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Patient-reported outcomes in patients with or without enthesitis at baseline | arthritis pain, enthesitis | REGRESSION, HAND ARTHRITIS, ENTHESITIS | Mean FACIT-F total scores for patients with enthesitis (LEI > 0 or SPARCC > 0) at baseline receiving tofacitinib and placebo are shown in Supplementary Fig. 4 (see Additional file At months 1 and 3, among patients with LEI > 0 at baseline, improvements in mean arthritis pain (VAS) scores were greater with tofacitinib 10 mg BID vs placebo across locations, except at month 1 in patients with enthesitis at the Achilles tendon insertion (Supplementary Fig. 4c [see Additional file In patients without enthesitis (LEI = 0 and SPARCC = 0) at baseline, mean FACIT-F total and arthritis pain (VAS) scores through month 3 were similar across treatments (Supplementary Fig. 4e, f [see Additional file PRO scores improved over time with tofacitinib treatment and were maintained to month 6 in patients with enthesitis (LEI > 0 or SPARCC > 0), regardless of baseline location and severity, and were maintained in patients without enthesitis (LEI = 0 and SPARCC = 0) at baseline (Supplementary Fig. 4a–f [see Additional file Multivariable linear regression analyses demonstrated that baseline enthesitis severity assessed by SPARCC was significantly associated with change from baseline in FACIT-F total score at months 3 (When each tofacitinib dose was assessed individually, baseline enthesitis severity assessed by SPARCC was significantly associated with change from baseline in FACIT-F total score with tofacitinib 10 mg BID at month 3 (Baseline enthesitis location and severity assessed by LEI and baseline enthesitis location assessed by SPARCC were not significantly associated with changes from baseline in FACIT-F total score at months 3 and 6, irrespective of tofacitinib dose.Similarly, baseline enthesitis location and severity assessed by LEI and baseline enthesitis location assessed by SPARCC were not associated with changes from baseline in arthritis pain score in the pooled tofacitinib dose group. However, baseline enthesitis severity assessed by SPARCC was significantly associated with change from baseline in arthritis pain score at month 3 (When each tofacitinib dose was assessed individually, enthesitis presence, assessed by LEI, at the lateral epicondyle humerus and Achilles tendon insertion in patients treated with tofacitinib 5 mg BID was significantly associated with change from baseline in arthritis pain score at month 3 (7.8 [1.2, 14.4], There were no significant associations between baseline enthesitis location assessed by SPARCC and change from baseline in arthritis pain score when each tofacitinib dose was assessed individually. | PMC10464128 |
Discussion | PsA, SpA, fatigue, PsA/Spondylarthritis, pain, enthesopathy, tofacitinib-treated, arthritis pain, enthesitis | ENTHESITIS, HAND ARTHRITIS, DISEASE, REMISSION, ENTHESOPATHY, REGRESSION, DISEASE, ENTHESITIS | In phase 3 studies of patients with PsA (OPAL Broaden and OPAL Beyond), greater improvements in enthesitis and more frequent enthesitis resolution were reported at month 3 with tofacitinib vs placebo [At month 3, improvements in LEI were greater with tofacitinib 10 mg BID vs placebo in patients with enthesitis at the lateral epicondyle humerus or medial femoral condyle at baseline (10 mg BID) and in patients with 3–6 affected sites (5 mg BID); while greater improvements in SPARCC were observed with tofacitinib vs placebo in patients with enthesitis in both upper and lower sites at baseline (10 mg BID at month 3) and in patients with > 2– ≤ 5 affected SPARCC sites at baseline (5 mg BID at month 1 and both doses at month 3). Improvements from baseline in enthesitis in tofacitinib-treated patients were observed as early as month 1 and maintained to month 6; greatest improvements were seen in patients with greatest severity at baseline. Regardless of baseline enthesitis location or severity, enthesitis presence generally decreased over time with tofacitinib treatment. At month 6, relapse of previously resolved enthesitis was observed in ≤ 40% of tofacitinib-treated patients with enthesitis at baseline. Disease activity remission rates and fatigue scores were generally similar across treatments. Tofacitinib treatment was associated with greater LDA rates or improvements from baseline in pain scores compared with placebo, though fluctuations were observed over time.Through month 6, presence of enthesitis, as assessed by LEI, was similar across baseline enthesitis location, indicating that no site was at a greater risk for enthesitis. Enthesitis by SPARCC was more common in patients with enthesitis in both upper and lower sites at baseline. These differences in treatment response are aligned with results from a previous analysis of the US CorEvitas (formerly Corrona) PsA/Spondylarthritis (SpA) Registry, where impact of enthesitis, assessed by SPARCC, on disease activity was highest in patients with enthesitis at both upper and lower sites, followed by lower sites only and upper sites only [Multivariable linear regression analyses demonstrated that enthesitis at the lateral epicondyle humerus and Achilles tendon insertion, as assessed by LEI, was significantly associated with change from baseline in arthritis pain scores at month 3 following treatment with tofacitinib 5 mg BID, suggesting that these sites may have a greater role on disease activity. When assessed by SPARCC, baseline enthesitis severity (specifically, > 5 vs 0 affected sites comparison) was significantly associated with change from baseline in FACIT-F total and arthritis pain scores in the pooled (months 3 and 6) and individual tofacitinib groups (tofacitinib 5 mg BID: month 6 for FACIT-F total and arthritis pain scores; tofacitinib 10 mg BID: month 3 for FACIT-F total scores, months 3 and 6 for arthritis pain scores); however, no significant association between baseline enthesitis location and change from baseline in FACIT-F total and arthritis pain scores was identified in the pooled or individual tofacitinib groups. This finding suggests that enthesitis severity, and not location, may have a greater impact on treatment response for patients; however, in the US CorEvitas PsA/SpA Registry analysis, enthesitis presence in lower or both upper and lower sites was significantly associated with greater pain and fatigue score [In this analysis, development of de novo enthesitis was low and similar for tofacitinib and placebo. Interestingly, when assessed by LEI, emerging enthesitis at the lateral epicondyle humerus was observed at all time points across treatments. It should be noted that enthesopathy at the lateral epicondyle humerus is not infrequent in the general population [The effects of other PsA treatments on individual enthesitis sites or differing enthesitis severities have been reported previously. Efficacy of ixekizumab on enthesitis resolution rates was generally consistent across locations when assessed by LEI [Limitations of this study include the post hoc nature of the analysis, low patient numbers in several enthesitis location or severity subgroups, and lack of adjustment for multiple comparisons. Additionally, comparisons with placebo were restricted to 3 months, and the effects of tofacitinib on enthesitis were only assessed up to month 6, consistent with the original study designs. The clinical enthesitis assessments used also have known limitations. While LEI was designed specifically to assess enthesitis in patients with PsA [ | PMC10464128 |
