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Reporting summary | Further information on research design is available in the | PMC10824665 |
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Supplementary information |
Supplementary Figs. 1–4.Reporting SummarySupplementary protocols.Supplementary Tables 1–10 | PMC10824665 |
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Source data |
Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Uncropped blots.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data. | PMC10824665 |
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Extended data | PMC10824665 |
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The effect of imetelstat on normal hematopoiesis. | Humanized
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Lipidomics analysis of imetelstat-treated | desaturation | Targeted lipidomics analysis on 593 lipid species and their desaturation levels.
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The effect of chemical perturbation of ferroptosis on imetelstat efficacy. | Celltiter-based cell growth analysis in a panel of
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Individual AML PDX responses to imetelstat. | Peripheral blood AML | Peripheral blood AML donor chimerism in the thirty individual PDX models.
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Extended data | is available for this paper at 10.1038/s43018-023-00653-5. | PMC10824665 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s43018-023-00653-5. | PMC10824665 |
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Acknowledgements | Leukaemia, P. | LEUKAEMIA | We acknowledge all current and past members of the Gordon and Jessie Gilmour Leukaemia Research Laboratory, particularly E. Cooper, G. Pali, E. Duce, R. Austin, T. Vu, M. Bywater and P. Tavakoli for technical assistance and fruitful discussions; S. Chun-Wei Lee (MSKCC) for help with library preparation for HemePACT sequencing; N. Waddell (QIMR Berghofer) for bioinformatics support particularly sequencing data processing; R. Fieth and J. Riches (Queensland University of Technology) for technical support and proofreading of the paper; L. Wockner and L. Marquardt (QIMR Berghofer) for help with statistical analyses; G. Chojnowski, M. Rist, P. Hall, T. Hong Nguyen and L. Leveque-ElMouttie (QIMR Berghofer) and Y. Ding (Frazer Institute) for help with imaging flow cytometry analysis and cell sorting; the current and past members from the QIMR Berghofer animal house facility, particularly S. Cassidy, J. Mauclair and D. McNeilly; P. Collins (QIMR Berghofer analytical core facility) for technical assistance regarding next-generation sequencing and routine genetic and functional analyses (STR profiling, | PMC10824665 |
Author contributions | C.B., L.J.B., L.B., F.H.H., M.M.H., G.A.K., H.A.P., O.A.W. and S.W.L. were responsible for conceptualization. The methodology was the responsibility of C.B., A.H.P., T.S., J.S., V.L., B.J., G.H. and S.W.L. Software was the responsibility of J.S. and G.H. Validation was carried out by C.B., A.H.P., A.P.S. and G.V.W. Formal analysis was carried out by C.B., A.H.P., G.V.W., T.S., J.S. and G.H. Investigation was conducted by C.B. and S.W.L. Resources were the responsibility of C.B., V.L. and G.A.K. Data curation was the responsibility of C.B., A.H.P., A.S., G.V.W., T.S., L.C., J.S., G.C., V.S.K., A.P.S., Y.J. and R.H. Writing of the original draft was carried out by C.B. and S.W.L. Visualization was carried out by C.B. and T.S. Supervision was conducted by C.B. and S.W.L. Project administration was carried out by C.B. and S.W.L. C.B. and S.W.L. were responsible for funding acquisition. | PMC10824665 |
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Peer review | PMC10824665 |
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Data availability | RNA-sequencing data have been deposited in the Gene Expression Omnibus under accession codes | PMC10824665 |
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Competing interests | S.W.L. has received research funding from Janssen related to imetelstat (2016–2018). For research beyond this study, S.W.L. has received funding from Celgene/Bristol Myers Squibb (2019–2022), consultancy from Abbvie (2021–2023) and advisory board fees from Abbvie and Astellas (2020–2021). The remaining authors declare no competing interests. | PMC10824665 |
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References | PMC10824665 |
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Background | Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil–lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population. | PMC10070409 |
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Methods | SOLID TUMOUR | We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020. | PMC10070409 |
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Results | The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96–1.70); RMH score 2, HR 2.27 (95% CI: 1.62–3.17); RMH score 3, HR 4.14 (95% CI: 2.62–6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24–2.04), | PMC10070409 |
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Conclusions | We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65–0.76]), and validated the RMH model in the largest Asian study to date. | PMC10070409 |
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Subject terms | PMC10070409 |
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Introduction | malignancies, tumour | MALIGNANCIES, TUMOUR, SIDE EFFECT | Our understanding of tumour biology has grown exponentially and a large number of novel molecularly targeted agents and immunotherapy have entered the clinic. Many of these agents have different side effect profiles compared to cytotoxic chemotherapy and their development plan may differ, with an emphasis on understanding target impact. Phase I studies include first-in-human studies as well as studies that combine two or more experimental drugs for the first time and may include patients who have exhausted standard therapies. Their objectives are to evaluate safety, pharmacokinetic and pharmacodynamic properties of these agents; to establish an optimal dose for Phase 2 efficacy trials; to describe initial antitumour response; and to gain information about the effect of a targeted agent on its target [A typical inclusion criterion for Phase 1 studies is ‘life expectancy >3 months’, however, the overall survival (OS) of patients with advanced solid malignancies is often difficult to predict, more so in the era of targeted therapy and immunotherapy. Prognostic scores have been developed to identify the prognosis of patients in Phase I studies. The Royal Marsden Hospital (RMH) prognostic score (which incorporates serum albumin, lactate dehydrogenase (LDH) levels, and the number of metastatic sites) is commonly used [ | PMC10070409 |
Methods | PMC10070409 |
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Study design and patient characteristics | cancer, death, tumour, Cancer | CANCER, SOLID TUMOUR, TUMOUR, CANCER | We conducted a retrospective review of patients with solid tumours participating in Phase I studies at the National University Cancer Institute, Singapore (NCIS) between October 2013 and December 2020. Patients enrolled in the studies fulfilled the eligibility criteria of the respective studies. Patient demographics, cancer and treatment history, clinical parameters including components of the RMH score and NLR ratio, tumour molecular information and date of death or last follow-up were retrieved from the electronic medical records between October 2013 and December 2020. The RMH score evaluates serum albumin (<35 g/dL constitutes 1 point), number of metastatic sites (3 or more sites constitute 1 point) and serum LDH (more than one-time upper limit normal constitutes 1 point); with scores 0–1 and 2–3 connoting good and poor prognosis, respectively. NLR ratio is calculated by dividing first encounter serum neutrophil count by serum lymphocyte count. The study was approved by the institutional review board. | PMC10070409 |
