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Dose reduction, suspension, or discontinuation of chemotherapy due to CIPN | CIPN | The incidences of chemotherapy dose reduction, suspension, and discontinuation due to all causes were 7.7%, 23.1%, and 34.6%, and those due to CIPN were 5.8%, 1.9%, and 3.8%, respectively (Table Incidence of dose reduction, suspension, or discontinuation of chemotherapy
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Changes in CIPN severity | CIPN | CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY, ADVERSE EVENT | At baseline, 92.3% (48/52) of patients had grade 2 CIPN (Fig. Numbers of patients with change in grade of chemotherapy-induced peripheral neuropathy according to the Common Terminology Criteria for Adverse Events over 12 weeks (full analysis set). Data are presented as percentage of patients. Changes in FACT/GOG-NTX and Modified TNSr total scores for the FAS and PPS are summarized in Supplementary Table | PMC10640752 |
Changes in EQ-5D-5L index value and PGIC score | The change in EQ-5D-5L index value from baseline to week 12 was 0.0128 (95% CI, − 0.0406 to 0.0663) ( | PMC10640752 | ||
Safety | treatment-emergent adverse events, chemotherapy-induced peripheral neuropathy, adverse drug reactions | CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY, ADVERSE DRUG REACTIONS | The incidence of treatment-emergent adverse events (TEAEs) was 76.9% (40/52 patients), and the incidence of AEs related to the study drug (ADRs) was 30.8% (16/52 patients) (Table Incidences of adverse drug reactions in patients with chemotherapy-induced peripheral neuropathy in the MiroCIP interventional study (safety analysis set)
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Discussion | CIPN | CIPN includes both painful and non-painful symptoms, both of which can lead to dose reduction or discontinuation of chemotherapy [ | PMC10640752 | |
Pain and tingling | neuropathic pain, Pain, cancer, CIPN, pain, Tingling, NRS | DIABETIC PERIPHERAL NEUROPATHY, TINGLING, CANCER | In the present study, NRS score decreased by − 1.5 (27.3%) by week 4 and remained stable at the end of the treatment period (− 1.7, 30.9% reduction at week 12 LOCF). Patients with a baseline NRS of ≥ 6 experienced a − 2.9 reduction (38.7%) in NRS score. Our results are similar to the effects of duloxetine observed in a double-blind placebo-controlled crossover phase 3 study, in which the changes in NRS score were − 1.06 in the duloxetine group and − 0.34 in the placebo group after the initial 5 weeks of treatment [The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations state that analgesia can be considered clinical meaningful if it reduces pain severity by ≥ 30% (moderately important improvement) [Tingling is one of the most frequent symptoms in patients with CIPN, but in clinical practice it is often difficult to distinguish between pain and tingling from the patient’s subjective complaints. Previous studies showed that mirogabalin may relieve tingling as well as pain in diabetic peripheral neuropathy [Patients may experience CIPN concurrently with pain related to cancer and/or treatment other than chemotherapy. It is likely difficult for patients to distinguish between CIPN and other causes of pain, and this is a common concern in real-world clinical practice. However, given the pharmacological mechanism of mirogabalin, its analgesic effect in the present study was probably against neuropathic pain. Evidence for this is provided by the consistency between changes in NRS scores for pain (including tingling) and changes in NRS scores for tingling. | PMC10640752 |
Completion of chemotherapy | CIPN | CIPN is often the main reason for dose modulation or discontinuation of chemotherapy, both of which can negatively affect patient outcomes [ | PMC10640752 | |
CIPN severity | peripheral neuropathy, CIPN, pain | MOTOR NEUROPATHY, PERIPHERAL NEUROPATHY | Use of symptomatic pain relief medications during chemotherapy may contribute to worsening of CIPN severity, because suppression of subjective symptoms may interfere with appropriate decisions on when to reduce or discontinue chemotherapy. To assess this risk in the present study, the severity of peripheral neuropathy other than pain was evaluated using the Modified TNSr, which is a physician’s objective assessment tool. There was no worsening in the severity of sensory and motor neuropathy assessed by Modified TNSr during the 12 weeks of mirogabalin treatment. We believe that this study provides some objective assessment of the risk that intervention with mirogabalin interferes with the appropriate management of chemotherapy. | PMC10640752 |
Safety | dizziness, cancer, somnolence | CANCER, EDEMA PERIPHERAL | Our results indicate that mirogabalin is well tolerated in patients with cancer during chemotherapy. Most ADRs in the present study were mild or moderate, and predominantly somnolence, oedema peripheral, and dizziness. These ADRs are similar to those reported for previous studies of mirogabalin and pregabalin [ | PMC10640752 |
Limitations | CIPN, multiple cancer, pain | MULTIPLE CANCER | There are some limitations in the present study. First, the study was an open-label, single-arm study without a comparator group; a placebo group could not be used due to ethical concerns. Therefore, the results cannot be definitively attributed to mirogabalin. However, the degree of pain improvement was similar to that found for duloxetine in previous controlled clinical studies [Second, in the present study, patients were evaluated mostly by oncologists who did not routinely carry out neurological examinations such as testing of tendon reflexes. Physicians were provided with training by viewing a neurologist’s instructional video prior to the start of the study. Previous clinical trials of CIPN often used patients’ subjective evaluations; however, physicians’ objective neurological evaluations are considered essential for accurate evaluation of CIPN severity. The present study design was established via collaboration between oncologists and neurologists and included standardization of assessment procedures, and in this regard may be helpful for future clinical trials of treatments for CIPN.Third, this was a short-term study (12 weeks). Because multiple cancer types and regimens were involved, a longer study period was not possible. However, chemotherapy with oxaliplatin or taxane is often completed in about 6 months [Fourth, no data were collected on modifications of chemotherapy regimens, such as dose reduction from pre-enrollment to enrollment (baseline) or at enrollment. Chemotherapy dose reduction may have had a significant impact on pain and tingling, and on the efficacy results of mirogabalin (its analgesic effects). | PMC10640752 |
Conclusions | CIPN, neurotoxic, pain | The MiroCIP interventional study shows that mirogabalin has an acceptable safety profile and is effective for pain and tingling due to CIPN in patients with colorectal, gastric, non-small-cell lung, and breast cancers who receives oxaliplatin- and taxane-based chemotherapy. The findings of this study suggest that mirogabalin may be useful for the continuation of chemotherapy and contribute to the management of patients with CIPN undergoing neurotoxic chemotherapy, thereby improving patient QOL and potentially patient outcomes. | PMC10640752 | |
Acknowledgements | The authors wish to thank the participants of this study and all the institutions and investigators who participated (listed in Supplementary Table Consortium NameOther investigators than authors in the MiroCIP study Group as follows: Go Saito
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Authors’ contributions | TD | SM, TD, TSuzuki, YN, TK, MT, TSuichi, and SKuwabara contributed to the conception or design of this study, and to the acquisition, analysis, and interpretation of data; they also drafted this manuscript. SKodama and KS contributed to the conception or design of the study. Finally, all named authors have made substantial contributions, meet the International Committee of Medical Journal Editors criteria for authorship of this article, and take responsibility for the integrity of this work as a whole. All authors have reviewed and approved the final manuscript. | PMC10640752 | |