Conclusion | PsA, pain, fatigue, enthesitis | DISEASE, ENTHESITIS | This post hoc analysis demonstrated greater improvements from baseline in enthesitis and disease activity measures in patients with PsA receiving tofacitinib vs placebo across several enthesitis locations and with varying enthesitis severity at baseline. An association between enthesitis at the lateral epicondyle humerus and Achilles tendon insertion and improvement in pain, and an association between enthesitis severity (assessed by SPARCC) and improvements in fatigue and pain were identified. These findings support tofacitinib as a treatment option for patients with PsA with enthesitis and affirm the importance of addressing enthesitis in the PsA treatment paradigm. | PMC10464128 |
Acknowledgements | Ann Intern Med 2022; 175: 1298-304 | Medical writing support, under the direction of the authors, was provided by Justine Juana, BHSc, CMC Connect, a division of IPG Health Medical Communications, and funded by Pfizer Inc, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med 2022; 175: 1298-304). | PMC10464128 | |
Authors’ contributions | P. | P. J. Mease, A-M. Orbai, O. FitzGerald, M. Bedaiwi, D. L. Fleishaker, R. Mundayat, P. Young, and P. S. Helliwell contributed to the study conception and design. R. Mundayat contributed to acquisition of data. All authors were involved in the analysis and interpretation of data, drafted the article, or revised it critically for important intellectual content, and gave final approval of the version of the article to be published. | PMC10464128 | |
Funding | This study was sponsored by Pfizer. | PMC10464128 | ||
Availability of data materials | Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See | PMC10464128 | ||
Declarations | PMC10464128 | |||
Ethics approval and consent to participate | OPAL Broaden and OPAL Beyond were conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. The study protocols were reviewed and approved by the Institutional Review Boards and/or an Independent Ethics Committee at each study center, and all patients provided written, informed consent. | PMC10464128 | ||
Consent for publication | Not appliable. | PMC10464128 | ||
Competing interests | P. | P. J. Mease has received grant/research support from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead Sciences, Janssen, Novartis, Pfizer Inc, Sun, and UCB; is a consultant for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead Sciences, Janssen, Novartis, Pfizer Inc, Sun, and UCB; and has been on speakers’ bureaus for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, and UCB. A-M. Orbai has received grant/research support from AbbVie, Amgen, Celgene, Eli Lilly, Horizon, Janssen, and Novartis; and has received consulting fees from Bristol Myers Squibb, Janssen, Novartis, Pfizer Inc, Sanofi, and UCB. O. FitzGerald has received research grants from AbbVie, Bristol Myers Squibb, Eli Lilly, Novartis, and Pfizer Inc, has received consulting fees from Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, and Pfizer Inc, and has been on speakers’ bureaus for AbbVie, Janssen, and Pfizer Inc. M. Bedaiwi has been on speakers’ bureaus for AbbVie and Pfizer Inc. D. L. Fleishaker, R. Mundayat, and P. Young are employees and shareholders of Pfizer Inc. P. S. Helliwell is a consultant for Eli Lilly and has received fees for educational services from Janssen, Novartis, and Pfizer Inc. | PMC10464128 | |
References | PMC10464128 | |||
Introduction | Competitive runners are on the constant quest for maximal performance. However, after decades of significant improvements, a trend towards more marginal changes has been observed in several disciplines including endurance runningRunning performance is inherently dependent on the efficiency of locomotion, which is often referred to as running economy (RE). How efficient a human moves over the ground is not only influenced by metabolic factors, but also by the quality of movement patterns and the mechanical characteristics of the locomotor systemResistance training, plyometrics, and stretching represent three popular methods used to target REAccording to the available evidence, the Achilles tendon (AT) has been demonstrated to play a significant role in REIn a pioneering study, Kawakami et al. | PMC10011548 | ||
Methods | PMC10011548 | |||
Study design and survey procedure | injuries, word of mouth | INFLAMMATION, DISEASES, DISORDERS | A two-arm randomized controlled trial was performed. Active amateur runners were allocated to a hopping exercise (HE) or control (CON) group. Randomization was counterbalanced and conducted using BiAS for Windows version 11.10 (Goethe University Frankfurt, Germany). The study was approved by the local ethics committee (Ethikkommission FB 05, Goethe University Frankfurt; reference number: 2018-17b) and registered at the German Register of Clinical Trials (DRKS00017373, date of registry: 03/09/2019). All participants provided written informed consent.Healthy adults were recruited using word of mouth, printed flyers, and social media advertising. To ensure a specific fitness level and thus that participants are able to complete the running protocol, individuals had to be amateur runners with a 10 km time < 55 min and younger than 40 years of age. Exclusion criteria encompassed contraindications for engagement in physical activity (tested by means of the Physical Activity Readiness Questionnaire), severe cardiovascular, metabolic, endocrine, neural, and psychiatric diseases, unhealed orthopaedic injuries and overuse disorders (particularly with regard to the knee and ankle region), local inflammation, pregnancy, self-reported use of supplements containing stimulants and anabolic–androgenic steroids. | PMC10011548 |
Measures | CORTEX | Before and after the intervention period, all exercise tests were performed on an electronically driven treadmill (mercury® med, h/p/cosmos sports & medical gmbh, Traunstein, Germany) without using a safety belt. To reduce intrasubject variability, the time of the day, the test equipment, as well as the type of running shoes worn were standardized for both, baseline and post-exercise tests. Participants were instructed to avoid exercise for 24 h and strenuous exercise for 48 h prior to testing. In addition, participants were asked to eat about 1.5 to 2 h before exercise testing, not to drink alcohol the day before, and not to consume any alcohol or cigarettes on the day of the test. Temperature was controlled by air conditioning and the difference in temperature between the baseline and post measurement did not exceed ± 0.5° Celsius.In accordance with Saunders et al.A breath-by-breath gas analyser was used to monitor gas exchange during exercise testing (Metalyzer, CORTEX Biophysik GmbH, Leipzig, Germany). Calibration of the gas as well as the flow sensor was performed according to manufacturer recommendations. Meyer et al. | PMC10011548 | |
Statistical analysis | All analyses were performed using Jamovi 1.8 (The jamovi project, | PMC10011548 | ||
Ethics approval and patient consent | The study was conducted according to the ethical guidelines of the Helsinki Declaration and was approved by the local ethical review board (Ethikkommission FB 05, Goethe University Frankfurt), number: 2018-17b. All participants provided written informed consent. | PMC10011548 | ||
