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Discussion | teeth movements, orthodontic | PLAQUE | Objective wear time of both groups demonstrated sub-optimal compliance with instructed wear time. The utilization of audiovisual instructions has shown a statistically significant positive effect on improving adherence with the recommended wear time in comparison to delivering verbal instructions only after 6 months. Nonetheless, periodontal outcomes did not differ between both groups. Participants’ experiences were similar in both groups, except for satisfaction with the way of delivering instructions, being favorably perceived by patients receiving the additional audiovisual instructions and weekly reminders.The assigned audiovisual instructional videos were chosen to promote the need to wear the retainer and were supplemented with weekly reminder messages on the WeChat application. A significant positive effect of the used protocol on compliance with retainer wear after six months was observed. This goes in line with results from previous literature, which did show an improvement in information retentionThe delivered audiovisual videos additionally focused on oral health promotion. Results have generally shown a non-significant difference between the groups after 6 months. Both groups had a significant improvement in oral health readings over time, except for the plaque scores in the control group. This is consistent with previous literature which has shown that significant deterioration in oral health occurred at the end of orthodontic treatment, which gradually improved after debondingParticipants’ experiences were more or less similar in both groups, except for satisfaction with the way of delivering instructions, being favorably perceived in the audiovisual group as recorded via the questionnaire. The administered questionnaire was developed depending on the perspectives of the National Health Service, which depend on questions that reflect patient satisfaction with the Hawley retainer, and the impact of clinical methods of communication and their results. Questionnaires were given to each participant after 6 months of observation to reflect their perspectives after a period under retention. Results demonstrate the benefit of the multimodal approach in delivering clear information in comparison to the usual methodsThe choice of the retainer type and retention protocol is still debatable in literature. In some practices, Hawley retainers are still preferred for their known advantages in occlusal settling, and their capacity to have incorporated modifications for simple teeth movements during retention. However, they are often associated with temporary speech changes and less desirable aesthetics due to the metal labial bow. In this trial, we aimed to reflect what aligns with traditionally known clinical practicesEffective communication and compliance are integral parts of successful treatment. Understanding effective ways of delivering information helps in the establishment of an effective rapport with clinicians. The information provision process must ensure that the patient receives, understands, and retains the information over long periods. The use of multimodal approaches by mixing the auditory and visual senses helps to retain information for a longer durationDigitized methods of communication and monitoring have recently accelerated the transformation toward the use of digital information and communication technologies | PMC10219970 |
Limitations | Microsensors have shown substantial accuracy in | PMC10219970 |
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Author contributions | K.W. contributed to conception, design, data acquisition and interpretation, analysis, drafted and critically revised the manuscript; H.M. contributed to conception, design, drafted and critically revised the manuscript; A.E.S. contributed to data analysis and interpretation, drafted and critically revised the manuscript; J.Z. W.X. Q.Y. contributed to data acquisition and interpretation, data analysis. All authors gave final approval and agree to be accountable for all aspects of the work. | PMC10219970 |
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Funding | This study was funded by the Health commission of Henan province, with number: SBGJ202002074. | PMC10219970 |
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Data availability | Datasets are available with the corresponding author upon reasonable request. | PMC10219970 |
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Competing interests | The authors declare no competing interests. | PMC10219970 |
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References | PMC10219970 |
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Background | ARDS | ARDS, ACUTE RESPIRATORY DISTRESS SYNDROME | The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN β) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN β, and therefore, we aimed at finding the reason behind this. | PMC10018638 |
Methods | We first sequenced the genes encoding the IFN α/β receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier: | PMC10018638 |
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Results | ARDS, coronavirus diseases | MINOR, DISEASE, ARDS | We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/β receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN β treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN β and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database. | PMC10018638 |
Conclusions | ARDS | ARDS | The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids. | PMC10018638 |
Graphical abstract | PMC10018638 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-023-04388-8. | PMC10018638 |
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Keywords | PMC10018638 |
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Methods | PMC10018638 |
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Clinical study populations | sepsis, pneumonia, ARDS | SEPSIS, ARDS, PNEUMONIA | The clinical study population has been extensively characterized and reported [The association of rs9984273 with survival is reported using the entire study population with genetic data available. For the IFN γ analyses, only patients with ARDS due to pneumonia or sepsis or pulmonary origin and using glucocorticoids were included as they best resemble COVID-19 ARDS patients. There were 75 of those patients with an available genetic consent and samples available. Daily serum samples were drawn for cytokine measurements. Pro-inflammatory cytokine levels were analyzed using Bio-Plex Cytokine Assay by Bio-Rad Laboratories (Hercules, USA). A repeated measurements ANCOVA (RMANCOVA) for change from the baseline in log scale (adjusted for baseline log-transformed value) was used to compare daily IFN γ and IL-6 levels between the patients according to the SNP rs9984273 status. | PMC10018638 |
