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However, patients excluded from the study complied with: | enamel hypoplasia, cavitated lesions | DENTAL FLUOROSIS, ENAMEL HYPOPLASIA, MEDICAL COMPLICATION |
Participant in another trial [Patients with tetracycline pigmentation, dental fluorosis, or enamel hypoplasia to avoid any false-positive results [Participants who had evidence of reduced salivary flow, systemic, or medical complications [Participants with cavitated lesions [Eligible patients were recruited from the outpatient clinic of the Conservative Dentistry department in the Faculty of Dentistry, Cairo University, according to the participant timeline and signed informed consent. | PMC9889428 |
Random sequence generation (randomization) | Simple randomization was assigned for participants by generating numbers from 1 to 58 using Random Sequence Generator, Randomness and Integrity Services Ltd ( | PMC9889428 |
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Allocation-concealment mechanism | The allocation of remineralizing agents to groups was performed through an opaque sealed envelope to ensure complete concealment. Figure | PMC9889428 |
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Blinding | The patient and assessors were blinded to the material assignment while the operator did not, due to the difference in material presentation and its application protocol. | PMC9889428 |
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Clinical examination of white spot lesions | WSLs, dryness | DEMINERALIZATION, OPACITY | Full dental and medical history for the patients was taken. A clinical examination of an active white spot lesion was performed to assess the color on the labial aspect of anterior teeth. WSLs defined as “white opacity” occur because of subsurface enamel demineralization that is located on smooth surfaces of teeth. These were assessed via dryness test by gentle drying for 5 s and via DIAGNOpen score [ | PMC9889428 |
Material application | strokes, tooth | PLAQUE, STROKES | Clinpro White Varnish, 3 M ESPE, 5% sodium fluoride was applied under manufacturer instructions as follows: dryness of the affected tooth was unnecessary as it sets in presence of saliva. Then, a thin layer of varnish was applied with a brush in strokes. No rinsing, suction, or drying was required. The patient was instructed to avoid solid foods, brushing, and flossing for 4 h after application treatment; during this time, soft food and liquid might be consumed.Curodont repair™ was applied according to the manufacturer’s instructions. Starting with the application of 2% NaOCl for 20 s to remove any plaque residual, then rinsed for 20 s and gently air-dried. The white spot lesion was etched with 35% phosphoric acid (Dental Technologies, Inc., USA) for 20 s, to open the pores to the subsurface lesion and then rinsed with water for 20 s and under moisture control [The remineralizing process of the white spot lesion was assessed quantitatively using the DIAGNOdent pen and qualitatively using the ICDAS scoring system according to time to the remineralizing agent used (T), where T0 represents the score taken before any treatment. T1 represents the score taken after 3 months follow-up and the T2 score represents the score taken after 6 months of follow-up.Patients in both groups were advised not to brush or chew food for at least 4 h after treatment. Only soft food and drink could be consumed. The patients were asked to use a soft toothbrush and fluoridated toothpaste as an oral hygiene regimen. | PMC9889428 |
Statistical methods | This study was performed to compare the qualitative and quantitative effects of two remineralizing agents on post-orthodontic white spot lesions comprising different theories. The first remineralizing agent is the self-assembling peptide P11-4 which follows the non-classical theory of remineralization while the second one is the fluoride varnish material that follows the classical theory for the remineralization.The mean and standard deviation values were calculated for each group in each test. Data were explored for normality using the Kolmogorov–Smirnov and Shapiro–Wilk tests, remineralizing process data showed parametric (normal) distribution, while ICDAS data showed non-parametric (not-normal) distribution.An independent sample The Mann–Whitney test was used to evaluate two groups in unrelated samples using non-parametric data. To compare more than two groups in related samples, the Friedman test was utilized. To compare two groups in related samples, the Wilcoxon test was utilized. The significance level was set at | PMC9889428 |
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Results | PMC9889428 |
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Demographic data
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Quantitative assessment of the remineralizing process using DIAGNOpen | PMC9889428 |
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Effect of time | PMC9889428 |
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Group B (biomimetic self-assembling peptides): | There was a statistically significant difference between T0, T1, and T2 groups where | PMC9889428 |
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Effect of groups | PMC9889428 |
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Baseline assessment before applying the remineralizing agents (T0) | GROUP B | There was no statistically significant difference between Group A (fluoride varnish) and Group B (self-assembling peptides) where | PMC9889428 |
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Assessment after the usage of the remineralizing agent by 3 months (T1) | GROUP B | There was a statistically significant difference between Group A (fluoride varnish) and Group B (self-assembling peptides) where | PMC9889428 |
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Assessment after the usage of the remineralizing agent by 6 months (T2) | GROUP B | There was a statistically significant difference between Group A (fluoride varnish) and Group B (self-assembling peptides) where | PMC9889428 |
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Qualitative assessment of the remineralizing process using ICDAS scoring system | The frequencies of ICDAS along with different time intervals of different groups are shown in Table The frequencies of ICDAS along with different time intervals of different groups | PMC9889428 |
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Effect of time | PMC9889428 |
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Group A (fluoride varnish with tricalcium phosphate) | There was a statistically significant difference between T0 (baseline assessment before applying any remineralizing agent), T1 (after applying the remineralizing agents by 3 months), and T2 (after applying the remineralizing agents after 6 months) groups where | PMC9889428 |