Funding | This study was supported by Daiichi Sankyo Co., Ltd., Tokyo, Japan, which also provided funding for medical writing support. Daiichi Sankyo Co., Ltd. was involved in the study design, planning of the data analysis, data interpretation, and development of the manuscript, but was not in data management or statistical analysis. CMIC Co., Ltd. was directly involved in data management and statistical analysis. The study results were not influenced by the commercial sponsor of this study (Daiichi Sankyo Co., Ltd.). | PMC10640752 | ||
Availability of data and materials | The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author and Daiichi Sankyo Co., Ltd., a study sponsor, on reasonable request. | PMC10640752 | ||
Declarations | PMC10640752 | |||
Ethics approval and consent to participate | CRB | The MiroCIP study was preapproved by the Chiba University Certified Clinical Research Review Board (CRB no. CRB3180015), which notified all participating centers of the approval.The study was carried out in accordance with the Clinical Research Act in Japan; the CRB conducted a central review, and after the study had been approved by the CRB, investigators at each site obtained permission from their administrator to start the research. Involvement of an ethical review committee at each facility is not required by the Clinical Research Act. The study was also conducted in accordance with the ethical principles, clinical research laws, and relevant notifications stipulated in the Declaration of Helsinki (as revised in 2013).Written informed consent was obtained from each patient after investigators had explained what participation in the MiroCIP study entailed, ensuring that they had the required understanding of the study procedures before agreeing to participation. | PMC10640752 | |
Consent for publication | Not applicable. | PMC10640752 | ||
Competing interests | TD | SM, TD, TSuzuki, YN, TK, MT, TSuichi, and SKuwabara received lecture fees from Daiichi Sankyo Co., Ltd. SKodama and KS are employees of Daiichi Sankyo Co., Ltd. | PMC10640752 | |
References | PMC10640752 | |||
Subject terms | PLASMA CELL DYSCRASIAS, MULTIPLE MYELOMA (MM), DISEASE, EVENTS, MINIMAL RESIDUAL DISEASE (MRD) | Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients). We found that MS negativity was significantly associated with improved progression-free survival (PFS) even in patients with complete response (CR) at all investigated follow-up time points. The prognostic impact was independent of established risk factors, such as the revised International Staging System. Combining MS and baseline cytogenetics improved the prediction of outcome: MS-positive patients with high-risk cytogenetics had a dismal PFS of 1.9 years (95% confidence interval [CI]: 1.6–2.3 years) from the start of maintenance. Testing the value of sequential MS prior to and after one year of maintenance, patients converting from MS positivity to negativity had an excellent PFS (median not reached) while patients converting from MS negativity to positivity progressed early (median 0.6 years, 95% CI: 0.3-not reached). Among patients with sustained MS positivity, the baseline high-risk cytogenetic status had a significant impact and defined a group with poor PFS. Combining minimal residual disease (MRD) in the bone marrow and MS allowed the identification of double negative patients with a favorable PFS (median 3.33 years, 95% CI: 3.08-not reached) and no overall survival events. Our study provides strong evidence that MS is superior to conventional response monitoring, highlighting the potential of MS to become a new standard. Our data indicate that MS should be performed sequentially and combined with baseline disease features and MRD to improve its clinical value.Clinical Trials Register: EudraCT No. 2010-019173-16 | PMC9812999 | |
Introduction | MULTIPLE MYELOMA (MM), MYELOMA | Novel therapeutics have significantly improved response rates as well as the depth of response in patients with multiple myeloma (MM) [The minimally invasive technology mass spectrometry (MS), which is amenable to automation, is emerging as a promising approach for detecting and monitoring monoclonal proteins in the peripheral blood (PB) [To provide further evidence of the clinical value of MS and to explore whether it provides independent prognostic information, we have retrospectively tracked treatment response by serum MS in patients who had been enrolled in the German-speaking Myeloma Multicenter Group (GMMG) multicenter phase III GMMG-MM5 trial (EudraCT No. 2010-019173-16). The primary endpoint of the trial investigated continuation versus omission of lenalidomide maintenance for patients achieving a CR [ | PMC9812999 | |
Patients and methods | PMC9812999 | |||
Study design and participants | newly-diagnosed MM, peripheral blood | For quantitative immunoprecipitation mass spectrometry (QIP-MS), we included peripheral blood (PB) serum samples from 480 GMMG-MM5 patients at baseline, from 444 of these patients after three cycles of either VCD or PAd induction therapy and prior to HDM/ASCT, from 305 patients prior to maintenance treatment or observation in case of CR in arm B of the trial, and from 227 patients after one year (±3 months) of maintenance treatment or observation. The design and main outcomes of the prospective, open-label, multicenter phase III trial GMMG-MM5 trial, which enrolled a total of 604 transplant-eligible patients with newly-diagnosed MM, have been previously reported [ | PMC9812999 | |
Mass spectrometry for detection of monoclonal immunoglobulins | QIP-MS was carried out using the automated EXENT | PMC9812999 | ||
Risk stratification by fluorescence in situ hybridization and the revised International Staging System | Interphase fluorescence in situ hybridization (FISH) analysis was performed as described previously [ | PMC9812999 | ||
Allele-specific oligonucleotide polymerase chain reaction for detection of minimal residual disease | SEPARATION | For MRD analyses, DNA was extracted after density gradient separation of lymphocytes from bone marrow (BM) aspirates, which was then stored at −20 °C until analysis. We used patient-specific quantitative allele-specific oligonucleotide PCR (qASO-PCR) assays on immunoglobulin heavy chain (IgH) and kappa/lambda (k/λ) light chain as recently described [ | PMC9812999 | |
Statistical design and analysis | death | REGRESSION, EVENT | The Kaplan-Meier method was used for survival analyses. PFS time was measured from the respective landmark to relapse or death from any cause, whichever occurred first. OS was defined as time from the respective landmark until death from any cause. For analyses of sustained MS from start of maintenance/observation until one year, PFS and OS were calculated from the second time point (after one year) and only patients who did not have a prior progression event were included. MS test results were evaluated in a multivariable Cox regression model including established risk factors. Main analyses were undertaken using R (v4.0.4) software. | PMC9812999 |
Results | PMC9812999 | |||
Mass spectrometry results are associated with outcome at multiple time points | tumor | TUMOR | We used the QIP-MS for longitudinal monitoring of 480 patients with PB serum samples at baseline and at least one additional time point. Combining MS for intact immunoglobulins and free light chains, a monoclonal immunoglobulin could be identified at baseline for each patient, which allowed us to longitudinally track the respective tumor clone in all patients. An example is shown in Fig. | PMC9812999 |
Prognostic value of mass spectrometry at defined time points. | DISEASE | Progression-free (PFS) and overall survival (OS) of GMMG-MM5 patients stratified by the mass spectrometry test result (negative/positive) after induction therapy (A recent study demonstrated that the extended half-life of IgG could impact disease monitoring by MS [ | PMC9812999 | |