Lung specimens | cancer | CANCER, LUNG | Lung specimen from 14 different individuals was obtained by postsurgical resection of anonymous lung tissue (typically for cancer resections). The lung sections from lung regions having normal macro- and microscopic appearance were used. Several small pieces were cut from all samples and 5–6 pieces/well/condition were cultured for 4 days in 24 well plates containing 1 ml of RPMI medium (supplemented with 10% fetal calf serum, 4 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin), IFN β (1000 UI/ml FP1201; Faron Pharmaceuticals), or placebo with and without hydrocortisone (40 µg/ml, Solucortef, Pfizer). After culturing, all pieces in each well were collected and frozen in OCT. All 14 samples were used for staining IFNAR1/IFNAR2 and 5 CT and 5 TT samples for STAT1, pSTAT1, STAT2, pSTAT2, and CD73 stainings.DNA was extracted from 3 to 5 frozen lung tissue sections (20 µm) with NucleoSpin DNA Rapid Lyse Kit (Macherey–Nagel). TaqMan SNP genotyping assays C_2443264_10 and C_11354003_30 (Thermo Fisher Scientific) for rs9984273 and rs2236757, respectively, were used in genotyping. The reactions were performed as in TaqMan SNP genotyping manuals (ThermoFisher). The plate was run on a QuantStudio 3 Real-Time PCR machine (ThermoFisher) with a run protocol for SNP genotyping as per manual. The results were analyzed using the Applied Biosytems® analysis modules for genotyping in Thermo Fisher Cloud computing platform (ThermoFisher Scientific). | PMC10018638 |
Immunohistochemistry | 9167S | SECONDARY | Five-µm-thick frozen sections were cut from lung pieces and fixed with acetone for 5 min. Thereafter, the endogenic peroxidase was blocked using Bloxall Blocking solution (Vector laboratories) for 15 min at room temperature RT. The first-stage antibodies were against alpha and beta chains (IFNAR1 and IFNAR2) of the IFN α/β receptor (St John's Laboratory STJ112765 and LS-Bio LS-B13369, respectively). The anti-alpha chain antibody was used 1:2000 and 1:5000, anti-beta chain 1:1000, anti-STAT1 (1:400, 9175S), anti-pSTAT1 (1:100, 9167S), anti-STAT2 (1:200, 72604S), and anti-pSTAT2 (1:50, 88410S) all from Cell Signaling. Rabbit Ig (1 µg/ml) was used as a negative control. The secondary step was performed with Vectastain Elite ABC rabbit IgG kit (Vector laboratories) and diaminobenzidine was used as a chromogen.Two different concentrations of the antibody against the alpha chain of the IFN α/β receptor were used to better recognize the differences between the samples. The staining intensity was blindly scored from 0 to 3 and the mean intensity obtained by these two concentrations was used as the score for the alpha chain; mean of this and that obtained for the beta chain intensity (0 to 3) is shown for IFNAR. The intensity of the STAT stainings was semi-quantitatively scored from 0 to 3 both at the whole cell level and separately in nuclei of positive cell types. CD73 was detected with a monoclonal anti-CD73 antibody (4G4) 10 µg/ml followed by Alexa Fluor488 conjugated goat anti-mouse IgG (Invitrogen). A negative class matched monoclonal antibody was used as a control. Number of positive vessels were counted and the staining intensity was scored from 0 to 4. On average of 20 fields/sample at 200× magnification were evaluated. All samples were treated in the similar way and analyzed blindly without knowledge of the patient identity. | PMC10018638 |
MX1 response | PBMCs were isolated from 9 mL of EDTA blood by Ficoll gradient centrifugation. The cells were plated 0.5 × 10 | PMC10018638 |
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Genetic analyses | The AmpliSeq® custom panel was used to sequence | PMC10018638 |
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Binding site analysis | We investigated putative binding sites of GR within the SNP rs9984273 region utilizing the Transfac database (version 2020.3) [ | PMC10018638 |
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COVID-19 host genetics initiative database analyses | DISEASE | The COVID-19 Host Genetics Initiative (COVID19-hg) GWAS meta-analyses rounds 4 and 6 summary results were used to identify the association of the SNP rs9984273 with disease severity [ | PMC10018638 |
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Statistics | REGRESSION | Several statistical methods such as repeated measures ANCOVA, multivariate Cox model, logistic regression analysis, Cochran's Q heterogeneity test, Chi-square test, two-way ANOVA with Šídák's multiple comparisons test, and two-tailed Mann–Whitney U-test were used. Their use is indicated in the text and/or figure legends. A | PMC10018638 |
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Results | PMC10018638 |
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Discovery of rs9984273 in clinical trials investigating intravenous IFN β-1a for the treatment of ARDS | death, ARDS | MINOR, DISEASE, ARDS | We have performed two significant clinical trials investigating the use of intravenous IFN β-1a for the treatment of ARDS [Further, pre-defined targeted resequencing and genetic analyses of entire gene regions were performed for genes encoding CD73 (The effect of the rs9984273 genotype on mortality and cytokine levels in the INTEREST trial investigating intravenous IFN β-1a for ARDS treatment. A genetic sample was available from 202/296 (104/144 in the IFN β-1a treatment arm and 98/152 in the placebo arm) of the study subjects. Number of the subjects at risk is indicated on the x- axis. The polymorphism affected differently the outcome of men and women in the INTEREST trial. Majority of the patients (70%) in the trial were male. 42.4% of men and 51.4% of women had CC/CT. Mortality of women was 11.8% for TT and 8.3% for CC/CT patients; mortality of men was 28.9% for TT patients and 12.5% for CC/CT patients. Thus, TT increases risks of death only in men, OR 2.85, Contribution of the SNP rs9984273 polymorphism was further investigated by a retrospective analysis, in which we performed focused genetic analyses of IFNAR2 on the earlier Phase I/II study population. Phase I/II and III study populations were comparable according to demographics and disease severity; however, we identified one major difference. In the Phase I/II study 40% of the study subjects receiving IFN β received overlapping glucocorticoids, but 73% of these patients had the rs9984273 the minor C allele. In contrast, in the phase III study 54% of the patients received glucocorticoids, but only 46% of the subjects receiving overlapping glucocorticoids with IFN β-1a carried the minor C allele. Hence, the rs9984273 C allele was highly enriched in the Phase I/II study population compared to the Phase III study, and more patients received glucocorticoids in the Phase III than in the Phase I/II study, thus suggesting a possible explanation for the difference between mortality in the studies. | PMC10018638 |
Rs9984273 associates with IFN γ and IL-6 production in patients receiving glucocorticoid treatment | ARDS | ARDS | The SNP rs9984273 locates in the 3’ untranslated region (3’-UTR) of the IFNAR2 gene (chr21:33,262,760 (GRCh38)). To investigate potential binding sites of GR in the region, we utilized position weight matrices compiled from individual genomic sites from the Transfac database (Transfac matrix table, Release 2020.3) or derived from the Encode ChIP-seq data for GR [Following our in silico evaluations, we next wanted to determine, whether rs9984273 was associated with the immune status of the patients when glucocorticoids were administered. The Phase III ARDS trial (INTEREST) was optimal to analyze this effect as it had cytokine profiling of the patients for the first 14 days. IFN γ and IL-6 were chosen as indicators of immune activation as they are also associated with poor outcome in ARDS and COVID-19 [ | PMC10018638 |