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Group B (biomimetic self-assembling peptides) | There was a statistically significant difference between T0 (baseline assessment before applying any remineralizing agent), T1 (after applying the remineralizing agents by 3 months), and T2 (after applying the remineralizing agents after 6 months) groups where | PMC9889428 |
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Effect of groups | PMC9889428 |
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Baseline assessment before applying the remineralizing agents (T0) | GROUP B | There was no statistically significant difference between Group A and Group B groups where | PMC9889428 |
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Assessment after usage of the remineralizing agent by 3 months (T1) | GROUP B | There was no statistically significant difference between Group A and Group B groups where | PMC9889428 |
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Assessment after usage of the remineralizing agent by 6 months (T2) | GROUP B | There was no statistically significant difference between Group A and Group B groups where | PMC9889428 |
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Correlation between the quantitative and qualitative analysis of the remineralizing process using DIAGNOdent pen and ICDAS: | As presented in Table Correlation between remineralizing process using DIAGNOpen and ICDAS | PMC9889428 |
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Representative photos illustrating the qualitative analysis using ICDAS | incisors | A preoperative photo shows a post-orthodontics white spot lesion spread along the surface of the left central incisors. It appeared as a line around the orthodontic bracket in the right central incisors. Both are located mainly in the cervical third of the labial surface of the incisors. The same description applies to the lateral incisors where the white lesion presented around the brackets; however, it took a more circular in the left lateral one. Taking ICDAS score 2 as it appears in both wet and dry conditions, as shown in Fig. The white lesion presented around the brackets
After 3 months of follow-up, the post-orthodontic white spot lesions began to fade and become less intense. They did, however, receive an ICDAS score of 2 because they appear in both wet and dry conditions as shown in Fig. The post-orthodontic white spot lesions began to fade and become less intenseSix months later and adhering to the oral hygiene instructions, the white lesions began to fade. Keeping an eye on the right central incisor, where the white line vanished in the wet condition, and assigning an ICDAS score of 1. The rest of the white spot lesions turn out to be less severe and on their way to normal color, as shown in Fig. The rest of the white spot lesions turn out to be less severe and on their way to normal colorICDAS score 2 for a prominent white spot non-cavitated lesion on the buccal surface of the upper left premolar that is visible in both wet and dry conditions (Fig. ICDAS score 2 for a prominent white spot non-cavitated lesion on the buccal surface of the upper left premolar that is visible in both wet and dry conditionsThe lesions shrank in size and color after 3 monthsLesions vanished after 6 monthsScatter plot representing the correlation
CONSORT 2010 flow diagram | PMC9889428 |
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Discussion | carious lesions, carious lesion, caries, caries lesion, Tooth enamel, carious enamel lesion, tooth | DENTAL CARIES, DEMINERALIZATION, GROUP B, DENTAL PLAQUE, CARIES, PLAQUE, HYDROXYAPATITE | Orthodontic therapy with fixed appliances may lead to a rapid increase in the volume of dental plaque with an elevated level of acidogenic bacteria. The low pH of dental plaque and subsequent imbalance of the remineralization-demineralization equilibrium favor demineralization in areas where optimum oral hygiene becomes difficult [Clinically, enamel carious lesions in their early stage look like white, opaque spots softer than the surrounding sound enamel, and their whiteness increases with air drying. The early carious enamel lesion is characterized by subsurface damage with an intact enamel surface. This progressive subsurface demineralization, if not reversed, will lead to cavitation and eventually needs to be restored. Moreover, natural remineralization is difficult to be attained due to low calcium, phosphate, and fluoride concentration in the saliva. That is why intervention using remineralizing agents is needed to promote the mechanism of ion exchange to reverse the lesion avoiding invasive interventions [Tooth enamel regeneration is the goal today, through the true regeneration of hydroxyapatite crystals in subsurface lesions. This in fact can be mimiced by guided enamel repair with the use of self-assembling peptide P11-4 (SAP11-4) where monomeric P11-4 diffuses through the pores of decalcified enamel, fiber formation is triggered, and the 3D matrix is produced [Kirkham J (2007) was the first to publish the proof of concept that self-assembling peptide P11-4 facilitates biomimetic enamel remineralization [In the current study, both quantitative and qualitative analyses using DIAGNOpen and ICDAS are used in the current study as none of the diagnostic methods alone is enough for the diagnosis of dental caries. DIAGNOdent device was evidenced to be an efficient addition to other detection methods in caries detection as stated by a systematic review in 2021 [The qualitative analysis using ICDAS is considered to be an easy chairside system that omits the use of sharp explorer that may endanger the enamel during caries detection, so it encourages preventative strategies that enable remineralization of non-cavitated lesions [The quantitative analysis utilizing DIAGNOpen can detect the initial carious lesion where the laser beam fluorescence of demineralized enamel is lower than that of normal sound enamel. Six hundred fifty nanometer red diode laser beam is applied to the surface of the tooth. It is collected using a single optical fiber, filtered by high-frequency light wavelengths, and calculated by a photodiode. The amount of low-frequency fluorescence that passes through the caries lesion is measured and quantified [In the study, both ICDAS and DIAGNOpen showed a significant increase in remineralization of post-orthodontic white spot lesions in both groups and over different time intervals. However, the remineralizing capacity of self-assembling peptides was superior to that of the