The mass spectrometry test result constitutes an independent prognostic factor | Next, we evaluated the prognostic value of MS testing at the three defined time points in a multivariable model, which included age at diagnosis, gender, treatment arm, R-ISS stages and gain(1q21) status (Fig. | PMC9812999 | ||
Independent prognostic impact of mass spectrometry and its combination with established high-risk markers. | Results of a multivariable model for PFS from the start of maintenance therapy/observation ( | PMC9812999 | ||
Mass spectrometry improves the prognostic value of established risk markers | DISEASE | The prognostic value of the depth of response, as assessed by conventional response, MRD in the BM or functional imaging, is impacted by baseline disease features, such as high-risk cytogenetics [ | PMC9812999 | |
Mass spectrometry in patients with complete response and the impact of lenalidomide maintenance | We recently showed that omitting maintenance in CR patients resulted in significantly worse outcomes [ | PMC9812999 | ||
Sequential testing improves the prognostic value of mass spectrometry | Long-term deep responses have been associated with improved survival in MM [ | PMC9812999 | ||
Mass spectrometry complements bone marrow minimal residual disease assessment | The position of MS regarding detection of MRD in the BM is one important question. MRD data were not systematically collected within the GMMG-MM5 trial. However, for 45 patients BM MRD (sensitivity 1 × 10 | PMC9812999 | ||
Discussion | tumor, MM | RESIDUAL DISEASE, TUMOR | MS has been proposed as a minimally invasive complementary approach for monitoring of residual disease in MM patients [In both the STAMINA [From a clinical point of view, it is an important question if QIP-MS results can be used to guide treatment decisions. While we show a significant impact of single MS testing on PFS, we demonstrate that sequential MS testing, and combination of test results with baseline biological tumor features, could strongly improve the clinical value of this technique. For instance, there were GMMG-MM5 patients who converted from MS positivity to negativity during lenalidomide maintenance. Although this subgroup showed a trend towards an enrichment of IgG MM, the excellent PFS indicates that an extended half-life of the monoclonal protein did not solely underlie this observation. Of note, the patients were not exposed to an immunomodulatory agent prior to HDM/ASCT. Thus, this subgroup most probably reflects an explicitly lenalidomide-sensitive treatment group. In contrast, patients who converted from negative to positive MS had the worst outcome, highlighting MS as a method for early detection of emerging relapse in line with other studies [In line with recent studies using conventional CR or MRD-negativity to define the level of response [In conclusion, MS is a promising tool for monitoring treatment response. Recent data from the STAMINA trial [ | PMC9812999 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41408-022-00772-9. | PMC9812999 | ||
Acknowledgements | MYELOMA | This project was supported by the Dietmar-Hopp Foundation. The GMMG-MM5 trial was supported by grants from Celgene, Janssen-Cilag, Chugai and The Binding Site. The GMMG thanks the Koordinierungszentrum für Klinische Studien (KKS) Heidelberg for the support of the trial and data monitoring. The GMMG also thanks all investigators, study centers and participating patients. E.K.M. was funded by the International Myeloma Society (IMS) Career Development Award 2021. | PMC9812999 | |
Author contributions | Conception and design: E.K.M., N.W. Provision of study material or patients: E.K.M., C.S., K.C.W., M.M., I.W.B., M.H., H.J.S., M.S.R., H.G. Coordinated processing of peripheral blood and bone marrow samples: D.H., A.S. Administrative support: U.B., H.G. FISH analyses: A.J. Mass spectrometry: O.B. Data analysis and interpretation: E.K.M., S.H., K.M., A.P., A.B., N.W. Wrote the first manuscript draft: E.K.M., N.W. Manuscript editing and further writing: all authors. Final approval of manuscript: all authors. | PMC9812999 | ||
Funding | The GMMG initiated and designed the GMMG-MM5 trial and the retrospective MS study. Celgene, Janssen-Cilag, Chugai, and The Binding Site funded the trial and investigational medicinal products (bortezomib, lenalidomide). The Binding Site performed and funded the MS testing. The Dietmar Hopp Foundation in part funded infrastructure and scientists working on this project. The data presented in this manuscript were analyzed by the GMMG. Interpretation, discussion of the data, and manuscript writing/revision were done by the GMMG. Celgene, Janssen-Cilag, Chugai, and The Binding Site reviewed the manuscript. The corresponding author had unrestricted access to all trial data and had final responsibility for the decision to submit for publication. Open Access funding enabled and organized by Projekt DEAL. | PMC9812999 | ||
Data availability | Data from the GMMG-MM5 trial and QIP-MS samples is not publicly available. For requests, please contact the corresponding author. | PMC9812999 | ||
Conflict of interest | E.K.M.: Consulting or Advisory Role, Honoraria, Research Funding, and Travel Accommodations and Expenses—Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline and Takeda. Oscar Berlanga is an employee of The Binding Site Group Ltd., UK. M.H.: Consulting or Advisory Role, Honoraria: Amgen, Bayer Vital, Celgene, Gilead, Glaxo Smith Kline, Jazz Pharmaceuticals, Novartis, Roche, Takeda. H.J.S.: Honoraria: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Chugai, GSK, Janssen, Oncopeptides, Pfizer, Sanofi, Sebia, TAD, Takeda; Travel, accommodations, expenses: Amgen, BMS, Celgene, Janssen, and Sanofi. The remaining authors declare no conflict of interest. | PMC9812999 | ||
References | PMC9812999 | |||
1. Introduction | habitual behaviors, habitual behaviors like substance, addictive behaviors, adverse health behavior measure, substance abuse | REGRESSION, SECONDARY | Vocational students are a risk group for problematic substance use and addictive behaviors. The study aim was to evaluate the effects of an app-based intervention on tobacco, e-cigarettes, alcohol, and cannabis use as well as gambling and digital media-related behaviors in the vocational school setting. A total of 277 classes with 4591 students (mean age 19.2 years) were consecutively recruited and randomized into an intervention (IG) or waitlist control group (CG). Students from IG classes received access to an app, which encouraged a voluntary commitment to reduce or completely abstain from the use of a specific substance, gambling, or media-related habit for 2 weeks. Substance use, gambling, and digital media use were assessed before and after the intervention in both groups with a mean of 7.7 weeks between assessments. Multi-level logistic regression models were used to test group differences. Intention-to-treat-results indicated that students from IG classes had a significantly larger improvement on a general adverse health behavior measure compared to CG (OR = 1.24, There is a substantial increase in substance use (tobacco, e-cigarettes, cannabis, alcohol) in the trajectory from adolescence to early adulthood [Apprentices and students in vocational training therefore represent an important target group for prevention and health promotion measures. In Germany, there are two settings for the implementation of those measures, either in companies or in vocational schools. While the organizational environment is particularly suitable for structural preventive measures, it is often difficult for companies to offer behavior-oriented measures. This especially applies to small and medium-sized enterprises (SMEs), which train 80% to 90% of apprentices in Germany [The majority of empirically evaluated school-based intervention programs is developed for regular school settings with younger target groups, while there has been a lack of comparable programs for vocational schools [A popular school-based prevention approach is the voluntary commitment to abstain from or reduce habitual behaviors like substance use. For example, one of the most widespread programs for the prevention of smoking in secondary schools in Germany is the smoke-free class competition “Be Smart—Don’t Start”. The core of the program is a joint voluntary commitment of school classes to stay smoke-free for a period of 6 months. It focuses on influencing social norms, promoting self-regulation, and addressing social influences by deploying cognitive-behavioral intervention techniques [To fill the gap in addiction prevention approaches for vocational students as a subpopulation with elevated risk for substance abuse and high media use, an app-based program has been developed, using a voluntary abstinence paradigm and addressing a wide selection of behaviors to incorporate a broad target group. The present study aimed to evaluate its effectiveness using a randomized design. It is expected that the intervention will increase the awareness of habitual behaviors (e.g., substance and digital media use) and will therefore lead to measurable reductions in these behaviors even after the end of the abstinence or reduction period. It is also expected that a temporary abstinence of a specific behavior will simultaneously affect other health behaviors and indicators of subjective well-being, even if the intervention does not directly address them. | PMC9915308 |
