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Background | allergic rhinoconjunctivitis | ALLERGIC RHINOCONJUNCTIVITIS | Edited by: Jamie Marie Orengo, Regeneron Pharmaceuticals, Inc., United StatesReviewed by: Sang Min Lee, Gachon University Gil Medical Center, Republic of Korea; Hideyuki Kawauchi, Shimane University, Japan†These authors have contributed equally to this workPediatric allergic rhinoconjunctivitis has become a public concern with an increasing incidence year by year. Conventional subcutaneous immunotherapy (SCIT) has long treatment time, high cost and poor compliance. The novel immunotherapy significantly shortens the course of treatment by directly injecting allergens into cervical lymph nodes, which can perform faster clinical benefits to children. | PMC10428014 |
Objective | By comparing with SCIT, this study aimed to evaluate the long-term efficacy and safety of intra-cervical lymphatic immunotherapy (ICLIT). | PMC10428014 |
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Methods | dust mite allergen, dust mite allergy, pain, allergic rhinoconjunctivitis | ADVERSE REACTIONS, SECONDARY, TSS, ALLERGIC RHINOCONJUNCTIVITIS | This is a prospective randomized controlled study. A total of 50 allergic rhinoconjunctivitis children with dust mite allergy was randomly divided into ICLIT group and SCIT group, receiving three cervical intralymphatic injections of dust mite allergen or three years of subcutaneous injection, separately. Primary outcomes included total nasal symptom scores (TNSS), total ocular symptom scores (TOSS), total symptom scores (TSS), total medication scores (TMS), and total quality of life score. Secondary outcomes included pain perception and adverse reactions during treatment. Other secondary outcome was change in | PMC10428014 |
Results | allergic symptoms, systemic adverse reactions, pain | ADVERSE REACTIONS, TSS | Both groups had significantly decreased TNSS, TOSS, TSS, TMS, and total quality of life score after 36 months of treatment (p<0.0001). Compared with SCIT, ICLIT could rapidly improve allergic symptoms (p<0.0001). The short-term efficacy was consistent between the two groups (p=0.07), while the long-term efficacy was better in SCIT group (p<0.0001). The pain perception in ICLIT group was lower than that in SCIT group (p<0.0001). ICLIT group was safer. Specifically, the children had only 3 mild local adverse reactions without systemic adverse reactions. The SCIT group had 14 systemic adverse reactions. At last, the serum Derp and Derf-specific IgE levels in ICLIT and SCIT groups decreased 3 years later (p<0.0001). | PMC10428014 |
Conclusion | allergic symptoms, pain | ICLIT could ameliorate significantly the allergic symptoms in pediatric patients with an advantage in effectiveness and safety, besides an improved life quality including shortened period of treatment, frequency of drug use and pain perception. | PMC10428014 |
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Clinical trial registration | PMC10428014 |
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Introduction | respiratory tract allergy, allergic rhinoconjunctivitis, Allergic rhinoconjunctivitis, dust mite allergy, Dust mite-induced allergy, allergic reactions | ALLERGIC REACTION, ALLERGIC RHINOCONJUNCTIVITIS | Allergic rhinoconjunctivitis refers to immunoglobulin E (IgE)-mediated transmitter release triggered locally by inhaled allergens in the nasal mucosa, and type I allergic reactions involving multiple cells and immunoactive factors (Dust mite-induced allergy accounts for 85% of all patients with respiratory tract allergy, of which As a conventional immunotherapy, subcutaneous immunotherapy (SCIT) has been confirmed by several meta-analyses and systematic reviews in terms of its sustained benefit and long-term clinical efficacy on allergic rhinoconjunctivitis children (Intra-cervical lymphatic immunotherapy (ICLIT) is a novel immunotherapy for patients with dust mite allergy, and its short-term efficacy and safety have been proved in clinical studies (This prospective randomized controlled study aimed to evaluate the long-term efficacy and safety of ICLIT among children with allergic rhinoconjunctivitis. | PMC10428014 |
Materials and methods | PMC10428014 |
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Study population | itching, Allergic Rhinitis, dust mite-induced allergic rhinoconjunctivitis, nasal itching, nasal congestion | ASTHMA, ALLERGIC RHINITIS | A total of 50 pediatric patients at outpatient department of otorhinolaryngology were recruited in our hospital from June 2018 to September 2018, and were then randomly divided into ICLIT group and SCIT group with a ratio of 1:1.The inclusion criteria were as follows: (1) aged 6 to 17 years; (2) confirmed history of dust mite-induced allergic rhinoconjunctivitis according to Allergic Rhinitis and its Impact on Asthma (ARIA); (3) main symptoms included four nasal symptoms (i.e., nasal itching, sneezing, runny nose, and nasal congestion) and two ocular symptoms (i.e., eye itching and lacrimation) ( | PMC10428014 |
Randomization | Eligible patients were randomly allocated in a 1:1 ratio to ICLIT or SCIT group. With random-number tables, we selected 50 random numbers in sequence starting from any random number and put them in numerical order. Numbers 1-25 and 26-50 were divided into ICLIT group and SCIT group, respectively. The randomization was conducted using SPSS, Version 27.0 (SPSS Inc., Chicago, IL, USA). | PMC10428014 |
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Study design | allergic symptoms, allergy, dust mite allergen extract, ’ pain | ADVERSE REACTIONS, ALLERGY | This is a prospective randomized controlled study with 25 patients receiving ICLIT (Study design. The trial included 1 pre-treatment screening visit, 3 treatment visits, 5 follow-up visits within 36 months after treatment. ICLIT, intra-cervical lymphatic immunotherapy; SCIT, subcutaneous immunotherapy Eav, eosinophils absolute value; SPT, skin prick test; tIgE, total IgE; sIgE, specific IgE.Eligibility was determined at the first visit when patients were required for a questionnaire including allergic symptoms, use of rescue medication, and quality of life. Also, The qualification of patients was determined by SPT and collecting blood samples of patients for evaluating eosinophils absolute value, total serum dust mite IgE and Derp and Derf-specific IgE. Based on the results of the allergy tests, and in accordance with the principle of randomization, patients received the first injection of Arroger-standardized dust mite allergen extract (Novo- Helisen-Depot, Allergopharma GmbH &Co. KG, Reinbek, Germany) with the specific injection regimen shown in 2.4. Patients’ pain perception and adverse reactions that occurred need to be recorded throughout the treatment. Patients were followed-up by hospital visit or phone interview for a questionnaire related to the first visit at 3 month, 6 month,12 month, 24 month and 36 month after treatment. Besides, SPT and blood sample were required at 12-month and 36-month follow-up so as to assess the effectiveness of treatment. | PMC10428014 |
Treatment process | PMC10428014 |