Rs9984273 contributes to the expression of IFNAR together with rs2236757 | ARDS | DISEASE, ARDS | After the discovery of rs9984273, and recognizing its role in the outcome of the previous clinical ARDS studies, we then investigated, whether this polymorphism contributes to the expression of the IFNAR (composed of IFNAR1 and IFNAR2 subunits) by immunohistochemistry using antibodies against IFNAR subunits of the receptor in surgical lung specimens from 14 patients. In this material, five samples had the major allele TT, 8 samples CT, and 1 CC for rs9984273. The primary antibody was titrated to the level, at which the alveolar epithelium and vasculature still remained strongly positive in a subset of the samples. The scoring was done without any knowledge of the genotype. The results clearly show that all high expressors of IFNAR were CT and overall the CT/CC group had statistically significantly higher IFNAR level than the TT group. However, four out of nine samples from the CC/CT group show medium level of expression, indicating that other factors are involved in regulating IFNAR expression. Therefore, we decided to analyze another SNP, rs2236757 in IFNAR2 that has been found to contribute to disease severity of COVID-19 [Rs9984273 is associated with the expression of IFNAR and regulation of We also analyzed the number of CD73 positive vessels and expression level of CD73 in lung specimens incubated for 4 days with IFN β. There were no differences in the number of CD73 positive vessels/mm | PMC10018638 |
CT and TT patients display different features in IFN β-induced STAT1 and STAT2 signaling and responsiveness to glucocorticoids | MINOR | As the immune status and IFNAR expression are at least partially under the control of rs9984273 and the formation of the signal transducer and activator of transcription 1/2 and interferon regulatory factor 9 (STAT1/STAT2/IRF9) complex and its translocation into the nucleus is required to trigger type I IFN responsive genes, we next examined STAT1, phosphorylated STAT1 (pSTAT1), STAT2 and pSTAT2 expression in the lung specimens cultured in the presence of IFN β with or without hydrocortisone (HC) [Patients homozygous for the major allele of rs9984273 (TT) have higher STAT2 expression in the lungs than the heterozygous patients with the minor allele (CT) and glucocorticoids do not inhibit its nuclear expression in TT patients. | PMC10018638 |
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Rs9984273 is associated with COVID-19 hospitalization | ARDS | DISEASE PROGRESSION, DISEASE, ARDS, MINOR | Adhering to our recent clinical and laboratory findings, and the outbreak of the SARS-CoV2, we also explored the role of rs9984273 in COVID-19 through publicly available databases. After all, without a doubt both endogenous and exogenous type I IFNs and steroids play a fundamental role in disease progression and survival concerning COVID-19. Recent genome-wide analyses of COVID-19 patients have revealed that SNP rs2236757 in IFNAR2 has a significant impact on disease severity [Associations of rs9984273 C allele* to disease severity of COVID-19 in meta-analyses*The patients with CC/CT vs TT were compared**Total number of cases and controls. Subjects involved in the calculation were 679 (distribution of cases and controls used in the calculation was not given in the original data)We also tested, whether carrying the minor alleles of rs9984273 C and rs2236757 A, correlated with mortality in our ARDS cohort. We found that patients possessing the minor alleles for both genotypes have significantly decreased mortality than those homozygous with the major allele for both genotypes. The lower mortality among the minor allele carriers ( | PMC10018638 |
Discussion | ARDS, ill | LUNG, MINOR, VIRAL INFECTION, CRITICAL ILLNESS, ARDS | Both type I IFN and cortisol responses are needed in viral induced critical illness, but at different times, IFNs first and steroids later. In most people, both endogenous and exogenous steroids block the organ protective effects of IFN β on the endothelium, if there is no preceding type I IFN response. We have discovered a genetic polymorphism rs9984273 that prevents GR affecting IFNAR expression, but allows glucocorticoids to shut down STAT1-STAT2 type I IFN signaling. A schematic picture (Fig. A schematic presentation regarding the mechanisms of action of glucocorticoids. In normal conditions, IFN β binding to its receptor triggers the formation of the ISG3 complex consisting of Stat1, Stat2, and IRF9. This complex then trans-locates from the cytoplasm to the nucleus where it binds to the interferon-stimulated response element (ISRE) in hundreds of interferon-stimulated genes (ISG) leading to the production of interferon-stimulated proteins. Glucocorticoids have at least two different forms of action in this setting. (1) Glucocorticoids prevent the formation of the ISG3 complex and thus prevent activation of the IFN-beta responsive genes. (2) Glucocorticoids bind to its receptor (GR) and this complex moves from the cytoplasm to the nucleus and binds to the glucocorticoid binding site of the IFNAR2 gene, if the individual has TT at SNP rs9984273. This seems to lead to repression seen as low expression of IFNAR2. In contrast, if the individual has CC or CT this binding does not efficiently take place resulting in higher expression of IFNAR2 than in TT individuals. The size and intensity of the glucocorticoid/GR complex and the IFNAR2 gene illustrate the relative magnitude of the phenomenon in CT vs TT patientsWe found TT patients to have a trend for lower total STAT1 expression and statistically significantly less pSTAT1 than the CT patients. In contrast, TT patients had significantly more STAT2 than the CT patients, while no statistically significant differences in pSTAT2 were observed suggesting that interferon signaling differ between these genotypes. However, detailed picture regarding the dynamics is impossible to draw based on the level of STAT1/STAT2 expression, because in addition to STAT1/STAT2/IRF9 complex JAK can phosphorylate and initiate complexes of STAT1 homodimers [We detected faster decrease in IFN γ and IL-6 levels in patients with the minor allele (CT or CC) compared to those homozygous with the major allele (TT) in rs9984273 when glucocorticoids were administered. Lung specimens of TT patients had also significantly more STAT2 than the CT patients and glucocorticoids did not decrease its nuclear expression like in CT patients. It has been shown that unphosphorylated STAT2 upregulates IL-6 via co-operation of the NF-κB pathway and can do it perfectly well without STAT1 [SNP rs9984273 is a relatively common polymorphism according to available data. Approximately 45% of people with African origin, 34% of Caucasians and 10% of Asians carry the polymorphism (C allele instead of T) Our findings regarding the IFNAR2 expression are also in line with the public data. The Genotype-Tissue Expression (GTEx) portal V8 release for significant variant-gene pairs showed that rs9984273 acts as an expression quantitative trait locus (eQTL) for IFNAR2 expression in lung tissue (One may argue that patients receiving glucocorticoid treatment were more severely ill than those without glucocorticoids and that explains our findings. To exclude that possibility, we earlier performed propensity matching for a matched dataset (The role of IFNAR in COVID-19 outcome is obvious as contribution of a third