2. Materials and Methods | PMC9915308 | |||
2.1. Study Design | We conducted a two-arm multicenter, cluster-randomized, wait-list controlled trial with repeated measurements. Data were collected class-wise in schools at baseline and follow-up by using digital questionnaires and throughout the app-based intervention (only IG, CG did not use the app). The detailed study protocol is available online [ | PMC9915308 | ||
2.2. Participants, Recruitment, and Randomization | RECRUITMENT, RECRUITMENT, STILL | Schools were consecutively recruited via local authorities or direct contact using digital and printed information materials, school conferences, etc. After initial agreement from school principalities, research staff, social school workers, or principals contacted the teachers at the participating school and informed them about the study’s aims and procedures. Due to the COVID-19 pandemic, we faced unusual challenges regarding school recruitment and teacher involvement. Since enrolment, data assessment, and introduction of the app was planned to take place in the classroom, teachers were considered an important factor for the implementation and motivation of students. Recruitment occurred on class level, and teachers or principals decided if their classes were part of the study. Still, all students decided voluntarily for themselves. Students that were not involved with their class were not able to take part individually. In some instances, teachers enrolled multiple classes.For randomization purposes, two classes were each paired into similar dyads based on three class characteristics: (1) frequency of in-school education, e.g., daily, twice a week, block lessons; (2) the educational area, e.g., technical/IT, services, and trade; and (3) year of training, e.g., first, second, third. Paired classes were then randomized into the Intervention Group (IG) or Control Group (CG).We consecutively recruited 17 schools to participate in the study between August 2020 and December 2022. The teachers of 277 classes agreed to participate and 4591 vocational students out of these classes completed the baseline survey between 16 March 2021 and 26 April 2022. In total, 139 classes were assigned to the intervention group, 138 classes to the control group. The average number of participating students per class was 16.6 with a minimum of two and a maximum of 31. A total of 864 students were lost to follow-up due to absence at the follow-up assessment date and for 861 students, baseline and follow-up data could not be matched due to missing codes. Overall, 14 classes collectively withdrew from the study before follow-up. After follow-up assessment, 2861 students’ baseline and follow-up questionnaires remained for primary data results in an Intention-to-Treat (ITT) analysis. The average time between the two assessments was 7.7 weeks (SD = 3.08), with IG at 8.1 weeks and CG at 7.4 weeks. | PMC9915308 | |
2.3. Intervention and Setting | “Meine Zeit ohne—Die Challenge“ (“My time off—the Challenge”) is an app-based intervention developed for implementation in vocational schools. It is based on the ideas of a project called “initiated abstinence” [ | PMC9915308 | ||
2.4. Data Collection and Outcomes | Participation in the survey and intervention (IG) was voluntary, so the number of participating students could differ noticeably from previously announced class sizes. There were no exclusion criteria. After interested teachers were identified at a respective school, assessment/introduction dates were set for each class individually. Due to the COVID-19 pandemic, some introductions and survey assessments were conducted via video chat projecting a research staff member onto a classroom monitor. All students received a random code on paper, which granted them access to the digital questionnaire. Codes were handed out by research staff members directly before data assessment. In cases where physical presence by research staff was not permitted, codes were sent to teachers beforehand. Research staff helped with technical difficulties or language issues. IG participants’ codes also served as login codes for the intervention app. All students were encouraged to take a smartphone picture of the code and keep their codes to gain access to the follow-up questionnaire. To provide optimal data protection, this code was the only possibility to match data of baseline and follow-up questionnaires as well as app usage data. Research staff also attended the follow-up data collection in presence or online. | PMC9915308 | ||
2.5. Measurements | substance-related behavior | Sociodemographic data included age, gender, income, parent’s migration history (yes/no), income, highest previous education, educational area, and educational progress. Primary outcomes were substance-related behavior in the last 30 days using binary answers (yes/no) as well as quantitative instruments. The assessment of alcohol use patterns was based on Audit-C assessing frequency and quantity of both drinking and binge drinking [For the present analysis, we created dichotomous health-promoting change variables (yes/no = 1/0) for all outcomes. For alcohol, gambling, and cannabis, a health-promoting change was defined as a positive 30-day prevalence at baseline vs. a zero 30-day prevalence at follow-up. For the use of cigarettes and e-products, change was defined as a reduction of at least 50% in the monthly number of cigarettes or e-product units from baseline to follow-up [ | PMC9915308 | |
2.6. Statistical Analysis | REGRESSION, REGRESSIONS | Based on previous studies [For descriptive baseline data, we used standard code to tabulate ratios for data on nominal and ordinal scale levels. Metric data are presented with means and standard deviations (SD). As part of the attrition analysis, linear regressions were applied to evaluate differences between students that completed the follow-up survey and students that dropped out of the study. Differences between groups for change of all dichotomous outcomes from baseline to follow-up were analyzed using multilevel logistic mixed-effects regression models to account for the clustered structure of the data, with clustering occurring within federal states, schools, and classes [ | PMC9915308 | |