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ICLIT group | Injections were performed under color Doppler ultrasound guidance using a 7-gauge needle, three times on the same side. Under strict aseptic procedures, 0.1ml (50TU) of 500TU/mL (concentration grade 2) of alum-adsorbed allergen extracts was injected into the superficial II or III area cervical lymph nodes (approximately 0.5-0.8 cm in size), after 28 days (4 weeks) and 56 days (8 weeks), the second and third injections were the same. Treatment interval was 4 weeks for a total period of 2 months( | PMC10428014 |
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SCIT group | The injection site was either lateral to the distal third of the upper arm or dorsal to the middle third of the forearm, and treatment consisted of two phases which were dose accumulation and dose maintenance.Allergen injection with a starting dose of 50 TU/mL was injected once a week for up to 15 weeks. In the first 12 weeks, patients were injected with (1) 0.1mL, 0.2mL, 0.4mL, and 0.8mL of allergen at 50 TU/mL (concentration grade 1); (2) 0.1mL, 0.2mL, 0.4mL, and 0.8mL of allergen at 500 TU/mL (concentration grade 2); (3) 0.1mL, 0.2mL, 0.4mL, and 0.6mL of allergen at 5000 TU/mL (concentration grade 3). In 13, 14 and 15 week, patients were injected with 0.8mL, 1.0mL and 1.0mL of allergen at 5000 TU/mL (concentration grade 3), respectively. Dose maintenance phase started after 15 weeks, during which the allergen injection 1.0mL dose of 5000 TU/mL (concentration grade 3) was kept unchanged, and the interval between each injection was 4 weeks with the total treatment course of 3 years. Evaluations of SCIT were in the same way as ICLIT. | PMC10428014 |
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Observation indicators | PMC10428014 |
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Primary indicators | allergic symptoms | Primary outcomes were assessed before treatment (baseline), at 3 month, 6 month, 12 month, 24 month and 36 month, including (1) change in allergic symptoms associated with dust mite was assessed by a four-scale system where 0=no symptoms, 1=mild symptoms, 2=moderate symptoms, and 3=most severe symptoms ( | PMC10428014 |
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Secondary indicators | pain | ADVERSE REACTIONS | Secondary outcomes included (1) pain perception during treatment was assessed by patients themselves (or assisted by their families) after each treatment using visual analogue scale (VAS). Scores were marked on the ruler with cartoon icon of facial expressions, ranging from 0 to 10 where 0=painless and 10=most painful. Total score was collected after the treatment (ICLIT ranged from 0 to 30 points and SCIT ranged from 0 to 520 points); (2) safety assessment was performed for each treatment by using a safety score table to record both local and systemic adverse reactions during treatment in all patients. | PMC10428014 |
Other secondary indicators | allergy, Peripheral venous blood | SECONDARY, ALLERGY | Other secondary outcomes were changes in circulating immunoglobulin level (serum dust mite-specific IgE) at baseline, 24 month and 36 month. Peripheral venous blood was taken and was separated by centrifugation at room temperature for 7 minutes at 3500 r/min, and then was stored at -80°C pending analysis. Serum Derp and Derf-specific IgE was detected using Thermo phadia 250 automatic fluorescence immunoassay analyzer and ImmunoCAP Specific IgE enzyme-labeled secondary antibody kit. Allergen criteria for detection were Derp and Derf positive with other allergens negative. The test results were graded from 0 to 6 according to Derp and Derf-specific IgE concentration. Grade 0 was defined as sIgE < 0.35 kU/L; Grade 1 was defined as sIgE ≥ 0.35 kU/L; Grade 2 was defined as sIgE ≥ 0.70 kU/L; Grade 3 was defined as sIgE ≥ 3.5 kU/L; Grade 4 was defined as sIgE ≥ 17.5 kU/L;Grade 5 was defined as sIgE ≥ 50 kU/L; Grade 6 was defined as sIgE ≥ 100 kU/L.Besides, Grade 0 indicated allergy (-) while Grade 1-6 indicated varying degrees of allergy,and Grade 1 and above was considered positive for sIgE. | PMC10428014 |
Ethics and permissions | The institutional review board of the First People’s Hospital of Foshan approved this randomized controlled study (approval number [2018]-10) and all participants or their families signed informed consent. This study was registered in Chinese Clinical Trial Registry (clinical trial registration number: ChiCTR1800017130). | PMC10428014 |
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Statistical analysis | Normal distribution was decided by D’Agostino-Pearson omnibus normality test.Continuous variables were expressed as mean (standard deviation) and categorical variables were presented as n (%).Intragroup comparation was evaluated by paired t test or Wilcoxon Signed Rank test for normally distributed and non-normally distributed continuous variables,respectively. Numerical differences between two groups were assessed by unpaired t test or Mann-Whitney U test for normally distributed and non-normally distributed continuous variables, respectively.Changes in allergen species and SPT results were assessed by Fisher’s exact test or Pearson chi-square test. The threshold for significance was P<0.05. All statistical analyses were conducted using GraphPad Prism software, Version 9.0 (GraphPad Software, San Diego, California, USA). | PMC10428014 |
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Results | PMC10428014 |
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General information | A total of 50 eligible patients were randomly divided into ICLIT group (n=25) and SCIT group (n=25) (Research flow chart. ICLIT, intra-cervical lymphatic immunotherapy; SCIT, subcutaneous immunotherapy.As shown in Baseline characteristics by treatment group.SPT, skin prick test; SI, skin index; ++, 0.5≤SI<1;+++, 1≤SI<2;++++, SI≥2。 Analysis and comparison of two groups of data: continuous variable data in accordance with normal distribution adopts unpaired t test, and non normal distribution adopts Mann-Whitney U test; Fisher's exact test or Pearson chi-square test is used for categorical variable data. | PMC10428014 |
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Primary outcomes | PMC10428014 |
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ICLIT had a significant long-term effect | TOSS | TSS | At baseline in ICLIT group, TNSS was 10.3 (1.7), TOSS was 2.4 (0.8), TSS was 12.3 (1.9), TMS was 3.5 (1.3), and total quality of life score was 92.8 (4.9). At baseline in SCIT group,TNSS was 10.4 (1.3), TOSS was 2.6 (1.2), TSS was 12.8 (2.1), TMS was 3.1 (1.0), and total quality of life score was 92.3 (7.5). No significant differences were found between the two groups in the above scoring system (p > 0.05). At 3, 6, 12, 24, and 36 month of treatment, scores at each time point were shown as follows. TNSS in ICLIT group were 7.7 (1.6), 6.7 (1.7), 6.1 (2.2), 5.7 (2.6), and 5.8 (3.3). TOSS in ICLIT group were 2.1 (0.5), 2.0 (0.8), 1.7 (0.7), 1.7 (0.9), and 1.6 (1.0). TSS in ICLIT group were 9.4 (1.7), 8.4 (2.0), 7.9 (2.9), 7.5 (3.3), and 7.8 (4.1). TMS in ICLIT group were 2.7 (1.2), 2.3 (1.0), 1.7(1.1), 1.3 (0.9), and 1.7 (1.2).Total quality of life scores in ICLIT group were 73.3 (9.1), 61.4 (15.2), 45.5 (24.0), 47.2 (25.3), and 45.3 (26.3). TNSS in SCIT group were 10.2 (1.3), 9.0 (1.4), 7.5 (1.5), 4.3 (1.6), 3.0 (2.8). TOSS in SCIT group were 2.5 (1.1), 2.4 (1.1), 1.9 (0.8), 1.2 (0.9), 0.7 (1.0). TSS in SCIT group were 12.5 (2.0), 11.3 (2.0), 9.1 (1.9), 5.4 (2.2), 3.6 (3.7). TMS in SCIT group were 2.9 (0.9), 2.2 (0.7), 1.4 (0.6), 0.6 (0.8), 0.3 (0.8). Total quality of life scores in SCIT group were 86.9 (6.8), 69.3 (7.5), 48.6 (11.9), 30.4 (11.6), 17.6 (16.1). Compared with baseline, children in both groups showed significant decrease in TSS (Comparison of overall efficacy between ICLIT and SCIT. Changes in TSS | PMC10428014 |
