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Results | PMC10646994 |
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Baseline characteristics | Stroke | STROKE | Of 948 enrolled patients in the RESCUE BT study, 435 had intracranial LAA etiology, 197 in the intravenous tirofiban group, among whom 175 (88.8%) had successful reperfusion, and 238 in the placebo group, among whom 207 (87.0%) had successful reperfusion (eTICI 2b50‐3) (Fig. Flowchart.Baseline characteristics and workflow measures.ASPECTS, the Alberta Stroke Program Early Computed Tomography Score; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale.
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Primary efficacy outcome | Stroke, Thrombolysis, Cerebral Infarction | REGRESSION, CEREBRAL INFARCTION, STROKE | Treatment with intravenous tirofiban was associated with independent functional outcome (mRS 0 to 2) at 90 days in 54.3% (95 out of 175) patients in the tirofiban group and 44.0% (91 out of 207) patients (44.0%) in the placebo group (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02–2.44; Efficacy and safety outcomes.CI, confidence interval; EQ‐5D‐5L, European Quality of Life 5‐Dimension 5‐level scale; eTICI, expanded Thrombolysis In Cerebral Infarction grade; IQR, interquartile range; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.Values were adjusted for age, baseline NIHSS score, baseline ASPECTS, occlusion site, and time from last known well to randomization.Values were calculated using ordinal logistic model.Values were calculated using linear regression model.Distribution of the Modified Rankin Scale score at 90 days. | PMC10646994 |
Secondary efficacy outcomes | SECONDARY | The secondary clinical efficacy outcomes were shown in Table | PMC10646994 |
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Safety outcomes | sICH | At 90 days, no significant difference was observed between the two groups in the incidence of sICH, 12 out of 175 (6.9%) versus 11 out of 207 (5.3%) (aOR, 1.41; 95% CI, 0.59–3.34; Safety outcomes of the cohort. | PMC10646994 |
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Subgroup analyses | SECONDARY | The effects of tirofiban stratified by reperfusion grade on the primary outcome, the secondary efficacy outcomes, and primary safety outcomes were shown in Figure Heterogeneity analysis for intravenous tirofiban effect on outcomes with stratified reperfusion grades.There was no significant heterogeneity of effect of the functional outcome across the subgroup: age, sex, baseline ASPECTS, occlusion site, time from last known well to randomization (Fig. Subgroup analysis. | PMC10646994 |
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Discussion | death, sICH, intracranial hemorrhage, stroke, cardioembolic, hemorrhagic transformation, infarcts, ischemic stroke, hemorrhage, LAA stroke, artery atherosclerotic disease, acute ischemic stroke | INTRACRANIAL HEMORRHAGE, STROKE, ISCHEMIC STROKE, HEMORRHAGE, SECONDARY | This study focused on the population of patients with acute ischemic stroke due to intracranial large artery atherosclerotic disease, which is a main cause of stroke in Asian patients and a determinant of poor outcome. Randomized studies evaluating the outcome of EVT in patients with intracranial LAA were sparse. Among intracranial LAA patients with successful reperfusion (eTICI 2b50‐3), periprocedural intravenous tirofiban treatment was associated with improved functional outcome at 90 days, and rates of death and sICH were comparable between the two groups. The magnitude of treatment effect was sizable, with the number needed to treat for one more functional independent outcome at 90 days of 9.7. Due to the post hoc secondary analysis design and limited size of successful population, all of the results were exploratory.In the overall RESCUE BT trial, mechanisms of qualifying ischemic stroke were LAA in 45.9%, cardioembolic in 42.8%, other in 2.3%, and unknown in 8.1% and tirofiban was associated with improved outcomes only in the LAA patients.Intriguingly, among LAA patients there was evidence of heterogeneity of treatment effect across different eTICI reperfusion levels. Tirofiban was associated with improved outcomes among patients with substantial reperfusion (eTICI 2b50), but no statistically significant effect was seen for patients with excellent (eTICI 2c) or complete (eTICI 3) reperfusion. This observation supports a role for tirofiban in resolving or stabilizing residual microcirculatory obstructions angiographically visible in distal fields at the end of the thrombectomy procedure. Conversely, this finding suggests that an effect of tirofiban upon microcirculatory reperfusion is less marked or absent.Among LAA patients with successful reperfusion, intravenous tirofiban was associated with an increased rate of any radiologic intracranial hemorrhage but not symptomatic intracranial hemorrhage or mortality. This finding suggests that the antiplatelet effect of intravenous tirofiban may increase rates of any hemorrhagic transformation of bland infarcts but may not predispose to major hemorrhage to the same degree. In addition, the extended EVT treatment time window may have contributed to increased rates of intracranial hemorrhage in both treatment groups in the current study.The strengths of our study included the large‐scale, double‐blind, and placebo‐controlled design. This study also has several limitations. First, it was a post hoc analysis, multiple testing may increase the risk of Type I errors. All the results should be interpreted with caution. Second, only Chinese patients with LAA stroke were enrolled in the trial, which may reduce the generalizability of study findings. Third, the selection for patients in the extended therapeutic window was based on ASPECTS score according to non‐contrast CT scan rather than CT perfusion assessment, as automated CT perfusion analysis software was not available in many of participating hospitals due to high cost. Fourth, end‐of‐procedure reperfusion grade is an early post‐randomizing rather than baseline patient characteristics, necessitating caution regarding subgroup findings. However, study treatment on average was started coincident with, not before, arterial puncture and only a small fraction of treatment agent was administered before reperfusion grade was assessed. Fifth, analyses are generally more statistically powerful when continuous measures are used rather than dichotomies in the subgroup analysis. Interpretation of the results should be more cautious. | PMC10646994 |
Conclusions | intracranial hemorrhage, vessel occlusion, artery atherosclerotic stroke | INTRACRANIAL HEMORRHAGE | Among patients with large vessel occlusion due to large artery atherosclerotic stroke and successful reperfusion after endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate or independent functional outcome, without higher rates of symptomatic intracranial hemorrhage or mortality. Confirmatory randomized trials in these patient populations are desirable. | PMC10646994 |
Author Contributions | Dr Wenjie Zi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. | PMC10646994 |
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Funding Information | This study was funded by National Natural Science Foundation of China (No.82071323). | PMC10646994 |
