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Methods | PMC10210318 | |||
Study patients | T1D | This was a phase 1b, dose-escalation, randomized, placebo-controlled study of IMCY-0098 in patients with recent-onset T1D. Additional information on the conduct of the study can be found in the study protocol (Additional file All participants provided signed informed consent. The study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines, local national laws (as applicable), and the Declaration of Helsinki. The study was approved by Independent Ethics Committees according to local regulations across the participating countries. The study was registered on ClinicalTrials.gov (NCT03272269) and in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT number 2016–003514-27). A long-term follow-up of a subset of these patients was conducted under a separate protocol (ClinicalTrials.gov: NCT04190693; EudraCT number: 2018–003728-35). | PMC10210318 | |
Study treatment | death, anaphylactic reaction, illness | ANAPHYLACTIC REACTION | Study patients were randomly allocated in a 3:1 ratio to receive IMCY-0098 or placebo. Treatment allocation at each site was performed using central randomization via an Interactive Web Response System.Treatment was injected subcutaneously in the upper arm (midway between the elbow and the shoulder); each dose was divided into two halves, which were administered concomitantly into both arms. Treatment was injected in both arms in order to stimulate the immune system via two draining lymph nodes and, consequently, to maximize the treatment-related immune response. Treatment was administered in four doses, given in 2-week intervals, with aluminum hydroxide adjuvant (alum) at a concentration of 500 μg/mL.Patients allocated to receive IMCY-0098 were sequentially enrolled to receive dose A (first administration 50 μg, followed by 3 × 25 μg), dose B (first administration 150 μg, followed by 3 × 75 μg) or dose C (first administration 450 μg, followed by 3 × 225 μg). In each cohort, the first four patients stayed in the hospital for a 24-h safety follow-up after each administration, and an interval of 2 days was observed between these four patients and other patients enrolled to receive the same dose. Patients allocated to receive placebo received matching volumes of placebo solution to maintain blinding.Interim safety evaluations were conducted by an independent Data and Safety Monitoring Board to allow inclusion of patients into the next cohort. Evaluations were conducted after four patients received their first administration and ≥ 3 patients received all four administrations of dose A (to allow inclusion of patients for dose B), and after four patients received their first administration and ≥ 3 patients received all four administrations of dose B (to allow inclusion of patients for dose C).Data were collected in a double-blind manner until all patients completed the study to Week 24 or were prematurely withdrawn from the study. Patients could be withdrawn from the study due to an AE, development of illness, pregnancy, or loss to follow-up. If a patient’s body temperature was > 37.5 °C, injection of study treatment was to be postponed until the temperature was < 37.1 °C. Study treatment was to be discontinued in case of an anaphylactic reaction to administration, any AE Grade > 2 as defined by U.S. Department of Health and Human Services (grade 1 – mild; grade 2 – moderate; grade 3 – severe or medically significant; grade 4 – life-threatening; grade 5 – death related to AE) [ | PMC10210318 |
Study procedures and assessments | PMC10210318 | |||
Safety | inflammation/swelling, Itching | INDURATION, BLOOD, INJECTION SITE REACTION | Study visits and procedures are shown in Additional file The intensity of injection site reactions was determined by study center staff for the first four patients of each cohort, either by visual assessment or through questioning the patient, and self-reported by the rest of the patients. Injection site erythema/redness, inflammation/swelling, and induration were classified using the longest diameter of the affected skin area as mild (grade 1; 0–30 mm), moderate (grade 2; 30–120 mm), or severe (grade 3; ≥ 120 mm). Pain/tenderness was classified based on patient perception as mild (grade 1; injection site is painful when pressed), moderate (grade 2; interferes with activity) or severe (grade 3; prevents daily activity). Itching was classified as mild (grade 1; mild or localized), moderate (grade 2; intense or widespread, intermittent, limiting instrumental activities of daily living) or severe (grade 3; intense or widespread, constant, limiting self-care, instrumental activities of daily living or sleep). Blood samples were taken at each visit for clinical chemistry and hematology assessment, and were analyzed with standardized techniques. | PMC10210318 |
Clinical response | Tecan | DISEASE PROGRESSION | Stimulated C-peptide secretion was assessed by the 2-h MMTT method at screening, Week 12, and Week 24. MMTT was performed in fasting patients using Ensure Plus (220 mL; 330 kcal; Abbott Laboratories) as a standardized meal administered between 07:00 h and 10:00 h, with 5 collection time points (before the meal and 30 ± 3 min, 60 ± 3 min, 90 ± 5 min and 120 ± 5 min after the meal). Patients were asked to withhold taking slow-acting insulin on the morning of the test but were allowed to take prandial insulin up to 2 h before the test. An additional clinical parameter was derived based on the difference between the normalized area under the curve (AUC) measured during MMTT tests and the AUC expected values given the general disease progression, as described previously [Antibody levels were assessed using blood samples collected at screening and at Weeks 0, 6, 12, and 24. Autoantibodies directed against insulin, IA-2, and GAD were detected using radioimmunoassays (Euroimmun, Lubeck, Germany) and a gamma counter; autoantibodies directed against ZnT8 were detected using enzyme-linked immunosorbent assay (RSR Limited, Cardiff, UK) and Tecan microplate reader (Tecan Group, Manedorf, Switzerland); all assays were used according to manufacturers’ instructions. | PMC10210318 |