ICLIT improved the overall efficacy more quickly | TSS | At 3 month of treatment, TSS in ICLIT group and SCIT group was 9.4 (1.7) and 12.5 (2.0), separately. Change of TSS in ICLIT group was 2.9 (1.2) with a decreased rate of 22.7% and change of TSS in SCIT group was 0.3 (0.5) with a decreased rate of 2.2%. ICLIT group showed significant degree of symptom improvement compared with SCIT group (p < 0.0001) ( | PMC10428014 |
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ICLIT was not as effective as SCIT in a long term | allergic symptoms | TSS | Short-term efficacy and long-term efficacy were observed for allergic symptoms at the first and third year after treatment in both groups. At baseline, there was no significant difference in TSS between ICLIT group (12.3 (1.9)) and SCIT group (12.8 (2.1)). At 1 year after treatment, TSS in ICLIT and SCIT group was 7.9 (2.9) and 9.1 (1.9), separately, indicating the significant symptom improvement in both groups. At 3 year after treatment, TSS in ICLIT and SCIT group was 7.8 (4.1) and 3.6 (3.7), separately, indicating the significant symptom improvement in both groups. In summary, ICLIT (ICLIT=4.7, SD=2.9) and SCIT (SCIT=3.6, SD=1.9) shared similar short-term efficacy (Comparison of short-term (1 year later) and long-term (3 years later) effects between ICLIT and SCIT. Compared with the two groups, | PMC10428014 |
ICLIT significantly improved the symptoms of most allergic rhinoconjunctivitis children | allergic symptoms | Short-term efficacy and long-term efficacy were observed for allergic symptoms at the first and third year after treatment only in ICLIT group. After undergoing ICLIT, 23 patients had significant symptom improvement (p < 0.0001) in both short-term (1 year after treatment) and long-term (3 year after treatment) (Symptom changes after ICLIT treatment. Compared with baseline, | PMC10428014 |
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Secondary outcomes | PMC10428014 |
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ICLIT had less pain | Pain, pain |
Pain perception were compared between patients in ICLIT and SCIT groups. The total pain score of patients injected into cervical lymph nodes and veins was recorded. ICLIT, intra-cervical lymphatic immunotherapy; SCIT, subcutaneous immunotherapy. | PMC10428014 |
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ICLIT had higher safety | redness, itching, wheezing, rash, urticaria, rhinitis, asthma, anaphylactic shock, hypotension, Systemic adverse reactions, muscular vascular edema | ADVERSE REACTIONS, ADVERSE EVENT, URTICARIA, INDURATION, RHINITIS, ASTHMA ATTACK, ASTHMA, ANAPHYLACTIC SHOCK |
Adverse events associated with intra-cervical lymphatic and subcutaneous injections.Local adverse reactions mainly include redness, itching, induration, rash, etc. at the injection site. Mild local adverse reactions refer to a diameter of ≤ 4 cm, moderate local adverse reactions refer to a diameter of>4 cm and>15 minutes, both of which disappear within 24 hours. Severe local adverse reactions with a diameter of>4 cm can lead to pseudopodia, which can occur immediately or within 15 minutes; Systemic adverse reactions are divided into 5 levels: Level 1: no systemic reactions (asymptomatic), Level 2: mild systemic reactions (rhinitis, local urticaria, and mild asthma), Level 3: moderate systemic reactions (slow onset, systemic urticaria, and/or moderate asthma), Level 4: severe systemic reactions (rapid onset, systemic urticaria, muscular vascular edema, and/or severe asthma) Grade 5: anaphylactic shock (rapid onset of systemic urticaria, flushing, itching, asthma attack, wheezing, hypotension, etc.). The data of the two groups are consistent with categorical variable, and Fisher's exact test is used for data analysis and comparison. | PMC10428014 |
Other secondary outcomes | PMC10428014 |
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ICLIT significantly decreased serum dust mite-specific IgE levels | sIgE was an important pathogenic antibody of AR, there were no significant differences in serum Derp and Derf sIgE between the two groups at baseline. After 3 years of treatment, serum Derp and Derf sIgE levels significantly decreased in both groups, but no significant difference in the changes was found between the two groups (Changes of serum Derp sIgE | PMC10428014 |
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Discussion | redness, dyspnea, itching, hoarseness, allergic rhinoconjunctivitis, ’, local adverse reactions, dysphonia, Allergic Rhinitis, allergic symptoms, obstruction of the airway, systemic adverse reactions, allergic diseases | ADVERSE REACTIONS, LARYNGEAL EDEMA, ALLERGY, ADVERSE EVENTS, AIRWAY OBSTRUCTION, MINOR, ALLERGIC RHINITIS, ALLERGIC RHINOCONJUNCTIVITIS, ADVERSE EFFECTS, ASTHMA, IMMUNE TOLERANCE | In recent years, pediatric allergic rhinoconjunctivitis has become a global health issue and one of the most concerned allergic diseases. As the first-line treatment recommended by Allergic Rhinitis and its Impact on Asthma (ARIA) guideline and European Academy of Allergy and Clinical Immunology (EAACI) guideline (In 2008, Senti et al. (In this study, we observed significant decreases in TNSS and TOSS, less dependence of rescue drugs, and improvements of quality of life at 3, 6 and 12 month after treatments. Also,at 24 and 36 month after treatments, patients in ICLIT and SCIT maintained the improvement of symptoms and quality of life, indicating that ICLIT had sustained and stable efficacy as SCIT.After 1 month of treatments, allergic rhinoconjunctivitis patients in ICLIT group had better improvements than SCIT group in terms of allergic symptoms, dependence on rescue drugs and quality of life, indicating that ICLIT could rapidly mediate immune tolerance. An animal experiment injected an equivalent amount of allergen into one area and found that the dose injected into the lymph nodes was approximately 100-fold higher than that injected subcutaneously into the vein (We compared both short-term and long-term efficacy between ICLIT group and SCIT group.It was found that the two groups had comparable 1-year short-term efficacy and consistent production of immune tolerance. Besides, ICLIT group had poorer 3-year long-term efficacy than SCIT group. After detailed investigation, patients in ICLIT group could be divided into 3 clusters. Cluster 1 referred to symptom improvement, including 14 patients with significant symptom improvement in both short-term and long-term after treatment. Cluster 2 referred to ineffectiveness, including 3 patients without significant symptom improvement in short-term or long-term after treatment. Also, they had no irritation response to ICLIT throughout the treatment period. Considering that these patients were insensitive to immunotherapy, molecular mechanisms could be investigated in this group of children in the future. Cluster 3 referred to poor efficacy, including 6 patients with significant symptom improvement in short-term, but poor symptom