Discussion | Tendon stiffness | The present study yielded three key findings. Firstly, six weeks of daily hopping exercise improve running economy and increase respiratory exchange ratio at higher running speeds (12 and 14 km/h) in amateur runners. Secondly, maximal aerobic capacity remains unaltered by hopping if regular running and exercise habits are maintained. Our findings are in line with earlier studies examining plyometric interventions in amateur athletesAlthough the present trial strengthens the evidence that plyometric exercise improves running economy, the relative contributions of factors driving the observed changes are still a matter of debate. Tendon stiffness has been shown to significantly correlate with running economyOur hypothesis assumed that repeated hopping would elicit morphological and functional adaptation in the tissue, which in turn improve energy storage capacity. The daily loading paradigm was chosen based on research elucidating optimal loading paradigms for collagenous connective tissuesIn addition to adaptations in the tendon, metabolic factors may have caused the alterations of REOur findings have implications for clinical practice and may open new avenues for future research. As indicated earlier, previous training paradigms predominantly focussed on complex and more time consuming interventions which are particularly used by professional athletes | PMC10011548 | |
Author contributions | Conception and design: K.K., J.W.; Acquisition of data: K.K., R.M.; Analysis and interpretation of the data: T.E., J.W.; Drafting of the article: T.E., K.K., J.W.; Critical revision of the article for important intellectual content: R.M., D.G.; Final approval of the article: all authors. | PMC10011548 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10011548 | ||
Data availability | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10011548 | ||
Competing interests | The authors declare no competing interests. | PMC10011548 | ||
References | PMC10011548 | |||
Clinical trial registration | AIDS, infection, vaginosis, vaginal microbiome dysbiosis | VAGINOSIS, INFECTION, AIDS | Edited by: Ian Marriott, University of North Carolina at Charlotte, United StatesReviewed by: Roberta Gaziano, University of Rome Tor Vergata, Italy; Andile Mtshali, Centre for the AIDS Programme of Research in South Africa (CAPRISA), South Africa†These authors have contributed equally to this work and share first authorshipBacterial vaginosis (BV) is a common infection of the lower genital tract with a vaginal microbiome dysbiosis caused by decreasing of lactobacilli. Previous studies suggested that supplementation with live
| PMC10415204 |
Introduction | microecological disorder | BACTERIAL VAGINOSIS, VAGINA, DISEASE | Bacterial vaginosis (BV) is a microecological disorder caused by decreased abundance of lactobacilli and an increased abundance of anaerobic bacteria, commonly affecting the female lower genital tract (16S rRNA amplicon sequencing technology has been widely used to characterize the microbiome of the vagina in healthy or BV states (Metronidazole (MET) has been recommended by the Centers for Disease Control and Prevention as a treatment method for BV (The probiotic strains used in this study are | PMC10415204 |
Materials and methods | PMC10415204 | |||
Trial population | VVC, infection, abnormal leucorrhoea symptoms, trichomonas | VAGINALIS, TRICHOMONAS, INFECTION, VULVOVAGINAL CANDIDIASIS | Women who attended the gynecology outpatient clinic of Peking University Shenzhen Hospital in China between June 2020 and April 2021 and presented with abnormal leucorrhoea symptoms were enrolled in this single-center, prospective, parallel-group, randomized controlled clinical trial. Inclusion criteria were: age of 18 - 55 years, premenopause, with a history of sexual activity, and a Nugent Score ≥ 7. Exclusion criteria were: vulvovaginal candidiasis (VVC), trichomonas vaginalis (TV) infection, This study was approved by the Peking University Shenzhen Hospital Medical Ethics Committee (ID: PUshenzhenH2020-009) and published on ClinicalTrials.gov (NCT04771728). Written consent was obtained from all subjects for this study. | PMC10415204 |
Study design | ADVERSE EVENTS, REPRODUCTIVE SYSTEM DISORDER, DRUG ALLERGIES | Patients with an initial Nugent Score ≥ 7 were informed of the study protocol. Those who met the criteria signed an informed consent form before the trial. Subjects were asked to complete a questionnaire containing information on demographic characteristics, vaginal health status, history of drug allergies, and history of reproductive system disorders. A random number table generated by SPSS 13.0 software was used to randomly assign subjects to the control or probiotic group using a 1:1 ratio. After enrollment, the probiotic group received MET vaginal suppositories (200 mg daily for 7 days) along with oral intake of probiotic solid drinks containing Follow-up visits were performed on day 14, 30, and 90 after the initiation of treatment. The investigator at enrolment distributed the intervention product. At each follow-up visit, the subject’s compliance, frequency of sex, vaginal health, and the occurrence of adverse events (AEs) were assessed by questionnaire. Subjects were required to avoid topical vaginal dosing during menstruation but continue to take the intervention product orally (Study design | PMC10415204 | |
Efficacy evaluation | REPRODUCTIVE DISORDER, DRUG ALLERGIES | Before treatment, all subjects were assessed for between-group differences in demographic characteristics, including age, height, weight, marital status, history of smoking, drug allergies, history of childbirth, and history of reproductive disorders. The diagnostic criteria for BV were based on the Nugent Score ( | PMC10415204 | |
Metagenomic sequencing and biological information annotation | Fecal and vaginal samples collected from participants during the initial and follow-up consultations were subjected to DNA extraction and metagenomic shotgun sequencing. Metagenomic shotgun sequencing (100bp paired reads) was performed on the DNBSEQ™ platform ( | PMC10415204 | ||
Statistical analysis | The Shannon and Simpson index and Bray-Curtis distance were used to calculate alpha diversity and beta diversity based on the relative abundance of species. The t-test and Mann-Whitney U-test were used to test for differences between two numerical variables in two groups, with 0.05 considered as the threshold for significant differences in p-values. The Chi-square test and Fisher’s exact test were used for differences between groups for categorical variables. Ward Linkage hierarchical clustering of species-level relative abundance of vaginal microorganisms using R Stats v3.5.3 with Jensen-Shannon distances. LEfSe ( | PMC10415204 | ||
Results | PMC10415204 | |||
Clinical trial process and efficacy evaluation | After screening 546 BV patients with Nugent Score ≥7 according to the inclusion and exclusion criteria, 67 patients were included in the clinical trial and randomized. Among them, 8 subjects were excluded (4 subjects were lost to follow-up, 2 subjects were terminated due to non-medication as prescribed, and 2 subjects withdrew from this study for personal reasons). Ultimately, 31 subjects in the control group and 28 subjects in the probiotic group were included in the efficacy evaluation and microbiome analysis (Demographic and behavioral characteristics of subjects at baseline.At all time-points, there was no significant improvement in the cure rate in the probiotic group compared to the control group. The cure rates for the probiotic and control groups were 72.73% and 84.00% at day 14, respectively; 57.14%, and 60.00% at day 30, respectively; 32.14% and 48.39% at day 90, respectively. Notably, in the group of cured participants, the proportion of those fully recovered (Nugent Score < 4) was higher in the probiotic group compared to the control group (87.50% and 71.43% on day 14, 93.75% and 88.89% on day 30, and 77.78% and 66.67% on day 90, respectively) (Although orally administrated | PMC10415204 | ||