Statistical analysis | DISEASE PROGRESSION | The study sample size was determined as adequate to provide a reliable safety assessment of the tested doses and to support the preliminary assessment of clinical response endpoints. The sample size used in this study was aligned with a similar study of peptide immunotherapy which found the safety profile to be as expected [All clinical response analyses were performed by dose and overall. For MMTT analysis, changes in the area under the curve (AUC) C-peptide from baseline at each visit were analyzed using a one-way analysis of covariance (ANCOVA) method. Fasting C-peptide was normalized by the glucose level and changes in fasting C-peptide and change in HbA1c were analyzed using one-way ANCOVA (F test). Change in insulin dose was analyzed using a Disease progression was measured as a primary endpoint. For this analysis, a linear mixed effect model (random effect – inter-patient variability; fixed effects – all available covariates) was used to model the progression of endpoint fasting C-peptide over time. Covariates were chosen from a list of candidates (baseline laboratory values, autoantibodies levels, HLA status, and patient characteristics); as there were multiple candidates, there were multiple possible combinations of covariates. Only covariates with strong associations with C-peptide/glucose at least at two visits were included. The combination of covariates was selected via a data-driven approach: they were retained if significantly associated with C-peptide/glucose change from baseline at Week 24 (Autoantibody levels were analyzed separately for each autoantibody using an ANCOVA model with ratio to baseline as dependent variable, baseline value as covariate, and treatment as factor. The ratios between each treatment group and placebo were analyzed using confidence interval and | PMC10210318 | |
Results | PMC10210318 | |||
Study patients | TYPE 1 DIABETES | Of 65 screened patients with recent-onset type 1 diabetes, 41 were randomized to receive placebo (Figure to show the sequential study design (The mean age was 24.0 years, and 31.7% of all participants were women. Mean age, BMI, and time from diagnosis were similar across cohorts; however, there were differences in cohort composition in terms of gender and the proportion of patients with different numbers of autoantibodies. There were also differences in HLA haplotype across cohorts, with DR3 | PMC10210318 | |
Clinical response | hypoglycemia | HYPOGLYCEMIA, PROGRESSION, TOLERANCE, EVENTS, EVENTS | In the ITT set, clinical response was assessed using the Mixed Meal Tolerance Test (MMTT) and total daily consumption of insulin (both slow- and fast-acting) (Fig. Progression of clinical response measured by AUC C-peptide from MMTT (During the study period, the levels of autoantibodies against GAD65 and ZnT8 decreased in IMCY-0098 dose C arm, and the level of autoantibodies against IA-2 decreased in IMCY-0098 dose A arm; however, the differences between treatment arms and placebo were not statistically significant, with the exception of ZnT8 at Week 24 (Additional file The estimated mean change from baseline to Week 24 in fasting C-peptide were − 0.012 for placebo and − 0.108, − 0.041, and − 0.040 for the IMCY-0098 dose A, B, and C groups, respectively. When comparing each IMCY-0098 dose group against placebo, none of the three doses gave a significant change in fasting C-peptide at the 5% significance level. The estimated mean change from baseline to Week 24 in HbA1c was − 0.528 for placebo and − 0.049, − 0.254, and 0.104 for the IMCY-0098 dose A, B, and C groups, respectively.Although no formal analysis was performed for the patient-reported glycemia data, no significant differences were observed for episodes of hypoglycemia (Fig. Mean total number of events of low glucose. Mean total number of low glucose events over the past 14 days. Data are shown for the intent-to-treat population. Error bars show standard deviation. Dose A: 50 μg at Week 0 followed by 3 × 25 μg; dose B: 150 μg at Week 0 followed by 3 × 75 μg; dose C: 450 μg at Week 0 followed by 3 × 225 μg. Events of low glucose were defined as being within the hypoglycaemic range (< 3.9 mmol/L or < 70 mg/dl or < 0.7 g/L) | PMC10210318 |
Long-term follow-up | A total of 30 patients from the ITT population participated in the follow-up to Week 48: placebo (Mean fasting C-peptide was similar between the treatment groups at baseline and no notable changes were observed in any group. The mean (SD) change from baseline to Week 48 was − 0.02 (0.12) nmol/L in the placebo group, 0.02 (N/A) nmol/L in the dose A group, − 0.06 (0.17) nmol/L (SD:0.17) in the dose B group, and − 0.12 (0.15) nmol/L in the dose C group. There were no significant differences between groups. | PMC10210318 | ||
Discussion | T1D | DISEASE PROGRESSION, DISEASE, COMPLICATIONS | Since the discovery of insulin therapy over 100 years ago, there have been no major changes in the clinical management of T1D apart from technical improvements in, for example, insulin variants, continuous glucose monitoring, and insulin pumps. These technologies clearly facilitate the daily control of blood glucose for patients but have had no impact on the underlying cause of the disease nor on the prevention of further disease progression. To date, there is still an important unmet need for disease-modifying therapies that would help patients with T1D achieve optimal glycemic targets, halt disease progression, and prevent β-cell loss. In this report, we have presented the first-in-human study of Imotope™ technology previously shown to eliminate pathogenic autoreactive T cells in an antigen- and disease-specific manner while