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Conflict of Interest | Dr Saver reported receiving contracted hourly payments for service on clinical trial steering committees advising on rigorous trial design and conduct from Medtronic, Cerenovus, NeuroVasc, Boehringer Ingelheim (prevention only);stock options for service on Clinical Trial Steering Committees advising on rigorous trail design and conduct from Rapid Medical; and contracted hourly payments for service on data safety monitoring committee advising on rigorous trial design, safety, and conduct from MIVI outside the submitted work. | PMC10646994 |
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Patient Consent for Publication | Not applicable. | PMC10646994 |
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Ethics Approval | This study was approved by the ethics of the Xinqiao Hospital, Army Medical University and all participating centers. Written informed consent was obtained from all the patients or their legally authorized representatives. | PMC10646994 |
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Supporting information |
Click here for additional data file. | PMC10646994 |
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Acknowledgments | We thank all study participants for their contribution to the study and the research staff at all the participating hospitals. | PMC10646994 |
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Data Availability Statement | Data are available upon reasonable request. | PMC10646994 |
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References | PMC10646994 |
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Subject terms | CAD | CORONARY ARTERY DISEASE, CAD | Systematic exercise training effectively improves exercise capacity in patients with coronary artery disease (CAD), but the magnitude of improvements is highly heterogeneous. We investigated whether this heterogeneity in exercise capacity gains is influenced by the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. Patients with CAD (n = 169) were randomly assigned to 12 weeks of exercise training or standard care, and 142 patients completed the study. The ACE polymorphism was determined for 128 patients (82% males, 67 ± 9 years). Peak oxygen uptake was measured before and after the 12-week intervention. The ACE I/D polymorphism frequency was n = 48 for D/D homozygotes, n = 61 for I/D heterozygotes and n = 19 for I/I homozygotes. Baseline peak oxygen uptake was 23.3 ± 5.0 ml/kg/min in D/D homozygotes, 22.1 ± 5.3 ml/kg/min in I/D heterozygotes and 23.1 ± 6.0 ml/kg/min in I/I homozygotes, with no statistical differences between genotype groups (Clinical trial registration: | PMC10600103 |
Introduction | CAD, death | CORONARY ARTERY DISEASE, CAD, DELETION | Coronary artery disease (CAD) is a leading cause of death worldwideImportantly, there is substantial inter-individual variability in the response to systematic exercise training, with training-induced improvements in VOA potentially decisive determinant of exercise capacity adaptability is the insertion (I) and deletion (D) polymorphism in the human angiotensin-converting enzyme (ACE) gene, which is located on chromosome 17 at heading 23 (17q23)Importantly, an effect of the ACE I/D polymorphism on VOGiven the potential link between the ACE genotype and exercise capacity trainability in patients with CAD, the present study was undertaken to determine whether the ACE I/D genotype affects the outcome of systematic supervised exercise training on exercise capacity in patients with CAD. | PMC10600103 |
Methods | PMC10600103 |
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Patients and study design | CAD | CAD | A total of 169 patients older than 18 years with angiographically confirmed CAD were recruited for the study, and parts of the obtained data have been reported elsewherePatient characteristics.Anthropometrics are presented as means ± standard deviation, and dichotomous data are expressed as numbers (percentages) in patients with the ACE D/D, ACE I/D or ACE I/I genotype. BMI: body mass index. The | PMC10600103 |
Exercise training | The prescribed exercise training programme has been described in detail previously | PMC10600103 |
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ACE genotyping | Determination of the patients’ ACE genotype was performed as previously described | PMC10600103 |
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Exercise capacity measurements | Patients reported to the exercise laboratory in a fasted state (> 1.5 h) and were explicitly told to refrain from tobacco, caffeine and alcohol on testing day and to avoid strenuous exercise for at least 24 h prior to exercise testing.Peak oxygen uptake (VOThe exercise protocol was conducted on a cycle ergometer to ensure that potential training-induced adaptations in exercise capacity and muscular efficiency were induced by physiological adaptations to the applied training intervention rather than familiarization with the rowing ergometer and/or improved rowing technique. | PMC10600103 |
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Statistics | Anthropometric and baseline exercise capacity measurements are presented as means with standard deviation and compared using a one-way ANOVA. Proportions are expressed in percentages and compared by Pearson’s chi-squared test if model assumptions were met and otherwise by Fisher’s exact test.Changes in exercise capacity and steady-state VOFinally, potential genotype-specific differences in average power output and relative power output during the exercise training sessions were assessed by a one-way ANOVA (D/D vs I/D vs I/I). Power output is presented as means with standard deviations. The level of statistical significance was set at | PMC10600103 |
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Results | The ACE I/D genotype distribution was n = 48 for D/D, n = 61 for I/D and n = 19 for I/I. As illustrated in Table | PMC10600103 |
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ACE genotype and pre-training exercise capacity | All obtained measures of exercise capacity were similar between genotype groups at baseline (Table Baseline exercise capacity.Values are presented as means ± standard deviations for patients with the ACE D/D, I/D or I/I genotype. The | PMC10600103 |
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Exercise training | For the patients allocated to exercise training, the ACE genotype distribution was n = 26, n = 21 and n = 12 for D/D, I/D and I/I, respectively. Patients with the ACE D/D, ACE I/D or ACE I/I genotype had similar gender and ACE inhibitor treatment distribution and were comparable in age, height, weight and BMI (Table Patients allocated to exercise training.Anthropometrics are presented as means ± standard deviation, and dichotomous data are expressed as numbers (percentages) in patients with the ACE D/D, ACE I/D or ACE II genotype. BMI: body mass index. The | PMC10600103 |
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Exercise power output and relative intensity | The average power output during the exercise intervals was similar between genotype groups (D/D: 139 ± 39 W vs. I/D: 139 ± 54W vs. I/I: 120 ± 42 | PMC10600103 |