SNP in IFNAR to COVID-19 severity is reported by Ma et al. [Is there a problem, if IFNAR expression is too high? In this context, the recent findings of Malle et al. [One limitation in our study is that we do not have data regarding which patients have viral induced ARDS vs bacterial, or both, or fungal in the INTEREST trial, and therefore, the results of INTEREST do not perfectly represent the situation in COVID-19. Exact microbial origin should be registered in future ARDS trials as interferon responses, specifically type 1 responses are somewhat differentially required between bacterial and viral infections. Moreover, the exact molecular mechanisms of the GR binding site in IFNAR2 and its possible additional effects to other reported SNPs in IFNAR2 require future investigations.We envision that the genetic polymorphism SNP rs9984273 reported in this paper has evolved and become enriched during previous viral outbreaks and pandemics in humans. Furthermore, we conclude that this polymorphism may, at least in part, explain the continuous controversy in studies investigating the use of glucocorticoids for ARDS, especially those of viral origin where type I IFN activity is needed. In summary, we have discovered a novel polymorphism in IFNAR2 containing a GR binding motif that is associated with the IFNAR2 expression level, IFN β response, and outcome of ARDS/COVID-19. Our study strongly indicates that simultaneous administration of IFN β and glucocorticoids should be avoided especially for those patients with TT allele in SNP rs9984273. | PMC10018638 |
Acknowledgements | The authors want to thank the INTEREST-trial study group for the data analyzed further in this manuscript. We also thank Sari Mäki and Teija Kanasuo for their expert technical help and Dr. Joe Hettinger and Miro Viitala for help and advice. | PMC10018638 |
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Author contributions | MH, JJ | JJ and SJ were involved in conceptualization, SK, TH, MH, KE, NW, LE, and SJ helped in methodology, JJ, SK, and SJ contributed to investigation, MH was involved in visualization, SJ and LE helped in funding acquisition, JJ and SK contributed to writing of the original draft and all authors contributed to writing, review and editing. All authors read and approved the final manuscript. | PMC10018638 |
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Funding | The EU FP7 program, Traumakine, the Finnish Academy, the Jane and Aatos Erkko Foundation, and the Sigrid Juselius Foundation. | PMC10018638 |
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Availability of data and materials | All data are available in the main text or the supplementary materials. Patient samples are not available. | PMC10018638 |
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Declarations | PMC10018638 |
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Ethics approval and consent to participate | Genetic analyses are part of the multi-center INTEREST trial (ClinicalTrials.gov Identifier: NCT02622724 | PMC10018638 |
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Consent for publications | Not applicable. | PMC10018638 |
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Competing interests | MH, JJ | JJ is an employee and TH consultant of Faron Pharmaceuticals, JJ, MH, and SJ own stocks of Faron Pharmaceuticals. | PMC10018638 |
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References | PMC10018638 |
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Purpose | AML | ACUTE MYELOID LEUKEMIA, AML | Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. | PMC9996548 |
Methods | AML | Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m | PMC9996548 |
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Results | thrombocytopenia, TEAEs, Treatment-emergent adverse, febrile neutropenia | THROMBOCYTOPENIA, FEBRILE NEUTROPENIA | Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia’s formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3–4. The most common grade 3–4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. | PMC9996548 |
Conclusion | Fractionated GO dosing regimen (3 mg/m | PMC9996548 |
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Trial registry | Clinicaltrials.gov ID: NCT03727750 (November 1, 2018). | PMC9996548 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00280-023-04516-9. | PMC9996548 |
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Keywords | PMC9996548 |
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Introduction | death, neutropenia, AML, thrombocytopenia, anemia, aggressive malignancy, CD33-positive AML, undifferentiated myeloblasts | NEUTROPENIA, THROMBOCYTOPENIA, ACUTE MYELOID LEUKEMIA, DNA DAMAGE, AML, ANEMIA | Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid clonal expansion of undifferentiated myeloblasts, leading to anemia, neutropenia, and thrombocytopenia [Gemtuzumab ozogamicin (GO) is a CD33-directed antibody–drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. GO binds to CD33, an antigen expressed on most AML blast cells. Once bound, the GO–CD33 complex is internalized, and the cytotoxic component is released intracellularly, leading to DNA damage and cell death [GO is indicated in the United States for the treatment of newly diagnosed CD33-positive AML in adult and pediatric (≥ 1 month) patients, and for relapsed/refractory (R/R) CD33-positive AML in adult and pediatric (≥ 2 years) patients [The clinical efficacy of GO was originally established with 3 open-label, single-arm phase II studies of patients with AML in first relapse who received GO monotherapy consisting of 2 × 9 mg/mConsequently, GO is approved in a fractionated dose of 3 mg/m | PMC9996548 |
Materials and methods | PMC9996548 |
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Study design and patients | CD33-positive AML | This was a single-arm, open-label, phase IV study (ClinicalTrials.gov ID: NCT03727750) of GO monotherapy in adult (≥ 18 years) and pediatric (≥ 12–17 years) patients with R/R CD33-positive AML. This paper focuses on adults only. Key eligibility criteria included: initial peripheral white blood cell counts < 30 × 10 | PMC9996548 |
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Study treatment | Patients received a fractionated dosing regimen of GO 3 mg/m | PMC9996548 |
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Study assessments | ADVERSE EVENTS, REMISSION | The primary endpoint was the mean change from baseline in QTc. Secondary endpoints included assessment of PK parameters, adverse events (AEs), incidence of antidrug antibodies (ADAs)/neutralizing antibodies (NAbs), overall survival (OS), and response rate (CR/CRi) (see Supplementary methods in the Online Resource). Triplicate electrocardiograms were performed at screening, baseline, and before serial PK draws on each day of dosing, using a 12-lead (with a 10-s rhythm strip) tracing. Response of remission status (CR/CRi) was evaluated after each treatment cycle, per European LeukemiaNet (ELN) 2017 recommendations [ | PMC9996548 |
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Results | PMC9996548 |