Inter-group differences in the abundance and microbial diversity of the intervention strains | VAGINA | In the fecal samples, the relative abundance of In addition, to investigate the effect of oral probiotics on the microbial community structure of the intestine and vagina, we observed the differences in alpha-diversity and beta-diversity in the intestine and vaginal microbiome before and after the intervention. No difference in microbial diversity was found between the probiotic and control groups, either in the intestine or the vaginal microbiome (all P > 0.05) ( | PMC10415204 | |
Heterogeneity of the vaginal microbiome and association with treatment outcomes | All of the vaginal samples were grouped into five clusters by hierarchical clustering method (Distribution of the baseline microbiome (BV microbiome) greatly associated with the treatment outcomes. The vaginal microbiome of 59 women sampled longitudinally at all time-points | PMC10415204 | ||
Differences in vaginal microbiome between the short-term cured subjects and the long-term cured subjects | To describe the differences in core species distribution and their interactions between the short-term cure group (A higher abundance of LEfSe analysis showed differences in vaginal microbiome at baseline between the short-term and long-term cure groups ( | PMC10415204 | ||
Discussion | VAGINA | In this study, there was no significant difference in BV cure rates between the probiotic and control groups at day 14, day 30, and day 90, suggesting a 30-day oral administration of The inability of the orally administered probiotic strains to reach or colonize the vagina may be the reason of the treatment failure in BV. Similarly, Husain et al. showed that the colonization rate of the intervention strains and the diversity of the vaginal microbiome did not differ between the probiotic and control groups (In this study, there was no difference in the relative abundance of We found that The abundance of key bacteria in the vagina influences whether BV can be cured in the long term (This study has some limitations. In terms of the clinical trial design, the participants completed their trials when diagnosed with BV, and there was no continuous follow-up for these patients. We were unable to provide a comprehensive description of the microbiome dynamics of BV treatment failure. Regarding bioinformatics analysis techniques, the relative abundance at the species level was insufficient to accurately calculate the number of intervention probiotic strains in the samples. In addition, the relatively small sample size is also one of the limitations of this study. Finally, future microbiome studies on probiotic interventions to assist in treating BV need to be supported by larger sample sizes and strain-level annotation techniques with higher resolution. | PMC10415204 | |
Conclusions | Although orally administrated | PMC10415204 | ||
Data availability statement | The data presented in the study are deposited in the Genome Sequence Archive ( | PMC10415204 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Medical Ethnic Committee of Peking University Shenzhen Hospital. The patients/participants provided their written informed consent to participate in this study. | PMC10415204 | ||
Author contributions | XZ, LX, and LG designed the research. SF, JL, LH, XL, YL, and YZh carried out the clinical trial. XZ, LG, FQ, JL and SZ supported the clinical trial and organized data. FQ, CF, ZH, YZo and SZ analyzed the data. FQ, XZ, CF, and ZH draft the paper. LX, SF and LG provided critical revisions of the article. LG, YZh, and HZ were responsible for the probiotic product support. XZ and XL supervised the project. All authors contributed to the article and approved the submitted version. | PMC10415204 | ||
Acknowledgments | We thank the principal investigators, researchers, and all the participants. | PMC10415204 | ||
Conflict of interest | Authors LG, YYZ, and HZ were employed by the company BGI Precision Nutrition Shenzhen Technology Company Limited.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10415204 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10415204 | ||
Supplementary material | The Supplementary Material for this article can be found online at: Shannon and Simpson index between the probiotics group and the control group in all time-points Click here for additional data file. | PMC10415204 | ||
References | PMC10415204 | |||
Abstract | PMC10417168 | |||
Background | breast cancer | BREAST CANCER | Despite the rising incidence and mortality of breast cancer among women in China, there are currently few predictive models for breast cancer in the Chinese population and with low accuracy. This study aimed to identify major genetic and life‐style risk factors in a Chinese population for potential application in risk assessment models. | PMC10417168 |
Methods | breast cancer | REGRESSION, BREAST CANCER | A case–control study in southeast China was conducted including 1321 breast cancer patients and 2045 controls during 2013–2016, in which the data were randomly divided into a training set and a test set on a 7:3 scale. The association between genetic and life‐style factors and breast cancer was examined using logistic regression models. Using AUC curves, we also compared the performance of the logistic model to machine learning models, namely LASSO regression model and support vector machine (SVM), and the scores calculated from CKB, Gail and Tyrer–Cuzick models in the test set. | PMC10417168 |
Results | REGRESSION | Among all factors considered, the best model was achieved when polygenetic risk score, lifestyle, and reproductive factors were considered jointly in the logistic regression model (AUC = 0.73; 95% CI: 0.70–0.77). The models created in this study performed better than those using scores calculated from the CKB, Gail, and Tyrer–Cuzick models. However, the logistic model and machine learning models did not significantly differ from one another. | PMC10417168 | |
Conclusion | breast cancer | REGRESSION, BREAST CANCER | In summary, we have found genetic and lifestyle risk predictors for breast cancer with moderate discrimination, which might provide reference for breast cancer screening in southeast China. Further population‐based studies are needed to validate the model for future applications in personalized breast cancer screening programs.Among all factors considered, the best model was achieved when polygenetic risk score, lifestyle, and reproductive factors were considered jointly in the logistic regression model (AUC = 0.73; 95% CI: 0.70–0.77). The performance of the models established in this study is better than that using scores calculated from CKB, Gail and Tyrer–Cuzick models. However, there is no significant difference between the machine learning models and logistic model.
