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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 o...
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
Allocation-concealment mechanism
The allocation of remineralizing agents to groups was performed through an opaque sealed envelope to ensure complete concealment. Figure 
PMC9889428
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
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. The...
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 inst...
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 ...
PMC9889428
Results
PMC9889428
Demographic data
PMC9889428
Quantitative assessment of the remineralizing process using DIAGNOpen
PMC9889428
Effect of time
PMC9889428
Group B (biomimetic self-assembling peptides):
There was a statistically significant difference between T0, T1, and T2 groups where
PMC9889428
Effect of groups
PMC9889428
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
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
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
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
Effect of time
PMC9889428
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
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
Effect of groups
PMC9889428
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
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
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
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
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...
PMC9889428
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 become...
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
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 re...
PMC9889428
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).
PMC9889428
Declarations
PMC9889428
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
Informed consent
Informed consent with an easy Arabic language was signed by the recruited participants.
PMC9889428
Conflict of interest
The authors declare no competing interests.
PMC9889428
References
PMC9889428
Key Points
PMC10600583
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
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 br...
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 Cli...
PMC10600583
Exposures
Non-Hispanic Black and Hispanic participants were compared with non-Hispanic White participants within subgroups of subtype (hormone receptor positive [HR+]/
PMC10600583
Main Outcomes and Measures
Recurrence-free survival (RFS) and overall survival (OS).
PMC10600583
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
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
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 ...
PMC10600583
Methods
PMC10600583
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
Results
PMC10600583
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 we...
PMC10600583
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 H...
PMC10600583
Survival and Race and Ethnicity
PMC10600583
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 st...
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
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
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
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 te...
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 o...
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...
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 ...
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 dispariti...
PMC10600583
Abstract
PMC10652308
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 sta...
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, abemac...
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...
PMC10652308
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 a...
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 sm...
PMC10652308
METHODS
PMC10652308
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 sta...
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 consi...
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), unacce...
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 wer...
PMC10652308
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 abemacicli...
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 abemaci...
PMC10652308
RESULTS
PMC10652308
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 Coo...
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 discontinuat...
PMC10652308
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 r...
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...
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
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...
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...
PMC10652308
AUTHOR CONTRIBUTIONS
PMC10652308
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
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, Ra...
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
PATIENT CONSENT STATEMENT
All patients provided written informed consent prior to participation in the study.
PMC10652308
Supporting information
APPENDIX
Appendix S1 Click here for additional data file.
PMC10652308
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 N...
PMC10652308
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...
PMC10652308
REFERENCES
PMC10652308
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...
PMC10234874
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 clip...
PMC10234874
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