control in long-term. The larger proportion of Cluster 3 resulted in the lower long-term symptom control in ICLIT group than that in SCIT group. After analysis of symptom improvement, we found that they actually had a higher sensitivity to ICLIT treatment at the beginning but gradually decreasing sensitivity over the long term, which was similar with the traditional immunotherapy. Tseng et al. (Safety remains a major concern during immunotherapy among pediatric patients with allergic rhinoconjunctivitis. Severe local adverse reactions and systemic adverse reactions may cause laryngeal edema, resulting in partial or complete obstruction of the airway, leading to life-threatening adverse events such as hoarseness, dysphonia, and even dyspnea. Therefore, before treatment, we should carry out emergency plans, the main emergency equipment includes: lathes that can lie flat, bedside breathing, pulse, blood pressure and blood oxygen saturation monitors, syringes, needles, intravenous infusion pumps and other items used to open venous channels, oxygen tanks, suction tubes, stethoscopes, laryngoscopes, tracheal tubes, masks, respiratory air bags, dental pads and other intubation items and instruments to relieve airway obstruction; The main emergency drugs include: antihistamines, rapid-acting β2 agonists, epinephrine solution (1:1000), and other emergency drugs. In this study, 23 patients with ICLIT underwent a total of 69 injections, and only 3 mild local adverse reactions occurred, 1 lymph node swelling/irritation, 1 itching around the puncture site, and 1 redness around the puncture site.All of them relieved within 24 hours without using emergency equipment or medication. There were no moderate to severe local adverse events or systemic adverse events during treatment. This trial is the same as ILIT causing only minor adverse effects in most previously reported studies (The principle of immunotherapy is to reduce the pathogenic antibody IgE, especially the serum specific IgE antibody, and to increase the protective antibody IgG at the same time. Studies have shown that specific IgE competes with IgG4 antibody for binding allergens, and successful SCIT refers to an increase in serum specific IgE at the beginning and a slow decrease for a long time period. In this study, we found that levels of Derp IgE and Derf IgE decreased after treatment of ICLIT and SCIT, and the degree of reduction was similar between the two treatments.There are some limitations in this study. First, this study is open-label study, so patients’ and investigators’ expectation to ICLIT and SCIT (placebo effect) and spontaneous improvement of natural course might affect on the study. Additionally,this was a single-center prospective randomized controlled study with a relatively small sample size. Second, we only investigated changes in IgE levels before and after treatment and did not include the protective antibody IgG4. Therefore, multicenter study with larger sample size is required in the future, as well as that for the molecular mechanisms of ICLIT-induced immune tolerance. ICLIT may become a new option among all AIT treatments. | PMC10428014 |
Conclusion | allergic symptoms, allergic rhinoconjunctivitis, pain | ALLERGIC RHINOCONJUNCTIVITIS | This study first demonstrated that ICLIT could significantly relieve the allergic symptoms, improve the safety and compliance, and reduce the pain response among children with allergic rhinoconjunctivitis. In summary, ICLIT was a novel immunotherapy that could improve the clinical symptoms, save time and economic costs of children with allergic rhinoconjunctivitis. | PMC10428014 |
Data availability statement | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors. | PMC10428014 |
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Ethics statement | The studies involving human participants were reviewed and approved by the institutional review board of the First People’s Hospital of Foshan. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. | PMC10428014 |
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Author contributions | QW wrote this manuscript and data analysis, KW independently completed the research design and concept, YQ collected data and followed up patients, YX and YG processed statistical data on the manuscript, WH, YL, and QY revised and proofread the manuscript, RZ reviewed and provided important guidance on the manuscript, JT solved complex issues in the manuscript, and made final review and finalization. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. | PMC10428014 |
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Acknowledgments | We would like to express our gratitude to Dr. Meihua Liu from the Otolaryngology Immunotherapy Center of Foshan First People's Hospital for his hard work in Intra-cervical lymphatic immunotherapy. We would also like to express our gratitude to Dr. Yue Xiong, an ultrasound doctor, for patiently administering Intra-cervical lymphotic injections to each patient. We appreciate the valuable comments and suggestions provided by the reviewers, which have enriched our manuscript and improved its quality. We sincerely thank every staff member of Frontiers Immunology Production Office. | PMC10428014 |
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Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10428014 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10428014 |
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References | PMC10428014 |
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Objective | T2DM | TYPE 2 DIABETES MELLITUS, CARDIOVASCULAR DISEASES | Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular diseases. This study aimed to assess the effects of soymilk plus probiotics co-administration on cardiovascular risk factors in T2DM patients. | PMC9912676 |
Methods | T2DM | One hundred patients with T2DM (aged 40–75 years old) were randomly assigned into 4 groups (soymilk + probiotics supplement, soymilk + placebo, conventional milk + placebo, and probiotics supplement) for 6 weeks. Standard protocols were followed for the collection of fasting blood samples, dietary intakes, and anthropometric measurements. | PMC9912676 |
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Results | It was shown that soymilk + probiotics consumption significantly decreased diastolic blood pressure (DBP) ( | PMC9912676 |
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Conclusion | T2DM | Soymilk and probiotics consumption might improve some cardiovascular risk factors in patients with T2DM. However, possible synergic effects while consumption of soymilk plus probiotics supplement didn’t show in this study which warranted further research. | PMC9912676 |
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Keywords | PMC9912676 |
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Introduction | cancer, T2DM, bone loss | CARDIOVASCULAR DISEASE, BONE LOSS, KIDNEY DISEASE, CANCER, TYPE 2 DIABETES MELLITUS | Globally, the number of people with type 2 diabetes mellitus (T2DM) is increasing rapidly [Soy and soy products have been shown to have protective effects against a variety of outcomes, including cardiovascular disease, kidney disease, bone loss, cancer, and menopausal symptoms [ | PMC9912676 |
Methods | PMC9912676 |