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ACE genotype and exercise capacity improvements | Twelve weeks of exercise training effectively increased (The figure shows mean values for peak oxygen uptake adjusted for body weight (The figure shows mean values for peak oxygen uptake adjusted for body weight ( | PMC10600103 |
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ACE genotype and steady-state VO | No significant within-group or between-group effect existed for changes in steady-state VOThe figure shows mean values for oxygen uptake at 30/50W (females/males) (The figure shows mean values for oxygen uptake at 30/50W (females/males) ( | PMC10600103 |
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Carriers of the I allele versus D/D homozygotes | Due to the low frequency of ACE I/I homozygotes and to ensure a more balanced genotype distribution in the statistical analysis, a sub-analysis, in which carriers of the I allele were combined into a single group (I/ +), was conducted. Patients with the ACE D/D or I/ + genotype had similar gender and ACE inhibitor treatment distribution and were comparable in age, height, weight and BMI (Table Patients allocated to exercise training.Anthropometrics are presented as means ± standard deviation, and dichotomous data are expressed as numbers (percentages) in patients with the ACE D/D or ACE I/ + genotype. BMI: body mass index. The Combining carriers of the I allele into one group did not significantly alter the results for any of the obtained markers of exercise capacity, with between-group | PMC10600103 |
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Discussion | CAD | CAD | We investigated the significance of the ACE I/D genotype for pre-training exercise capacity and whether the ACE I/D genotype impacts the outcome of 12 weeks of whole-body high-intensity interval training on exercise capacity in patients with stable CAD. The pre-training exercise capacity was independent of the ACE genotype. The applied low-volume high-intensity exercise protocol efficiently improved exercise capacity in the ACE D/D, ACE I/D and ACE I/I genotype groups, but the magnitude of improvements was similar between groups. Thus, our findings indicate no interaction between the ACE I/D genotype and pre-training exercise capacity and exercise capacity trainability in patients with CAD. | PMC10600103 |
ACE genotype and exercise capacity | cardiovascular conditionsIn | Exercise capacity is a powerful predictor of the risk of all-cause mortality in patients with cardiovascular conditionsIn our study, we assessed the impact of the ACE I/D genotype on baseline exercise capacity and training-induced adaptations in exercise capacity, since previous research has reported that the I/I genotype is associated with greater baseline exercise capacityFinally, we also performed a sub-analysis to assess the effect of the ACE genotype on baseline exercise capacity as well as exercise capacity trainability for the patients not treated with ACE inhibitors. Excluding ACE inhibitor users from the analysis did not significantly modify any of the obtained measures of exercise capacity, and hence no significant between-group effect was observed for pre-training exercise capacity or the magnitude of exercise capacity improvements. Our findings should, however, be interpreted with care because the low sample size in conjunction with the large variations in exercise capacity measurements augments the risk of undetected effects. | PMC10600103 |
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ACE genotype and muscular efficiency | Muscular efficiency is critical for endurance performance | PMC10600103 |
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Strengths and limitations | It is a strength that we recruited a well-described clinical population in which improvement in exercise capacity is highly important. The adherence to the prescribed supervised exercise sessions was high and the drop-out was low, which is a strength. The sample size is relatively high in terms of a training study, but low in terms of differentiating between different genotype sub-groups, and hence our findings should be interpreted with caution due to potential statistical type II errors in the comparisons between genotype groups. Furthermore, the unequal genotype group sample sizes may represent a limitation, as this can negatively affect statistical power and Type I error rates | PMC10600103 |
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Conclusion | CAD | CAD | Both baseline exercise capacity and exercise capacity improvements following 12 weeks of whole-body low-volume high-intensity exercise training seem to be independent of the ACE genotype in patients with CAD. Thus, the present findings do not support a clinically important role for the ACE genotype as a modulator of intrinsic or acquired exercise capacity in this patient group. | PMC10600103 |
Acknowledgements | The authors want to express their sincere gratitude to all the study participants for their keen commitment and determined participation, and to the laboratory technicians Gunnrið Jóanesarson and Nina Djurhuus for their assistance in the ACE genotyping process. Finally, the rowing specialist, Toni Dam, is acknowledged for organizing the training. | PMC10600103 |
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Author contributions | T.S., J.K., N.B.N., E.L.G., A.M.H., S.D.K. and M.M. conceived and designed the research. T.S., J.K., L.N.L. and N.O.G. performed the experiments. T.S. and J.K. analyzed the data. T.S., J.K. and M.M. interpreted the results of the experiments. T.S. prepared the figures and drafted the manuscript. All authors edited and revised the manuscript and approved the final version. | PMC10600103 |
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Funding | The present study was supported by the Research Council Faroe Islands (project number 0352) and the National Hospital of the Faroe Islands. | PMC10600103 |
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Data availability | The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10600103 |
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Competing interests | N.O.G. | The authors report the following general conflicts. E.L.G. has no conflicts related to the present study but has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, MSD, Novo Nordisk, Lundbeck Pharma and Organon. He is serving as investigator in clinical studies sponsored by AstraZeneca, Idorsia, and Bayer and has received unrestricted research grants from Boehringer Ingelheim. T.S., J.K., N.B.N., N.O.G., L.N.L., S.D.K., A.M.H., and M.M. have no competing interests to declare. | PMC10600103 |
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References | PMC10600103 |
