408131 |
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Declarations | PMC10408131 |
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Ethics approval and consent to participate | The study was appoved on 6 March 2019 by the Ethics Commission of Huadong Hospital affiliated to Fudan University (Chaiperson Prof. Yue Zhu) under the approval number 201900. All patients were informed about the research purposes along with the practical aspects and gave written informed consent prior to inclusion. All methods were carried out in accordance with relevant guidelines and regulations. | PMC10408131 |
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Consent for publication | Not applicable. | PMC10408131 |
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Competing interests | The authors declare no competing interests. | PMC10408131 |
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References | PMC10408131 |
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Summary | glioblastoma, cancer, death | GLIOBLASTOMA, CANCER, SOLID TUMORS | These authors contributed equallyLead contactTherapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors.In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2–14.7) compared with 9 months (95% CI, 4.2–13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24–0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world. | PMC10213810 |
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