preserving general immune system function in animal models.The main focus of the study was safety. As T1D can be effectively controlled with insulin, clinical development of any novel treatments, including disease-modifying therapies, has to include a broad assessment of safety parameters to meet very stringent criteria before the treatment can enter clinical practice [Overall, the lack of differences observed in different clinical parameters was expected due to the small sample size and short duration of follow-up among an adult population, who are known to show slower disease progression [Insulin therapy transformed the treatment of T1D, however, it does not modify the underlying cause of the disease or prevent complications [This study has demonstrated an encouraging safety profile of IMCY-0098 for three dosages and with a dosing scheme including four administrations. Patients treated with IMCY-0098 dose C showed no deterioration and a tendency for a slight improvement in clinical parameters compared with the expected natural history of the disease, but the results from a larger, ongoing phase 2 study are needed to explore dosing regimens and make the final dosing decision. Future studies are also needed to fully elucidate the immune response and level of β-cell protection following treatment with IMCY-0098. As IMCY-0098 targets both DR3 and DR4, these HLA haplotypes being represented in 95% of the T1D population [Autoantibody levels have been discussed in the context of assessing disease severity in T1D [Limitations of this study include the small sample size and short duration of the study. There were also imbalances in cohort composition in regards to DR3 | PMC10210318 |
Conclusions | T1D | This first-in-human study showed that IMCY-0098 has a promising safety profile in patients with recent-onset T1D at all doses tested. The safety profile of IMCY-0098 supports further investigation and risk/benefit optimization for different doses and schedules of this novel treatment. This will be further evaluated in an ongoing phase 2 study (NCT: NCT04524949) with improved dosing and a higher sample size designed to provide clinical proof of concept of the Imotope™ technology as well as deeper characterization of the expected mechanism of action. | PMC10210318 | |
Acknowledgements | The authors would like to thank the patients and their families, all participating investigators, sites, and site teams. A full list of sites can be found in Additional file | PMC10210318 | ||
Authors’ contributions | LVE, NB | RECRUITMENT | JVR, VC, RRA, EG, NB, LVE, MVM, PV: laboratory analysis; MK, FP: (specialized) statistical analysis; JVR, PA, RDL, MAA, CD, BK, KRO, NB, CB, PV: clinical study concept and design. PA, RDL, MAA, CD, BK, KRO, CB: patient recruitment and treatment. All authors: data analysis and interpretation, critical review of the manuscript, approval of the final version of the manuscript. All authors read and approved the final manuscript. | PMC10210318 |
Authors' information | Twitter handles: Jean Van Rampelbergh: @JeanRampelbergh; Katherine Owen: @drkathowen. | PMC10210318 | ||
Funding | Imcyse S.A. (Liège, Belgium), EU FP7 program (N°602515), DG06 (Walloon Region, Belgium, N°7873). | PMC10210318 | ||
Availability of data and materials | De-identified patient data can be provided to independent qualified researchers upon submission of a written application/research proposal that should be approved by the study sponsor, Imcyse S.A. | PMC10210318 | ||
Declarations | PMC10210318 | |||
Ethics approval and consent to participate | The study was conducted across multiple countries and institutions and was approved by all relevant ethics committees and national authorities. Belgium: Medical Ethics Committee UZ Brussel—Ref 2017/122, Denmark: Capital Region of Denmark—Centre for Health—Scientific ethics Committee—Ref: H-17009698, France: Comité de Protection des Personnes Sud Méditerranée I—Ref 17 45, Germany: Technical University of Munich—Faculty of Medicine—Ethics Committee—Ref 128/17 Af, Lithuania: Lithuanian Bioethics Committee—Ref 2018–03-21 No. P-I 8–20/2, Sweden: Regional Ethical Review Board in Gothenburg—Ref 189–18, United Kingdom: London—Chelsea Research Ethics Committee—Ref 17/LO/0633. All patients signed informed consent before taking part in the study. | PMC10210318 | ||
Consent for publication | Data of individual patients were de-identified and used for statistical analysis; no individual patient data are presented in the manuscript. | PMC10210318 | ||
Competing interests | LVE, Nordisk, NB, Diabetes | KIDNEY, APC, DIABETES | JVR, VC, RRA, EG, NB, LVE, MVM, and PV are employees or contractors of Imcyse S.A., Liège, Belgium, and may hold stock options. RDL’s institution received study funding and materials from Imcyse. RDL received an honorarium from DMRR and took part in advisory boards for Diamyd and Provention. MAA’s institution received study funding and materials from Imcyse. MAA received medical writing and APC support from Imcyse; received grants from EFSD, Wellcome Trust, Cardiff University, Wales Kidney Research Unit, and INNODIA; received honoraria from Sanofi Diabetes, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, MSD, Novo Nordisk and Bayer; received meeting support from Sanofi Diabetes, Eli Lilly, Takeda, Abbott, Merck, Novo Nordisk, NAPP, Miltenyi Biotec and Servier. CD, BK, and CB’s institutions received study funding and materials from Imcyse. CD received consultancy honoraria, medical writing, and APC support from Imcyse. PA and KRO declare no competing interests. | PMC10210318 |
References | PMC10210318 | |||
Background | candidiasis, RAU | CANDIDIASIS, RECURRENT APHTHOUS ULCER | Although topical steroids constitute the first-line therapy for recurrent aphthous ulcers (RAUs), their long-term use often leads to candidiasis. Although cannabidiol (CBD) can be an alternative for pharmacologically managing RAUs due to its analgesic and anti-inflammatory in vivo effects, there is a lack of clinical and safety trials concerning its use. The aim of this study was to evaluate the clinical safety and efficacy of topical 0.1% CBD for managing RAU. | PMC9940329 |