Statistical considerations | death | REGRESSION | Categorical variables were summarised based on counts and percentages while continuous variables were described in terms of median and interquartile range (IQR).Overall survival (OS) duration was measured from the start of therapy to the date of death. Patients who remained alive at the end of study were censored at the date of last follow-up. Survival curves were estimated via the Kaplan–Meier method. To compare survival distributions between groups, the log-rank test was employed. Multivariable Cox regression models were applied to validate the RMH and RMH + NLR50 models for mortality. The effect estimates were quantified based on the hazard ratio (HR) and its 95% confidence interval (CI). The proportional hazards assumption was evaluated using scaled Schoenfeld residuals. | PMC10070409 |
Model validation | Both the RMH and RMH + NLR50 models were externally validated using the NCIS data, and their performances were evaluated using Harrell’s C-statistic and time-dependent area under the curve (AUC( | PMC10070409 |
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Model update | tumour | TUMOUR | In addition to the RMH score, the following covariates were considered for the model update: gender, age, ECOG performance status (PS), number of co-morbidities, number of prior therapies, aspartate aminotransferase (AST), platelets, haemoglobin, NLR, tumour classification, and whether they were treated with chemotherapy, immunotherapy, targeted therapy and/or vaccines. Significant variables (All statistical evaluations were made assuming a two-sided test at the 5% level of significance. Statistical analyses were conducted using STATA version 15.0. In addition, analyses of AUC( | PMC10070409 |
Results | PMC10070409 |
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Study population | head and neck cancers, gynaecological cancer, lung cancer, Arkenau, lymphoma | LUNG CANCER, OTHER CANCER, HEPATOCELLULAR CARCINOMA, HEAD AND NECK CANCER, LYMPHOMA | There were 414 patients (157 [38%] male and 257 [62%] female) recruited in 40 Phase I studies at NCIS (Table Baseline and treatment characteristics.Note: 1. The figures are presented in terms of frequency and percentage, unless otherwise stated.2. Arkenau et al. [3. In total, 12 patients in the NCIS study population did not have ECOG PS recorded.4. Median albumin was 36 (IQR 33–39) in Kumar et al. [5. LDL was presented based on the institutional upper limit of normal i.e., 580 IU/L for NCIS study population and 192 U/L for Arkenau et al. [6. For Arkenau et al. [7. For Arkenau et al. [8. Other cancers for the NCIS population included lymphoma (3.4%), hepatocellular carcinoma (6.3%), head and neck cancers (8.0%), lung cancer (8.2%) and gynaecological cancer (12.8%). | PMC10070409 |
Development of the NCIS Prognostic Score | tumour | TUMOUR | From the updated NCIS model comprising the following significant predictors (RMH score, ECOG PS and tumour type) (Table NCIS prognostic scoring.Overall survival according to NCIS Prognostic Score for patients enrolled in Phase I trials.The three prognostic models performed similarly in predicting 90-day mortality with AUC ranging between 0.71 and 0.72 (Table | PMC10070409 |
Discussion | cancers, cancer, tumour, deaths, Cancer | CANCER, CANCERS, TUMOUR, CANCER | Similar to other studies, we found the 90-day mortality rate in Phase I studies in our patient population to be ~17%, but treatment-related deaths were very rare [Compared to the original RMH score validation cohort [Our study is one of the first studies aiming to validate the RMH score in the Asian population participating in Phase 1 studies. Minami et al. [Although other groups have shown the prognostic ability of NLR [The NCIS score holds its place amongst prognostic scores. The inclusion of variables such as ECOG PS and tumour type does improve the predictive ability of the score. This was confirmed and applied in the MD Anderson Cancer Centre (MDACC) score which also incorporates ECOG PS and tumour type [A key strength of this study is the analysis of the prognostic scores’ predictive strengths over time, based on iAUC and AUC(As previously mentioned, another strength of the paper is that this is the first paper to validate the RMH score in a population of Asian Phase I patients, and one of the largest validation studies of Phase I patients in general. The NCIS prognostic score is also developed in patients on more contemporary treatments such as immunotherapy and vaccine therapy. While additional variables may be more challenging to apply in clinical practice, such information is routinely obtained and unlikely to be a hindrance. It would also be very possible to incorporate automated calculation onto electronic clinical records platforms to facilitate decision making, thus meaningful to validate this score prospectively.There are however limitations to this study. As a retrospective analysis, it is subject to selection bias. We attempted to minimise bias by having clear inclusion criteria and including all patients who met the inclusion criteria within the time frame of analysis. This resulted in a broad sample of various cancer types and histologies. We also recognise the varying prognosis of different cancers from the point of diagnosis, with the rapid progression of cancer therapy. Thus including all cancer types might appear to result in a highly heterogeneous population. The target population of our study however are cancer patients being considered for Phase I clinical trials, who are usually heavily pre-treated and have exhausted standard therapy. The outcome measure is survival from point of first visit, which is more homogeneous amongst different cancer types than overall survival from the point of diagnosis. Furthermore, a prediction of 90-day mortality from the time of study enrolment is a standard inclusion criterion for Phase I trials. Phase 1 studies consist of the basket and non-basket trials. Thus having a simple score that applies to all tumour types and different Phase 1 trial designs allow for easier and hence broader uptake at the point of the first visit. This is also a single-centre study with a modest sample size, and would require additional studies before clear conclusions can be made of the Asian oncology population at large. The limited sample size also resulted in inadequate power to establish statistical significance in the comparison of AUC( | PMC10070409 |
Author contributions | JL and CEC were responsible for the concept and design of the study. JL, JW and JC were involved in data collection. BCT and AC were involved in data analysis. JL, AC, BCT and CEC drafted the manuscript. All authors critically revised the manuscript for important intellectual content. CEC supervised the study. All authors had full access to all the data in the study, and CEC had the final responsibility for the decision to submit for publication. | PMC10070409 |
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Funding | This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its NMRC Centre Grant Programme, NMRC/CG/012/2013. | PMC10070409 |