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Design and participants | diabetic, T2DM, allergic | BREAST CANCER | This study included patients with T2DM aged 40–75 years old who were referred to Motahari hospital in Shiraz city, Iran. The patients were considered diabetic if they had an FBS level of 126 mg/dL or higher or were taking glucose-lowering agents or insulin injections. They were not allowed to participate if they were pregnant, lactating, using hormone replacement therapy, drinking alcohol, or smoking cigarettes. Additionally, we did not include people with breast cancer, allergic to soy milk or cow's milk, and people who took antibiotics three weeks before or during the study period. A patient who consumed food or products containing probiotic bacteria three weeks before or during the study period, who changed the dosage of oral antidiabetic drugs, insulin therapy or lipid-lowering drugs, or who did not follow the recommended diet, was excluded from study.The sample size for this study was calculated based on the results of a previously published study (n = | PMC9912676 |
Study procedure | T2DM | DISEASE | This double-blind randomized clinical trial was conducted on T2DM patients who were referred to Motahari hospital in Shiraz city, Iran. In the beginning, a participant's disease was diagnosed with the help of an endocrinologist. Then, the study procedure was explained to the participants and informed written consent was obtained from all. After that, the participants entered a two-weeks run-in period. During the run-in time, they had to stop taking any soy product, probiotics food or probiotics supplements. After the run-in time, the patients were randomly allocated to 4 groups using the software as follows; group 1; received soymilk (240 cc) + probiotics capsule, group 2; received soymilk + placebo capsule, group 3; received conventional milk (240 cc) + placebo capsule, and group 4; received probiotics capsule. Also, each participant's energy intake was calculated using the estimated energy requirement formula, and the weight stability diet was written for all of them. Energy distribution for all subjects consisted of 55% carbohydrate, 18% protein, and 27% fat. In group 4, the energy that groups 1 and 2 received through soymilk was compensated through other food groups. All patients were asked to maintain their usual diet and physical activity throughout the study period. | PMC9912676 |
Interventions preparation and compliance to study protocol | Soymilk and cow milk were respectively produced by Soya Sun Company and Mihan-Dairy Company in Iran. The amount of soymilk that should be consumed was determined based on a study conducted in Iran [ | PMC9912676 |
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Measurements | Anthropometric measurements, including height and body weight, were assessed in all patients at baseline and at the end of the study period. Standing and shoeless heights and body weight were measured while participants were minimally clothed with no shoes using digital scales. Body mass index (BMI) was calculated as body weight (kg)/height | PMC9912676 |
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Statistical analysis | Statistical tests were conducted using SPSS 22 and | PMC9912676 |
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Discussion | T2DM, TG, tumor necrosis | TUMOR NECROSIS | This randomized double-blind clinical trial aimed to examine the effects of soymilk and probiotics supplement co-administration on cardiovascular risk factors in patients with T2DM. The results showed soymilk plus probiotics supplement consumption significantly improved DBP, TC, TG, HDL-C, and insulin levels after 6 weeks of treatment. Also, soymilk consumption had significant beneficial effects on DBP, TG, HDL-C, and insulin levels. Moreover, probiotics supplementation significantly improved the levels of SBP, HDL-C, and insulin. The results of between-group comparisons showed that probiotics supplement significantly reduced SBP levels compared to conventional milk. As far as we know the majority of previous studies focused on fermented soymilk with specific probiotics and no studies have been conducted on soymilk plus probiotics co-administration.In this study, we failed to show a significant difference in the reduction of anthropometric measurements, blood pressure, lipid profiles, and glucose tolerance indices by soymilk between the study's groups. However, within-group comparison showed significant beneficial effects of soymilk on DBP, TG, HDL-C, and insulin levels. A systematic review and meta-analysis investigated the effects of soymilk consumption on cardiovascular risk factors and reported inconsistent findings. Accordingly, soymilk consumption significantly decreased SBP, DBP, TC, LDL-C, waist circumference (WC), C-reactive protein (CRP), and tumor necrosis factor-alpha compared to the control group. However, it was not effective in the reduction of other risk factors including body weight, BMI, HDL-C, TG, FBS, and fasting insulin. The results differed from ours because the authors did not take into account the health status of the subjects and pooled data from healthy and sick subjects in the analysis. Also, none of the primary studies included in the meta-analyses were performed on patients with T2DM [In our study, probiotics supplementations significantly improved the levels of SBP, HDL-C, and insulin after 6 weeks of intervention. The results of between-group comparisons also showed that probiotics supplement significantly reduced SBP levels compared to conventional milk. In a systematic review and meta-analysis of 13 RCTs, the authors found that multi-strain probiotics supplementation compared to the control group significantly improved FBS, HOMA-IR, TC, TG, SBP, and DBP, but not HbA1c, fasting insulin, HDL-C, and LDL-C [Finally, this study indicated that soymilk plus probiotics supplement consumption significantly improved DBP, TC, TG, HDL-C, and insulin levels after 6 weeks of treatment. However, between-group comparisons didn't show significant differences. Few RCTs have investigated the effects of fermented soymilk on cardiovascular risk factors [This study has some strengths. As far as we know this study for the first time has investigated the effects of soymilk plus probiotics supplement in patients with T2DM. Also, in our study, the effectiveness of the main group (soymilk plus probiotics supplement) was compared with a control (conventional milk) and its two components (soymilk and probiotics). Moreover, compliance with the study protocol was assessed during and at the end of the study, and major confounders were controlled for in the analyses. Like any other study, our study also has some limitations. First, our study seems to have a short duration which resulted in non-significant results. Second, the isoflavone content of the soymilks was not assessed. Third, we haven’t evaluated the survival rate of probiotics bacteria during passage through the gastrointestinal tract. | PMC9912676 |
Acknowledgements | We are grateful to the Isfahan soymilk company that provided soymilk products for the present study. We would like to express our special thanks to all patients that participate in our study. | PMC9912676 |