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1. Introduction | obesity, weight loss, metabolic disorders | OBESITY, OBSTRUCTIVE SLEEP APNEA, ARTHROPATHIES, METABOLIC DISORDERS | Background: Protein-sparing modified fast (PSMF) diet is a very-low-carbohydrate ketogenic diet administered to patients with obesity, which preserves lean mass and suppresses appetite as well as continuous enteral feeding. Thus, we aim to evaluate the effect of the PSMF diet administered continuously by nasogastric tube (NGT) or orally. Methods: Patients with a body mass index (BMI) > 34.9 kg/mIn recent decades, worldwide obesity has tripled and is currently reaching epidemic proportions, since in 2016 over 650 million people were affected by obesity [Traditional approaches for managing obesity, such as lifestyle modification with a balanced Mediterranean diet, regular exercise, behavior therapy and drug administration, generally suffer from low long-term compliance [In clinical practice, very-low-carbohydrate ketogenic diets (VLCKDs) are commonly used to achieve rapid weight loss, particularly in patients affected by severe or complicated obesity (i.e., metabolic disorders, obstructive sleep apnea or severe arthropathies) and in patients who need rapid weight loss for severe comorbidities or for scheduled surgery [The protein-sparing modified fast (PSMF) diet is a VLCKD with a high-quality protein content (1.2–1.5 g/kg/day), a carbohydrate amount less than 20–30 g/day and a low-fat intake (about 10–20 g/day); additionally, it requires a significant amount of water (above two liters) as well as vitamin and mineral supplementation [Thus, the continuous enteral nutrition (EN) of a high-protein diet administered through a nasogastric tube (NGT) may be a valid approach for counteracting the catabolism of lean mass [To date, no evidence reports a comparison between a PSMF diet administered continuously via NGT and the equivalent PSMF diet taken orally on anthropometric and body composition data in patients with obesity. Therefore, our study aims to evaluate the effect of a PSMF diet on anthropometric and body composition parameters when supplied continuously by NGT or administered per os. Secondly, we examine the impact of the PSMF diet on blood glucometabolic markers. | PMC10674249 |
2. Materials and Methods | PMC10674249 |
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2.1. Study Design and Subjects | obesity | OBESITY | The present study is a pilot single-center randomized clinical trial designed to test the efficacy of a PSMF diet administered via NGT (ProMoFasT) compared with the same PSMF diet taken orally in patients with obesity. Subjects were evaluated and enrolled in the Dietetics and Clinical Nutrition Unit of the IRCCS Policlinic San Martino Hospital, University of Genoa (Italy) according to the following inclusion and exclusion criteria. We included patients with obesity with a BMI above 34.9 kg/mInformed written consent for the use of personal data was obtained from patients. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the IRCCS Policlinic Hospital San Martino in Genoa (Italy) (n.reg CEA 125/10) in February 2011 and was registered on | PMC10674249 |
2.2. Nutritional Protocol | Patients were randomized 1:1 to a PSMF diet administered continuously during 24 h via NGT (ProMoFasT) or to the same PSMF diet administered orally. The protocol included 5 cycles of active PSMF nutrition lasting 10 days alternated to 20 days of a balanced oral low-calorie diet for a total of 150 days. The PSMF diet administered in both two groups was based on a whey protein formula (The endpoints were assessed in the intention-to-treat population. | PMC10674249 |
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2.3. Naso-Gastric Tube Placement and Home’s Enteral Nutrition Management | After a 12-h overnight fast, an 8 French polyurethane NGT was placed in a day-hospital setting in the Dietetics and Clinical Nutrition Unit of the IRCCS Policlinic San Martino Hospital, University of Genoa, Italy. Patients were provided with tools to carry out home EN and they were elucidated about the use of the infusion pump and any possible side effects of EN. | PMC10674249 |
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2.4. Statistical Analysis | IBM SPSS Statistics, Version 25.0 (SPSS Inc., Chicago, IL, USA, | PMC10674249 |
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3. Results | PMC10674249 |
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3.1. Study Population | Twenty patients (75.0% females and 25.0% males; median age 49.0 years, IQR 41.0–53.0) were randomized to the administration via NGT (ProMoFasT group), while 24 patients (58.3% females and 41.7% males; mean age 49.0 years, IQR 39.0–56.5) were assigned to the PSMF diet administration orally (oral group) ( | PMC10674249 |
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3.3. Biochemical Parameters | TG | As shown in TC, LDL-C and TG plasma levels were significantly reduced, and HDL-C plasma levels were significantly increased in the ProMoFasT group from baseline to follow-up visit, while TC, HDL-C and LDL-C levels were significantly increased, and TG levels were significantly reduced in the oral group from baseline to follow-up visit. Nonetheless, no significant differences in the lipid profile were observed between the two groups after 150 days. Calcium and phosphorous levels were significantly increased in both groups from baseline to follow-up visit. | PMC10674249 |
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4. Discussion | obesity, MM, FM, appetite suppression, weight loss, TG, glucometabolic | OBESITY, SEVERE OBESITY, INSULIN RESISTANCE | VLCKDs are valid and well-recognized strategies in the treatment of severe obesity and the PSMF diet falls into this group of dietary interventions, but its peculiarity is that not only carbohydrates are restricted to less than 30 g/day, but also lipids are limited to less than 20 g/day, making proteins the primary source of calories. This dietary approach seems to have a protein-sparing effect, preventing muscle catabolism. Furthermore, the consistent administration of a whey-protein-rich diet is more effective in preventing lean mass catabolism and inducing appetite suppression [Given this knowledge, we found that the PSMF diet administered by NGT is an effective and safe dietary intervention with a high level of compliance that leads to a rapid improvement in body composition parameters and glucometabolic markers when compared to administering the same diet orally. Specifically, we observed improvements in body composition parameters, with significantly lower levels of FM (kg) and FM (%) and higher levels of FFM (%), MM (%). From a pathophysiological perspective, it is known that nutrition administered via NGT determines a greater suppression of appetite in human subjects due to alterations in appetite-suppressing gut hormones, and may increase the levels of glucagon-like peptide 1 and peptide YY as reported by a recent randomized controlled trial (RCT) [This latter remark could be supported by the conflicting results of the improvement in muscle anabolism when using intermittent boluses of amino acids versus their continuous administration [Another intriguing finding from our study was the possibility of maintaining lean body mass throughout the administration of whey protein as a sole source of protein in PSMF. Whey proteins are rich in leucine, a branched chain amino acid that stimulates human muscle protein synthesis by activating the mTOR signaling pathway independently by Insulin-like growth factor receptor 1, resulting in a muscle anabolism enhancement. Moreover, whey proteins inhibit food intake and