fluoride varnish.Fluoride follows the concept of ion-to-ion attachment for eventual enamel crystal growth. It is also called Fluoride varnish presents a successful non-invasive treatment modality for reversing the lesion in its early stage as it contains high concentrations of fluoride in comparison to the daily used toothpaste and mouthwash. So, surface fluoridation is maintained owing to the high level of fluoride ions. Moreover, it was suggested by some researchers that the combined formulation of fluoride varnish with tricalcium phosphate (TCP) with its mild acidity affects the saliva buffering capacity and plaque pH whereas the baseline salivary pH after immediate application of the fluoride varnish with tricalcium phosphate (TCP) is 6.7 that reaches 6.9 after 12 weeks [Perhaps, it is attributed to the use of fluoride varnish that contains 5% sodium fluoride and tricalcium phosphate. During the manufacturing process, there is a protective barrier around the calcium ions. Once the varnish becomes in contact with the enamel surface and saliva, this barrier is broken, making fluoride, phosphate, and calcium ions enhance ion remineralization [The remineralizing process of self-assembling peptide P11-4 showed significantly superior ability in enamel repair when compared to fluoride-based material. There was a statistically significant difference between Group A (fluoride vehicle material) and Group B (self-assembling peptides) groups where Brunton et al. [In post-orthodontic white spot lesions, self-assembling peptides P-114 displayed greater remineralization properties when mineral content was measured through radiographic and digital subtraction radiography, as in the case series by Schlee M [Welk et al. (2020) documented a noticeable decrease in impedance readings (using CarieScan) after self-assembling peptide P11-4 application. The mean impedance value of the self-assembling peptides group showed 46.7 that decreased to 19.7 after 180 days. Also, the lesion size decreased from 8.8 to 6.5 after 180 days of SAP application [As for the qualitative analysis using ICDAS, there is harmony between the results of the current study and the clinical study that was verified by other researchers [In the present clinical trial, there was a moderate positive relationship between quantitative analysis through the remineralizing process and visual or qualitative assessment using the ICDAS scoring system. This may be contributed to the occurrence of remineralization whether through the classical theory or the non-classical theory by decreasing in laser fluorescence. Also, it was revealed visually by fading the lesions. This agreed with other researchers [All these findings support the repair potential of the self-assembling peptide that can perform a true stable 3D scaffold. Thanks to the surface pre-treatment through conditioning the surface followed by surface etching, which allows high surface reactivity for better peptides diffusion, then again negatively charged scaffold formation acting as binding sites for positively charged calcium and phosphate ions confirming subsurface remineralization in a bottom-up direction [Eventually, enamel repair through biomimetic remineralization utilizing self-assembling peptides is considered to be a new avenue for remineralizing, reversing, and repair the early enamel lesion. Without a doubt, it will open the door to regenerative dentistry.According to the previously discussed results of this study, the null hypothesis is rejected where self-assembling peptides have a superior remineralizing potential over fluoride-based delivery systems quantitatively using laser fluorescence; however, both materials have the same visual effect on masking the early lesion. This new approach possibly reverses and masks off post-orthodontics white spot lesions. | PMC9889428 |
Conclusions | REGRESSION | Within the limitation of the present study, biomimetic remineralization promoted by self-assembling peptides has achieved successful subsurface remineralization making the material a promising guide to lesion regression in post-orthodontic therapy. | PMC9889428 |
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Recommendations | carious lesions, cavitated lesions | FOUNDER, DENTIN HYPERSENSITIVITY |
Clinical trials with further long-term follow-up studies are recommended.Further investigations are needed to assess self-assembling peptides on advanced and cavitated lesions.The material’s efficacy in the management of dentin hypersensitivity needs to be investigated.Investigating the material as a founder to the remaining dentin in deep carious lesions is also recommended.Research studies are needed to evaluate the synergistic effect of self-assembling peptides with other agents based on ion crystallization theory. | PMC9889428 |
Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC9889428 |
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Declarations | PMC9889428 |
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Ethics approval | The protocol of the current study was registered on clinical trials with a unique identification number (I.D. NCT03930927). Ethical approval was obtained before the start of the study. The study was approved by the Research Ethics Committee (CREC), Faculty of Dentistry with an ethical approval number (19754). | PMC9889428 |
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Informed consent | Informed consent with an easy Arabic language was signed by the recruited participants. | PMC9889428 |
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Conflict of interest | The authors declare no competing interests. | PMC9889428 |
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References | PMC9889428 |
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Key Points | PMC10600583 |
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Question | BREAST CANCER | Are there racial and ethnic disparities in survival among participants enrolled in clinical trials receiving standardized initial care for early-stage breast cancer? | PMC10600583 |
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Findings | tumor | TUMOR | In this cohort study with 9479 participants, pooled survival data suggest that survival differences exist even within clinical trial participants receiving similar initial care. Subgroups, defined by tumor subtype, age, and/or body mass index, that may drive racial and ethnic disparities in survival were identified. | PMC10600583 |
Meaning | tumor, breast cancer | TUMOR, BREAST CANCER | These findings suggest potential factors contributing to racial and ethnic disparities in survival of patients with breast cancer; it is critical to evaluate interventions for improvement.This cohort study assesses the association of race and ethnicity with survival among clinical trial participants with early-stage breast cancer according to tumor subtype, age, and body mass index (BMI). | PMC10600583 |