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Authors’ contributions | A.H. contributed to data collection and wrote the primary draft of the manuscript; SM.M and M.SH. designed the study and revised the manuscript; S.B. managed the study and supervised the final manuscript. The authors read and approved the final manuscript. | PMC9912676 |
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Funding | shiraz | This study was financially supported by shiraz university of medical sciences (grant number: 93–06-115–5566). | PMC9912676 |
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Availability of data and materials | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC9912676 |
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Declarations | PMC9912676 |
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Ethics approval and consent to participate | All procedures were under Helsinki declaration and approved by the Research Council and Ethics Committee of Shiraz University of Medical Sciences (IR.SUMS.REC.1394.62). Written informed consent was obtained from all participants. | PMC9912676 |
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Consent for publication | Not applicable. | PMC9912676 |
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Competing interests | The authors declare no competing interests. | PMC9912676 |
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References | PMC9912676 |
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Objective | knee dislocation | The purpose of this study was to evaluate the clinical outcomes of two-stage reconstruction (peripheral reconstruction in phase I and central anterior cruciate ligament (ACL) / posterior cruciate ligament (PCL) reconstruction in phase II) with remnant preservation for patients with knee dislocation. | PMC10704695 |
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Methods | knee dislocation | A total of 70 patients (10 IIIM, 17 IIIL, and 43 IV) with knee dislocation were randomly divided into the remnant-preserved group and the simple reconstruction group. Patients underwent two-stage reconstruction, including the reconstruction of collateral ligament in phase I and the reconstruction of ACL/PCL in phase II (12 weeks after phase I). Grafts were harvested from the semitendinosus and gracilis tendons from both lower limbs. After the surgery, the joint flexion and extension, bone tunnel and ligament healing, and joint stability were evaluated. | PMC10704695 |
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Results | After the surgery, the lateral stability recovered in all patients, and X-ray revealed a good position of bone tunnel. Follow-up was performed at 12 months postoperatively and ranged from 24 to 91 months. At the final follow-up, knee flexion angle, IKDC, Lysholm, and Tegner scores were all higher in both groups compared to the preoperative period. Notably, the remnant-preserved group showed superior results in these parameters compared to the simple reconstruction group. There was statistical significance between the two groups in terms of the Lachman test. | PMC10704695 |
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Conclusion | The knee function was well recovered after two-stage ligament reconstruction with remnant preservation. | PMC10704695 |
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Keywords | PMC10704695 |
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Introduction | Remnant, automobile accidents, dislocation, knee dislocation | Knee dislocation is an uncommon and severe injury that frequently induced by high-energy impact injuries, ranging from automobile accidents to contact sports [Until now, the treatment principle for cruciate ligament injuries following knee dislocation is still controversial. Some scholars recommend that ligament reconstruction should be performed as early as possible after knee dislocation [Remnant preservation is a technology to make full use of the remnant to improve the surgical outcomes of ligament reconstruction, especially for ACL reconstruction [In this study, a two-stage reconstruction was performed in patients with knee dislocation. In the phase I, we performed a simple reconstruction of the collateral ligament. When the knee flexion and extension recovered to preoperative range following phase I reconstruction for at least 12 weeks, ACL/PCL reconstruction was subsequently performed. This study aimed to evaluate the clinical effects of two-stage reconstruction of ACL/PCL with remnant preservation, providing a good choice for the treatment of knee dislocation. | PMC10704695 |
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Materials and methods | PMC10704695 |
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Subjects | traffic accidents, right knee injuries, knee dislocation, left knee injuries, injuries, sports-related | MAY | A total of 70 patients (10 IIIM, 17 IIIL and 43 IV) with knee dislocation were screened at our hospital from May 2010 to August 2020. All patients were randomly divided into two groups: the remnant-preserved group and the simple reconstruction group (Phase I reconstruction + Phase II reconstruction without remnant preservation). In the remnant-preserved group, there were a total of 48 patients, comprising 36 males and 12 females, with an average age of 33.58 ± 7.90 years. Among them, 31 patients had injuries in their left knees, and 17 had injuries in their right knees. The injuries in this group were caused by traffic accidents in 35 cases, sports-related incidents in 7 cases, and falls in 6 cases. The simple reconstruction group included 22 patients, with 17 males and 5 females, and an average age of 34.05 ± 8.17 years. Among these, 15 cases involved left knee injuries, and 7 cases involved right knee injuries. The injuries in this group resulted from traffic accidents in 16 cases, sports-related incidents in 3 cases, and falls in 3 cases. There was no statistical significance between the two groups in terms of age, male, injured part, injury cause, and follow-up time (P > 0.05; Table
Comparison of general data between the two groups | PMC10704695 |
Phase I reconstruction | avulsion injury of the MCL, fracture, knee joints, avulsion injuries | In phase I, the collateral ligament was repaired first following detumescence (within 2 weeks of injury). For the avulsion injury of the MCL, the broken end was sutured and fixed at the femoral end or the tibial side using anchor nails, and the substantial fracture was directly sutured. For avulsion injuries of the LCL, the insertion point was fixed directly, and substantial injury or that combined with posterior lateral corner tear was turn-back repair using ipsilateral biceps femoris tendon. Turn-back repair was a surgical procedure in which a damaged or torn tendon was partially detached from its point of insertion, then folded back on itself and reattached. This technique was commonly employed to reinforce repaired tendons and ligaments, enhancing their strength and stability.All injured knee joints, including those underwent collateral ligament repair, required immobilization in the fully extended position with braces for 3 weeks before starting rehabilitation exercises. After 2 weeks of exercise, the exercise intensity was gradually increased until reaching the maximum tolerable or preoperative range of flexion and extension. Patients began with contact weight-bearing walking using crutches, followed by partial weight-bearing walking during the first 6 weeks, before transitioning to full weight-bearing walking. | PMC10704695 |