tend to improve oxidative balance in rats with obesity as this source of proteins was associated with a slight increase in total glutathione both in the liver and in the blood as compared to a casein-based diet [In our study, we observed a lower level of fasting blood insulin after 150 days of the PSMF diet in the ProMoFasT group compared to the oral group. This effect has several beneficial effects on human health, as it is well known in the literature that an insulin-sensitizing diet can improve strong outcomes in both diabetic and non-diabetic patients such as the reduction in cardiovascular mortality [Although it has been established that prolonged exposure to excessive amino acids diminished AMPK activity leading to insulin resistance [Another interesting result emerging from our study is the significant improvement in the lipid profile of the ProMoFasT group from baseline to follow-up, characterized by a decrease in LDL-C and TG and an increase in HDL-C. On the other hand, patients who received the oral PSMF diet experienced a worsening of LDL-C levels. The different results from baseline to follow-up observed in the ProMoFasT group could be attributed to the levels of fasting blood insulin, which appear to be significantly lower in the ProMoFasT group compared to the oral group. In fact, insulin has a well-recognized stimulatory influence on endogenous cholesterol synthesis [Based on our findings, calcium and phosphorus plasma levels increase in both groups from baseline to follow-up, although it is still possible to hypothesize that a protein-sparing diet may not negatively impact bone metabolism. In fact, it is well-known that a higher protein diet raises insulin-like growth factor-1, a crucial mediator of bone health [Finally, we observed a significant reduction in body weight, BMI and waist circumference during 150-day cycles of PSMF, whether administered via NGT or orally. In this field, a recent study suggested the effectiveness and safety of the PSMF diet as an outpatient weight loss strategy for adolescents affected by severe obesity [To the best of our knowledge, this is the first RCT that compared the safety and the efficacy in terms of body composition and glucometabolic improvement of a PSMF diet administered by NGT, compared to the same diet supplied orally. The limitations of our study include a small sample size and a relative high number of patients lost to follow-up; thus, the findings should be considered as preliminary. Furthermore, the lack of quality-of-life data could be another limitation of the study; in fact, quality of life encompasses significant aspects of well-being such as physical, mental, and emotional health, which are important for assessing the overall effectiveness and sustainability of any dietary intervention in a real-world setting. Another limitation was the non-statistically different distribution of male gender between the two groups, slightly favoring the ProMoFasT group and which may have an impact on the body composition. Nevertheless, we did not observe any differences among all parameters evaluated with the BIA analysis. | PMC10674249 |
5. Conclusions | SEVERE OBESITY | Compared to the same PSMF diet given orally, the ProMoFasT is an effective and safe nutritional intervention that has a good compliance rate and results in improvements in body composition with an insulin-lowering effect among subjects with severe obesity. Further RCTs are needed to confirm these preliminary findings. | PMC10674249 |
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Author Contributions | Conceptualization, S.G.S.; formal analysis, I.S. and E.F.; investigation, R.G. and C.R.; data curation P.G. and C.R.; writing—original draft preparation, E.F.; writing—review and editing, L.P. and S.G.S.; supervision, S.G.S. All authors have read and agreed to the published version of the manuscript. | PMC10674249 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of IRCCS Policlinic San Martino Hospital, University of Genoa (Italy) on 15 February 2011 (n.reg CEA 125/10). | PMC10674249 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10674249 |
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Data Availability Statement | Data for the reported results are available upon a reasonable request, in accordance with ethical principles. | PMC10674249 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10674249 |
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References | muscle mass, FM | BLOOD, INSULIN RESISTANCE | The CONSORT flowchart of the study. Abbreviations: ITT: intention-to-treat; ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube.Comparison of the body weight between the two groups. Abbreviations: ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube.Comparison of the muscle mass (%) and the fat-free mass (%) between the two groups. Abbreviations: ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube.Comparison of the fat mass (kg) and the fat mass (%) between the two groups. Abbreviations: ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube.Comparison of the fasting blood insulin and HOMA-IR between the two groups. Abbreviations: HOMA-IR: homeostasis model assessment of insulin resistance; ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube.Composition of the whey protein formula administered to both groups.Baseline characteristics of the study population.Abbreviations: IQR: interquartile range; ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube.Anthropometrical and body composition parameters between baseline and follow-up and comparison between the two groups after 150 days.Data are expressed as median and interquartile range. No significant differences were found between the two groups at baseline. Abbreviations: ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube; BMI: body mass index; BCM: body cellular mass; FFM: fat-free mass; MM: muscle mass; FM: fat mass; TBW: total body water; ICW: intracellular water. Bold font indicates statistical significance.Blood parameters between baseline and follow-up and comparison between the two groups after 150 days.Data are expressed as median and interquartile range. No significant differences were found between the two groups at baseline. Abbreviations: ProMoFasT: Protein-Sparing Modified Fast diet by nasogastric tube; HbA1c: glycated hemoglobin; HOMA-IR: homeostasis model assessment of insulin resistance; GGT: gamma-glutamyl transferase; ALP: alkaline phosphatase; AST: aspartate amino transferase; ALT: alanine amino transferase; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TG: triglycerides. Bold font indicates statistical significance. | PMC10674249 |
Introduction | hypovolemia, IDH | INTRADIALYTIC HYPOTENSION, PATHOGENESIS, COMPLICATION | Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of IDH has been attributed to the rapid reduction of plasma volume during hemodialysis and the inadequate compensatory mechanisms in response to hypovolemia, such as the lack of vasoconstriction. This may be due to the increased production of vasodilators, such as bradykinin. In this study we test the hypothesis that bradykinin B | PMC10176680 |
Methods | We performed a post-hoc analysis of a double-blind, placebo-controlled, randomized, 2 × 2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B | PMC10176680 |