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Data availability | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10070409 |
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Competing interests | RS, Cancer | ONCOLOGY, CANCER | WPY has advisory roles for Abbvie/Genentech, Amgen, Astra Zeneca, Bristol-Myers Squibb, Ipsen and Novartis. He is part of the Speakers’ Bureau for Bayer, Eisai, Lilly, MSD Oncology, Sanofi/Aventis, Taiho Pharmaceuticals. He has received funding for travels and accommodations from Pfizer. RS (Raghav Sundar) has received honoraria from Bristol-Myers Squibb, Lilly, Roche, Taiho, Astra Zeneca, DKSH and MSD; has advisory activity with Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD and Astra Zeneca; received research funding from MSD and Paxman Coolers; and has received travel grants from Astra Zeneca, Eisai, Roche and Taiho Pharmaceutical. Financial disclosures: RS is supported by the National Medical Research Council (NMRC) (NMRC/TA/0014/2020). AW has research funding from Otsuka Pharmaceuticals, and has advisory roles for Pfizer, Novartis, Eisai, and Astra Zeneca. JSL has advisory and consulting activity with Pfizer, MSD, AZD, Novartis, Roche, Eisai and DKSH. JSL has received funding for speaker engagement from Pierre Fabre and Eisai. She has received travel grants from Astra Zeneca and Pfizer. She has research grants from CTI biopharma. DST has received honoraria and consulting fees from Astra Zeneca, Eisai, MSD, Roche, GSK and Bayer. He has grant support from National Medical Research Council Singapore and Pangestu Family Foundation Gynaelogical Cancer Research Fund. He has received funding for travel and accommodations from Astra Zeneca, Bayer, Roche and Clovis. RS (Ross Soo) is on the Advisory Board of Amgen, Astra Zeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lilly, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Yuhan. He has Research grant with Astra Zeneca and Boehringer Ingelheim. SCL receives Grant support and has Research Collaborations from Pfizer, Eisai, Taiho, ACT Genomics, Bayer, MSD, Adagene. She is on the Advisory Board and has had Speaker Invitations from Pfizer, Novartis, Astra Zeneca, ACT Genomics, Eli Lilly, MSD, Roche, Eisai and Daiichi-Sankyo. She has received Conference support from Amgen, Pfizer, Roche. CEC has received honoraria from Astra Zeneca and Roche/Genentech. She has a consulting or advisory role with Guardant Health AMEA. She has received travel grants from Taiho Pharmaceutical. JL and GBC declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | PMC10070409 |
Ethics approval and consent to participate | The study was approved by the institutional review board. The need for consent was waived by the institutional review board. | PMC10070409 |
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Consent to publish | Not applicable. | PMC10070409 |
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References | PMC10070409 |
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2. Materials and Methods | PMC10096552 |
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2.1. Research Ethics and Participants | The present study adhered to the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Documents such as the study protocol, the investigator’s brochure, the explanation form, and the consent form were submitted to the ethics committee of the Faculty of Health and Sports Science, Juntendo University, and the study was conducted following approval by the committee (approval number: 29–13). This study was registered at the University Hospital Medical Information Network Clinical Trial Registry as UMIN000028717.The study design was a randomized, placebo-controlled, double-blinded, parallel-group trial for healthy Japanese student volunteers. In August 2017, we recruited students from Juntendo University, who were aged 18 years or older, who belonged to the long-distance track and field team, and who regularly exercised at least four times a week, by posting a notice at the Faculty of Health and Sports Science, Juntendo University. The experiment was conducted from late August to September 2017.The minimum sample size was estimated on the basis of CD86 expression, which is one of the activation markers of pDCs. Our previous study reported that the standard deviation for CD86 was 20%, and the difference between the pre- and post- ingestion mean value was 15% [ | PMC10096552 |
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2.2. Test Food | The study used LC-Plasma capsules containing heat-killed dry LC-Plasma (Kyowa Hakko Bio CO., Ltd., Tokyo, Japan) (≥1.0 × 10 | PMC10096552 |
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2.3. Study Design | The schematic representation of the study is shown in The participants were instructed to maintain their daily habits (e.g., for diet and sleep) and to avoid foods containing a large amount of lactic acid bacteria (e.g., yogurt, fermented cheese, pickles, and lactic acid bacteria supplement) within the test period. For three days prior to the study, participants stayed at rest without exercise to unify their initial state as much as possible. During the 14 days of ingesting the test foods, the participants performed exercise under the supervision of a track and field coach every day. The experimental period was same as the previous study [In the participants’ diary, they recorded test food intake, exercise (type and duration), meal details, and their physical conditions. From the exercise record, the amount of exercise was evaluated as metabolic rate–hour (MET-h), an index of physical activities based on energy expenditure [The blood collection on days 1 and 15 before exercise were conducted at the same time of day (between 08:00 and 10:00 a.m.). The blood samples were collected using a vacutainer blood collection tube with a syringe. | PMC10096552 |
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2.4. Evaluation of pDC and mDC Activity | Peripheral blood mononuclear cells (PBMCs) were isolated from the blood [ | PMC10096552 |
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2.5. Evaluation of Hematological Indices | inflammation | INFLAMMATION, OXIDATIVE STRESS | To investigate the influence of exercise load and LC-Plasma intake on the objective parameters, hematological indices known to be associated with exercise-induced inflammation and oxidative stress were measured. The levels of transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) were measured using an ELISA kit (R&D systems). The levels of cathepsin L, adrenaline, hydroxy-8-deoxyguanosine (8-OHdG), testosterone, and leptin were measured using separate ELISA kits (R&D systems, Minneapolis, MN, USA; R&D systems; Arigo Biolaboratories Corp, Hsinchu City, Taiwan; Northwest Life Science Specialties, Portland, OR, USA; and R&D systems, Cosmo Bio, Tokyo, Japan, respectively). The levels of creatine phosphokinase (CPK) were measured by Hoken Kagaku, Inc. (Kanagawa, Japan) using the Japan Society of Clinical Chemistry standardization method. | PMC10096552 |
2.6. Evaluation of Physiological Indices | fatigue | The low frequency to high frequency ratio (LF/HF), which is indicative of sympathetic to parasympathetic autonomic balance, was measured to assess the degree of fatigue, using the autonomic measurement device VM302 (Hitachi Systems, Tokyo, Japan) [ | PMC10096552 |