Shuqing Zou, Yuxiang Lin and Xingxing Yu these authors contributed equally to this work and share first authorship. | PMC10417168 |
INTRODUCTION | breast cancer, cancer, Breast cancer, deaths, Machine learning | CANCER, BREAST CANCER, BREAST CANCER | Breast cancer is the most common type of cancer in women globally and the leading cause of cancer‐related deaths in women.Many different factors contribute to breast cancer, including lifestyle risk factors and genetic factors.Machine learning techniques have been extensively employed to create risk assessment models in order to obtain more efficient and accurate decision‐making for the identification of breast cancer, including least absolute shrinkage and selection operator (LASSO), support vector machines (SVMs), artificial neural networks (ANNs), and Bayesian networks (BNs).In order to provide a reference for risk assessment, we evaluated breast cancer risk using several statistical models. In addition, the discriminatory performances of the models established in this study were compared with the scores calculated from CKB model, Gail model and Tyrer–Cuzick models. | PMC10417168 |
MATERIALS AND METHODS | PMC10417168 | |||
Study population | cancer, tumor, primary breast cancer, breast cancer | CANCER, TUMOR, BREAST CANCER | Women diagnosed with primary breast cancer at Fujian Medical University Union Hospital in southeast China between the ages of 18 and 90 years during the period from January 2013 to March 2016 were asked to participate in this study. The cancer diagnosis was provided and confirmed by two pathologists in Fujian Medical University Union Hospital, together with the information on estrogen receptor (ER) status and tumor stage. The healthy controls were selected from women who participated in opportunistic or organized health examinations in the same hospital during the corresponding period without history of cancer. We only collected information for those woman within age 18–90 years. From 2013 to 2016, a total of 1350 cases and 2053 controls were collected, after excluding participants with missing data, 1321 breast cancer patients and 2045 healthy controls were analyzed using a complete‐case approach. All the participants in this study were permanent residents in Fujian Province, southeast China. They answered a structured questionnaire during a face‐to‐face interview to gather comprehensive data on sociodemographic characteristics and possible breast cancer risk factors. The participants also donated blood for genotyping. | PMC10417168 |
Risk factor selection and polygenic risk score | breast cancer | BREAST CANCER | According to earlier researches on breast cancer risk factors in Chinese women's,All participants' blood samples were genotyped using an SNPscan Kit (Genesky Biotechnologies) that was created specifically for this study. The kit was developed using double ligation and multiplex fluorescence PCR. From our earlier research | PMC10417168 |
Statistical analyses | cancer, hospital‐based, breast cancer | REGRESSION, CANCER, BREAST CANCER | In this hospital‐based case–control study, participants were split into a training set and a test set at random in a 7:3 ratio, with 2356 participants in the training set and 1010 participants in the test set. The ideal model was created using the training set, and its performance was assessed using the test set. The distinctions between cases and controls in terms of general demographic and characteristic were assessed using the t‐test for continuous variables or In order to enhance the model's performance, we also created machine learning models, namely the LASSO regression model and support vector machine (SVM), using gglassoFor the evaluation of the developed models, we used the test dataset. We estimated the breast cancer risk score using the CKB model, Gail model, and Tyrer–Cuzick model to compare their discrimination with the models developed in our study. The 5‐year CKB risk score was calculated based on the breast cancer risk prediction model developed using data from the China Kadoorie Biobank covering ten areas across China. This model takes into account factors like age, height, BMI, education, place of residence, age at menarche, parity, and family history of cancer.All the analyses were performed in R studio version 4.1.0. Statistical significance was determined using the threshold | PMC10417168 |
RESULTS | PMC10417168 | |||
General demographic characteristics in the training set and test set | breast cancer | BREAST CANCER | Table Characteristics of breast cancer cases and health controls in training set and test set. | PMC10417168 |
Results from the training set | breast cancer, ovarian cancer, abortion | REGRESSION, OVARIAN CANCER, BREAST CANCER | For the training set, 12 variables were included in the backward logistic regression model, which ended up with 9 variables (Table Logistic regression analyses on associations between established risk factors and breast cancer.Similar to the results from the feature selection procedure in the backward logistic regression, LASSO regression model also selected age, age at menarche, age at first live birth, number of birth, number of abortion, family history and prior breast surgery as the main predictors for breast cancer. However, BMI and breast feeding period ≥12 months were associated with breast cancer in the LASSO model, but not involved in the backward logistic regression model. For SVM, all the 12 risk factors for breast cancer were included in the training procedure. Among the 12 variables, the top three important variables were abortion, family history of breast cancer and ovarian cancer and prior breast surgery (Table | PMC10417168 |
Comparing different models in the test set | PRS, abortion, ER+ breast cancer, breast cancer | OVARIAN CANCER, BREAST CANCER, SENSITIVITY, REGRESSION, ER+ BREAST CANCER | We examined the performance of various models we had created in the test set, as well as risk scores calculated from established breast cancer risk prediction tools (Table The comparison of all the models in the test set.Model 1: logistics regression model that includes only traditional risk factors; model 2: logistics regression model that includes both traditional risk factors and PRS; model 3: lasso regression model; model 4: SVM model; model 5: CKB model; model 6: Gail model; model 7: Tyrer–Cuzick model.P (1) represents comparison with model 1, P (2) represents comparison with model 2, P (3) represents comparison with model3, P (4) represents comparison with model 4, P (5) represents comparison with model 5, P (6) represents comparison with model.Receiver‐operating characteristic (ROC) curves for different risk assessment models of breast cancer. (A): ROC curves of logistic model that include only traditional risk factors compared with the models based on CKB score, Gail score and Tyrer–Cuzick score. (B): ROC curves of logistic model that include only traditional risk factors compared with logistics regression model that include both traditional risk factors and PRS. (C): ROC curves of logistic model that include only traditional risk factors compared with LASSO regression model and SVM m.The 8 variables included in the model for ER+ breast cancer were age, age at menarche, age at first live birth, number of live birth, number of abortion, use of exogenous hormones, family history of breast cancer and ovarian cancer, and prior breast surgery, with an AUC of 0.73 (95% CI: 0.69–0.77, Sensitivity 41.7% and Specificity 92.8%). Only four factors, BMI, number of abortion, use of exogenous hormones and family history of breast cancer and ovarian cancer, were included in ER‐ breast cancer model, which had an AUC of 0.64 (95% CI: 0.57–0.72, Sensitivity 34.5% and Specificity 94.0%). However, there was no statistically statistical difference between the overall model and the risk prediction model stratified by ER status (Table | PMC10417168 |