Methods | ulcer, Pain, RAU | ULCERS, ULCER | A CBD patch test was performed on 100 healthy subjects. CBD was applied on the normal oral mucosa of 50 healthy subjects 3 times/day for 7 days. Oral examination, vital signs, and blood tests were performed pre- and post-CBD use. Another 69 RAU subjects randomly received one of three topical interventions: 0.1% CBD, 0.1% triamcinolone acetonide (TA), or placebo. These were applied on the ulcers 3 times/day for 7 days. The ulcer and erythematous size were measured on day 0, 2, 5, and 7. Pain ratings were recorded daily. The subjects rated their satisfaction with the intervention and completed a quality-of-life questionnaire (OHIP-14). | PMC9940329 |
Results | TA reduced, ulcer, allergic reactions, pain | ULCER, ALLERGIC REACTION | None of the subjects exhibited allergic reactions or side effects. Their vital signs and blood parameters were stable before and after the 7-day CBD intervention. CBD and TA significantly reduced ulcer size more than placebo at all time points. The erythematous size reduction was higher in the CBD intervention than the placebo on day 2, while TA reduced the erythematous size at all time points. The pain score in the CBD group was lower compared with placebo on day 5, whereas TA reduced pain more than placebo on day 4, 5, and 7. The subjects receiving CBD reported higher satisfaction than placebo. However, the OHIP-14 scores were comparable among the interventions. | PMC9940329 |
Conclusions | ulcer, RAU | ULCER | Topical 0.1% CBD reduced ulcer size and accelerated ulcer healing without side effects. CBD exerted anti-inflammatory effects in the early stage and an analgesic effect in the late RAU stage. Thus, topical 0.1% CBD might be more appropriate for RAU patients who decline to take topical steroids, except for cases where CBD is contraindicated. | PMC9940329 |
Trial registration | Thai Clinical Trials Registry (TCTR) Number TCTR20220802004. Retrospectively registered on 02/08/2022. | PMC9940329 | ||
Keywords | PMC9940329 | |||
Background | pseudomembranous, inflammation, pain, RAU, ulcer | INFLAMMATION, RECURRENT APHTHOUS ULCER, ULCER, ADVERSE EFFECT | Recurrent aphthous ulcer (RAU) is the most common painful oral lesion and affects patients’ quality of life (QoL) [RAU presents as an ovoid or round well-defined ulcer, with a pseudomembranous yellowish gray center, and an erythematous circumscribed border [Currently, there are no curative therapies for RAU. Thus, RAU management primarily focuses on pain relief, reducing inflammation, and promoting wound healing. Topical steroids are an acceptable first-line pharmacological intervention for RAU [In recent years, there is considerable public interest in the use of cannabis for medical purposes. Cannabinoids are one of the major medicinal components of cannabis. They are synthesized in the human body and produced by the cannabis plant. The two active medical components from the cannabis plant are ΔMedicinal cannabis products are defined as dried female flowers of The safety of CBD has been demonstrated in animal and human studies. It has a low adverse effect profile, including when chronically used [CBD might be an alternative approach for RAU management due to its known clinical benefits, particularly in reducing pain and inflammation and promoting wound healing [ | PMC9940329 |
Methods | PMC9940329 | |||
CBD preparation | A 5%w/w CBD (CBD-5CC) extract was obtained from | PMC9940329 | ||
Study design and sample | The clinical phases of this study were conducted at the Oral Medicine Clinic, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand and performed with informed consent following protocols approved by the Human Research Ethics Committee of the Faculty of Dentistry, Chulalongkorn University (certificate number HREC-DCU 2021–048 approved on 9 July 2021). Informed consent was obtained from all subjects. All methods were performed in accordance with the Declaration of Helsinki. | PMC9940329 | ||
Phase 1: CBD patch test outcomes on human skin | allergic reaction, allergic reactions | CONTACT DERMATITIS, CONTACT DERMATITIS, ALLERGIC REACTION | To investigate the possible allergic reactions on the skin (e.g., contact dermatitis) while using CBD oral paste, 100 healthy subjects (50 males and 50 females, 18–65 years old) were recruited to participate in this study. 0.1% CBD was loaded in four Finn Chambers (Epitest, Tuusula, Finland) and placebo (pure oral paste) was loaded in four other chambers. The chambers were applied to the subjects’ skin on the upper back. After 48 h, the chambers were removed and 15 min later, any allergic reaction was scored according to the International Contact Dermatitis Research Group (ICDRG) standards [ | PMC9940329 |
Phase 2: CBD safety clinical outcomes after application on normal oral mucosa | To assess the local and systemic side effects of CBD oral paste after applying it on healthy oral mucosa, 50 healthy subjects (25 males and 25 females, 18–65 years old) were recruited to participate in this study. The subjects were instructed to apply CBD over their lower labial mucosa with a provided calibrated spoon 3 times/day after meals for 7 d. Oral examination, vital signs, and blood tests were performed before and after CBD use. The blood parameters evaluated comprised glucose, hematocrit, sodium, potassium, chloride, total CO | PMC9940329 | ||
Phase 3: CBD efficacy outcomes in subjects with RAU | PMC9940329 | |||
Study design | RAU | A randomized parallel double-blind controlled trial design was performed in phase 3. To measure the efficacy of CBD for treating RAU, 72 subjects with RAU randomly received one of three topical interventions: 0.1% CBD, 0.1% triamcinolone acetonide (TA), or placebo using simple randomization according to a manually generated list of random numbers with a 1:1:1 allocation ratio. | PMC9940329 | |