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Patient characteristics | Fifty-one adult patients (median [range] age of 67 [22–82] years) were enrolled in the study. Among enrolled patients, 27 (52.9%) had received 1 prior induction regimen; 11 (21.6%), 8 (15.7%), and 4 (7.8%) had received 2, 3, or > 3 prior induction regimens, respectively (see Supplementary Table 1 in the Online Resource). Five (9.8%) patients had received ≥ 1 allogeneic HSCT prior to GO treatment. There were 19 (37.3%) patients classified as adverse-risk according to the ELN 2017 recommendations [ | PMC9996548 |
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QT interval | The upper limit of the 2-sided 90% confidence interval (CI) for least squares (LS) mean differences in QTc using Fridericia’s formula (QTcF) was < 10 ms for all time points during Cycle 1, including those on D4 and D7 assessed in the primary analysis (Fig. QTcF change from baseline during C1. Baseline is defined as the last average of the planned triplicate 12-lead electrocardiogram measurements available prior to the first dose of GO. LS means estimated from a linear model with visit/time post-dose as fixed effect and unstructured variance/covariance matrix for the repeated measurements with CI using approximate t-distribution with degree of freedom by the Kenward–Roger method. The time points assessed in the primary analysis of QTcF were D4 (at 0 h) and D7 (at 0, 2, 4, and 6 h). | PMC9996548 |
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Pharmacokinetics | Following administration of multiple fractionated infusions of GO at 3 mg/m | PMC9996548 |
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Immunogenicity | pyrexia, anaphylaxis, urticaria | ANAPHYLAXIS, SEQUELAE, HYPERSENSITIVITY, URTICARIA | Of 50 patients treated with GO, 12 (24.0%) had positive ADAs against GO at baseline. This was likely due to pre-existing host antibodies that were cross-reactive with GO. There was no treatment-boosted ADA response.Treatment-induced ADA was detected in 6 (12.0%) patients. No patients experienced anaphylaxis, hypersensitivity, or other clinical sequelae related to ADA. Among the 6 patients positive for treatment-induced ADA, 2 (33.3%) experienced an infusion-related reaction, both pyrexia (grade 1 and grade 3). Among the 44 patients negative for treatment-induced ADA, 7 (15.9%) patients experienced infusion-related reactions. All were grade 1 or 2, except for 1 instance of grade 3 urticaria.Of the 18 patients who had positive ADAs against GO, none were positive for NAbs at baseline; therefore, no patients had a treatment-boosted response. Treatment-induced NAbs were detected in 1 (2.0%) patient. | PMC9996548 |
Efficacy | ELN, deaths | DISEASE PROGRESSION | The best overall response was CR in 2 (3.9% [95% CI 0.5–13.5]) patients and CRi in 3 (5.9% [95% CI 1.2–16.2]) patients (see Supplementary Table 3 in the Online Resource), with an overall rate of 9.8% (95% CI 3.3–21.4). CR + CRi was achieved by 3 (6.0%) of the 50 patients in Cycle 1. Nine of the 50 patients receiving Cycle 1 proceeded to Cycle 2, of whom 3 (33.3%) patients achieved CR + CRi in Cycle 2. Among the 5 patients who achieved CR or CRi (see Supplementary Table 3 in the Online Resource), there were 2 and 3 patients stratified with ELN favorable or intermediate risk, respectively. One patient who achieved CR/CRi had previously received 2 HSCTs, 1 had previously been treated with 3 induction regimens, and the remaining patients had received 1 or 2 prior induction regimens.The median OS was 2.8 (95% CI 1.7–4.2) months, with 45 deaths reported (88.2%; see Supplementary Fig. 1 in the Online Resource). Of the 45 deaths, disease progression was the most common cause in 35 (77.8%) patients. | PMC9996548 |
Discussion | AML, anaphylaxis | ANAPHYLAXIS, SEQUELAE, HYPERSENSITIVITY, AML | This study showed that fractionated dosing of GO (3 mg/mAs part of a review of the PK for the prior marketing application of GO, a population PK model was used to simulate exposure for the fractionated GO regimen, based on 8 previous trials in patients with R/R AML or de novo AML [This current study enables comparison of the data from the simulated PK model with clinical PK data. The geometric mean AUC and Safety data were consistent with the known safety profile of the fractionated regimen of GO [In this study, the incidence of ADAs and NAbs was 12% and 2%, respectively. None of the patients experienced anaphylaxis, hypersensitivity, or other clinical sequelae related to ADAs, suggesting that the presence of ADAs to GO did not appear to be associated with any potential safety issues following GO treatment.A best overall response based on CR + CRi was achieved in 9.8% of patients, with a median OS of 2.8 months; both inferior than previously reported in the MyloFrance-1 study [In conclusion, this study showed that the effect of fractionated dosing of GO (3 mg/m | PMC9996548 |
Acknowledgements | This study was sponsored by Pfizer. The authors thank the patients and their families/caregivers, investigators, research nurses, study coordinators, and operations staff who contributed to this study. Medical writing support was provided by Simon Stones, PhD, of Engage Scientific Solutions, and was funded by Pfizer. | PMC9996548 |
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Data availability | Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See | PMC9996548 |
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Declarations | PMC9996548 |
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Conflict of interest | Pierre | Pau Montesinos has served as a consultant for Agios, Astellas, Celgene, Daiichi Sankyo, Forma Therapeutics, Glycomimetics, and Tolero Pharmaceutical; has been an advisor for AbbVie, Astellas, Celgene, Daiichi Sankyo, Incyte, Janssen, Karyopharm, Novartis, Pfizer, Sanofi, and Teva; has received research funding from AbbVie, Astellas, Celgene, Daiichi Sankyo, Janssen, Karyopharm, Novartis, Pfizer, and Teva; and has participated in speakers bureau for AbbVie, Astellas, Celgene, Daiichi Sankyo, Incyte, Janssen, Novartis, Pfizer, Sanofi, and Teva. Vamsi Kota has served as a consultant for Novartis and Pfizer; and has received research funding from Incyte. Joseph Brandwein has received honoraria from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Jazz, Pfizer, Roche, and Taiho. Pierre Bousset, Rebecca J. Benner, Erik Vandendries, and Ying Chen are employees of Pfizer and own stock in Pfizer. Mary Frances McMullin has been an advisor for AbbVie, Bristol Myers Squibb, Celgene, and Novartis; has received research funding from AOP Health and Bristol Myers Squibb; and has participated in speakers bureau for AOP Health and Novartis. | PMC9996548 |
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References | PMC9996548 |
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Subject terms | RCC, NRS | RCC | Many intensive care unit patients who undergo endotracheal extubation experience extubation failure and require reintubation. Because of the high mortality rate associated with reintubation, postextubation respiratory management is crucial, especially for high-risk populations. We conducted the present study to compare the effectiveness of oxygen therapy administered using high-flow nasal cannulae (HFNC) and noninvasive positive pressure ventilation (NIPPV) in preventing reintubation among patients receiving prolonged mechanical ventilation (PMV). This single-center, prospective, unblinded randomized controlled trial was at the respiratory care center (RCC). Participants were randomized to an HFNC group or an NIPPV group (20 patients in each) and received noninvasive respiratory support (NRS) administered using their assigned method. The primary outcome was reintubation within7 days after extubation. None of the patients in the NIPPV group required reintubation, whereas 5 (25%) of the patients in the HFNC group required reintubation (ClinicalTrial.gov ID: NCT04564859; IRB number: 20160901R.Trial registration: ClinicalTrial.gov ( | PMC10033681 |