Importance | tumor, breast cancer | TUMOR, BREAST CANCER | Black women in the United States have higher breast cancer (BC) mortality rates than White women. The combined role of multiple factors, including body mass index (BMI), age, and tumor subtype, remains unclear. | PMC10600583 |
Objective | tumor | TUMOR | To assess the association of race and ethnicity with survival among clinical trial participants with early-stage BC (eBC) according to tumor subtype, age, and BMI. | PMC10600583 |
Design, Setting, and Participants | 49907, Leukemia, Cancer | ONCOLOGY, GROUP B, LEUKEMIA, CANCER | This cohort study analyzed survival data, as of November 12, 2021, from participants enrolled between 1997 and 2010 in 4 randomized adjuvant chemotherapy trials: Cancer and Leukemia Group B (CALGB) 9741, 49907, and 40101 as well as North Central Cancer Treatment Group (NCCTG) N9831, legacy groups of the Alliance of Clinical Trials in Oncology. Median follow-up was 9.8 years. | PMC10600583 |
Exposures | Non-Hispanic Black and Hispanic participants were compared with non-Hispanic White participants within subgroups of subtype (hormone receptor positive [HR+]/ | PMC10600583 |
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Main Outcomes and Measures | Recurrence-free survival (RFS) and overall survival (OS). | PMC10600583 |
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Results | Of 9479 participants, 436 (4.4%) were Hispanic, 871 (8.8%) non-Hispanic Black, and 7889 (79.5%) non-Hispanic White. The median (range) age was 52 (19.0-89.7) years. Among participants with HR+/ | PMC10600583 |
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Conclusions and Relevance | In this cohort study, racial and ethnic survival disparities were identified in patients with eBC receiving standardized initial care, and potentially at-risk subgroups, for whom focused interventions may improve outcomes, were found. | PMC10600583 |
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Introduction | cancer, breast cancer | CANCER, BREAST CANCER | For several decades, non-Hispanic Black women have had substantially higher breast cancer (BC) mortality rates than non-Hispanic White women.A previous pooled analysis of SWOG clinical trials showed that, while no racial disparities were observed for most cancer types, non-Hispanic Black women with BC were more likely to die than non-Hispanic White women. | PMC10600583 |
Methods | PMC10600583 |
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Data and Patients | Leukemia, Cancer | GROUP B, LEUKEMIA, CANCER | We included participants enrolled in 4 adjuvant chemotherapy trials: Cancer and Leukemia Group B (CALGB) C9741 ( | PMC10600583 |
Flow Diagram of Participants | Leukemia, Cancer | GROUP B, LEUKEMIA, CANCER | CALGB indicates Cancer and Leukemia Group B; NCCTG, North Central Cancer Treatment Group. | PMC10600583 |
Measures and Outcomes | death, Tumor | EVENTS, RECURRENCE, TUMOR | Tumor hormone receptor (HR) and RFS events included local, regional, or distant BC recurrence or death due to any cause. | PMC10600583 |
Statistical Analysis | Median follow-up was estimated using the reverse Kaplan-Meier method. | PMC10600583 |
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Results | PMC10600583 |
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Patient Characteristics | Of 10 011 women enrolled in the included trials, 9479 (94.7%) had available survival and race and ethnicity data and were included in this pooled analysis. Their median (IQR) follow-up time was 9.8 (6.7-13.2) years, and 435 participants (4.6%) were designated as lost to follow-up. All participants were female. There were 436 (4.6%) Hispanic, 871 (9.2%) non-Hispanic Black, 7889 (83.2%) non-Hispanic White participants, and 283 (3.0%) patients with another race and ethnicity ( | PMC10600583 |
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Participant Baseline Characteristics | obesity, Leukemia, Cancer | OBESITY, GROUP B, LEUKEMIA, DISEASE, CANCER | Abbreviations: −, negative; +, positive; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CALGB, Cancer and Leukemia Group B; HR, hormone receptor; NCCTG, North Central Cancer Treatment Group.Other race and ethnicity includes American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander.BMI groups were determined based on Center for Disease Control and Prevention definitions of underweight, healthy weight, overweight, and obesity as follows: less than 18.5, 18.5 to less than 25.0, 25.0 to less than 30.0, and 30.0 or greater respectively. | PMC10600583 |
Survival and Race and Ethnicity | PMC10600583 |
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Survival Within Tumor Subtypes by Race and Ethnicity | tumor | TUMOR | We evaluated differences in RFS and OS among racial and ethnic groups for participants with the same BC subtype. Of all 9479 participants, 8588 (90.6%) had available tumor subtype data and were included in these analyses. Global tests for the association of the race and ethnicity variable with tumor subtype were not statistically significant within any subtype. However, we did observe an association among participants with HR+/ | PMC10600583 |
Forest Plots of Hazard Ratios Comparing Survival in Tumor Subtype by Race/Ethnicity | − Indicates negative; +, positive; HR, hormone receptor; OS, overall survival; and RFS, recurrence-free survival. | PMC10600583 |
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Survival Within Age Categories by Race and Ethnicity | We next evaluated survival differences within age groups. All 9479 participants had available age data and were included in these analyses. Within the middle age group, ages 50 to younger than 65 years, race and ethnicity were associated with RFS (global | PMC10600583 |
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Forest Plots of Hazard Ratios Comparing Survival in Age Category by Race/Ethnicity | OS indicates overall survival; RFS, recurrence-free survival.When further analyzed within subgroups jointly defined by subtype and age, race and ethnicity were associated with RFS in older participants with HR+/ | PMC10600583 |
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Survival Within BMI Categories by Race and Ethnicity | obesity | OBESITY | We also studied survival differences between race and ethnicity groups within BMI categories. Of all 9479 participants, 9352 (98.7%) had available BMI data and were included in these analyses. For participants with underweight and obesity, race and ethnicity were not significantly associated with RFS or OS on global testing. However, among participants with overweight, race and ethnicity were significantly associated with RFS (global | PMC10600583 |