DISCUSSION | ovarian cancer, hospital‐based, breast cancer, cancer, abortions, abortion, non‐genetic | OVARIAN CANCER, CANCER, BREAST CANCER | In the current study, we created a moderate performing risk prediction model for breast cancer in southeast China. We confirmed that age, age at menarche, age at first live birth, number of births, abortions, family history of breast cancer and ovarian cancer and prior breast surgery are strong risk predictors for breast cancer. In addition, the performance of the model established in this study was better than models based on CKB score, Gail score and Tyrer–Cuzick score. However, the logistic model have no statistically significant difference between the LASSO model and SVM model. Our study also suggested that adding PRS can increase the predictive ability of the model.Our study confirmed the association between several reproductive factors and breast cancer, including age at menarche, age at first live birth and number of births.Abortion is a substantial and persistent risk factor for breast cancer in Chinese women, as further evidenced by the current study. An earlier meta‐analysis in China found that when the rate of abortion rose, so did the risk of breast cancer.With the best AUC values of 0.735 and 0.762, the Gail score and the Tyrer–Cuzick score are the two most popularly used breast cancer risk scores in American and European countries.In China, several breast cancer risk assessment models have been developed based on data from other regions, with AUC varying from 0.573 to 0.658.Few models of breast cancer risk incorporate both non‐genetic and genetic components.SVM previously demonstrated the best performance when compared to other machine learning techniques for predicting breast cancer risk,Several studies have shown that developing risk models based on ER status of breast cancer may improve prediction and enable targeted screening and prevention in the future.This study has several advantages. Both genetic and non‐genetic factors were included in the model, which to some extend improved the power of the model. In addition, this study also applied machine learning methods, including LASSO and SVM, to compare different models. Other than the advantages mentioned above, this study has several limitations. First of all, this study is a hospital‐based case–control study with potential selection bias from the participants. We have a small proportion of patients with old age at diagnosis and late stage cancer. Therefore, our prediction model could not be generalized to these women. The reporting on the reproductive and familial risk factors could have been different between patients and controls due to recall bias. Further independent validation studies based on prospective cohorts are needed to test its accuracy and robustness. Thirdly, image‐based risk predictors for breast cancer such as mammographic density and micro‐calcification were not collected in current study, which might have reduced the performance of the model. BRAC mutations were not genotyped in our dataset, and therefore considered as missing in the calculation of Tyrer–Cuzick score, which might have reduced the performance of the model. However, as these variants are too rare in Chinese women, even in the cases, | PMC10417168 |
CONCLUSIONS | breast cancer, ovarian cancer, abortion | OVARIAN CANCER, BREAST CANCER | In summary, we confirmed that abortion, age, age at menarche, age at first live birth, number of births, family history of breast cancer and ovarian cancer and prior breast surgery are strong risk predictors for breast cancer. Our research also indicated that adding PRS might improve the model's capacity for risk prediction. These results can provide reference for personalized breast cancer screening in southeast China. | PMC10417168 |
ETHICAL APPROVAL | This study was approved by the ethics committee of Fujian Medical University Union Hospital (No. 2014021). | PMC10417168 | ||
CONSENT TO PARTICIPATE | Informed consent was obtained from all participants. | PMC10417168 | ||
AUTHOR CONTRIBUTIONS | PMC10417168 | |||
FUNDING INFORMATION | Haomin Yang is supported by the Natural Science Foundation of China [grant no: 82204132], Natural Science Foundation of Fujian Province [grant no: 2021 J01721], the Startup Fund for High‐level Talents of Fujian Medical University [grant no: XRCZX2020007], and Startup Fund for Scientific Research, Fujian Medical University [grant no: 2019QH1002]. The sponsor of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10417168 | ||
Supporting information |
Tables S1–S4
Click here for additional data file. | PMC10417168 | ||
DATA AVAILABILITY STATEMENT | Upon reasonable request and with the associated author's consent, data are accessible from the authors. | PMC10417168 | ||
REFERENCES | PMC10417168 | |||
Background | ataxia telangiectasia-mutated, oesophageal cancer | SOLID TUMOUR, OESOPHAGEAL CANCER | Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. | PMC10844302 |
Methods | Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). | PMC10844302 | ||
Results | toxicities, DLTs, rash | No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m | PMC10844302 | |
Conclusions | oesophageal cancer | ADVANCED CANCER, OESOPHAGEAL CANCER | Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. | PMC10844302 |
Clinical trials identifier | EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547. | PMC10844302 | ||
Subject terms | PMC10844302 | |||
Background | tumour, oesophageal cancer | COLLAPSE, TUMOUR, OESOPHAGEAL CANCER | Radiotherapy (RT) is a standard of care treatment for a number of tumour types, including oesophageal cancer [In the context of oesophageal cancer treatment chemo-radiotherapy may be employed with both palliative and curative intent and commonly cisplatin and a fluoropyrimidine (either 5FU or capecitabine) are the chemotherapy agents of choice to be given concurrently [Cisplatin is a DNA-damaging platinum-based chemotherapy agent that promotes the formation of intra-strand DNA crosslinks thereby inducing replication fork collapse. Preclinical studies have shown that ATR is activated following cisplatin treatment and that ATR inhibition can profoundly sensitise tumour cells, including oesophageal cancer cells to platinum-based chemotherapy and radiotherapy [The combined in vitro and preclinical model studies suggest that the combination of radiation with an ATR-inhibitor will be an efficacious combination in human studies [ | PMC10844302 |
Methods | PMC10844302 | |||
Patients | tumour, arrhythmia, trachea-oesophageal fistula | UNCONTROLLED HYPERTENSION, ARRHYTHMIA, BRAIN METASTASES, EVENT, THIRD-DEGREE HEART BLOCK, TUMOUR | For both stages, A1 and A2, eligible patients were ≥16 years of age, with ECOG performance score 0–1 and life expectancy of at least 12 weeks with adequate bone marrow, liver and kidney function, with previous chemotherapy completed at least 28 days before first study dose. Additionally, for Stage A1, eligible patients required histologically confirmed ACA or SCC of the oesophagus, suitable for palliative RT, tumour length 15 cm or less, no oesophageal stent in situ. For Stage A2, eligible patients required histologically confirmed solid metastatic or unresectable tumour where cisplatin-capecitabine treatment was deemed appropriate.Key exclusion criteria included patients with multiple or untreated brain metastases, significant cardiovascular event within 6 months before study entry, symptomatic arrhythmia or requiring treatment, uncontrolled hypertension, second or third-degree heart block or prolonged QTc interval on ECG (>450 ms in males, >470 ms in females), presence of trachea-oesophageal fistula or invasion of the tracheo-bronchial tree, and use of strong CYP3A inhibitors and inducers or haemopoetic growth factors within 14 days before start of treatment. For Stage A2, patients with dihydropyrimidine dehydrogenase were excluded. | PMC10844302 |