Introduction | Approximately 10–15% of intensive care unit (ICU) patients who undergo endotracheal extubation experience extubation failure and require reintubationHigh-flow oxygen therapy can be administered using a nasal cannula | PMC10033681 |
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Results | COPD | CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD | A total of 40 patients were enrolled and assigned to the NIPPV and HFNC groups, with 20 patients in each group (see Supplementary Fig. Characteristics of patients at inclusion.Data are presented as frequencies (%), medians [interquartile range] or mean ± standard deviations.NIPPV: noninvasive positive pressure ventilation; HFNC: high-flow nasal cannula; APACHE: acute physiology and chronic health evaluation; ICU: intensive care unit; COPD, chronic obstructive pulmonary disease; MV: mechanical ventilation; RSBI: rapid shallow breathing index; RR: respiratory rate; MAP: mean arterial pressure; PaOReintubation and related outcomes.Data are presented as frequencies (%) or means ± standard deviations. *NIPPV: noninvasive positive pressure ventilation; HFNC: high-flow nasal cannula; NIV: noninvasive ventilation, NRS: noninvasive respiratory support.One minus Kaplan–Meier curves for mortality reintubation in the NIPPV and HFNC groups during the 90-day follow-up period. NIPPV: noninvasive positive-pressure ventilation; HFNC: high-flow nasal cannula.The results of the comparison of the patients’ physiological parameters and arterial blood gas analysis results at 1 h before and 2 h after extubation are presented in Table Physiological parameters 1 hour before and 2 hours after extubation.Data were presented as mean ± standard deviation.*Indicated significant difference before and after extubation within one group.NIPPV: noninvasive positive pressure ventilation; HFNC: high-flow nasal cannula; RR: respiratory rate; MAP: mean arterial pressure; HR: heart rate; PaO | PMC10033681 |
Discussion | atelectasis, pulmonary edema, postextubation respiratory failure, RCC, NRS | ATELECTASIS, PULMONARY EDEMA, RCC | The results of this RCT indicate that patients with PMV who undergo HFNC have a higher intubation rate than do those who receive NIPPV. All the patients in this study had been receiving mechanical ventilation for more than 2 weeks (30 and 26 days on average in the NIPPV and HFNC groups, respectively). A total of 25% of the patients in the HFNC group required reintubation, whereas none of the patients in the NIPPV group were reintubated (Fig. One minus Kaplan–Meier curves for reintubation in the NIPPV and HFNC groups during the 90-h follow-up period. NIPPV: noninvasive positive-pressure ventilation; HFNC: high-flow nasal cannula.The mechanisms by which NIPPV has benefits to reduce reintubation rates include the following: (1) positive airway pressure can increase intrathoracic pressure, decreasing right ventricular preload and afterload; (2) adequate level of positive end-expiratory pressure (PEEP) increases functional residual capacity and prevents alveolar atelectasis; and (3) positive airway pressure can counterbalance hydrostatic forces leading to pulmonary edema and can help maintain airway patencyThe Acute Physiology and Chronic Health Evaluation II scores of most patients in the present study were ≥ 12 on the day of extubation. Several risk factors for reintubation have been identified, and these factors may vary by the cause of reintubationThe groups’ average length of hospital and RCC stay and time to liberation from NRS were comparable. The in-RCC mortality, in-hospital mortality rates and numbers of ventilator-free days were similar between the groups. Although the morbidity and mortality risks related to reintubation could not be determined in the present study, reintubatation with or without side effects is a preferable outcome to mortality.This study has several limitations. First, the patients and attending teams could not be blinded because of the nature of the treatments. The researchers were excluded from clinical decisions to minimize bias; however, completely eliminating bias was impossible. Second, the NIPPV provided a higher level of PEEP than did the HFNC. Because we did not measure the actual FiOLarger prospective RCTs on this topic should be conducted in the future. Although HFNC is increasingly being used often as a form of postextubation NRS, HFNC may not be as effective as NIPPV in preventing reintubation among patients who have been receiving PMV for at least 2 weeks. NIPPV may be used as rescue therapy for patients receiving PMV who experience postextubation respiratory failure after receiving HFNC alone. Additional studies evaluating HFNC as an alternative to NIPPV for patients receiving PMV are warranted. | PMC10033681 |
Methods | PMC10033681 |
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Study design | RCC, NCT04564859 | RCC | This single-center, prospective, nonblinded RCT and equivalent RCT that compared NIPPV (intervention group) and HFNC (control group) after extubation was conducted between January 2017 and December 2020 at the respiratory care center (RCC) of Shin Kong Wu Ho-Su Memorial Hospital in Taipei, Taiwan. The study was approved by the Institutional Review Board of Shin Kong Wu Ho-Su Memorial Hospital (IRB number: 20160901R), and written informed consent was obtained from all the participants or their relatives. The trial was registered at ClinicalTrials.gov (NCT04564859 25/09/2020). | PMC10033681 |
Participants | RCC | RCC, NEUROMUSCULAR DISEASES | Patients aged more than 20 years who were ready for extubation, had received mechanical ventilation for more than 6 h per day for at least 14 consecutive days, and who had been transferred from the ICU to the RCC were immediately enrolled into this study. The exclusion criteria for this study were tracheostomy, do-not-intubate status, pregnancy, neuromuscular diseases, and unplanned extubation.In Taiwan, an integrated delivery system was launched to reduce the average length of ICU stay and improve the quality of care of patients with PMV | PMC10033681 |
Intervention | NRS | The clinical weaning protocol involved a daily evaluation of weaning readiness up to the time of extubation, and the readiness was determined on the basis of the following criteria: recovery from the precipitating illness; respiratory measures of PaOAfter undergoing extubation, each patient was randomly assigned to the HFNC and NIPPV groups (in a 1:1 ratio) and received noninvasive respiratory support (NRS) administered using their assigned method. Randomization was achieved through the use of a website ( | PMC10033681 |
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NRS weaning protocol | All participants were screened for weaning readiness daily according to the following criteria: (1) pH value of ≥ 7.35; (2) oxygen saturation (SpO | PMC10033681 |
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Failure criteria | Postextubation respiratory failure | Postextubation respiratory failure was defined as follows: (1) lack of improvement in pH or in the partial pressure of carbon dioxide (PaCO | PMC10033681 |