Sample size | ulcer | ULCER | The sample size was calculated using the G*Power program version 3.1.9.7 for 80% power, 95% confidence level, and 0.4 effect size according to the range of ulcer sizes reported in a previous study [ | PMC9940329 |
Subjects | allergy, ulcers, Crohn’s disease, Behcet’s disease, RAU, anemia, diabetes mellitus, ulcer, trauma | SYSTEMIC DISEASE, MINOR, ALLERGY, INFECTIONS, ULCERS, ANEMIA, DIABETES MELLITUS, APHTHOUS ULCERS, ULCER | The subjects fulfilled the following inclusion criteria: age between 18–65 years old, willing to participate and provide informed consent, and had a history of RAU (at least 2 times/year) on nonkeratinized oral mucosa, presenting with 1–3 minor aphthous ulcers (of ≤ 48 h duration) that were 2–10 mm in diameter and easily accessible for evaluation. The exclusion criteria for phase 3 comprised: history of allergy to CBD, pregnancy/lactation, concurrent oral bacterial/fungal/viral infections, ulcers as a manifestation of a systemic disease, e.g., Crohn’s disease, Behcet’s disease, or anemia, ulcers from trauma, diabetes mellitus patients, treatment with systemic steroids, oral retinoids, or other immunomodulatory agents within 1 week, treatment with acetaminophen, nonsteroidal anti-inflammatory drugs, or oral topical medications within 48 h or during project participation, history of dental surgery within 2 weeks of entering the study, or orthodontic braces or retainers that might come in contact with the ulcer. | PMC9940329 |
Allocation concealment and blinding | The pharmacological compounds were sealed in sequentially numbered identical containers. The placebo was matched to the CBD oral paste for taste, color, appearance, and smell. A research assistant (WK) generated the random allocation sequence, enrolled the subjects, and assigned the subjects to the interventions. The subjects and investigator (CU) were blinded to the type of intervention. | PMC9940329 | ||
Interventions | ulcer, ulcers, RAU | ADVERSE REACTIONS, ULCERS, ULCER | The subjects were randomly placed into one of the three interventions: 0.1% CBD, 0.1% TA, or placebo. Seventy-two subjects (24 subjects for each intervention) were enrolled in this study. The interventions were applied with a provided calibrated spoon to the ulcers 3 times/day after meals for 7 days. When the subjects developed RAU more than one time (at least 2 weeks apart), they could reenter the study, and received a different topical intervention. Each subject was interviewed at each visit by the same investigator regarding the emergence of any adverse reactions. The ulcers were diagnosed by an oral medicine specialist. If there was more than one ulcer, the ulcer with the easiest access was selected for investigation. | PMC9940329 |
Outcomes | PMC9940329 | |||
Ulcer severity score (USS) | ulcer, pain | DISEASE, ULCER | The USS is indicative of the disease severity. This score incorporated six ulcer characteristics: number, size, duration, ulcer-free period, site, and pain [ | PMC9940329 |
Ulcer size | pseudomembranous ulcer, ulcer, ulcers | ULCER, ULCERS | The ulcer size was measured on day 0, 2, 5, and 7. Two ulcer size parameters consisting of the pseudomembranous ulcer size and erythematous border size were measured. The ulcer diameters were measured using a calibrated dental probe with millimeter markings, and the ulcer sizes were calculated using formulas for the surface area of a circle or ellipse. The ulcers were photographed alongside a visual reference of known size, and a researcher drew the boundary of the pseudomembranous ulcer and erythematous border size on the captured image. The images were analyzed using computer software (Image-Pro Plus version 4.5 for Windows, Media Cybernetics, Rockville, MD, USA). | PMC9940329 |
Daily pain ratings | Pain, pain | Pain ratings using a visual analog scale (VAS) consisting of a 100-mm horizontal line between the endings marked “no pain” and “unbearable pain” were recorded daily by the subjects. | PMC9940329 | |
Subject satisfaction | On the last day, the subjects rated their satisfaction with the intervention used on a scale of 0 (not satisfactory) to 10 (the most satisfactory). The subjects who used all three topical interventions were asked to rank the interventions according to their preference (from most to least preferred). | PMC9940329 | ||
QoL improvement | The subjects completed a QoL questionnaire using the Thai Oral Health Impact Profile-14 (OHIP-14) at the first and last visit. | PMC9940329 | ||
Statistical analysis | pseudomembranous ulcer, pain | The background and demographic data were summarized using descriptive statistics. In phase 2, the normal distribution for each variable was determined using the Shapiro–Wilk test. Matched paired differences of vital signs and blood tests before and after CBD use were analyzed using the paired t-test (normally distributed variables) or the Wilcoxon signed-rank test (not normally distributed variables). In phase 3, the normal distribution for each variable was determined by the Kolmogorov–Smirnov test. Group differences among the three interventions were compared using one-way ANOVA followed by the Bonferroni post hoc test (normally distributed variables) or the Kruskal–Wallis test/Median test followed by Bonferroni correction for multiple tests (not normally distributed variables) for pseudomembranous ulcer size, erythematous border size, pain level, satisfaction, and OHIP-14 score at each monitoring point. The OHIP-14 scores at the first and last visit in each group were compared using the paired t-test (normally distributed variables) or the Wilcoxon signed-rank test (not normally distributed variables). The data were analyzed using SPSS software (SPSS 28 for Windows; SPSS, Chicago, IL, USA). A | PMC9940329 | |
Results | PMC9940329 | |||