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Results | reduction of systolic blood pressure, IDH | Seven of the patients had IDH, defined as a reduction of systolic blood pressure equal to or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in patients with IDH [blood pressure at average nadir (2.5 h after hemodialysis): Placebo,114.3 ± 8.9 vs. icatibant, 125.6 ± 9.1 mmHg, mean ± S.E.M]. Icatibant did not affect blood pressure in the group of patients without IDH. | PMC10176680 |
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Conclusion | IDH | Bradykinin B2 receptor blocker may prevent the occurrence of IDH. Further studies should evaluate the hemodynamic effects of icatibant during hemodialysis and the symptomatology associated with IDH. | PMC10176680 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12882-023-03192-4. | PMC10176680 |
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Keywords | PMC10176680 |
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Introduction | nausea, ESKD, intradialytic hypotension, cramps, dizziness, headache, hypovolemia, IDH | COMPLICATION OF HEMODIALYSIS, INTRADIALYTIC HYPOTENSION, END-STAGE KIDNEY DISEASE, PATHOGENESIS | Patients with end-stage kidney disease (ESKD) on maintenance hemodialysis (MHD) have a decreased life expectancy and increased mortality risk [Intradialytic hypotension (IDH), a common clinical complication of hemodialysis, is defined as a decrease in systolic blood pressure (SBP) of 20 mmHg or more, and it is usually accompanied by symptoms such as cramps, dizziness, headache, and nausea [The pathogenesis of intradialytic hypotension has been attributed to the inappropriately rapid reduction of plasma volume during hemodialysis and the inadequate mechanisms to respond to hypovolemia in patients on MHD [In this study, we tested the hypothesis that blocking the B | PMC10176680 |
Materials and methods | PMC10176680 |
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Study population | acute infection, myocardial infarction, malignancy, liver disease, cough, angioedema | ACUTE INFECTION, MYOCARDIAL INFARCTION, EVENT, LIVER DISEASE, ANGIOEDEMA, CONNECTIVE TISSUE DISEASE, GASTROINTESTINAL DYSFUNCTION | The study was approved by the Vanderbilt University Institutional Review Board and performed according to the Declaration of Helsinki. Two-hundred and two patients were pre-screened for eligibility, and 16 patients were approached and assessed for eligibility. Patients with a history of functional transplant less than six months prior to the study or anticipated live donor kidney transplant were excluded. Patients with a history of active connective tissue disease, acute infection within one month prior to the study, advanced liver disease, gastrointestinal dysfunction requiring parental nutrition, or active malignancy were not included in the study. Use of the following medications was also excluded: anti-inflammatory medication other than aspirin at a dose less than 325 mg per day, immunosuppressive drugs within one month prior to the study, vitamin E at a dose higher than 60 IU per day, or vitamin C at a dose higher than 500 mg per day. Subjects with a history of myocardial infarction or cerebrovascular event within three months prior to the study or with an ejection fraction lower than 40% were excluded. Other exclusion criteria were a history of ACEi-associated angioedema or cough, pregnancy, or breastfeeding. Three patients were excluded based on their inability to undergo magnetic resonance imaging (MRI). Thirteen patients provided written informed consent and agreed to participate in the study, but two withdrew from participation before any intervention. Therefore, 11 patients completed the study. Figure
Flowchart of study participation and randomization | PMC10176680 |
Study protocol | hemodialysisIntradialytic hypotension, hypotension | The study procedures were performed in the Vanderbilt University General Clinical Research Center (GCRC). Patients participated in a randomized placebo-controlled two by two crossover study, in which they received either, the bradykinin B
Study design. The study was a randomized, cross-over, double-blind, placebo-controlled study to study the effects of icatibant in mitochondrial function and blood pressure during hemodialysisIntradialytic hypotension was defined as a reduction of SBP equal to or greater than 20 mmHg during hemodialysis. We restricted the analysis of blood pressure to the first three hours of hemodialysis since the duration of hemodialysis varies from 3.25 to 4.5 h and most episodes of hypotension occurred during the first hour of hemodialysis. | PMC10176680 |
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Laboratory procedures | For bradykinin measurements, blood was collected into polypropylene tubes containing chilled ethanol and let the mixture stand for 30 min at 4 °C. Samples were then centrifuged and the supernatant was stored frozen at -80 until processing. Bradykinin was measured by high-perfomance liquid chromatography (HPLC) following by electrospray inoisation mass spectrometry (ESI-MS) as previously described [ | PMC10176680 |
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Statistical methods | intradialytic hypotension | INTRADIALYTIC HYPOTENSION | Data are presented as mean ± SEM or median and interquartile range. We also estimated the area under the curve for the change from baseline over time in blood pressure and heart rate, calculated by summing the numerical values of successive linear segments for every 15 min intervals. We used McNemar’s test to compare the occurrence of intradialytic hypotension between the treatment groups. The effect of treatment on blood pressure and heart rate were analyzed by comparing the areas under the curves with the Wilcoxon paired test. | PMC10176680 |
Results | PMC10176680 |
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Baseline patient characteristics | Baseline characteristics are shown in Table
Baseline characteristicsACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. Data are presented as mean ± SD | PMC10176680 |
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Effect of hemodialysis and bradykinin receptor blockade on blood pressure | reduction of blood pressure, decrease in systolic blood pressure, IDH, intradialytic hypotension | INTRADIALYTIC HYPOTENSION, HEART | Icatibant treatment did not affect blood pressure during hemodialysis compared to placebo treatment in the overall group (Figure We next analyzed the effect of icatibant on blood pressure in patients with and without intradialytic hypotension.The hemodialysis variables in patients with and without intradialytic hypotension are shown in Table
Hemodialysis variables in patients with and without intradialytic hypotensionVariables are expressed as mean ± SD, median (range), unless otherwise specified. IDH, intradialytic hypotension (decrease in systolic blood pressure equal to or greater than 20 mmHg). spKt/V, single pool Kt/V. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CCB, calcium channel blockers
Effect of icatibant on systolic blood pressure (SBP) during hemodialysis in patients with a reduction of blood pressure ≥ 20 mmHg (n = 7).