Forest Plots of Hazard Ratios Comparing Survival in Body Mass Index Category by Race/Ethnicity | obesity | OBESITY, DISEASE | Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) groups were determined based on Center for Disease Control and Prevention definitions of underweight, healthy weight, overweight, and obesity as follows less than 18.5, 18.5 to less than 25.0, 25.0 to less than 30.0, and 30.0 or greater, respectively. Point estimates and 95% CIs for overall survival (OS) of participants in the non-Hispanic other race and ethnicity group with underweight could not be estimated. RFS indicates recurrence-free survival.Analysis of subgroups jointly defined within BMI and subtype showed that, among patients with HR+/ | PMC10600583 |
Discussion | obesity, Obesity, Breast Cancer, tumor, HR+ BC, overweight, Cancer | OBESITY, OBESITY, TUMOR, BREAST CANCER, DISEASE, CANCER | We identified disease and patient subgroups with similarities and differences in survival among racial and ethnic groups for participants enrolled in 4 Alliance adjuvant chemotherapy clinical trials for eBC. While race and ethnicity, in general, were not associated with survival when stratified by subtype, non-Hispanic Black patients with HR+/Prior work within the National Comprehensive Cancer Network Breast Cancer Outcomes Database and in the Carolina Breast Cancer Study demonstrated that racial disparities vary by tumor subtype, with differences in survival between non-Hispanic Black and non-Hispanic White patients with HR+ BC and no differences for patients with triple negative or There are multiple plausible explanations for the differences observed between non-Hispanic Black and non-Hispanic White participants with HR+/We found that, overall, young non-Hispanic Black and Hispanic patients have worse OS than young non-Hispanic White patients. It is reported that non-Hispanic Black and Hispanic women are more likely to be diagnosed with BC at a young age compared with non-Hispanic White women.It is unclear why Hispanic participants in this study had significantly worse RFS than non-Hispanic White participants if they had overweight, but there was no such association in patients with obesity. Obesity has been associated with increased BC mortality in several studies, although more recent studies suggest that this association holds in White women but not in Black women.The strengths of this pooled analysis of clinical trials, including prospective collection of survival data with long follow-up, are particularly important given the outcomes of RFS and OS. Within each clinical trial, participants received similar initial treatment, and outcomes have been well ascertained. In addition to adjustment for baseline clinicopathologic risk factors, our analysis was adjusted for chemotherapy treatment received, thereby facilitating study of other factors associated with survival. By studying racial and ethnic disparities in survival in the clinical trial setting, which standardized initial care and treatment, our results emphasize that other factors, such as inequities in subsequent treatment, survivorship care, or biological differences, may contribute to these disparities. As such, this study extends the understanding of potential contributors to disparities in BC survival. We hope this will inform ongoing efforts to mitigate disparities in BC survival, such as patient navigation programs and the GETSET study | PMC10600583 |
Limitations | tumor, death | TUMOR | This study has limitations. Despite the pooled nature of this analysis, there are small sample sizes within certain strata. For example, small numbers of very young patients precluded our ability to specifically study women under the age of 40 years, a group that has been shown to exhibit differences in tumor genomics and worse BC outcomes. It is possible that such biologic heterogeneity affected outcomes in the group of women younger than 50 years.Information on cause of death could not be reliably ascertained from all 4 of the included studies and therefore we were unable to examine differences in BC-specific survival. Additionally, as specified previously, there is not documentation of how race and ethnicity were collected for participants in every trial, which may have led to misclassification of race and ethnicity in some participants. | PMC10600583 |
Conclusions | tumor | TUMOR | In this cohort study of clinical trial participants treated for eBC, we observed worse survival among Black or Hispanic participants within subgroups defined by age, BMI, or tumor subtype. These data suggest that, in addition to addressing the social and structural factors that contribute to racial and ethnic disparities overall, it may be necessary to identify and address subgroup-specific mechanisms underlying the observed associations. It is critical to evaluate specific contributors to racial and ethnic disparities in survival as these may inform future interventions to improve these disparities. | PMC10600583 |
Abstract | PMC10652308 |
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Background | PDAC | PANCREATIC DUCTAL ADENOCARCINOMA | Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin‐dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. | PMC10652308 |
Methods | PDAC | DISEASE | This Phase 2 open‐label study enrolled patients with metastatic PDAC who progressed after 1–2 prior therapies. Patients were enrolled in a safety lead‐in (abemaciclib plus galunisertib) followed by a 2‐stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib‐containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression‐free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. | PMC10652308 |
Results | One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4–1.8), 1.8 months (95% CI: 1.3–1.9), and 3.3 months (95% CI: 1.1–5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. | PMC10652308 |
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Conclusion | PDAC.Pancreatic ductal adenocarcinomas, PDAC | DISEASE | In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This phase 2 randomized study for refractory metastatic PDAC patients showed that the CDK4/6 inhibitor abemaciclib, alone or in combination with the PI3K/mTOR LY3023414, does not improve disease control or progression‐free survival compared to standard chemotherapy.
| PMC10652308 |
INTRODUCTION | cancer deaths, PDAC, Abemaciclib | PANCREATIC DUCTAL ADENOCARCINOMA | Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and the fourth leading cause of cancer deaths worldwide, with a 5‐year survival of only 10%.