Phase 1: CBD patch test outcomes on human skin | erythema, allergic reactions | ERYTHEMA, CONTACT DERMATITIS, ALLERGIC REACTION, ULCERATION | None of the subjects exhibited allergic reactions (signs of erythema, vesicles, or ulceration) or contact dermatitis on any CBD-treated area. | PMC9940329 |
Phase 2: CBD safety clinical outcomes after application on normal oral mucosa | jaundice, liver dysfunction, nausea,, pain | ADVERSE REACTION, ANAPHYLACTIC REACTION, ALLERGIC REACTION | None of the subjects experienced or reported an obvious adverse reaction (irritant response or allergic reaction) on their oral mucosa. Furthermore, no anaphylactic reactions were observed in the respiratory or circulatory system and no signs of liver dysfunction were reported (e.g., nausea, vomiting, jaundice, right upper quadrant pain, or dark urine). The subjects’ vital signs and blood parameters were stable before and after the 7-day CBD intervention ( | PMC9940329 |
Ulcer size reduction | pseudomembranous ulcer, Pseudomembranous ulcer, ulcer | REMISSION, ULCER | The ulcer size was adjusted to a percentage compared with baseline (100%). The ulcer size reduction analysis among the three interventions indicated that the pseudomembranous ulcer size was almost 100% smaller in the CBD group on day 5 (Fig. Pseudomembranous ulcer size reduction. The Y-axis values represent percentages. Error bars display the standard error of the mean (SEM). Significance is portrayed as * Erythematous border size reduction. The Y-axis values represent percentages. Error bars display the SEM. Significance is portrayed as *The pseudomembranous ulcer and erythematous border size after treatment with placebo (representing spontaneous remission) were larger than before treatment, whereas CBD and TA continually decreased the ulcer size at every monitoring point. Thus, CBD and TA accelerated ulcer healing compared with natural healing. | PMC9940329 |
Daily pain ratings | ulcer pain, pain | The ulcer pain scores (VAS) were adjusted to a percentage compared with baseline (100%). Comparing the daily pain ratings between the three interventions, topical CBD and TA decreased the pain levels from day 1 onwards, while the placebo markedly increased the pain levels on day 1–2 and then gradually decreased the pain levels from day 3 onwards, as demonstrated in Fig. Daily pain ratings. The Y-axis values represent percentages. Error bars display the SEMRAUs typically become larger and more painful over the first few days of their development and then gradually spontaneously heal in 4–14 days [ | PMC9940329 | |
Subject satisfaction with topical interventions | The subjects who received the TA and CBD topical interventions were more satisfied with the intervention (average satisfaction score of 8.32 vs. 7.48, respectively,At the end of the study, four subjects had been treated with all three interventions. When these subjects ranked the interventions in order of preference, three subjects (75%) selected TA as the most preferred intervention followed by CBD, and placebo was the least preferred. One subject (25%) picked CBD as the most preferred intervention followed by TA and placebo. | PMC9940329 | ||
QoL improvement | The statistical analysis of the OHIP-14 score reduction in each group revealed that the three interventions significantly reduced the OHIP-14 scores between first and last visit ( | PMC9940329 | ||
Discussion | allergic reaction, ulcer size reduction, pain, RAU, pseudomembranous ulcer, ulcer | ULCER, ALLERGIC REACTION, HEALING ULCERS | In recent years, complementary and alternative medicine (CAM) has been increasingly used worldwide. CAM is defined as a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine [The present study evaluated the use of 0.1% CBD as a topical treatment for RAU. None of the subjects experienced an allergic reaction to 0.1% CBD either on their skin or oral mucosa. Applying CBD to normal oral mucosa for 7 days did not affect the subjects’ vital signs, glucose, hematocrit, electrolyte levels, or liver and kidney function. These results indicate that topical 0.1% CBD is safe for human skin and oral mucosa application.In this study, phase 3 was conducted as a randomized controlled trial (RCT) in which ulcer size, erythematous border size, pain level, satisfaction, and OHIP-14 score were evaluated. These are the standard variables or factors that are often assessed when evaluating the pharmacological efficacy for RAU management. The findings from the present randomized, double-blind controlled clinical trial study indicate that CBD treatment reduced pseudomembranous ulcer and erythematous border size and alleviated pain during the 7-day application. The pseudomembranous ulcer size was significantly reduced due to CBD’s wound healing promotion and anti-inflammatory effects [The pain scores of the three intervention groups decreased over time [A study revealed that RAUs affect patient QoL due to pain (during talking, eating, and swallowing), discomfort (impaired food and liquid intake), interpersonal relationship problems, and self-confidence [A previous study [This study has some limitations that must be carefully considered. One limitation was the two-dimensional measurement of the ulcer. Because ulcer size reduction and pain relief are not the only signs of improvement in healing ulcers, decreases in ulcer depth should also be measured. If the ulcer depth variable is incorporated into the ulcer healing outcomes, the findings may be more comprehensive. However, USS was used at baseline and some parts of the USS overlapped with other measurements, i.e., ulcer size and pain score, that were recorded at each monitoring visit; and the ulcer numbers and sites were collected at baseline. A comprehensive score that includes QoL outcomes for assessing improvement rates during RAU treatment interventions would be relevant to use in further clinical investigations. Furthermore, topical CBD dosages above 0.1% have not been investigated in early trials and should be considered in future RCTs for RAU management to improve the clinical efficacy while comparing CBD side by side with TA.To our knowledge, this is the first randomized clinical trial investigating the clinical effects of 0.1% CBD for RAU topical treatment. The efficacy of CBD was clinically meaningful, specifically on reducing the pseudomembranous ulcer and erythematous border size and on pain relief. | PMC9940329 |