4. Discussion | multiple behaviors, unhealthy behaviors | Our study shows first indications of a positive effect of the app-based intervention in terms of an overall improvement of health-related behavior among vocational students.With that, the study assessed behavior changes that exceeded the 2-week period of the challenge. It should be stressed that students were not encouraged to abstain from or reduce any behavior further than the period of the challenge, and the observed longer behavior changes can thus be assumed to be completely intrinsically motivated. Two driving forces, prompted through participation in the IG, can be assumed to underly this continuing behavior change; first, an elevated awareness for problematic use of substance or media, and second, techniques which were applied during the challenge.On a general level, this study replicates the finding that school-based interventions that encourage students to commit themselves to abstain from unhealthy behaviors can lead to lasting future changes in health behavior [One new feature was the digital format and exclusive app control of the intervention. eHealth interventions targeting multiple behaviors offer increased student engagement, fidelity, and scalability for initially face-to-face based approaches. This facilitated reach of the target population and enabled individual challenges that were independent from the school context and teacher responsibility as is considered important [Another empirical question relates to the size of the found intervention effects, i.e., their practical significance. The absolute difference between the two study groups must be seen as rather small (6.5% absolute difference for social media reduction, 3.7% absolute difference for GAHBI). Relevance in this context has two aspects, one on public health and one on the individual level. Following the principles of the prevention paradox, even small individual effects on health behavior have a large impact on public health when the intervention is applied on a large scale and therefore reaches many individuals. From an individual perspective, the chosen cut-points for change in the measured indicators seem meaningful, too. For example, evidence by Brailovskaia and colleagues indicated that a daily 20-min reduction of the use of Facebook can have lasting positive effects on Facebook involvement, on psychological well-being as well as healthy lifestyle [ | PMC9915308 | |
Limitations | REGRESSION, ASSOCIATED CONDITIONS, RECRUITMENT | This study has a number of limitations. First, randomization on class level reduced the overall clusters to 277. Despite efforts like pairing randomization units by similar characteristics, differences between the IG and CG participants were found, leading to possible selection bias. This has been taken into account by adding the respective variable as a covariate into the outcome analyses. Second, the attrition rate is high, which was partly caused by the anonymization procedure, allowing a link between baseline and follow-up data without collecting any personal information. While about 19% of participating students did not take part due to absence, another 19% could not be included into the main analysis because of a missing code and thus missing link to baseline data. Third, attrition analysis showed a number of highly significant differences between drop-outs and completers, which reduces the external validity of the study. However, we found no evidence to suggest that this affected the interpretation of findings across groups. Fourth, deviant from the study protocol we did not report primary outcomes as metric scores but as dichotomous changes across all or within one behavioral area. This procedure helps illustrating the results but reduces variance in the outcomes. To ensure that the presented results are not solely due to the dichotomization, the regression models were repeated using continuous outcomes and comparable results were found. For example, there was also a significant difference between the IG and CG groups in the absolute minutes used for social media. Fifth, it was not possible to study longer-term effects of the intervention as the observational period was too short. Lastly, the COVID-19 pandemic and associated conditions for schools and teachers clearly impacted the recruitment process. The pandemic—among others—was a regular argument for schools to not fully participate in the study. Digital components like the app itself or video calls helped greatly if the presence of research staff was not allowed because of contact restrictions. However, the recruitment might have been significantly easier and less selective in non-pandemic times. | PMC9915308 | |
5. Conclusions | SECONDARY | Substance use and digital media exposure are major health risks for adolescents and young adults beyond secondary school. At the same time, they form habits over time, which are already present at young adulthood. This is the first time that a prevention program for vocational schools was rigorously evaluated in a randomized study in Germany. Although the recruited sample cannot be considered representative of vocational schools in Germany, the generalizability of the results is facilitated by the inclusion of a broad range of vocational sectors (i.e., service industries, business, and administrative professions as well as industrial-technical professions) within schools from three different states across Germany. The “Meine Zeit ohne” intervention was found to have promising results at feasibility for the target group and small but significant effects regarding students’ health behavior. In particular, participants choosing to reduce a specific substance- or media-related behavior seem to be successful at reducing this behavior for a short term. Implications for future research are the need for longer-term follow-up and to examine participant characteristics and the intervention mechanisms’ impact on app usage as well as effectiveness. The study also indicates that a large number of adolescents and young adults can be reached using a digital, low-threshold application, which can be used independently from the school or work context. | PMC9915308 | |
Author Contributions | M.M., R.H., N.A., R.T., K.L. and L.K. conceived the study, initiated the study design and obtained funding; B.P., M.R. and K.G. were responsible for data curation, B.P. and M.M. for the data analysis. M.M., N.A., K.L., L.K., M.R., E.G.d.M. and B.P. developed the methodology for the intervention app and all study materials. B.P. and M.M. drafted the original manuscript. All authors have read and agreed to the published version of the manuscript. | PMC9915308 | ||
Institutional Review Board Statement | Approval for the study was obtained from the ethics committee of the Center for Psychosocial Medicine at the University Medical Center Hamburg Eppendorf and the responsible school authorities at each study site (Center for Education Monitoring and Quality Development at schools in Hamburg, IfBQ; the Center for Prevention at the Institute for Quality Development at Schools in Schleswig-Holstein, IQ.SH; and the Bavarian State Ministry for Education and Cultural Affairs) prior to data collection. The study is conducted in accordance with the CONSORT guidelines and complies with the principles laid down in the Declaration of Helsinki. It is registered in the DRKS public database (trial registration number DRKS00023788). Written informed consent was obtained from all participants prior to study enrollment. All substantial protocol deviations or modifications were communicated to the Ethics Committee and DRKS register. | PMC9915308 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9915308 | ||
Data Availability Statement | The study material (information sheets) is available to the public and can be found on the following website | PMC9915308 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9915308 | ||
References | ’ behavior | Participants flow chart.Change in IG participants’ behavior compared to the control group (odds ratios adjusted for highest education with 95% CI).Baseline statistics, attrition analysis, and differences between the intervention and control groups.Assessed behavioral and well-being variables, criteria on which a health-promoting change from baseline to follow-up was defined, distribution of these changes in the IG and CG, and challenges started in each area (IG only).* = General Adverse Health Behavior Improvement; ** = Monthly; α = For cigarettes and e-products technically the same challenge had to be selected.Odds ratio with 95% CI for intervention group behavior change compared to the control group—full IG sample and sensitivity analysis including only participants who chose a challenge in the respective health behavior area.* = General Adverse Health Behavior Variable; α = For cigarettes and e-products technically the same challenge had to be selected. | PMC9915308 | |