Preclinical data with the CDK4/6 inhibitors, palbociclib and abemaciclib, demonstrated variable single‐agent efficacy in PDAC models.Abemaciclib is a potent, selective small‐molecule CDK4/6 inhibitor and is FDA‐approved as monotherapy and in combination with endocrine therapy for hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2‐) advanced breast cancer,Given the relevance of the CDK4/6 pathway in PDAC, the preclinical activity of CDK4/6 inhibition in PDAC models, including in | PMC10652308 |
METHODS | PMC10652308 |
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Study design | PDAC | DISEASE PROGRESSION | Study I3Y‐MC‐JPCJ was an international, multicenter, adaptive, randomized, open‐label, Phase 2 study in patients with metastatic PDAC who had disease progression after 1 or 2 prior therapies. The study aimed to evaluate the safety and efficacy of abemaciclib monotherapy or in combination with targeted agents versus standard chemotherapy of physician's choice, using a 2‐stage design (Figure Dose selection for abemaciclib as monotherapy and in combination with LY3023414 or with galunisertib, as well as doses for LY3023414 and galunisertib were based on previously reported Phase 1 studies. | PMC10652308 |
Patients | PDAC | DISEASE PROGRESSION, DISEASE, DIABETES MELLITUS, CENTRAL NERVOUS SYSTEM METASTASES, ONCOLOGY | Eligible patients were ≥18 years of age with metastatic PDAC and disease progression following 1 or 2 prior lines of therapy. Patients were required to have measurable disease as defined by RECIST v1.1, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, adequate organ function, and be considered appropriate candidates for single‐agent chemotherapy with capecitabine or gemcitabine. Patients with insulin‐dependent diabetes mellitus, symptomatic central nervous system metastases, or those previously treated with CDK4/6, PI3K, and/or mTOR inhibitors were not eligible.The study protocol was approved by the appropriate institutional review boards and ethics committees and conducted in accordance with the Good Clinical Practice of the Declaration of Helsinki. All patients provided written informed consent. Patients were enrolled at 32 sites in 8 countries. | PMC10652308 |
Randomization and treatment | toxicity, PD, death, toxicities | DISEASE | An interactive web response system assigned treatment. Investigational treatments were administered orally with or without food on a 28‐day cycle, unless otherwise noted. Standard chemotherapy was administered according to prescribing label recommendations. Treatment was continued until progressive disease (PD), unacceptable toxicity, death, or withdrawal from the study.In the safety lead‐in, patients received abemaciclib continuously (150 mg twice daily [BID]) plus galunisertib (150 mg BID) for 14 days followed by a 14‐day rest period. In Stage 1, patients were randomized 1:1:1 to receive abemaciclib monotherapy (200 mg twice daily), abemaciclib (150 mg BID) plus LY3023414 (150 mg BID), or SOC chemotherapy of the physician's choice with gemcitabine (1000 mg/mDose modifications of investigational agents were allowed for treatment‐related toxicities and followed protocol guidance. Standard chemotherapy dose modifications followed on‐label recommendations.Patients received full supportive care during the study per institutional guidelines. The use of granulocyte‐colony stimulating factors and erythropoietin was permitted in accordance with American Society of Clinical Oncology/American Society of Hematology guidelines. | PMC10652308 |
Safety and efficacy assessments | Cancer | ADVERSE EVENT, ADVERSE EVENT, CANCER | Adverse events (AEs) were collected and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. | PMC10652308 |
Pharmacokinetics | pre‐dose | For patients receiving abemaciclib, PK samples were collected on Cycle 1 Day 1 approximately 2 h after dosing and pre‐dosed on Day 1 of Cycles 2, 3, and 4. During the safety lead‐in, PK samples were collected pre‐dose on Cycle 1 Days 1 and 14, and at 0.5‐, 1‐, 2‐, 4‐, 6‐, and 8‐h post‐dose. Pharmacokinetics samples were analyzed for galunisertib, abemaciclib, and its metabolites (LSN2839567 [M2] and LSN3106726 [M20]) (QFor the safety lead‐in, non‐compartmental analysis methods were used to compute standard PK parameters of abemaciclib, M2, M20, and galunisertib. For Stage 1, average concentrations of abemaciclib, M2, M20, and LY3023414 were reported at each planned PK sampling time. | PMC10652308 |
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Endpoints | tumor, SD, death | DISEASE, TUMOR | Stage 1 primary endpoint was disease control rate (DCR) defined as the proportion of patients with a best tumor response of CR, PR, or SD (DCR = CR + PR + SD) in the intent‐to‐treat population. Responses and SD did not require confirmation. Secondary endpoints included ORR (CR + PR), pharmacokinetics (PK) of abemaciclib, its metabolites and LY3023414, and safety.Stage 2 primary endpoint of progression‐free survival (PFS) was defined as the time from randomization until progression or death from any cause. Secondary endpoints included DCR, clinical benefit rate (CR + PR + SD ≥6 months), ORR, duration of response (time from response until progression or death), and overall survival (OS). | PMC10652308 |
Statistical analyses | tumor | TUMOR | The study had a two‐stage design. During Stage 1, approximately 25 patients per arm were planned to provide a preliminary assessment of DCR and safety. The DCR of abemaciclib (Arm A) and abemaciclib plus LY3023414 (Arm B) were compared to SOC chemotherapy (Arm D). The null hypothesis assumed the DCR with SOC or abemaciclib treatment to be 50%. The probability of stopping at the end of Stage 1 was 11% if the DCR with abemaciclib treatment was 65% (i.e., DCR difference of abemaciclib vs. SOC was +15%). Conversely, the probability of stopping at the end of Stage 1 was 72% if the DCR with abemaciclib was 40% (i.e., DCR Difference of abemaciclib vs. SOC was −10%). At the end of Stage 1, an additional 50 patients were planned to enroll in each treatment arm with a DCR at least as good as SOC (i.e., DCR difference of abemaciclib vs. SOC ≥0), totaling approximately 75 patients in each arm. All efficacy analyses were performed on the intent‐to‐treat (ITT) population (all randomized patients). Stage 1 analysis was performed approximately 16 weeks after the last patient entered treatment.All tumor assessments were used to determine DCR and ORR. Each of these rates, point estimates, and confidence intervals (CIs) (using the normal approximation to the binomial) were calculated by the treatment arm. Kaplan–Meier (KM) method was used to estimate the PFS and OS for each treatment arm.The safety population included all patients who received any study treatment. Safety data were summarized by treatment arms. The PK population included patients who had ≥1 evaluable PK sample. | PMC10652308 |
RESULTS | PMC10652308 |
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Patients | fluoropyrimidine‐based | ONCOLOGY | From January 2017 to December 2017, 7 patients were treated with abemaciclib plus galunisertib (safety lead‐in), and 99 patients were randomized to receive abemaciclib (Arm A: Summary of patient disposition.Demographics and baseline characteristics (safety lead‐in and ITT population).Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; Baseline characteristics are missing for 1 patient.Some categories do not add up to 100% due to rounding.6 patients (1 in abemaciclib plus galunisertib, 2 in abemaciclib monotherapy arm, and 3 in SOC arm) had missing stage at diagnosis.Categories do not add up to 100% as nearly half of the patients previously received both gemcitabine‐ and fluoropyrimidine‐based therapies. | PMC10652308 |
Treatment | Median duration of abemaciclib treatment was 7.9 weeks (galunisertib safety lead‐in), 6.7 weeks (Arm A), 4.1 weeks (Arm B), 10.6, and 5.1 weeks with gemcitabine and capecitabine (Arm D), respectively. At the data cutoff, a total of 86 patients (86.9%) had discontinued study treatment. Reasons for treatment discontinuation are summarized in Figure | PMC10652308 |
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Efficacy | deaths, tumor | DISEASE, BEST, TUMOR | Sixty‐one of 99 patients enrolled (61.6%) were evaluable for response, and 38 patients (38.4%) did not have a post‐baseline scan and were considered non‐evaluable. Of these non‐evaluable patients, 8 (21.1%) were randomized but never treated, 21 (55.3%) died before imaging assessment, and 9 (23.7%) withdrew consent or refused follow‐up prior to the first disease response assessment.In the ITT population (Summary of best overall response (ITT population).