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2.7. Participant Diary and Questionnaire | fatigue, pharyngeal pain, ’ mood, pain, cough, muscle pain | Participants were asked to record the degree of each clinical symptom (physical conditions, nasal congestion/nasal discharge, pharyngeal pain, cough, joint pain, chill, fatigue, malaise, and muscle pain) daily using a five-point Likert scale modified with reference to a previous report [To evaluate the participants’ mood during the intake period, the Profile of Mood States 2 (POMS2) test [The visual analog scale (VAS) questionnaire was used to evaluate subjective conditions. The participants were asked about fatigue or physical state questions. In each of the questions, subjects were instructed to mark a spot on a 100 mm straight line according to their feelings (left end 0 = best, right end 1000 = worst). The distance of the mark from the left end was measured and used as the VAS score. A low VAS score indicates a good mood state. | PMC10096552 |
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2.8. Statistical Analysis | SECONDARY | The primary endpoints were pDC activity, mDC activity, participant diary records, POMS2, and TGF-β, IL-6, CPK, cathepsin L, and adrenaline levels between the PL group and the LC-Plasma group on day 15. The secondary endpoints were VAS score, LF/HF, and 8-OHdG, testosterone and leptin levels. Data were expressed as the mean and standard deviation for each intake group. For intragroup comparisons of hematological and physiological indices, the paired | PMC10096552 |
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3. Results | PMC10096552 |
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3.2. Assessment for Continuous Exercise | fatigue, pain | We first analyzed the effect of LC-Plasma on continuous exercise. There was a significant decrease in pDC activity (CD86) on day 15 compared with that on day 1 in both groups, and on day 15, the level in the LC-Plasma group was significantly higher than that in the PL group (The cumulative days of fatigue in the participants’ diary revealed a significant decrease in the LC-Plasma group compared with that in the PL group. The cumulative days of joint pain showed a significantly higher in the LC-Plasma group compared with that in the PL group (Hematological and physiological indices, commonly known to be associated with fatigue, including TGF-β, CPK, adrenaline, and 8-OHdG levels, and LF/HF showed significant changes within each group; however, no significant difference were found in the intergroup comparison ( | PMC10096552 |
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3.3. Assessment for Strenuous Single Exercise | muscle pain, listlessness | Next, we analyzed the effect of LC on a single exercise session following long-term exercise. There were no significant differences in DC activity and the POMS2 score in the intra- or intergroup comparisons. The score for the item “Are you tired?” and “Are you feeling physical listlessness?” in VAS showed a significant increase in the intragroup comparison in both groups, and “Are you feeling muscle pain?” showed a significant increase in the intragroup comparison only in the PL group ( | PMC10096552 |
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4. Discussion | heart and skeletal muscle, fatigue, Fatigue | CONTRACTION | The primary aim of this study was to confirm the effects of LC-Plasma on fatigue caused by a continuous high training load. All the participants in this study belonged to the same sports club. Since the participants had had 3 days of rest without exercise before the start of the test, it is considered that the fatigue state at the start of the experiment was stable. During the intake period of continuous exercise, the average intensity of exercise of the 31 participants was 13.2 ± 2.8 MET-h/day. This is higher than the intensity in our previous study (12.4 ± 3.9 MET-h/day). It has been reported that individuals who run more than 14 km per day (approximately 14 MET-h/day) are more susceptible to URTI [Our results suggested that the CD86 of pDCs in the LC-Plasma group was significantly higher than the level found in the PL group after continuous exercise. The HLA-DR in pDCs significantly decreased in the PL group only in the intragroup comparison. As for the sense of fatigue, cumulative days of fatigue in the participant diary significantly decreased in the LC-Plasma group. The scores of Fatigue–Inertia in POMS2 and “Are you tired?” in VAS showed a worsening trend in the PL group only. These results are similar to those of our previous study [We also assessed the effects of LC-Plasma intake on the objective indices (TGF-β, IL-6, cathepsin L, adrenaline, 8-OHdG, testosterone, leptin, and CPK) associated with fatigue. Some factors in the hematological indices were significantly changed in the intragroup comparison after both the continuous and single exercise; however, no significant difference was observed between the groups. Adrenaline was the index that changed after both the continuous and single exercise in the intragroup comparison. Adrenaline is released with exercise and helps the body to resist stress conditions. It affects the cardiovascular system, producing a rapid powerful vasopressor effect, and increasing heart rate, the force of contraction, the respiratory rate, and blood flow towards the brain, heart and skeletal muscle [We also performed a short-term single exercise test after the continuous exercise for the purpose of assessing the impact of LC-Plasma on fatigue in more detail. However, no significant difference in CD86, HLA-DR, or subjective analysis of fatigue was observed in the intergroup comparison. This may be due to the insufficient intensity of the single exercise session, because no change in CPK was observed. However, it should be noted that in the index of the sympathetic and parasympathetic autonomic balance, the LF/HF value was significantly low and improved in the LC-Plasma group after the single exercise session, although no significant difference was detected between the groups after the continuous exercise. LF/HF has been reported to be linked with fatigue [We set the target sample size at 20 subjects in each group, when the power was set at 0.8 based on the results of CD86 expression of previous experiments. As a result of the final sample size of each group being 15 and 16 due to the exclusion of participants, the standard deviation was larger than in past measurements. Therefore, the power of this experiment was 0.6, which was lower than expected. A larger number of subjects may have been required for a more appropriate LC-Plasma evaluation.There are some limitations to this study that may affect the results. The subjects were limited to athletes aged around 20 years, who performed exercise routinely. The intensity of exercise was also limited. The tracing of lifestyle factors such as meal records, heart rate, and blood pressure during the study period are insufficient to omit the possibility of confounders. In addition, since the short-term single exercise was performed the day after the end of the continuous exercise, it is possible that the influence of the continuous exercise on the subject’s fatigue accumulation cannot be completely excluded.In the future, further studies are needed with participants from more diverse backgrounds, at a more appropriate timing, with stricter lifestyle controls, and with more hematological investigations to reveal the impact of LC-Plasma on fatigue. | PMC10096552 |
5. Conclusions | fatigue | The present study demonstrated that supplementation with LC-Plasma reduced the accumulation of subjective feelings of fatigue after continuous exercise in participants who routinely exercised, potentially by maintaining pDC activity. In addition, the possibilities of improvements in indices of fatigue, such as the normalization of autonomic balance, was demonstrated in a strenuous single exercise session. | PMC10096552 |