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Outcome measurement | RCC, NRS | SECONDARY, RCC | The primary outcome was reintubation within 72 h after extubation. The secondary outcomes were reintubation within 7 days of extubation, changes in physiological parameters and arterial blood gas analysis results, time to liberation from NRS, duration of respiratory support, length of RCC and hospital stay, ventilator-free days at 28-day and 90-day mortality. Successful liberation from NRS was defined as the time point at which a patient was alive and free of NRS (HFNC or NIPPV) for more than 48 h. | PMC10033681 |
Statistical analysis | The primary outcome of this study was the reintubation rate. We assumed the reintubation rates of the HFNC and NIPPV groups to be 50% and 10%, respectively. A sample size of 20 for each group was required to achieve an alpha level of 5% (two tailed) and power of 80%. Sample size calculation was conducted using G*Power, version 3.1.9.4 (University of Kiel, Kiel, Germany). The clinical characteristics and outcomes of the patients in the NIPPV and HFNC groups were compared using Fisher’s exact test (for categorical variables) or an independent-samples | PMC10033681 |
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Ethics approval and consent to participate | We conducted the trial in accordance with good clinical practice guidelines and the Declaration of Helsinki. The study was approved by local institutional review committees (IRB number: 20160901R). Informed written consent was obtained from all participants. | PMC10033681 |
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Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-31444-8. | PMC10033681 |
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Author contributions | C.W.T., K.Y.C., H.L.W., C.C.L., and H.S.H. designed the study and prepared the clinical protocol; C.W.T., KYC, HLW, and CCL implemented the clinical trial and were involved in data acquisition; CWT and KYC analyzed and interpreted data; CWT, KYC and HSH drafted and revised the manuscript, KYC, HLW, CCL and HSH contributed to the manuscript. All authors have read and approved the manuscript. | PMC10033681 |
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Funding | This work was supported by a research grant from Shin Kong Wu Ho-Su Memorial Hospital (SKH8302106NDR05). This funding source had no role in the design of this study and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results. | PMC10033681 |
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Data availability | The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. | PMC10033681 |
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Competing interests | The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. | PMC10033681 |
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References | PMC10033681 |
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Purpose | CIN | CERVICAL CANCER, CIN | Cervical cancer screening by visual inspection with acetic acid (VIA) during colposcopy can be challenging and is highly dependent on the clinical experience of the examiner. Health-care systems lack qualified physicians able to perform the examination in both industrialized and low- and middle-income countries. Previous work has shown the general potential of hyperspectral imaging (HSI) to discriminate CIN from normal tissue, but clinical translation has been limited due to the lack of medically approved HSI systems. | PMC10520109 |
Methods | CIN | CIN | In this study, we evaluate the feasibility of a commercially available HSI system for CIN detection in a prospective monocentric clinical trial. | PMC10520109 |
Results | CIN | CIN | By obtaining spectral fingerprints of 41 patients with CIN 1–3 we show that HSI-based differentiation between CIN and normal tissue is possible with high statistical significance. Major spectral differences were seen in the 555–585 wavelength area. | PMC10520109 |
Conclusion | CIN | CIN | HSI advances tissue differentiation by associating each pixel with high-dimensional spectra and thereby obtains morphological and biochemical information of the observed tissue. Currently available and medically approved HSI systems may represent a contact- and marker-free examiner-independent method for the diagnosis of CIN. | PMC10520109 |
Supplementary Information | The online version contains supplementary material available at 10.1007/s00404-023-07171-w. | PMC10520109 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10520109 |
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What does this study add to the clinical work | PMC10520109 |
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Introduction | cancer, precancerous lesions, inflammation | PRECANCEROUS LESIONS, VASCULARIZATION, CANCER, DYSPLASTIC, DISEASE, INFLAMMATION, CERVICAL CANCER, CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN), SEVERE DYSPLASIA | Cervical intraepithelial neoplasia (CIN) refers to a spectrum of serious precancerous lesions and is classified into three grades based on the extent and severity of cellular and architectural abnormalities. Whereas CIN1 represents mild dysplastic lesions, CIN2 and CIN3 indicate moderate to severe dysplasia. Cervical cancer still is the fourth most common cancer among women worldwide (270,000 deaths/year) and is associated with severe lifelong physical and emotional burdens due to both the disease and radical therapy [The colposcopic examination and visual inspection with acetic acid (VIA) pose significant challenges and are heavily reliant on the clinical expertise of the examiner. Moreover, access to qualified colposcopy departments remains limited, even in industrialized nations. This issue is further exacerbated in low- and middle-income countries (LMICs), where patients with cervical intraepithelial neoplasia (CIN) lesions rarely have access to skilled colposcopists. Several studies in the literature have reported a wide range of false-negative rates for VIA, ranging from 13 to 69% [In recent years, there have been extensive efforts to apply hyperspectral imaging (HSI) technology in different areas of health care, including tissue differentiation, blood perfusion, wound vascularization and inflammation [The objective of this prospective, monocentric proof-of-principle study was to assess the suitability of the TIVITA | PMC10520109 |
Materials and methods | PMC10520109 |
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Study design | The present prospective, monocentric study (DRKS00013486) aimed to investigate the suitability of the TIVITA | PMC10520109 |
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HSI system | For hyperspectral imaging of the portio, the TIVITA | PMC10520109 |
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Statistics | For data analysis, HSI images were compared with the high-resolution images of the colposcopic assessment by VIA. Ten respective HSI spectra of 500–995 nm were extracted from the HSI images out of the most representative area of VIA changes and an unsuspicious control area using the TIVITA | PMC10520109 |
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Results | PMC10520109 |