Abbreviations: CR, complete response; The best percentage change in tumor size relative to baseline was greater for those in Arm D than in any of the abemaciclib arms (Figure Best percentage change in tumor size in patients with measurable disease.Median PFS was 1.7 months (95% CI: 1.35–1.84) for abemaciclib, 1.8 months (95% CI: 1.28–1.91) for abemaciclib plus LY3023414, and 3.3 months (95% CI: 1.05–5.65) for SOC (Figure (A) Progression‐free survival in ITT population. (B) Overall survival in ITT population. ARM A, abemaciclib 200 mg; ARM B, abemaciclib 150 mg plus LY3023414; ARM D, SOC (gemcitabine or capecitabine); HR, Hazard Ratio; NC, not calculable. Hazard ratio was calculated using stratified Cox model with number of prior systemic therapy as the stratification factor. 2‐sided At the time of data cutoff, 22 deaths (66.7%) occurred in Arm A, 21 (63.6%) in Arm B, and 12 (36.4%) in Arm D. Median OS was 2.7 months (95% CI: 1.97–5.36) in Arm A and 3.3 months (95% CI: 1.97–5.03) in Arm B. Median OS was not reached in Arm D (Figure | PMC10652308 |
Safety | neutropenia, fatigue, toxicity, thrombocytopenia, TEAEs | ADVERSE EVENTS, THROMBOCYTOPENIA, NEUTROPENIA | Treatment‐emergent adverse events (TEAEs) occurred in >99% of the treated patients (Treatment‐emergent adverse events occurring in ≥15% of patients (Safety Population).Abbreviations: Grade 4 neutropenia in 1 (14.3%) patient.Grade 4 thrombocytopenia in 1 (3.1%) patient.Grade 4 thrombocytopenia in 3 (9.1%) patients.Grade 4 thrombocytopenia and neutropenia in 2 patients each [7.7%], respectively.In Stage 1, 84.4%, 75.8%, and 88.5% of patients treated with abemaciclib, abemaciclib plus LY3023414, and SOC, respectively, experienced at least 1 Grade ≥3 TEAE, mostly hematologic toxicity and fatigue (Table Serious AEs regardless of causality were observed in 55.1% of patients. Two patients (28.6%) in the safety lead‐in, 4 (12.5%) in Arm A, 11 (33.3%) in Arm B, and 7 (26.9%) in Arm D experienced SAEs related to treatment. Nine patients (9.2%) died due to AEs while on treatment ( | PMC10652308 |
Pharmacokinetics | The PK parameters for abemaciclib and galunisertib in the safety lead‐in arm and for abemaciclib plus LY3023414 in Arm B were consistent with the PKs observed in single agent studies (Table Similarly, steady‐state exposures for abemaciclib, its metabolites, galunisertib, and LY3023414 (Figure | PMC10652308 |
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DISCUSSION | nausea, fatigue, diarrhea, toxicity, toxicities, gastrointestinal AEs, PDAC, anemia | ADVERSE EVENTS, ADVANCED CANCER, CANCER PROGRESSION, ANEMIA |
Following a safety lead‐in of abemaciclib plus galunisertib, testing of this combination was stopped by the sponsor for reasons unrelated to safety, and it did not advance to Stage 1. In Stage 1, no abemaciclib‐containing arms demonstrated DCRs superior to SOC chemotherapy in the ITT population (15.2% and 12.1% vs. 36.4%). Thus, no treatment arms advanced to Stage 2 and the study was closed early due to futility. Our primary endpoint was the DCR in the ITT population rather than the response‐evaluable population, due to our intent not to exclude patients who discontinued study treatment early due to clinical deterioration for either toxicities or cancer progression. In this study, 12 patients withdrew consent after starting treatment, some possibly due to clinical deterioration, 14 discontinued due to disease‐related adverse events or treatment‐related toxicities, and 7 patients died while on study treatment. This reflects an advanced cancer population with grim prognosis.Median PFS was inferior with abemaciclib monotherapy (1.7 months) and abemaciclib in combination with LY3023414 (1.8 months) compared to standard chemotherapy (3.3 months). Of note, SOC performed better than anticipated (assumed median PFS of 1.5 months). OS rates were similarly lower in the abemaciclib‐containing arms compared with chemotherapy (abemaciclib: 2.7 months; abemaciclib plus LY3023414: 3.3 months; SOC: not reached). These results are comparable with those observed in a phase 1 study (To date, CDK4/6 inhibitors have been consistently ineffective for metastatic PDAC, possibly due to resistance mechanisms such as compensatory activation of the PI3K/mTOR and RAF/MAPK pathways.Hematologic side effects were common, but no significant differences were observed compared to SOC. More patients withdrew from treatment in Arm B compared to Arms A or D, possibly due to toxicity with increased rates of gastrointestinal AEs. Most common treatment‐related AEs with abemaciclib were fatigue, diarrhea, and nausea, whereas fatigue, anemia, and nausea were most common with SOC.The PK profile of abemaciclib was consistent with previous evaluations in patients with advanced cancer, | PMC10652308 |
LIMITATIONS | PDAC | DISEASE | Patients with metastatic PDAC have rapidly progressive disease, and few clinical trials, especially in the absence of a chemotherapy backbone, have demonstrated clinical benefit for patients with such advanced disease and an absence of targetable molecular alterations. | PMC10652308 |
CONCLUSION | PDAC | Abemaciclib monotherapy or in combination with the PI3K/mTOR inhibitor LY3023414 did not improve DCR, PFS, or OS compared to standard chemotherapy in pretreated metastatic PDAC.Given the aggressive nature of metastatic PDAC, molecularly guided interventions will need to account for complex signaling pathways and select biomarkers to identify patients most likely to benefit. | PMC10652308 |