Study assessment and end-points | toxicity, tumour, cardiac abnormalities, Cancer | ADVERSE EVENT, SOLID TUMOUR, OESOPHAGEAL CANCER, SECONDARY, TUMOUR, CANCER | The primary objective of Stage A1 was to determine the RP2D of berzosertib that can be administered concomitantly with palliative radiotherapy in oesophageal cancer. The primary objective of Stage A2 was to determine the RP2D of berzosertib that can be administered concomitantly with cisplatin and capecitabine chemotherapy in solid tumours. Secondary objectives for both A1 and A2 included (1) safety and toxicity profile of the combination, (2) feasibility of delivering the combination and (3) efficacy of the combination.The corresponding primary end-point was the highest treatment schedule resulting in a ≤25% dose limiting toxicity (DLT) rate for A1 and ≤30% DLT rate for A2; corresponding secondary end-points were (1) Grade ≥3 toxicity rate and time for toxicity resolution, (2) proportion of patients completing at least 75%, 90% and 100% of the planned dose of Radiotherapy (A1) and chemotherapy (A2) and (3) objective tumour response by RECIST 1.1, PFS and OS (and in-field RT control rate in A1).Treatment-related side-effects were reported as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.03. The DLT assessment window was confined to weeks 1–9 for A1 and weeks 1–4 for A2. DLT was generally defined as grade ≥3 haematological or organ toxicity or cardiac abnormalities. Detailed DLT criteria are provided in the | PMC10844302 |
Results | RECRUITMENT | Thirty-six patients (A1 = 16; A2 = 20) were recruited between December 2018 and March 2022. The A1 component stopped short of its original recruitment target of 20 patients due to conclusion of planned recruitment period. At that point, the A1 cohort was one patient away from hitting an early stopping rule for the success of recruiting 10 on a schedule (Schedule 6). Although 20 patients were recruited to A2, two patients withdrew before any trial treatment was delivered. | PMC10844302 | |
Patient demographics and disposition | melanoma, tumour, oesophageal cancer | MELANOMA, DISEASE CHARACTERISTIC, TUMOUR, OESOPHAGEAL CANCER | The median ages (Inter Quartiles) of patients recruited to A1 and A2 were 65 (59.0–75.3) and 64.5 (53.5–68.0), respectively. In the A1 cohort, 14/16 (87.5%) of participants were male and all had a diagnosis of oesophageal cancer (6 SCC and 10 ADA). In A2, 9/20 (45%) of participants were male and the most common tumour subgroup was melanoma. Further details of baseline patient and disease characteristics of the 36 enroled patients are presented in Table In A1, all 16 patients were evaluable for primary safety analysis and 12/16 were assessable for 12-week overall RECIST efficacy analysis. In A2, 18/20 patients were evaluable for primary safety analysis and 8/20 were assessable for 12-week overall RECIST efficacy analysis.The patient flow for A1 and A2 are described in CONSORT diagrams in the | PMC10844302 |
Dose escalation, DLTs and MTD | Toxicities, DLTs, neutropenia, toxicity, toxicities, vomiting, dehydration, pyrexia, sepsis | DEHYDRATION, SEPSIS, ADVERSE EVENTS, NEUTROPENIA | In the A1 cohort, 16 patients were enroled and completed final (week 12) visit. No DLTs were reported in cohort A1. The TiTE-CRM recommended dose escalation for each dose level until the maximum level. Berzosertib 240 mg/m2 twice weekly (schedule 6) was identified as the RP2D in this combination.In the A2 cohort, 18 patients started treatment, with two patients experiencing DLT; grade 3 neutropenia and grade 3 pyrexia in the first patient and sepsis, vomiting and dehydration (all grade 3) in the second patient. Both patients who experienced DLT received berzosertib at 140 mg/m² once a week (schedule 3). Although no dose-limiting toxicities (DLTs) were recorded according to the study protocol with 140 mg/m² twice a week (schedule 4), some patients experienced toxicities that nearly met the definition of DLTs, such as toxicity that resulted in the missed administration of two consecutive doses of berzosertib across cycles. DLTs observed in both cohort A1 and A2 are presented in Table Dose Limiting Toxicities observed in cohort A1 and A2.Number of participants included in the primary safety analysis and 12-week overall RECIST efficacy reporting for both stages are included in the a: Five most common system organ classes to experience adverse events by grade in A1. b: Five most common system organ classes to experience adverse events by grade in A2.Berzosertib 140 mg/m | PMC10844302 |
Toxicity, safety, treatment compliance | deaths, neutropenia, Neutropenia, chest pain, vomiting, pyrexia, sepsis | DISEASE PROGRESSION, NEUTROPENIA, ADVERSE EVENTS, NEUTROPENIA, SEPSIS | RT metrics: planning target volumes mean 466 cc (range: 257–912), mean lung dose 7.36 Gy (range 3–8.9 Gy), spinal cord max dose to 0.1 cc mean 27.65 Gy (range 34.5–18 Gy). (See In Cohort A2, 10 out of the 18 (56%) patients who started treatment stopped their capecitabine treatment before the end. The main reasons for early stoppages were Disease Progression and Neutropenia, accounting for 70% (seven out of 10) of all stoppages. 70% (seven out of 10) stoppages occurred in the first two cycles of treatment. Nine out of the 18 (50%) patients who started treatment stopped their Cisplatin treatment before the end. The main reason for early stoppages was Disease Progression 67% (six out of nine) of all stoppages.In cohort A2, there were five SAEs in the cohort, occurring in three patients: pyrexia, neutropenia, sepsis, vomiting and chest pain. There were no treatment-related deaths.A summary of all the five most common MedDRA System Organ Classes affected by adverse events for both stages is presented in Table | PMC10844302 |
Efficacy | tumour | DISEASE PROGRESSION, DISEASE, TUMOUR, BEST | In cohort A1, efficacy data was evaluable for 11 patients, with two showing partial response, six showing stable disease and three showing disease progression at 12 weeks quantified by RECIST 1.1 (Fig. Best overall response for cohorts A1 and A2 by patient treatment schedule. All response categories were determined according to RECIST 1.1 criteria.Progression-free survival times for all patients, including censoring and tumour type annotations.Figure Patient case: 3 axial CT slices at radiotherapy planning, 3 months of treatment w/ berzosertib, 10-month follow-up.In cohort A2, efficacy data was evaluable for eight patients, with three showing radiographic partial response, four displaying stable disease, and one displaying disease progression quantified by RECIST 1.1 at 12 weeks (Fig. | PMC10844302 |
Discussion | oesophageal cancer, toxicity, toxicities, tumours, rash, tumour, myelosuppression, ATM, oesophageal stricturing, Oesophageal cancer | ESOPHAGEAL CANCER, SOLID TUMOUR, OESOPHAGEAL CANCER, TUMOURS, DNA DAMAGE, ADVERSE EVENT, TUMOUR | The conventional chemoradiotherapy for oesophageal cancer can result in considerable treatment-related side effects, however, a complete clinical response is achieved only in a minority of patients (30%) [Recently, radiotherapy in combination with radiosensiters such as PARP inhibitors and immunotherapy have been investigated in oesophageal cancer, indicating a shift towards investigating novel drug-radiotherapy combinations [In this study, we evaluated two dose escalation cohorts, cohort A1, the combination of berzosertib with palliative radiotherapy in advanced oesophageal cancer and cohort A2, the combination of berzosertib with cisplatin and capecitabine in patients with any solid tumour as a preamble to testing in the definitive setting for chemoradiation in oesophageal cancer.Berzosertib has previously been shown to be safe and well tolerated alone and in combination with a variety of DNA-damaging cytotoxic drugs [Overall, the combination of berzosertib with radiotherapy was considered well tolerated as there were no