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Author Contributions | H.N. | Conceptualization, Y.K., K.S. and T.F.; methodology, Y.K., K.F., Y.I. and T.F.; validation, K.S., H.N. and H.D.; investigation, Y.K., K.F., Y.I. and T.K.; writing—original draft preparation, Y.K. and T.K.; writing—review and editing, K.S., H.N., T.F. and H.D.; supervision, K.S., H.N. and H.D.; project administration, Y.K. and K.F.; funding acquisition, Y.K., T.F. and T.K. All authors have read and agreed to the published version of the manuscript. | PMC10096552 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Faculty of Health and Sports Science, Juntendo University (approval number: 29–13). The protocol was registered in University Hospital Medical Information Network Clinical Trial Registry as UMIN000028717. | PMC10096552 |
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Informed Consent Statement | Informed consent was obtained from all participants involved in the study. | PMC10096552 |
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Data Availability Statement | Not applicable. | PMC10096552 |
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Conflicts of Interest | The study was funded by Kirin Holdings Company, Limited. Y.K., T.F. and T.K. are employees of this company. Although conducted in a double-blind study, they were involved in the investigation, analyses, and writing of the manuscript. The authors declare no other conflict of interest. | PMC10096552 |
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Background | xerostomia, LA-SCCHN, squamous cell carcinoma of the head and neck (, ototoxicity | XEROSTOMIA, ADVERSE EVENTS, DYSFUNCTION, HYPOTHYROIDISM, OTOTOXICITY | Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. | PMC10626703 |
Methods | LA-SCCHN, oropharynx cancer, tumors | TUMORS, OROPHARYNX CANCER | This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m | PMC10626703 |
Discussion | If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT. | PMC10626703 |
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Trial registration | This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( | PMC10626703 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12885-023-11503-z. | PMC10626703 |
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Keywords | PMC10626703 |
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Background | dysphagia, two-step40, LA-SCCHN, squamous cell carcinoma of the head and neck (, oropharyngeal cancer | DYSPHAGIA, RECURRENCE, ADVERSE EVENTS, OROPHARYNGEAL CANCER, PRIMARY TUMOR | Chemoradiotherapy (CRT) with concurrent high-dose cisplatin (CDDP) is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) [Intensity-modulated radiation therapy (IMRT) has emerged as a current standard method for definitive CRT for LA-SCCHN. Although the advantage of IMRT is its highly conformal dose distribution to the primary tumor and involved lymph nodes with sufficiently low exposure to organs at risk, severe late adverse events after CRT remain a significant problem to be resolved.Several strategies aiming at less invasive CRT using IMRT for LA-SCCHN have been investigated, including (i) reducing the total irradiation dose, (ii) alternative concurrent pharmacotherapy to CDDP, and (iii) reducing the irradiation dose in prophylactic field. However, an increase in local recurrence by using reduced total dose radiation was noted even in HPV-positive oropharyngeal cancer with favorable clinical outcomes [A randomized controlled trial was conducted to investigate reduction of the dose of RT to the elective nodal sites, with 50 Gy in the standard arm and 40 Gy in the experimental arm. The results revealed a trend toward less dysphagia at 6 months in the 40 Gy arm though not statistically significant (38.4% vs. 48.6%), without compromising outcome and survival [Based on these backgrounds, we have launched a randomized controlled trial to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy using two-step40 IMRT method (2-step40) to standard dose prophylactic radiation with 56 Gy using simultaneous integrated boost (SIB56) in terms of the time to treatment failure for patients with clinical stage III-IVB (except N3a) LA-SCCHN according to UICC-TNM 8th . | PMC10626703 |
Methods/design | PMC10626703 |
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Study design | ONCOLOGY, MAY | This study is a multi-institutional, two-arm, open-label, randomized phase III study. The study protocol was reviewed by the Japan Clinical Oncology Group (JCOG) Protocol Review Committee and approved by as the JCOG1912 (NEW BRIDGE) in January 2021. The certificated review board approved in March 2021, and patient accrual was started at May 2021. The trial registry number is jRCTs031210100 ( | PMC10626703 |
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Endpoints | death | ADVERSE EVENTS, EVENT, EVENTS, SECONDARY, RESIDUAL DISEASE | The primary endpoint is time to treatment failure (TTF) 1 in all randomized patients. TTF1 is defined as time from randomization to the date of progression, or determination of residual disease after the completion of the protocol treatment, or death from any cause, whichever occurred first, and it is censored at the last day the patient is alive without any evidence of progression. The secondary endpoints are overall survival (OS), complete response rate, progression-free survival (PFS), locoregional relapse-free survival, TTF2, acute and late adverse events, quality of life (QOL) score, and swallowing function score. OS is defined as the time from randomization to death from any cause and is censored on the last contact day for a surviving patient. PFS is defined as the time from randomization to the earliest date of progression or death from any cause and is censored on the last contact day when the patient is alive without any evidence of relapse. In the definition of TTF2, clinical residual disease in TTF1 events is not regarded as an event or censor of TTF2, if complete resection is conducted by salvage surgery and subsequent histopathological examination reveals pathological complete response. | PMC10626703 |
Eligibility criteria | Active infection, Psychiatric disorder, cancers, myocardial infarction, Tumor, head and neck cancers, head and neck surgeon, valvular disease, intramucosal tumors, human immunodeficiency virus antibody test., Fever, squamous cell carcinoma, tumors, head or neck lesions | CANCERS, UNCONTROLLED HYPERTENSION, MYOCARDIAL INFARCTION, LYMPH NODE METASTASES, TUMOR, DILATED CARDIOMYOPATHY, POSITIVE, UNSTABLE ANGINA, HYPERTROPHIC CARDIOMYOPATHY, OROPHARYNGEAL CANCER, HEAD AND NECK CANCER, ONCOLOGY, SQUAMOUS CELL CARCINOMA, TUMORS, POORLY CONTROLLED DIABETES MELLITUS | The inclusion criteria are as follows:
Primary lesions are located in the oropharynx, hypopharynx, or larynx.Histologically proven squamous cell carcinoma on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer.Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification.Age of ≥ 20 years.Eastern Cooperative Oncology Group performance status of 0 or 1.Measurable lesions are not required.No prior chemotherapy for any cancers and no prior RT for brain, head or neck lesions. No prior surgery for head and neck cancers, except for a biopsy of neck lymph nodes for a diagnosis.Any of the following conditions:
Both the primary lesion and regional lymph node metastases are technically or functionally unresectable. Tumor resectability will be determined through a review by a head and neck surgeon.Although the tumors are resectable, patients do not wish to undergo surgical resection.