1. Introduction | colorectal cancer, tumor, Tumor, CRC, malignant cancer, cancer, TCGA, deaths, Cancer | COLORECTAL CANCER, INFILTRATION, TUMOR, TUMOR, CANCER, CANCER | It’s well known that N6-methyladenosine (m6A) modification is the most abundant modification in multiple RNA species. miRNAs play important roles in m6A modification and are closely related with occurrence and development of colorectal cancer (CRC). Thus, the aim of this study was to identify the prognostic value of m6A-related miRNAs and explore the correlation between the miRNAs and immune microenvironment in CRC. The differentially expressed m6A regulators and differentially expressed miRNAs between CRC tissues and adjacent normal tissues were identified based on TCGA dataset, and the m6A-related miRNAs were screened. The CRC patients from TCGA were randomized (1:1) into training set and validation set, and the risk score was established in the training set. Next, risk score was verified in the validation set and GSE92928 from GEO datasets. Besides, the relationship among tumor mutational burden, immune microenvironment and risk score were analyzed. What’s more, RT-qPCR were used to explore the expression levels of the miRNAs in risk score between SW480 and SW620. A total of 29 m6A-related miRNAs were screened out, and a 5-differentially expressed miRNAs risk score was established. Kaplan–Meier analysis and ROC curves revealed the risk score could predict the prognosis of CRC, accurately. Similarly, the patients in the high-risk group had shorter overall survival in GSE92928. The risk score was relevant with the tumor mutational burden and immune infiltration, and the expression of HAVCR2 was significant difference between 2 risk groups. The expression levels of miR-328-3p, miR-3934-5p, miR-664b-5p and miR-3677-3p were down-regulated in SW620 compared with SW480, only the expression level of miR-200c-5p was up-regulated in SW620. The findings provided the new insights into the correlation between miRNAs and m6A regulators. The m6A-related miRNAs could predict the prognosis of CRC and provide the valuable information of immunotherapy in CRC patients.As one of the most common malignant cancer, colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second cause of tumor related deaths worldwide according to the global cancer statistics.N6-methyladenosine (m6A) modification was first detected in 1970s, which is the methylation of the sixth N atom of adenosine in mRNAs or ncRNAs.MicroRNAs (miRNAs) belong to the noncoding RNA family, which contain 19-25 nucleotides.In present study, the m6A-related miRNAs were identified and a novel risk score was established based on the Cancer Genome Atlas (TCGA). Tumor mutational burden (TMB) and immune checkpoint genes were found to be associated with risk score. The relationship between the risk score and immune microenvironment was also assessed with ESTIMATE and CIBERSORT algorithm. Otherwise, drug resistance between different risk score groups were further explored. | PMC10659607 |
2. Materials and Methods | PMC10659607 | |||
2.1. Data collection | CRC | The date of miRNA sequencing, mRNA sequencing (FPKM value), mutation expression, and corresponding clinical information of CRC were acquired from TCGA. The mRNA sequencing was transformed into log2(TPM+1). A total of 25 m6A modification regulators were selected from previous research including 8 writers (METTL3, METTL14, METTL16, WTAP, VIRMA, ZC3H13, RBM15, and RBM15B), 2 erasers (ALKBH5 and FTO), and 15 readers (YTHDC1, YTHDC2, YTHDF1, YTHDF2, YTHDF3, HNRNPC, FMR1, LRPPRC, HNRNPA2B1, IGFBP1, IGFBP2, IGFBP3, RBMX, LAVL1, and EIF3B). | PMC10659607 | |
2.2. Identification of m6A-related miRNAs | tumor | TUMOR | The workflow was showed in Figure Workflow of the whole study. DEMs = differentially expressed miRNAs, TMB = tumor mutation burden. | PMC10659607 |
2.3. Construction of risk score | CRC | REGRESSION | In order to select the survival-related miRNAs, univariate Cox regression analysis was applied on m6A-related miRNAs, and the acquired miRNAs were adopted into the next analysis. To explore the mechanisms of the miRNAs in CRC, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used via the website tool DIANA-mirPath v.3 (The expression profiles of m6A-related miRNAs and corresponding clinical information were divided into training set and validation set randomly with a 1:1 ratio. The miRNA expression profiles were normalized by log2 before analysis. The least absolute shrinkage and selection operator (LASSO) cox regression analysis was performed to construct of risk score in training set via “glmnet” package.To estimate the independent prognostic value of clinical data and risk score of CRC, univariate and multivariate Cox regression analyses was used in all CRC patients. Besides, hazard ratio (HR) and 95% confidence interval (CI) were also calculated. Furthermore, to improve the prediction power, the nomogram was constructed via “rms” package, including age, gender, TNM stage and risk score. | PMC10659607 |
2.4. TMB and tumor immune microenvironment | CRC | INFILTRATION | TMB is defined as the total number of mutations per million bases and was reported to be related with immune checkpoint inhibitors.To explore the correlation between degree of immune cell infiltration and risk score, ESTIMATE algorithm was performed to calculate Immune score, Stromal score and Estimate score using “estimate” package. Additionally, the proportion of 22 marked immune cell subtypes in CRC patients was also calculated via “CIBERSORT” package. Next, the Wilcoxon’s test was conducted to compared the differences of 22 immune cell subtypes between high-risk group and low-risk group. And Spearman correlation test was used to evaluate the relationship between risk score and immune cell subtypes. | PMC10659607 |
2.5. Drug sensitivity of risk score | Considering the potential of risk score to predict drug sensitivity, the half-maximal inhibitory concentration (IC50) of the selected drugs was compared between high-risk group and low-risk group via “pRRophetic” package. | PMC10659607 | ||
2.6. Total RNA extraction and quantitative real-time PCR | PRIMARY TUMOR, METASTASIS, METASTATIC TUMOR | To explore the roles of the miRNAs in CRC metastasis, the expression of the miRNAs was compared between SW480 and SW620 cells, which were isolated from primary tumor and metastatic tumor in abdomen of single CRC patient, respectively. Total RNA was isolated from the cell lines using Total RNA Extractor (No. B511311; Sangon Biotech, Shanghai, China). Reverse transcription reactions were performed using miRNA First Strand cDNA Synthesis Tailing Reaction Kit (No. B532451; Sangon Biotech). The quantitative real-time PCR experiment was performed using a MicroRNAs qPCR Kit (SYBR Green Method) (no. B532461; Sangon Biotech) on an CFX96 Real-Time PCR Detection System (Bio-Rad). | PMC10659607 | |
2.7. Statistical analysis | All statistical analysis was conducted by R language 4.0.3 ( | PMC10659607 | ||
3. Results | PMC10659607 | |||
3.1. Identification of m6A-related miRNAs | tumor, TCGA, CRC | TUMOR | After differential expression analysis, a total of 526 DEMs were selected (309 upregulated and 217 downregulated) between CRC and normal colorectal tissues in the TCGA dataset (Fig. (A and B) Heatmap and Volcano plot showed the differentially expressed miRNAs between tumor and adjacent normal tissues. (C) The expression of 25 m6A modification regulators between tumor and adjacent normal tissues. | PMC10659607 |