Effect of icatibant on heart rate during hemodialysis in patients without (n = 4, A) and with (n = 7, B) intradialytic hypotension (IDH, a reduction of blood pressure ≥ 20 mmHg). Heart rate was measured every 15 min before and during hemodialysis
Episodes of intradialytic hypotension during icatibant and placebo treatmentsIDH, intradialytic hypotension (decrease in systolic blood pressure equal to or greater than 20 mmHg).Icatibant did not affect heart rate during hemodialysis in patients with intradialytic hypotension (Fig. | PMC10176680 |
Effect of icatibant on bradykinin concentrations | hypotension, intradialytic hypotension | INTRADIALYTIC HYPOTENSION | Bradykinin concentrations were measured prior to, at the beginning of hemodialysis, at 30, and 60 min after initiation of hemodialysis. There was no effect of icatibant versus placebo on bradykinin levels during hemodialysis. In addition, patients who experienced intradialytic hypotension had similar bradykinin levels compared to patients who did not experience hypotension [80.9 (37.5, 104.8) vs. 85.9 (45.0, 155.1) fmol/ml, median (interquartile range), at 30 min, p = 0.66]. | PMC10176680 |
Adverse events | dizziness, cramps, hypotension | ADVERSE EVENT | There was no adverse event related to the study intervention. Three patients delevop symptoms associated with hypotension. All of them reported cramps and one of them also complain of dizziness. | PMC10176680 |
Discussion | dialysis-induced hypotension, hypovolemia, hemodialysis-induced hypotension, intradialytic hypotension | COMPLICATION OF HEMODIALYSIS, INTRADIALYTIC HYPOTENSION, VASODILATION, HEREDITARY ANGIOEDEMA | In this pilot study, we found that bradykinin BThe lack of vasoconstriction in response to hypovolemia is one of the impaired responses during intradialytic hypotension. Previous studies suggest that vasopressin, nitric oxide, and adenosine are associated with the occurrence of intradialytic hypotension [Bradykinin is a potent vasoactive peptide that results from the cleavage of high molecular kininogen by tissue and plasma kallikreins and causes vasodilation through the activation of the bradykinin BIntradialytic hypotension is a common clinical complication of hemodialysis, and it is associated with increased morbidity and mortality [Bradykinin usually peaks within the first 15 min of hemodialysis, [We have not measured the clearance of icatibant by the dialyzer, however, vitamin B12 has similar biophysical properties compared to icatibant, such as molecular weight and water solubility. In this study, the KoA (dialyzer mass transfer area coefficient) for vitamin B12 was 312 ml/min (at blood and dialysate flow of 300 and 500 mL/min, respectively). Thus, some amount of icatibant may be cleared during hemodialysis and limit its effectiveness. For this reason, icatibant was continuously infused before and during hemodialysis. Nevertheless, further studies should evaluate the clearance of icatibant during hemodialysis.This study has some limitations: First, our study should be considered exploratory since our inclusion criteria did not specifically select patients with a documented history of hemodialysis-induced hypotension, and the primary objective of the study was to study mitochondrial function and blood pressure during hemodialysis, but not intradialytic hypotension. While our results are intriguing, future studies should target patients with a history of dialysis-induced hypotension to confirm our findings. Second, this study included young, predominantly male, and African American patients. Thus, the results of the study may not be generalized to a more diverse population of patients on hemodialysis. There were also numerous exclusion criteria that may limit the generalization of the results. Finally, while we used a cross-over design, our sample size is relatively small, and our results should be interpreted with caution.In conclusion, our study suggests that endogenous bradykinin contributes to the decrease in blood pressure during hemodialysis. Pharmacological therapies that block the effect of bradykinin or inhibit the activation of the kallikrein-kinin system, such as the ones approved for use in hereditary angioedema, represent potential novel treatments for the prevention of intradialytic hypotension. | PMC10176680 |
Acknowledgements | WRIGHT | We would to thankc Patricia Wright, Anthony Dematteo, and Shouzuo Wei for their valuable technical assistant. We also like to thank all the participants for their dedication to the study. | PMC10176680 |
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Authors’ contributions | CM | The study design was contributed by JLG, NJB, and TAI. The formal analysis was contributed by JLG, HN, and CY. Writing the original draft was contributed by JLG, NJB, TAI. Experiment and data acquisition were contributed by JLG, CM, and AC. Writing and editing the manuscript were contributed by JLG, CM, AC, HN, CY, TAI, and NJB. All the authors approved the final version of the manuscript. | PMC10176680 |
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Funding | This study is supported in part by 1UL-1RR024975 and K23DK100533 grants from the National Institutes of Health, and drug supply through Investigator-Initiated Research Support (IIR-USA-000344 from Shire/Takeda). The sponsors did not influence the design, execution, and analysis of the results of the study. | PMC10176680 |
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Data Availability | The data that support the findings of this study are included in the article and supplementary material. Further inquiries can be directed to the corresponding author. | PMC10176680 |
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Declarations | PMC10176680 |
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Ethics approval and consent to participate | All the study participants had given written informed consent before enrollment. Prior to the initiation of the study, we obtained approval from Vanderbilt Institutional Review Board (IRB #131602). This study was conducted in accordance with the Declaration of Helsinsky. | PMC10176680 |
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Consent for publication | Not applicable. | PMC10176680 |
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Competing interests | BROWN | Shire/Takeda provided icatibant for the study through an Investigator Initiated Research Support grant. Drs. Brown and Gamboa serve as consultants to Pharvaris. Dr. Brown serves on the scientific advisory board for Alnylam Pharmaceuticals. The remaining authors have declared no conflict of interests. | PMC10176680 |
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References | PMC10176680 |
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Background | breast cancer | MPBC, BREAST CANCER | Metaplastic breast cancer (MpBC) is a rare histological subtype of breast cancer. This study aims to establish a competitive risk model for older women with MpBC to predict patients’ survival accurately. | PMC10349515 |
Methods | death | MPBC | Data on patients diagnosed with MpBC from 2010 to 2019 are from the Surveillance, Epidemiology and End Results (SEER) program in the United States. All patients were randomly assigned to the training set and validation set. The proportional sub-distribution risk model was used in the training set to analyze the risk factors affecting patient death. Based on the risk factors for cancer-specific mortality (CSM) in patients, we constructed a competitive risk model to predict patients’ 1-, 3-, and 5-year cancer-specific survival. Then we used the concordance index (C-index), the calibration curve and the area under the receiver operating characteristic curve (AUC) to validate the discrimination and accuracy of the model. | PMC10349515 |
Results | tumor | MPBC, TUMOR | One thousand, four hundred twelve older women with MpBC were included in this study. Age, T stage, N stage, M stage, tumor size, surgery and radiotherapy were risk factors for CSM. We established a competitive risk model to predict 1-, 3-, and 5-year cancer-specific survival in older women with MpBC. The C-index of the model was 0.792 in the training set and 0.744 in the validation set. The calibration curves in the training and validation sets showed that the model’s predicted values were almost consistent with the actual observed values. The AUC results show that the prediction model has good accuracy. | PMC10349515 |
Conclusion | MPBC | We developed a competitive risk model based on these risk factors to predict cancer-specific survival in older women with MpBC. The validation results of the model show that it is a very effective and reliable prediction tool. This predictive tool allows doctors and patients to make individualized clinical decisions.