Adequate organ function.
Neutrophil ≥ 1,000/mmHemoglobin ≥ 9.0 g/dL.Platelet ≥ 100,000/mmTotal bilirubin ≤ 2.0 mg/dL.Aspartate aminotransferase ≤ 100 U/L.Alanine aminotransferase ≤ 100 U/L.CCr ≥ 60 mL/min.
Written informed consent for participation.Exclusion criteria.
Synchronous or metachronous (within 5 years) double cancers, except for intramucosal tumors curatively resected with local therapy.Active infection requiring systemic therapy.Fever over 38.0 °C.Female during pregnancy, within 28 days of postparturition, or during lactation. Male who wants partner’s pregnancy.Psychiatric disorder difficult to participate in this clinical study.Requirement of systemic steroid medication or immunosuppressant treatment.Poorly controlled diabetes mellitus.Poorly controlled hypertension.Unstable angina within 3 weeks or with a history of myocardial infarction within 6 months before trial enrollment.Poorly controlled valvular disease, dilated cardiomyopathy, or hypertrophic cardiomyopathy.Positive hepatitis B surface antigen test.Positive human immunodeficiency virus antibody test.Inability to quit smoking and drinking. | PMC10626703 |
Randomization | METASTASIS | After eligibility has been confirmed, registration is performed using a web-based system at the JCOG Data Center. Patients are randomized to the standard arm (SIB56) or experimental arm (2-step40). Randomization is stratified according to the institution, presence or absence of lymph nodes metastasis, and the primary sites (oropharynx vs. hypopharynx vs. larynx). | PMC10626703 |
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Treatment methods | tumor, SCCHN | SQUAMOUS CELL CARCINOMA, TUMOR, PRIMARY TUMOR | Patients in both arms receive definitive CRT with CDDP at a dose of 100 mg/m
Study scheme. SCCHN, squamous cell carcinoma of the head and neck; CDDP, cisplatin; SIB, simultaneous integrated boostRadiation planning is performed 2 weeks before the start of RT. The cervical computed tomography (CT) is performed using a thermoplastic mask for fixation. In the 2-step40 method group, another planning CT scan is performed at a dose of 30 Gy per the boost IMRT plan. RT is delivered with 4–10 MV photons using IMRT at a total dose of 70 Gy in 35 fractions over 7 weeks in both arms. The gross tumor volume (GTV) is defined as the volume of the primary tumor and the metastatic lymph nodes measuring 10 mm along the short axis. The clinical target volume (CTV) includes the GTV with a 0.5- 1- cm margin. The regional lymph nodes include the bilaterally cervical lymph nodes, and details on the prophylactic field are determined according to the primary site [ | PMC10626703 |
Statistical analysis and evaluation criteria for the endpoints | dysphagia, dry mouth | DYSPHAGIA, ADVERSE EVENTS, HEARING IMPAIRMENT, HYPOTHYROIDISM, DRY MOUTH | A 3-year TTF1 of 50% is assumed for both arms. According to the Schoenfeld and Richter’s method [If the experimental arm is non-inferior to the standard arm in terms of TTF1 and superior in terms of safety endpoints, the 2-step40 method will be considered the more efficacious treatment. However, it is unacceptable that a point estimate of 3-year OS in the experimental arm is more than 5% lower than that in the standard arm. Based on mathematical models, the rates of key late adverse events of grade 2 or higher are expected to be reduced by approximately 15%, 7%, 7%, and 10% for hearing impairment, hypothyroidism, dry mouth, and dysphagia, respectively. If the experimental arm shows sufficient improvement in at least one of these key late adverse events, the study treatment will be considered as beneficial. If the non-inferiority of the experimental arm in terms of the primary endpoint is not demonstrated, the SIB56 method will be considered a useful treatment. | PMC10626703 |
Interim analysis and monitoring | Two interim analyses considering multiplicity will be conducted using the Lan and DeMets method along with the O’Brien and Fleming-type alpha spending function [In the first interim analysis, if both the non-inferiority and superiority of the experimental arm over the standard arm in terms of the primary endpoint are demonstrated with an adjusted alpha level, the study will be terminated. If the non-inferiority of the experimental arm at the primary endpoint is not demonstrated or its non-inferiority but not superiority is demonstrated, the study will be continued. In the second interim analysis, the study will be terminated if the non-inferiority of the experimental arm to the standard arm in the primary endpoint is demonstrated with an adjusted alpha level. If the non-inferiority of the experimental arm in the primary endpoint is not demonstrated, the study will be continued. In both interim analyses, if the point estimate of the hazard ratio of TTF1 exceeds the non-inferiority margin (1.32), the study will be terminated because of futility.In-house monitoring will be performed every 6 months by the JCOG Data Center to evaluate and improve study progress, data integrity, and patient safety. All enrolled patients are evaluated for compliance with the RT protocol at the time of completion of RT. The purpose of this assessment is to confirm whether the actual treatment at each participating institution is performed according to the protocol regulations and to provide feedback for the treatment of subsequently enrolled patients. | PMC10626703 |
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Cases review | RECURRENCES, RECURRENCE, HEAD AND NECK CANCER | Cases of patients who undergo salvage surgery after the completion of the protocol treatment will be presented at the JCOG Head and Neck Cancer Study Group conference held every 6 months to review indications for surgery and the appropriateness of the surgical procedure. Cases with regional recurrence will be reviewed at the JCOG Radiation Therapy Study Group conference every 6 months to investigate whether the regional recurrences occur inside or outside the elective nodal sites. The RT plan, imaging data, and clinical course during the protocol treatment will be evaluated in each case. | PMC10626703 |