3.2. Development and validation of risk score | CRC | REGRESSION, COLORECTAL CANCER, INTERACTION | A total of 29 m6A-related miRNAs were found to be related with survival via univariate Cox regression analysis. These miRNAs may play important roles in m6A modification of CRC, so KEGG pathway analysis was used and the results showed that these miRNAs were enriched in MAPK signaling pathway, Ras signaling pathway, Wnt signaling pathway, Hippo signaling pathway, TGF-β signaling pathway and so on (Fig. (A) KEGG enrichment analysis was used based on website tool DIANA-mirPath v.3. (B) Interaction network showed the correlation among m6A modification regulators and m6A-related miRNAs. The red diamonds meant m6A modification regulators and the green ellipses meant miRNAs.We screened these miRNAs by the LASSO Cox regression and only 5 miRNAs were selected into the model in training set (Fig. (A) The optimum lambda value was selected in LASSO cox regression analysis. (B) Change of coefficients with different lambda value in the model. (C and D) Risk score, survival time and heatmap of 5 miRNAs between high-risk group and low-risk group in training set and validation set.(A and B) ROC curves of risk score based on the 5 miRNAs to predict 5-yr survival rate in training set and validation set, respectively. (C and D) K–M survival curves of different risk groups were performed in training set and validation set, respectively. (E) Univariate and multivariate Cox regression analyses were used in all CRC patients. CRC = colorectal cancer, K–M, Kaplan–Meier.To investigate the independent risk factor of all CRC patients, univariate and multivariate Cox regression analysis were used. As is shown in Figure | PMC10659607 |
3.3. Establishment of nomogram | CRC | COLORECTAL CANCER | To make risk score more applicable in the clinic, nomogram was established using risk score and clinicopathological parameters, which could provide a better prognostic evaluation for the individual patient. The nomogram contained age, gender, TNM stage and risk score, and risk score was the largest contributors to prognosis compared with the others (Fig. (A) Construction of nomogram for predicting the prognosis of CRC patients. (B) ROC curves of risk score to predict the 1-, 3-, and 5-yr survival times. (C) Calibration curves showed the deviation of nomogram in 1-, 3- and 5-yr survival probability, respectively. CRC = colorectal cancer. | PMC10659607 |
3.4. TMB analysis of the risk score | tumor | TUMOR | Immunotherapy has been a promising treatment in CRC, and evidences implied that TMB was closely related to sensibility of immunotherapy. In present study, TMB was significantly higher in the low-risk group ((A) Comparison of TMB levels between high-risk group and low-risk group. (B) The correlation among TMB levels and risk score. (C) The differential expression analysis of immune checkpoint genes between high-risk group and low-risk group. TMB = tumor mutation burden. | PMC10659607 |
3.5. Correlation of the risk score and tumor immune microenvironment | tumor, TCGA, CRC | TUMOR | The ESTIMATE algorithm was applied to investigate the correlation of the risk score and the immune microenvironment in CRC. Next, Stromal score, Immune score, and ESTIMATE score of all CRC patients were calculated. As is Figure Risk score was associated with tumor immune microenvironment. (A) The boxplot showed the difference of risk score in stromal score, immune score, and ESTIMATE score, respectively. (B) Cellular fraction of different immune cells between high- and low-risk groups in TCGA datasets. (C) The correlation among risk score and activated dendritic cells, activated memory CD4To identify which immune cells take part in immune response of CRC, CIBERSORT algorithm was used to investigate the correction of risk score and 22 immune cell type (Fig. | PMC10659607 |
3.6. Drug sensitivity analysis of the risk score | The “pRRophetic” package was performed to investigate the correction between drug sensitivity and risk score. IC50 of cisplatin was lower in low-risk group compared to high-risk group (The IC50 of cisplatin (A) and gemcitabine (B) in high- and low-risk groups. IC50 = half-maximal inhibitory concentration. | PMC10659607 | ||
3.7. The expression of the miRNAs | PRIMARY TUMOR, METASTASIS, METASTATIC TUMOR | As the 5 miRNAs in risk score were related with the CRC prognosis, we suspected that the miRNAs were related to CRC metastasis. Therefore, the expression of the miRNAs was explored between SW480 and SW620, which were respectively separated from primary tumor and metastatic tumor of CRC. The results showed that miR-328-3p, miR-3934-5p, miR-664b-5p, miR-200c-5p and miR-3677-3p were down-regulated in SW620 compared with SW480, in contrast, miR-200c-5p was up-regulated in SW620 (Fig. The expression of the 5 miRNAs in risk score was compared by qRT-PCR between SW480 and SW620. (A) miR-328-3p. (B) miR-3934-5p. (C) miR-664b-5p. (D) miR-200c-5p. (E) miR-3677-3p. | PMC10659607 | |
4. Discussion | cancers, tumor, CRC, head and neck squamous cell carcinomas, TCGA, malignant tumor | CANCERS, METASTASIS, TUMOR, PROLIFERATION, MALIGNANT TUMOR, COLD | It’s known that CRC is a common malignant tumor with high incidence and mortality.In previous studies, miRNAs have been proved to be good prognostic biomarkers in various cancers. The study reported that immune-related miRNA signature could be used to effectively predict the prognosis of head and neck squamous cell carcinomas.It’s well known that CRC metastasis was a crucial prognostic factor, but the roles of the 5 miRNAs in CRC metastasis were not clear. Due to this, the expression levels of the 5 miRNAs were compared between SW480 and SW620. The result showed that the miRNAs were all down-regulated in SW620 expect for miR-200c-5p, which indicated these miRNAs might participate in CRC progression and metastasis. Studies have reported that miR-328-3p was down-regulated in CRC and could inhibit CRC proliferation and metastasis via inhibiting the PI3K/Akt signaling pathway.Immunotherapy is a novel anti-cancer method and has been a focal point in various cancers, recently. However, CRC is regard as a cold tumor, which less responses to immunotherapy.To date, immune microenvironment was considered to be an important role in development and treatment in cancers. Recently, accumulating studies has revealed that m6A methylation could regulate tumor immune microenvironment, which led to occurrence and progression in various cancers.Since studies reported miRNAs could affect drug resistance,However, there are several limitations should be considered in this study. Firstly, risk score still needs to verify in more external cohort. Secondly, the clinical information of TCGA cohort is not complete, so some CRC samples were excluded, which might affect research results. | PMC10659607 |
5. Conclusion | CRC | INFILTRATION | Present study is the first to investigate the prognostic value of m6A-related miRNAs and constructed a risk score for further application. The risk score was correlated with TMB and immune cells infiltration, which could provide the important information in immunotherapy but also the direction to explore the mechanisms among immune cells and CRC. To sum up, the results suggested that m6A-related miRNAs could be a good prognostic predictor and provided novel insights into immunotherapy in CRC patients. | PMC10659607 |
Acknowledgments | The authors thank the public availability of the GEO ( | PMC10659607 | ||
Abbreviations: | TCGA, Cancer | COLORECTAL CANCER, CANCER | confidence intervalcolorectal cancerdifferentially expressed miRNAshazard ratiothe half-maximal inhibitory concentrationKyoto Encyclopedia of Genes and Genomesthe least absolute shrinkage and selection operatorN6-methyladenosineThe Cancer Genome Atlastumor mutational burdenXQ and DC contributed equally to this work.The present study was supported in part by the National Natural Science Foundation of China (no. 82260579), the Natural Science Foundation of Guangxi, China (2020GXNSFAA159056), the Guangxi Senior Medical Talents “139” Training Plan Project (G202003016), Development and Promotion Project for Traditional Chinese Medicine of Guangxi (GZSY21-56), and the Natural Science Foundation Fostering Project of the Second Affiliated Hospital of Guangxi Medical University, China (GJPY2018010).Informed consent was obtained from all participants.The data used in this study met the following criteria: these relevant data were obtained on basis of the TCGA and GEO ethics committee, which is open access and public; therefore, there is no need to worry about approval.The authors have no conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are publicly available.Supplemental Digital Content is available for this article.How to cite this article: Qiu X, Chen D, Huang S, Chen N, Wu J, Liang S, Peng P, Qin M, Huang J, Liu S. Identification and verification of m6A-related miRNAs correlated with prognosis and immune microenvironment in colorectal cancer. Medicine 2023;102:46(e35984). | PMC10659607 |