Conclusions | allergic, alcohol addiction, mood disorders, RAU, pain, ulcer | ULCER | This clinical study demonstrated that topical 0.1% CBD reduced ulcer size and accelerated ulcer healing without any reported local (signs of allergic and anaphylactic reactions) or systemic (vital sign and blood test alteration) side effects. Furthermore, in the RCT, topical CBD exerted an anti-inflammatory effect by reducing the erythematous border size in the early stage and decreased pain intensity in the late stage of RAU. Thus, CBD may be appropriate for RAU patients who choose not to take topical steroids, except for cases where CBD is contraindicated, such as being allergic to CBD, a history of drug or alcohol addiction, and a history of mood disorders. | PMC9940329 |
Acknowledgements | We thank Dr. Joao Ferreira for his assistance in reviewing this manuscript, Dr. Kevin Tompkins for his assistance in revising the English language, Dr. Witchapat Kengtong for his kind assistance as a research assistant, and Dr. Nawaporn Pengpis for all support. | PMC9940329 | ||
Authors’ contributions | KB contributed to the study conception and design, funding acquisition, methodology, project administration, supervision, and writing-review & editing. CU contributed to data collection, formal analysis and interpretation of the data, investigation, validation, visualization, and writing-original draft. DC and JL prepared the CBD oral pastes and placebos. All authors read and approved the final manuscript. | PMC9940329 | ||
Funding | This study was funded by Thailand Science Research and Innovation Fund Chulalongkorn University (CU_FRB65_hea (1)_007_32_02). | PMC9940329 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC9940329 | ||
Declarations | PMC9940329 | |||
Ethics approval and consent to participate | The present study was performed with informed consent following protocols approved by the Human Research Ethics Committee of the Faculty of Dentistry, Chulalongkorn University (certificate number HREC-DCU 2021–048 approved on 9 July 2021). Informed consent was obtained from all subjects. All methods were performed in accordance with the Declaration of Helsinki. | PMC9940329 | ||
Consent for publication | Not applicable. | PMC9940329 | ||
Competing interests | The authors declare no competing interests. | PMC9940329 | ||
References | PMC9940329 | |||
Introduction | low anterior resection syndrome | LOW ANTERIOR RESECTION SYNDROME | The incidence of low anterior resection syndrome (LARS) has increased over time owing to an increasing rate of sphincter-sparing surgery | PMC10416684 |
Methods | enema, colorectal or coloanal anastomosis | This multicentre (7 centres) open-label RCT included patients with a low colorectal or coloanal anastomosis who had major LARS (LARS score at least 30)SOC was delivered by the treating physician to every patient based on a pathway of bowel management, including a low-fibre diet, laxatives and/or loperamide, physiotherapy (biofeedback and pelvic floor retraining), and small-volume enemas (over 150 ml). For patients allocated to TAI, specific education and training was undertaken by a dedicated nurse or the treating physician in a consultation dedicated to patient education. Subsequently, irrigations were administered by the patient daily, starting with a maximum 1-litre enema, with a self-reported diary being used to record daily irrigation efficacy.A minimal difference in LARS score of 7 between the TAI and SOC groups was deemed clinically relevant. Based on data from a previous study | PMC10416684 | |
Results | abdominal spasms, lower anterior resection syndrome, pain | INCONTINENCE, ADVERSE EVENTS, SECONDARY, SYNDROME, EVENTS | Some 64 patients with severe LARS were considered eligible. Of these, 32 (22 men) met the inclusion criteria and were randomized. One patient in each group was excluded (1 performed TAI in SOC group and was excluded; 1 deferred performing the enemas in TAI group and was no longer eligible) (Study flow chart and changes in lower anterior resection syndrome score from baselineBy 3 months, the mean LARS score in the overall population had decreased from 38.3 to 26.5 (Results for primary and secondary endpoints: comparison between groupsTAI, transanal irrigation; SOC, standard of care; LARS, lower anterior resection syndrome; FIQL, Faecal Incontinence Quality of Life; EQ-5D-5L™, EuroQol Five Dimensions 5L (EuroQol Group, Rotterdam, the Netherlands); VAS, visual analogue scale. *Unpaired A total of 17 adverse events occurred in 14 patients (none severe). Seven events in five patients were related to irrigation pain at the anus (2), and abdominal spasms and transit disturbance during irrigation (5). The mean(s.d.) volume of water used per irrigation per day was 718(135) ml. The time spent on bowel management per day decreased significantly in TAI group as compared to SOC group ( | PMC10416684 |