| PMC10349515 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12905-023-02513-x. | PMC10349515 |
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Keywords | PMC10349515 |
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Introduction | cancer, Breast cancer, breast cancers, breast cancer | BREAST CANCER RECURRENT, BREAST CANCER, MPBC, CANCER, BREAST CANCER | Breast cancer is the most common cancer in women. Metaplastic breast cancer (MpBC) is a rare histological subtype, accounting for 0.25–2% of breast cancers [Breast cancer is widespread in older women. However, because of the lack of standard treatment for older breast cancer patients, undertreatment leads to higher rates of breast cancer recurrence and mortality [The nomogram is a simple and reliable predictive tool that can predict patient survival based on risk factors affecting patient survival [ | PMC10349515 |
Materials and methods | PMC10349515 |
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Data resources | cancer, tumor | MPBC, TUMOR, CANCER | Data on patients diagnosed with MpBC from 2010 to 2019 are from the Surveillance, Epidemiology and End Results (SEER) program. The SEER database is a population-based cancer database in the United States, including 18 cancer registries, covering about 30% of the US population. Since the patient’s personal information in the SEER database cannot be identified, this study does not require ethical approval and informed consent. All the research methods in this study comply with the provisions of the SEER database.This study collected data from older women with MpBC. Inclusion criteria: 1) the diagnosis year is 2010–2019; 2) age ≥ 65 years old; 3) women; 4) the pathological diagnosis was MpBC. Exclusion criteria: 1) TNM stage unknown; 2) tumor size is unknown; 3) surgical procedure is unknown; 4) estrogen receptor(ER), progesterone receptor(PR) and human epidermal growth factor receptor-2(HER2) status unknown; 5) survival time less than one month. The patient screening process is shown in Fig. The flow chart of patient selection | PMC10349515 |
Variables definition | squamous cell carcinoma, spindle cell carcinoma, tumor, death, cancer, adenosquamous carcinoma, adenocarcinoma, metaplastic carcinoma | CANCER, TUMOR, ADENOCARCINOMA | The clinicopathological information of patients, including age, race, marriage, histological type, histological grade, TNM stage, ER, PR and HER2 status, tumor size, and treatment (surgery, radiotherapy and chemotherapy), were obtained from the SEER database. The race is divided into white, black and others (American Indian/AK Native, Asian/Pacific Islander). Marriage is divided into married or unmarried. Histological types included metaplastic carcinoma, squamous cell carcinoma, spindle cell carcinoma, adenosquamous carcinoma and adenocarcinoma mixed. Histological grades, including grades I-IV, were highly differentiated, moderately differentiated, poorly differentiated and undifferentiated, respectively. Surgery is divided into surgery and non-surgery. Radiotherapy and chemotherapy are also divided into yes or No. ER, PR and HER2 status were classified as negative or positive. Patients’ survival status is divided into survival, death from cancer, or death from other causes.Among these variables, age and tumor size are treated as continuous variable inputs to the model, while marital status, tumor laterality, pathological type, histological grade, TNM stage, surgery, radiation therapy, chemotherapy, ER status, PR status, and HER2 status are treated as categorical variable inputs to the model. | PMC10349515 |
Development and validation of the competitive risk model | In order to ensure the accuracy of model validation, we divided the data into two relatively independent datasets. All patients were randomly assigned to the training set (70%) and validation set (30%). In the training set, the proportional sub-distribution risk model proposed by Fine and Gray [ | PMC10349515 |
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Clinical utility | Decision Curve Analysis (DCA) is a new algorithm to calculate the net profit under different thresholds. DCA was used to calculate the potential clinical value of the new model and compared it with the traditional TNM staging system. In addition, according to the risk value calculated by the competitive risk model, the patients were divided into a high-risk group and a low-risk group by using the Youden index of the receiver operating characteristic curve (ROC) to take the best cut-offcut-off value. Kaplan–Meier (K-M) curve and Log-rank test were used to analyze the survival difference between the low-risk and high-risk groups. | PMC10349515 |
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Statistical analysis | All statistical methods were analyzed by R software 4.1.0 and SPSS 26.0. Continuous variables were described by mean and standard deviation, and a nonparametric U test was used to compare differences between groups. Categorical variables were described by frequency, and chi-square tests were used to compare group differences. The proportional sub-distribution hazard model analyzed the risk factors of CSM and OCM. The Log-rank test and Kaplan–Meier curve analyzed the survival difference between groups. A | PMC10349515 |
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