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Phase II arthroscopic reconstruction of ACL and PCL | After phase I reconstruction for at least 12 weeks, phase II arthroscopic reconstruction of anterior and posterior cruciate ligaments was performed. | PMC10704695 |
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Graft acquisition | Semitendinosus and gracilis tendons of both lower limbs were separated from patients as grafts. Both ends of tendons were folded into four strands for backup after measuring the diameter. | PMC10704695 |
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Bone tunnel establishment | ACL | ADHESION, BENDING | Femoral tunnel- Arthroscopy was performed routinely and concomitant injuries were treated. The adhesion between the anterior and posterior cruciate ligaments was removed to prevent damage to the ligament remnants. The internal opening of the femoral tunnel of the ACL is located at the end point of the anteromedial fasciculus. After cleaning the residual ligament tissues at the end point, the posterior wall of the lateral femoral condyle was exposed. Subsequently, the knee was bent for 120PCL tibial tunnel- After bending the knee for 90
Important steps in the reconstruction of ACL and PCL. ACL tibial tunnel- ACL tibial tunnel locator (Smith&Nephew) was also placed via anterior medial entrance at an angle between 40° and 45°. The locator tip was positioned in the non-impact area at internal posterior side of original ACL tibia attachment remnant (Fig. Outer part of tunnel-The inner opening of the PCL femoral tunnel was located at the anterolateral bundle end of the PCL footprint (Fig. | PMC10704695 |
Graft fixation | CAVITY | Under arthroscopy, the PCL/ACL-Retrobutton compound was pulled into the joint cavity through the tibial tunnel, and then into the femoral tunnel with a traction line. The Retrobutton was fixed after the femoral end was turned over. When the Drawer and Lachman tests were negative, the knee was bent for 70 | PMC10704695 |
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Postoperative rehabilitation exercise | tenesmus | A mild rehabilitation plan was applied according to the rehabilitation of PCL. To protect the reconstructed PCL during rehabilitation exercises, shinbone tenesmus should be avoided. From the second week post-surgery, knee flexion training was performed twice a day and gradually increased to 90°. The knee flexion reached to 120° within 8 weeks and then expanded to its maximum degree. Only contact weight-bearing exercises with crutches were allowed within 6 weeks after the surgery, and full weight-bearing exercises with adjustable support of mathematical chuck were performed after the surgery for 10 weeks. Swimming and other mild exercises were allowed at 3 months post-surgery, jogging was allowed at 6 months post-surgery, and strenuous exercises were allowed at 12 months post-surgery. | PMC10704695 |
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Postoperative evaluations | After the surgery for 12 months, the symptoms, range and stability of joint flexion and extension, Lysholm score, Tegner score, and IKDC score were evaluated. X-ray and MRI were performed to reveal the changes of bone tunnel and ligament healing. Lachman, Drawer, Valgus/Varus stress, and axial displacement tests were performed to evaluate the stability of the knee joint. | PMC10704695 |
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Results | PMC10704695 |
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Collateral ligament reconstruction in patients | Within 2 weeks after the injury of collateral ligament of knee joint, repair surgery was performed in patients in different ways, including the posterolateral structure of knee joint (N = 12), lateral termination of the fibula (N = 8), ipsilateral partial biceps femoris tendon reentry (N = 15), MCL (suture of broken end and anchor fixation of broken end; N = 45), and MCL + LCL (suture of broken end and anchor fixation of broken end; N = 5). The duration from when the patient received treatment for the injury to the conclusion of phase II reconstruction amounted to 14.28 weeks (12–21 weeks). | PMC10704695 |
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Postoperative outcomes | postoperative knee flexion angle was 132.4 ± 5.1 | POSTOPERATIVE COMPLICATIONS | No intraoperative and postoperative complications were observed in all patients. After the surgery, the lateral stability recovered in all patients. In the remnant-preserved group, the remnants of both the ACL and PCL were retained. The postoperative knee flexion angle was 132.4 ± 5.1 | PMC10704695 |
Postoperative imaging | After the surgery, X-ray revealed a good position of the bone tunnel, and the position of the internal orifice of ACL tunnel (AT) and PCL tunnel (PT) is consistent with the normal attachment position (Fig.
X-ray images revealed that the internal orifice of anterior cruciate ligament tunnel (AT) and posterior cruciate ligament tunnel (PT) on the lateral radiograph is similar to the tibial attachment point of the normal anterior and posterior cruciate ligament after the surgery
MRI images revealed good fusion of ligamentous remnant with anterior cruciate ligament graft (AG) and posterior cruciate ligament graft (PG) after the surgery | PMC10704695 |
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Follow-up evaluation | POSTOPERATIVE COMPLICATIONS | All enrolled 70 cases were followed up for 24–91 months (average 60.3 ± 17.9 months). Follow-up results showed that all patients had no intraoperative and postoperative complications. Compared with the preoperative period, the knee flexion angle, IKDC score, Lysholm score, and Tegner score were significantly improved in both groups at the last follow-up (P < 0.05). In addition, the knee flexion angle, IKDC score, Lysholm score, and Tegner score of patients in the remnant-preserved group were significantly higher than those of patients in the simple reconstruction group at the last follow-up (P < 0.05; Table
Comparison of knee joint function scores between the two groups
Comparison of knee stability between the two groups at the last follow-up | PMC10704695 |
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Acknowledgements | Not applicable. | PMC10704695 |
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Author Contributions | Wenpu Ma and Yiqun Yang: conception, design and analysis of data, performed the data analyses and wrote the manuscript; Xin Ha: contributed to the conception of the study; wrote the manuscript; All authors have read and approved the manuscript. | PMC10704695 |
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Funding | Not applicable. | PMC10704695 |
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Data Availability | This study did not use public datasets. All data in the manuscript is available through the responsible corresponding author. | PMC10704695 |
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Declarations | PMC10704695 |
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Ethical approval and consent to participate | This retrospective study was approved by the institutional ethical review board of Liaocheng People’s Hospital. All the study participants have signed written informed consent. | PMC10704695 |