exacerbations of lung, cardiac or oesophageal toxicities seen due to local thoracic treatment despite some subjects incurring large volumes of thorax being irradiated. A maculopapular rash was the only serious adverse event that was considered possibly related to berzosertib. This was transient and resolved following administration of topical medications.The majority of patients in A1 (81%) had received at least one line of prior systemic treatment, including checkpoint immunotherapy in two cases due to prior participation in a separate clinical trial. Median overall survival observed for first-line therapy in the treatment of advanced oesophageal cancer varies between 9 and 14 months [Cohort A2 evaluated the combination of cisplatin, capecitabine and berzosertib with a view to informing dosing for a future chemo-radiotherapy combination study with berzosertib in oesophageal cancer. Expected mechanism-based myelosuppression was the predominant toxicity and two patients experienced dose limiting toxicities. The recommended phase II dosing schedule was determined to be cisplatin 60 mg/mIdentifying biomarkers for selection of patients to target tumours harbouring ATM truncating mutations or ATM protein loss, TP53 mutations, BRCA1 or BRCA2 mutations, or other alterations conferring homologous recombination repair deficiency is key for treatment success. Oesophageal cancer is a top candidate as it has been shown that accumulated DNA Damage repair (positive staining for γH2AX and phospho-ATM) was evident within tumour tissue and significantly increased in non-malignant tissue surrounding the tumour cells although activation of p53 by phosphorylation at serine 15 was observed only in tumour tissue ([This study has several limitations. Firstly, the small number recruited and the absence of pharmacodynamic data makes it challenging to precisely understand the radiation dose-response relationship of berzosertib. As often in phase I studies the absence of comparative arms involving chemotherapy, ATR inhibition, or radiation therapy hinders our ability to make direct comparisons among these treatment modalities. Lastly, late toxicities due to chemoradiation such as oesophageal stricturing were not assessed beyond the 12-week follow-up.To address these limitations and refine the understanding of the optimal combination of systemic therapy, ATR inhibition, and radiation therapy in curative radiotherapy setting, further dose-finding investigations are warranted.In summary, this study is the first clinical trial to evaluate the combination of an ATR inhibitor with radiotherapy. Berzosertib is well tolerated when scheduled with radiotherapy and encouraging clinical activity was observed. We consider that further clinical study is warranted, including combination with chemo-radiotherapy. | PMC10844302 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41416-023-02542-1. | PMC10844302 | ||
Acknowledgements | Cancer | CANCER | The authors would like to thank patients, investigators, co-investigators and the study teams at each of the participating centres and at Merck KGaA, Darmstadt, Germany. The UK sites all received funding from Cancer Research UK. | PMC10844302 |
Author contributions | MH | SL, FK, DM, SM: acquisition of the data. SRJ, SL, SEB, AO, MH: analysis and interpretation of the data. MH, SL, SM, TM, RH, DM, GR, PS, AO: study supervision. MH, TM, JH: conception and design. RH, AO: administrative, technical or material support. All authors read and approved the final paper. | PMC10844302 | |
Funding | Cancer | ONCOLOGY, CANCER | The CHARIOT trial was sponsored by the University of Oxford. Trial management was provided by the Oncology Clinical Trials Office (OCTO) at the University of Oxford as part of the UKCRC Oxford Clinical Trials Research Unit (OCTRU). This work was funded by Cancer Research UK (C43735/A20874). Additional financial support was provided by Merck KGaA, who also supplied berzosertib free of charge. | PMC10844302 |
Data availability | The data collected for the study, including individual participant data and a data dictionary defining each field in the set, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be de-identified participant data and will be available for 5 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement. | PMC10844302 | ||
Competing interests | RS, Stock, Cancer | ONCOLOGY, EVENTS, BREAST CANCER, CANCER | SL – Honoraria: Eisai, Prosigna, Roche, Pfizer, Novartis, Sanofi. Advisory: Shionogi, Sanofi, GLG consulting, Rejuversen, Oxford Biodynamics. Research grant funding: CRUK, NIHR, Against Breast Cancer, Pathios Therapeutics. Travel/Accommodation/Expenses: Pfizer, Roche, Synthon, Piqur Therapeutics. Stock holding: Mitox Therapeutics. Previous employment: Pfizer. My institution has received funding for clinical trials for which I am chief investigator or principal investigator from Cancer Research UK, Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Carrick Therapeutics, Sanofi, Merck KGaA, Synthon, Roche, Exscientia, BioInvent, RS Oncology. TM – Consulting agreements: AstraZeneca, Ground Truth Laboratories, Perspectum, Teysuno. Employment: National Cancer Research Institute. PS – Honoraria: AZ. Support to attend conferences/educational events: BMS/Takeda. Advisory roles: BMS/Takeda. MAH – Receives funding from University College London Hospitals Biomedical Research Centre. All other authors—no completing interests to declare. | PMC10844302 |
Consent to publish | Consent for publication was obtained for use of de-identified trial data. | PMC10844302 | ||
Ethics | The study was conducted in accordance with the ethical principles of the International Council for Harmonization guideline for Good Clinical Practice, the Declaration of Helsinki and applicable local regulations. All patients provided written informed consent before any study procedures were performed. The study sites received ethical approval from the South Central Oxford A Ethics Committee(16/SC/0395). | PMC10844302 | ||
References | PMC10844302 | |||
Aims | T2DM, Diabetes | DIABETIC PERIPHERAL NEUROPATHY, TYPE 2 DIABETES MELLITUS, DIABETES | Edited by: Habib Yaribeygi, Semnan University of Medical Sciences, IranReviewed by: Huabing Zhang, Peking Union Medical College Hospital (CAMS), China; Rizaldy Taslim Pinzon, Duta Wacana Christian University, Indonesia†These authors have contributed equally to this work‡ORCID: Lingling Xu, This article was submitted to Clinical Diabetes, a section of the journal Frontiers in EndocrinologyTo assess the association of rectus femoris mass index (RFMI) with diabetic peripheral neuropathy (DPN) in individuals with type 2 diabetes mellitus (T2DM). | PMC10160655 |
Methods | T2DM | Totally 948 T2DM cases were enrolled. Nerve conduction parameters, quantitative sensory threshold and rectus femoris cross-sectional area (RFCSA) were obtained, and rectus femoris mass index (RFMI=RFCSA/height | PMC10160655 | |
Results | T2DM | Motor/sensory nerve amplitude and conduction velocity (CV) were significantly lower in the low-level RFMI groups (all P<0.05). RFMI was positively associated with mean motor/sensory nerve amplitude and CV (both P<0.05). T2DM duration above 10 years and RFMI below 2.37cm²/m² had significant associations with DPN (both P<0.001). Receiver operating characteristic (ROC) curve analysis demonstrated cutoffs for T2DM duration and RFMI of 7 years and 2.2 cm²/m², respectively (AUC=0.75, 95% CI: 0.72-0.79; sensitivity, 68.4%; specificity, 66.8%). | PMC10160655 | |
Conclusion | muscle mass, T2DM, reduced RFMI | DPN is significantly associated with reduced RFMI in T2DM patients. Decreased muscle mass seems to be associated with motor/sensory nerve amplitude and CV. RFMI combined with T2DM duration may represent a potent tool for predicting DPN occurrence in T2DM cases. | PMC10160655 | |
Clinical trial registration | PMC10160655 |
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