References | PMC10659607 | |||
Objectives: | IOL | To compare the subjective and objective visual quality more comprehensively after surgery of the commonly used multifocal intraocular lenses (IOL) and monolocal IOL implants through long-term systematic clinical observation, providing reference and basis for clinical application. | PMC10187746 | |
Methods: | SE, visual disturbance | IOL, NEAR VISION, LENS | Non-randomized controlled trial. A total of 91 (138 eyes) patients between June 2020 and December 2020 were implanted trifocal IOL or monofocal IOL after phacoemulsification in a tertiary class hospital in Wuhan. Monocular testing 3 months after surgery included best-spectacles corrected and uncorrected visual at distant, intermediate, and near vision; spherical equivalent (SE); defocus curve; modulation transfer function (MTF); dysfunctional lens index (DLI); Strehl ratio (SR); mesopic contrast sensitivity function; quality-of-life, spectacles independence, visual disturbance, and surgical satisfaction surveys 3 months post-surgery. | PMC10187746 |
Results: | IOL | There was statistically better uncorrected vision acuity with trifocal IOLs in all range, while monofocal IOL had statistically better mesopic contrast sensitivity at specific spatial frequencies and statistically worse defocus curves, spectacles independence, and surgical satisfaction. The trifocal IOL performed better in subjective quality of vision and life and spectacles independence questionnaires, and the objective quality of vision had no statistical significance. | PMC10187746 | |
Conclusion: | cataracts | CATARACTS, IOL | Compared to monofocal IOL, trifocal IOL could provide a full range of clear vision for the majority of patients with simple cataracts, improve the rate of spectacles independence and patient satisfaction. And the objective quality of vision did not show any difference. | PMC10187746 |
Keywords: | IOL, NEAR VISION |
Although patients can have good distance vision after the implantation of monofocal IOL, their vision in intermediate and near remain poor due to the loss of accommodation. Most of the individuals are spectacles independent, but the overall contentment is not high. The new IOL can improve the postoperative distance, intermediate, and near vision while providing depth of focus and patient satisfaction. Previous studiesCurrently, many late-model inspection instruments are putting into clinical use. This study uses multiple inspection instruments to compare the subjective and objective visual quality more comprehensively after surgery of the commonly used multifocal IOL and monolocal IOL implants through long-term systematic clinical observation, providing reference and basis for clinical application. | PMC10187746 | |
Methods | PMC10187746 | |||
Search method used to find prior related research | LENS | Conduct relevant literature searches on websites such as PubMed, Web of Science, SCI-HUB, with the search keywords including MIOL, contrast sensitivity (CS), and modulation transfer function (MTF); Dysfunctional lens index (DLI), and so on. | PMC10187746 | |
Patient enrollment | age-related cataracts | After approval by the ethics committee, 91 (138 eyes) patients between June 2020 and December 2020, aged >40-years-old, with age-related cataracts, were enrolled consecutively in a non-randomized controlled trial comparing AT LISA tri 839MP (Carl Zeiss Meditec, Jena, Germany) (A group; n=65) and Mi60 (Bausch and Lomb, New York, American) (B group; n=75) implantation in a tertiary class hospital in Wuhan (- Characteristics of study participants.Person’s age at the time of eye surgery,+All comparisons were not significant (UCVA: uncorrected vision acuity,BCVA: best-corrected vision acuity | PMC10187746 | |
Surgical procedure | All the operations were performed by the same doctor. The patients underwent small incision phacoemulsification with an incision at the steep meridian and a central continuous curvilinear capsulorhexis, <5.5 mm in diameter. | PMC10187746 | ||
Intraocular lens selection, IOL power calculations, and targeted refraction | IOL, Barrett universal II formula | IOL, NEAR VISION | A detailed medical history inquiry and explanation of postoperative results were essential before MIOL implantation.Barrett universal II formula was used for all patients. Emmetropia was the targeted refraction for AT LISA tri 839MP, and -0.25D could be used if patients had special requirements for near vision. For Akreos Mi60, according to the patients’ needs, refraction was targeted between -0.25 D and -0.75 D, while monofocal IOL did not have good near vision and required close work. | PMC10187746 |
Subjective visual quality | SE | LENS | Uncorrected vision acuity (UCVA) at a distance (5 m), intermediate (80 cm), and near (40 cm), spherical equivalent (SE), and best-corrected vision acuity (BCVA) at a distance and near were recorded. Also, the best-corrected visual at intermediate was not recorded. We averaged the logarithm of the minimum angle of resolution (logMAR) visual acuities. The equivalent spherical lens was recorded 3 months after the operation. The postoperative testing was on day 7 and months 1 and 3. In the best-corrected vision, contrast sensitivity (CS) was measured at 1.5, 3, 6, 12, and 18 cycles per degree (cpd) using CSV-1000 (Vector vision Inc., Greenville, USA). The defocus curves under monocular UCVA and area-of-focus metric were measured. | PMC10187746 |
Objective visual quality | LENS | Modulation transfer function (MTF) average height, dysfunctional lens index (DLI), and Strehl ratio (SR) were recorded at 3 months after implantation using the iTrace aberrometer (Tracey Technologies Co., Houston, USA). MTF values were measured at spatial frequencies of 5, 10, 15, 20, 25, and 30 cpd at 3-mm pupil diameter. | PMC10187746 | |
Statistical analysis | EYE | The SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, N.Y., USA) was used for statistical analyses. Confirm all data distribution were normal distribution. For each parameter, the mean values and standard deviations were calculated. Independent sample t-test was used between groups A and B, and statistical significance was indicated by We followed the tenets of the Declaration of Helsinki, and obtained written informed consent from all participants prior to their inclusion in the study, and all experiments were approved by the Ethics Committee of Wuhan Aier Hongshan Eye Hospital (acceptance number: HS2020IRBKY01). | PMC10187746 | |
Results | In group A, 2 patients had fundus lesions that were not detected before the operation, and 3 patients in group B were lost to follow-up after the operation. None of these 5 patients were included in the follow-up data analysis. | PMC10187746 | ||
Monocular vision | SE | DISEASE, NEAR VISION | Uncorrected vision acuity at distant - Distance, intermediate, and near vision at 3 months after surgery with LISA tri 839MP and Mi60.n represented the number of eyes followed up after surgery (one case in group A was lost to follow-up, and there were 2 cases of fundus disease in group B not found before the operation. These 3 patients were not included in the postoperative statistical analysis).All visual acuity was expressed in logMAR,UCVA: uncorrected visual acuity,BCVA: best-corrected visual acuity,SE: spherical equivalent- Visual acuity distribution of each group. | PMC10187746 |
Contrast sensitivity function | Across all spatial frequencies, group B scored higher on the monocular, best spectacles corrected contrast sensitivity test except 1.5 cpd without glare than group A at 1 and 3 months (- Contrast sensitivity function and modulation transfer function (MTF) of each group after surgery. CS: contrast sensitivity, cpd: cycles per degree | PMC10187746 |
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