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Consent for publication | Not applicable. | PMC10704695 |
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Competing interests | The authors declare no competing interests. | PMC10704695 |
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References | PMC10704695 |
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Supplementary Information | AML, tumor | ACUTE MYELOID LEUKEMIA, AML, TUMOR | Long-term survival in patients with acute myeloid leukemia (AML) remains low, and current treatment modalities are inadequate. Milademetan (DS-3032, RAIN-32), a small-molecule specific murine double minute 2 inhibitor, has shown a p53 status-dependent antitumor effect in vitro studies. This is the first phase I study report of milademetan monotherapy in relapsed/refractory (R/R) AML patients evaluating the safety, tolerability, pharmacokinetics, and preliminary tumor response for further clinical development. Fourteen patients received 90 (starting dose, The online version contains supplementary material available at 10.1007/s12185-022-03464-z. | PMC9813109 |
Keywords | PMC9813109 |
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Introduction | AML, tumors, tumor | TUMOR, ACUTE MYELOID LEUKEMIA, AML, REMISSION, TUMORS, HEMATOLOGICAL MALIGNANCY | Acute myeloid leukemia (AML) is a hematological malignancy characterized by an autonomous growth of myeloid blast cells that cannot differentiate or further develop into mature white blood cells. Moreover, it has a diverse clinical presentation [While AML is now treatable and curable, the long-term survival rate after complete remission (CR) with chemotherapy remains low at about 40%, and the relapse rate remains high [Intermolecular interactions with murine double minute 2 (MDM2) frequently inhibit the tumor suppressor protein p53 activity in human tumors harboring wild-type p53. MDM2 promotes p53 nuclear export or p53 degradation via the ubiquitin–proteasome pathway, which maintains low p53 activity levels [Milademetan (DS-3032, RAIN-32) is an orally administered small-molecule MDM2 inhibitor, and in vitro studies show that it inhibits the MDM2–p53 interaction and has a p53 status-dependent antitumor effect [ | PMC9813109 |
Materials and methods | PMC9813109 |
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Study design and treatment | toxicity, lymphomas, AML, hematologic malignancies | MYELODYSPLASTIC SYNDROME, SOLID TUMORS, AML, HEMATOLOGIC MALIGNANCIES, LYMPHOMAS | This phase I, open-label, and dose-escalation study conducted at eight centers in Japan recruited patients with R/R AML. Four fixed-dose milademetan schedules were planned (Supplementary Fig. 1A). Increases in the milademetan dose were guided by the modified continual reassessment method (mCRM), with a planned maximum dose of 160 mg/day (Supplementary Fig. 1B). Each cohort (90, 120, and 160 mg) consisted of three to six patients. The first cycle was defined as the dose-limiting toxicity (DLT) evaluation period where patients required hospitalization. The number of treatment cycles was not specified, and the study treatment for each patient was continued unless the discontinuation criteria were met.A phase I study conducted in the USA (NCT02319369) administered oral milademetan once daily for 14 days, followed by 14 days of rest in a 28-day cycle (QD 14/28-day schedule, data not published), with other treatment schedules for hematologic malignancies like R/R AML and high-risk myelodysplastic syndrome. The maximum tolerated dose (MTD) was 160 mg, while it was 90 mg on a QD 21/28-day schedule for the Japanese phase I study (Japic CTI-142693) in patients with solid tumors or lymphomas [In this study, we only assessed the patients with schedule A‒milademetan was administered once daily on days 1–14 followed by a 14-day rest in a 28-day cycle. | PMC9813109 |
Study population | toxicity, chronic myeloid leukemia, AML | DISEASE PROGRESSION, ADVERSE EVENTS, MYELODYSPLASTIC SYNDROME, BLAST CRISIS, GRAFT-VERSUS-HOST DISEASE, AML, CENTRAL NERVOUS SYSTEM LEUKEMIA, ACUTE PROMYELOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, REMISSION, ONCOLOGY | This study included patients ≥ 20 years old with R/R AML and those with a history of myelodysplastic syndrome. Also eligible were patients who failed to achieve remission with at least one cycle of prior induction therapy, who relapsed after achieving remission with prior therapy, could not achieve persistent remission with standard treatment, had failed to complete potentially curative treatment, or had no treatment options with expected therapeutic efficacy. The Eastern Cooperative Oncology Group performance status (ECOG PS) scores for these patients ranged from 0 to 2. This study excluded those with a diagnosis of acute promyelocytic leukemia, chronic myeloid leukemia in a blast crisis (positive for a breakpoint cluster region-c-Abelson [BCR-ABL] fusion gene), history of or concurrent central nervous system leukemia, history of hematopoietic stem cell transplant within 60 days before the initiation of this study, graft-versus-host disease, and grade ≥ 2 clinically significant or irreversible nonhematological toxicity related to transplantation.Although confirmation of Patients were disqualified from the study if an apparent disease progression was noted, adverse events (AEs) made it difficult to continue milademetan treatment, consent was withdrawn, milademetan was administered on < 75% of the specified dosing days, or the investigators deemed it inappropriate to continue the study. In the case of the latter, the investigators always recorded the date and reasons for discontinuation. | PMC9813109 |
Objectives | AML, tumor | SECONDARY, AML, TUMOR | This study primarily aimed to evaluate the safety, tolerability, and MTD of milademetan monotherapy in Japanese patients with R/R AML. The secondary objective was to determine the PK profile and tumor response. Additionally, the recommended dose of the further study was determined. Furthermore, the | PMC9813109 |
Safety evaluation | DLTs, toxicities, failure, primary disease, disability or incapacity | ADVERSE EVENTS, EVENTS, COMPLICATIONS | Relative dose intensity (in percentage) was calculated as a proportion of dose intensity/planned dose intensity (proportion of dose administered/total treatment duration). Safety assessments were completed by documenting the AEs, ECOG PS, laboratory data, body weight, vital signs, and the results of 12 lead ECGs. Serious adverse events (SAEs) were defined as any AEs that caused mortality, were life-threatening, required hospitalization or prolonged existing hospitalization, caused disability or incapacity, or represented other medical conditions. Patients were followed up until the AEs resolved.Patients were evaluated for DLT during the first 28 days of cycle 1, defined as any nonhematological AEs of grade ≥ 3 unless attributed to the primary disease course, complications, or concomitant medications. Nonhematological toxicities classified as DLTs were grade 4 AST/ALT, grade 3 AST/ALT lasting ≥ 3 days, grade 3 AST/ALT with grade ≥ 2 total bilirubin, or an inability to complete at least 75% of the prescribed milademetan doses in cycle 1 (28 days) due to grade ≥ 2 events. Hematological toxicities classified as DLTs included failure to recover neutrophil and platelet counts to ≥ 500/mm | PMC9813109 |