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Discussion | toxicity, toxicities, LA-SCCHN, deaths, JAVELIN, ototoxicity | ADVERSE EVENTS, DISEASE, OTOTOXICITY | The current CRT regimen for patients with LA-SCCHN is associated with severe late adverse events, decreased QOL, and increased noncancer-related deaths in long-term survivors. The ideal treatment for patients with LA-SCCHN is a modality that is satisfactory for both disease control and the patients’ daily lives. Our trial addresses the question of whether a reduced dose of RT to the prophylactic field without reducing the dose to the target lesion and a concurrent CDDP dose is non-inferior to standard-dose prophylactic RT. Reducing the dose to the prophylactic field is expected to reduce late toxicity by minimizing the irradiation of normal organs.If our study demonstrates that the experimental arm could achieve fewer adverse events without a reduction in efficacy, reduced-dose prophylactic IMRT could be a new standard method of definitive CRT for LA-SCCHN. Numerous clinical studies have investigated the combination strategy of RT and immune checkpoint inhibitors (ICIs). However, the JAVELIN head and neck 100 trial [One significance of this trial is the prospective follow-up for late toxicities, focusing on swallowing function, hearing function, and thyroid functions. Of these, ototoxicity is caused by cochlear toxicity due to CDDP and irradiation, and is irreversible, and is likely to reduce the QOL in patients treated with CRT [ | PMC10626703 |
Participating institutions | Cancer | INFECTIOUS DISEASES, SHIGA, HEAD AND NECK CANCER, CANCER | This study is a within-JCOG intersubgroup study collaborating between the Radiation Therapy Study Group and the Head and Neck Cancer Study Group. The participating institutions are those that meet the criteria for RT quality control and quality assurance and have approval from the JCOG Radiation Therapy Committee to perform IMRT. All participants will be recruited from the following 52 hospitals: Saitama Cancer Center, Sapporo Medical University, Aichi Cancer Center, Kindai University Hospital, Hiroshima University, Tochigi Cancer Center, Hyogo Cancer Center, Niigata Cancer Center, Tohoku University, Kobe University, Okinawa Prefectural Chubu Hospital, Yokohama City University Hospital, Osaka International Cancer Institute, Iwate Medical University, National Hospital Organization Tokyo Medical Center, National Canter Center Hospital, Tokai University, Kyoto University, National Hospital Organization Shikoku Cancer Center, Miyagi Cancer Center, Chiba University, Tokyo Medical and Dental University, National Cancer Center Hospital East, Hokkaido University, Tokyo Medical University Hospital, Nara Medical University, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, University of Tokyo, Jichi Medical University, Fujita Health University, Nagoya University, Kyushu University, Saitama Medical University International Medical Center, Showa University, NHO Kyushu Cancer Center, Institute of Medicine, University of Tsukuba, Kansai Medical University Hospital, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, The Jikei University Hospital, Shizuoka Cancer Center, Kitasato University School of Medicine, Okayama University Hospital, Osaka University, Kochi Medical School Hospital, Osaka Metropolitan University Hospital, Juntendo Hospital, Nihon University Itabashi Hospital, Chiba Cancer Center, University of Yamanashi Hospital, Keio University, Shiga General Hospital, and Kanagawa Cancer Center. | PMC10626703 |
Acknowledgements | ONCOLOGY, ADVERSE EVENT, HEAD AND NECK CANCER | The authors thank in advance all the patients, investigators and institutions involved in this trial. The authors thank Ms. Shoko Todo and Ms. Naoko Otomo in JCOG Data Center for data management for this trial, and Ms. Harumi Suzuki in Data and Safety Monitoring Committee Office of the JCOG for support to adverse event reporting. We thank Editage (A full list of consortium members and their affiliations for Japan Clinical Oncology Group Radiation Therapy Study Group and Japan Clinical Oncology Group Head and Neck Cancer Study GroupJapan Clinical Oncology Group Radiation Therapy Study GroupTomoya Yokota
Japan Clinical Oncology Group Head and Neck Cancer Study GroupTomoya Yokota
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Authors' contributions | The study concept was conceived by TY, SZ, TK, and NK. The study was designed by TY, SZ, TK, NK, RT, YF, and KW. TY, SZ, TK, and NK are the primary authors of the protocol; however, all authors have contributed in this regard to some extent. TY, SZ, TK, and NK wrote the manuscript. RT, YF, NK, and KW play central roles in radiological physics, procedures for the evaluation of the swallowing function, quality-of-life assessment, and procedures for the evaluation of the hearing function, respectively. All the authors have read and approved the final manuscript. | PMC10626703 |
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Funding | Cancer | CANCER | This study was supported by The Japan Agency for Medical Research and Development (AMED) (JP22ck0106751) and the National Cancer Center Research and Development Funds (2020-J-3, 2023-J-03). The funding body has peer reviewed the study design. However, the funding agencies had no influence on the study design and data collection, analysis, or interpretation. | PMC10626703 |
Availability of data and materials | Not applicable. | PMC10626703 |
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Declarations | PMC10626703 |
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Ethics approval and consent to participate | CRB, Cancer | CANCER | The study protocol was approved by the National Cancer Center Hospital East Certified Review Committee (CRB) on January 2021 first (CRB3180009). Modifications to the study protocol will be communicated to the CRB. The CRB will revise the informed consent materials to be given to participants and adapt them in accordance with the institution’s guidelines. The study protocol was revised as version 1.4.0 as of March 2023. Participants’ personal information such as names and addresses will not be collected.All patients will be required to provide written informed consent to participate.This trial is performed in accordance with the Clinical Trials Act, the Enforcement Rules for the Clinical Trials Act and relevant notifications published by Japan’s Ministry of Health, Labour, and Welfare and the modified Act on the Protection of Personal Information as well as the Declaration of Helsinki. | PMC10626703 |
Consent for publication | All patients will be required to provide written informed consent for the publication of the results. | PMC10626703 |
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Competing interests | The authors declare no competing interests. | PMC10626703 |
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References | PMC10626703 |
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Key Points | PMC10034662 |