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Patient characteristics | CIN1/2 lesions, CIN, anxiety | CIN | From 06/2018 to 01/2020, we assessed 110 participants for study eligibility. HSI was prospectively applied in 41 patients with histologically proven CIN 1–3 in a controlled clinical trial (DRKS00013486) at the Department of Women’s Health, Tübingen, Germany. CIN was histologically diagnosed by colposcopy-directed biopsy prior to study enrollment. The present prospective, monocentric study included 41 patients aged between 28 and 71 years with histologically confirmed CIN (Patient’s characteristicsThe key inclusion criteria for study participation were ≥ 18 years of age, histologically confirmed CIN1-3 with indication for LEETZ, and ectocervical visibility of the lesion margin. Indication for LEETZ was only given in case of either CIN3 lesions, persisting CIN1/2 lesions over 24 months, or by the patient’s compelling wish for therapy (urgent desire to conceive, severe anxiety, and/or significant psychological stress). Prior to HIS measurement, the patients provided written informed consent in accordance with the approved ethical protocol (650-2017BO1) and were informed about the experimental nature of the measurement. CIN1–3 lesions were applied to HSI at native state after disinfection, lateral fixation by sutures, and manual externalization. After contact- and marker-independent HSI measurements, the individual CIN lesions were visualized using colposcopy and VIA, and photodocumented. After performing LEETZ under colposcopic guidance and mapping of CIN localization, the lesion again was histologically confirmed in the conisate. Primary end point was the accuracy of CIN detection and differentiation compared to intraindividual benign regions of the portio according to histological assessment. Figure Schematic of the intraoperative setup and experimental workflow. The portio uteri is externalized by lateral sutures. HSI is applied contact and marker independent on native state portio. VIA visualizes the location of the lesion for photodocumentation. CIN lesions are histologically confirmed after LEETZ | PMC10520109 |
Statistical comparison of absorption per wavelength between CIN lesions and healthy tissue | CIN lesions | The comprehensive analysis of the entire wavelength spectrum, ranging from 500 to 990 nm, revealed substantial and statistically significant differences between CIN lesions and healthy tissue of the portio (Obtained HSI spectra of CIN lesions vs. control. Graphs depict the mean accumulative reflectance of CIN lesions (red) as well as healthy control areas (green) ± 1 standard deviation (SD) with wavelengths from 500 to 995 nm on the x-axis and relative reflectance in arbitrary units on the y-axisDeeper analysis of the obtained HSI spectra highlights the specific wavelength range of 555–585 nm as particularly sensitive for distinguishing between CIN lesions and healthy cervical tissue. The absorption of this wavelength region demonstrated statistically significant differences represented by calculated Wavelengths with statistically significant hyperspectral differences between lesions and benign tissue regions | PMC10520109 |
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Discussion | CIN | DYSPLASTIC, INVASIVE CERVICAL CANCER, CIN, CERVICAL CANCER, CAVITY | Colposcopy, as the current gold standard, plays a vital role in evaluating cervical abnormalities. It has significantly contributed to cervical cancer screening, diagnosis, and decision-making processes. By providing enhanced visualization of the cervix, colposcopy, combined with VIA and iodine staining, enables the identification of subtle changes and abnormalities. It facilitates targeted biopsy of suspicious areas and provides visual guidance during treatment procedures, leading to improved accuracy of diagnosis and treatment. Through early detection and evaluation of CIN, colposcopy plays a critical role in preventing the progression to invasive cervical cancer. However, it is important to acknowledge that the accuracy and interpretation of colposcopic findings can vary among practitioners. Generally, the highest accuracy is achieved by highly experienced colposcopists, which presents a challenge for ensuring universal access to quality healthcare services. While colposcopy demonstrates good sensitivity, it exhibits only moderate specificity. This often results in frequent and burdensome biopsy procedures for patients [In recent years, several groups have investigated spectroscopic technologies just like fluorescence spectra and reflectance spectra [Several research groups have explored the feasibility of employing a hyperspectral approach to differentiate between normal and dysplastic cervical tissue, by investigating the spectral signatures of cervical tissue across a range of wavelengths [Despite recent successes in tissue differentiation using HSI, the clinical application and further research in this field face limitations. Current challenges include the bulky setup and high costs of experimental HSI systems, as well as the time-consuming nature of data acquisition and processing. The availability of medically approved HSI systems that could be easily applied for evaluating the technology remains limited. These factors impede the broader adoption and exploration of HSI in medical settings. To overcome these limitations, we acquired hyperspectral cubes using the TIVITAThe primary objective of the current investigation was to assess the feasibility of utilizing the TIVITABesides the promising results of this study, it involves several limitations based on the technical issues described above and the performed data analysis. In the clinical setup it is not practical to externalize the cervix uteri by lateral sutures to enable accessibility for HSI. HSI sensors must be able to enter the vaginal cavity to achieve high-resolution HSI images. The extraction of HSI spectra by hand based on the information of colposcopy and VIA lacks reproducibility and may be a source of bias. The statistical comparisons on mean values using two-way ANOVA and Šidák’s multiple comparison test may entail overperformance of the results. In future, the clustering of hyperpixel information by machine learning algorithms could be an interesting strategy to illustrate HSI-based differences in tissue composition. Further limitations of this proof-of-principle study include the small sample size of 41 patients and the uneven distribution of included CIN lesions. Large-scale confirmatory clinical trials involving diverse patient populations, along with the integration of advanced image analysis techniques as well as machine learning algorithms and neuronal networks, will be crucial to optimize the clinical utility of HSI in the detection and management of cervical abnormalities. Further confirmatory prospective clinical studies are under development to verify the results of this study with second generation HSI devises overcoming the above described technical limitations. | PMC10520109 |
Acknowledgements | This work was supported by Erbe Elektromedizin GmbH, Tübingen (loaner of the TIVITA | PMC10520109 |
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Author contributions | All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by MW, LS, and MW. The first draft of the manuscript was written by LS and MW and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. | PMC10520109 |
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