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AUTHOR CONTRIBUTIONS | PMC10652308 |
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FUNDING INFORMATION | The work was supported by Eli Lilly and Company (Indianapolis, IN, USA). Eli Lilly and Company had a role in the study design, collection, analysis, and interpretation of the data, writing of the manuscript, and submission of the manuscript for publication. | PMC10652308 |
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CONFLICT OF INTEREST STATEMENT | Cancer, Novocure | CANCER | E. Gabriela Chiorean reports personal fees from AstraZeneca, Bayer, Celgene, Eisai, Ipsen, Legend, Merck, Novartis, Noxxon, Pfizer, Seattle Genetics, Sobi, and Stemline, and grants from Boehringer–Ingelheim, Bristol–Myers Squibb, Celgene, Clovis, Corcept, Fibrogen, Halozyme, Incyte, Lonza, Lilly, MacroGenics, Merck, Rafael, Roche, and Stemline. V. Picozzi reports research funding from Abbvie, FibroGen, Ipsen, Merus, NGM Biopharmaceuticals, and Novocure and a consulting or advisory role with TriSalus Life Sciences, and stock and other ownership interests with Amgen and Johnson & Johnson. C‐P. Li reports no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. M. Peeters reports no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. J. Maurel reports research funding from Carlos III Health Institute; Catalan Agency for Management of University and Research Grants; Fundació la Marató de TV3; Olga Torres Foundation, and a consulting or advisory role with Advance Medical; Amgen; AstraZeneca; Bayer; Biocartis; Cancer Expert Now; Fundación Clínica Universitaria; Incyte; Merck; NanoString Technologies; Pierre Fabre; Roche; Sanofi; SERVIER; Shire; Sirtex Medical. J. Singh reports no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. T. Golan reports honoraria from MSD, consulting or advisory roles with Abbvie, AstraZeneca, MSD, and Teva, speakers' bureau from Abbvie, AstraZeneca, and institute research funding from AstraZeneca and MSD. J‐F. Blanc reports consulting or advisory roles for Bayer, Ipsen, Eisai, Bristol–Myers Squibb, Roche and AstraZeneca, Servier, Incyte. S. C. Chapman, A. M. Hussain, and E. L. Johnston are full‐time employees of Eli Lilly and Company and are Eli Lilly and Company shareholders. H. Hochster reports personal fees from Bayer and Genentech and personal fees and nonfinancial support from Elion and TRIGR. | PMC10652308 |
ETHICS STATEMENT | The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments, the International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable local regulations. It was approved by the ethics committees of participating centers. | PMC10652308 |
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PATIENT CONSENT STATEMENT | All patients provided written informed consent prior to participation in the study. | PMC10652308 |
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Supporting information | APPENDIX |
Appendix S1
Click here for additional data file. | PMC10652308 |
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ACKNOWLEDGEMENTS | The authors are grateful to the patients, their families, and caregivers for participating in this study. The authors thank the study investigators and site staff for their participation. The authors would like to acknowledge Dr. Howard Burris for reviewing the protocol. Writing and editorial support were provided by Nicholas Pulliam, PhD, and John Hurley, employees of Eli Lilly and Company. Funding was provided by Eli Lilly and Company. | PMC10652308 |
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DATA AVAILABILITY STATEMENT | Eli Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date for data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at | PMC10652308 |
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REFERENCES | PMC10652308 |
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Background | COMPLICATIONS | Many training curricula were introduced to deal with the challenges that minimally invasive surgery (MIS) presents to the surgeon. Situational awareness (SA) is the ability to process information effectively. It depends on general cognitive abilities and can be divided into three steps: perceiving cues, linking cues to knowledge and understanding their relevance, and predicting possible outcomes. Good SA is crucial to predict and avoid complications and respond efficiently. This study aimed to introduce the concept of SA into laparoscopic training. | PMC10234874 |
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Methods | This is a prospective, randomized, controlled study conducted at the MIS Training Center of Heidelberg University Hospital. Video sessions showing the steps of the laparoscopic cholecystectomy (LC) were used for cognitive training. The intervention group trained SA with interposed questions inserted into the video clips. The identical video clips, without questions, were presented to the control group. Performance was assessed with validated scores such as the Objective Structured Assessment of Technical Skills (OSATS) during LC. | PMC10234874 |
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Results | 72 participants were enrolled of which 61 were included in the statistical analysis. The SA-group performed LC significantly better (OSATS-Score SA: 67.0 ± 11.5 versus control: 59.1 ± 14.0, | PMC10234874 |
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