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Question | depression | Is practitioner-supported mindfulness-based cognitive therapy self-help (MBCT-SH) clinically effective and cost-effective compared with practitioner-supported cognitive behavioral therapy self-help (CBT-SH) for adults experiencing mild to moderate depression? | PMC10034662 |
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Findings | depression, depressive | In this randomized clinical trial of 410 participants with mild to moderate depression, practitioner-supported MBCT-SH led to significantly greater reductions in depressive symptom severity at 16 weeks postrandomization compared with practitioner-supported CBT-SH. The probability of MBCT-SH being cost-effective compared with CBT-SH exceeded 95%. | PMC10034662 |
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Meaning | depression, depressive | Practitioner-supported MBCT-SH for mild to moderate depression was clinically effective and cost-effective compared with currently recommended practitioner-supported CBT-SH and should be made routinely available to adults experiencing mild to moderate depression.This randomized clinical trial evaluates whether practitioner-supported mindfulness-based cognitive therapy self-help is superior to practitioner-supported cognitive behavioral therapy self-help at reducing depressive symptom severity at 16 weeks postrandomization among patients with mild to moderate depression. | PMC10034662 |
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Importance | depression, Depression | Depression is prevalent. Treatment guidelines recommend practitioner-supported cognitive behavioral therapy self-help (CBT-SH) for mild to moderate depression in adults; however, dropout rates are high. Alternative approaches are required. | PMC10034662 |
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Objective | depressive, depression | To determine if practitioner-supported mindfulness-based cognitive therapy self-help (MBCT-SH) is superior to practitioner-supported CBT-SH at reducing depressive symptom severity at 16 weeks postrandomization among patients with mild to moderate depression and secondarily to examine if practitioner-supported MBCT-SH is cost-effective compared with practitioner-supported CBT-SH. | PMC10034662 |
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Design, Setting, and Participants | depression | RECRUITMENT | This was an assessor- and participant-blinded superiority randomized clinical trial with 1:1 automated online allocation stratified by center and depression severity comparing practitioner-supported MBCT-SH with practitioner-supported CBT-SH for adults experiencing mild to moderate depression. Recruitment took place between November 24, 2017, and January 31, 2020. The study took place in 10 publicly funded psychological therapy services in England (Improving Access to Psychological Therapies [IAPT]). A total of 600 clients attending IAPT services were assessed for eligibility, and 410 were enrolled. Participants met diagnostic criteria for mild to moderate depression. Data were analyzed from January to October 2021. | PMC10034662 |
Interventions | Participants received a copy of either an MBCT-SH or CBT-SH workbook and were offered 6 support sessions with a trained practitioner. | PMC10034662 |
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Main Outcomes and Measures | The preregistered primary outcome was Patient Health Questionnaire (PHQ-9) score at 16 weeks postrandomization. The primary analysis was intention-to-treat with treatment arms masked. | PMC10034662 |
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Results | depression, −2.6 | Of 410 randomized participants, 255 (62.2%) were female, and the median (IQR) age was 32 (25-45) years. At 16 weeks postrandomization, practitioner-supported MBCT-SH (n = 204; mean [SD] PHQ-9 score, 7.2 [4.8]) led to significantly greater reductions in depression symptom severity compared with practitioner-supported CBT-SH (n = 206; mean [SD] PHQ-9 score, 8.6 [5.5]), with a between-group difference of −1.5 PHQ-9 points (95% CI, −2.6 to −0.4; | PMC10034662 |
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Conclusions and Relevance | depression | In this randomized clinical trial, practitioner-supported MBCT-SH was superior to standard recommended treatment (ie, practitioner-supported CBT-SH) for mild to moderate depression in terms of both clinical effectiveness and cost-effectiveness. Findings suggest that MBCT-SH for mild to moderate depression should be routinely offered to adults in primary care services. | PMC10034662 |
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Trial Registration | isrctn.org Identifier: | PMC10034662 |
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Introduction | depression, Depression | Depression has a lifetime prevalence of 10.8% worldwide.To widen access, cognitive behavioral therapy self-help (CBT-SH) supported by a trained practitioner is recommended in the treatment of mild to moderate depression in national treatment guidelines.Mindfulness-based cognitive therapy (MBCT) is an in-person group program recommended in national treatment guidelines for depression.Practitioner-supported MBCT-SH is one solution to widen access. MBCT-SH overcomes the barrier of fixed group session times, enabling people with inflexible work or domestic commitments to engage at a convenient time and place. Evidence is emerging supporting the potential of MBCT-SH for depression. A randomized clinical trial (RCT) with students found that unsupported-MBCT-SH was superior compared with waitlist in reducing depression symptom severity,We report findings from an RCT examining the clinical and cost-effectiveness of practitioner-supported MBCT-SH compared with practitioner-supported CBT-SH for adults experiencing mild to moderate depression. The prespecified primary hypothesis | PMC10034662 |
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Method | PMC10034662 |
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Design | depression | This was a multicenter, pragmatic, assessor- and participant-blinded (participants were unaware of which intervention was hypothesized to be superior), parallel, superiority RCT with 1:1 allocation comparing practitioner-supported MBCT-SH with CBT-SH for adults experiencing mild to moderate depression in 10 Improving Access to Psychological Therapies (IAPT) services in England. The trial was preregistered, and the trial protocol was published. | PMC10034662 |
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Participants | Inclusion criteria were that participants (1) were 18 years or older; (2) met criteria on the Clinical Interview Schedule–Revised (CIS-R) | PMC10034662 |
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