Discussion | RECTAL PERFORATION | In this study, there was a marked improvement in LARS score in patients using TAI compared with the SOC group at study termination after 3 months. These positive results of TAI with a cone mirror outcomes reported in other preliminary studies with a balloon catheterSelection of the best candidates for colonic irrigation is still a matter of debate, and the optimal postoperative period for starting the irrigations has not been clearly defined. In the present study, the majority of patients had chronic LARS, and so future studies should validate earlier use of the device. Education when introducing TAI is crucial, and the use of a cone catheter requires training for patients to orientate the device and maintain the catheter during irrigation. The major advantage is the safety of the anatomical design. Other studies with a balloon catheter have reported greater difficulties with the use of TAI. Pieniowski The risk of rectal perforation during TAI should be acknowledged. Perforations were reported when TAI was used for other indications, including neurogenic sources of incontinenceDespite these promising results, the present study is limited by the short follow-up of 3 months. These results must be confirmed with longer follow-up to allow conclusions to be drawn regarding the long-term efficacy of TAI and evaluation of the patient’s comfort with the cone | PMC10416684 | |
Supplementary Material | Click here for additional data file. | PMC10416684 | ||
Funding | This study was promoted and funded by Coloplast. Coloplast provided the medical device and support for study design, data collection, and statistical analysis. | PMC10416684 | ||
Author contributions | HANSEN | Guillaume Meurette (Conceptualization, Formal analysis, Investigation, Project administration, Supervision, Writing—original draft, Writing—review & editing), Jean Luc Faucheron (CRediT contribution not specified), Eddy Cotte (Investigation, Writing—review & editing), Quentin Denost (Investigation, Writing—review & editing), Guillaume Portier (CRediT contribution not specified), Jerôme Loriau (Investigation, Methodology), Andreas Wolff Hansen (Formal analysis, Funding acquisition, Methodology, Writing—review & editing), Eric Vicaut (Formal analysis, Methodology, Validation, Writing—review & editing), and Zaher Lakkis (Investigation, Methodology, Project administration, Supervision, Validation, Writing—original draft, Writing—review & editing) | PMC10416684 | |
Disclosure | A.W. H., who is currently an employee of Coloplast, participated in the study design and management, but without commercial involvement in the device itself. The authors declare no other conflict of interest. G.M is member of Coloplast Medical Advisory Board. | PMC10416684 | ||
Supplementary material | PMC10416684 | |||
Data availability | All the data reported in this study are available for further information (clinical trial identifier NCT04586634). | PMC10416684 | ||
References | PMC10416684 | |||
Subject terms | SECONDARY, RECURRENCE, RECTAL CANCER | Traditional total mesorectal excision (TME) for rectal cancer requires partial resection of Denonvilliers’ fascia (DVF), which leads to injury of pelvic autonomic nerve and postoperative urogenital dysfunction. It is still unclear whether entire preservation of DVF has better urogenital function and comparable oncological outcomes. We conducted a randomized clinical trial to investigate the superiority of DVF preservation over resection (NCT02435758). A total of 262 eligible male patients were randomized to Laparoscopic TME with DVF preservation (L-DVF-P group) or resection procedures (L-DVF-R group), 242 of which completed the study, including 122 cases of L-DVF-P and 120 cases of L-DVF-R. The initial analysis of the primary outcomes of urogenital function has previously been reported. Here, the updated analysis and secondary outcomes including 3-year survival (OS), 3-year disease-free survival (DFS), and recurrence rate between the two groups are reported for the modified intention-to-treat analysis, revealing no significant difference. In conclusion, L-DVF-P reveals better postoperative urogenital function and comparable oncological outcomes for male rectal cancer patients.Total mesorectal excision (TME) for rectal cancer can require partial resection of Denonvilliers’ fascia (DVF). Here the authors report the secondary outcomes of a randomized trial to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function and oncological safety in male patients with mid-low rectal cancer. | PMC10589235 | |
Introduction | Rectal cancer | MALIGNANT TUMORS, RECURRENCE, RECTAL CANCER, RECTAL CANCER | Rectal cancer (RC) is one of the most common malignant tumors in the worldTraditional TME surgery required dissection anterior to Denonvilliers’ fascia (DVF) and thus DVF should be partly resectedWith studies on both cadavers and surgical videos, we demonstrated a surgical landmark line for intraoperative identification of DVFThus, we, together with the Chinese Postoperative Urogenital Function (PUF) Research Collaboration Group, conducted a prospective, multicenter, randomized clinical trial (PUF-01) to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function protection and oncological safety in male patients with MLRC (In this work, with the updated analysis of urogenital function and follow-up oncological outcomes of the PUF-01 trial, we investigate both function protection and oncological safety of DVF preservation during laparoscopic TME for male rectal cancer patients. The per-protocol analysis reveals that the postoperative urogenital function was better in the L-DVF-P group. The modified intention-to-treat analysis for oncological data reveals no significant differences in 3-year overall survival (OS), 3-year disease-free survival (DFS), and recurrence rate between the two groups. Taking together, L-DVF-P reveals better postoperative urogenital function and comparable oncological outcomes for male rectal cancer patients. | PMC10589235 |
Results | PMC10589235 | |||
Study population | MAY | From August 26, 2015, through May 6, 2020, a total of 262 patients were enrolled and randomly assigned to the Exp-group or Con-group ( | PMC10589235 | |
Urogenital functions | According to protocol, patients undergoing Non-R | PMC10589235 | ||
Postoperative recovery and surgical outcomes | As shown in Supplementary Table | PMC10589235 | ||
Overall survival and disease-free survival | cardiovascular deaths, stroke, tumor-related deaths, non-tumor-related diseases | STROKE | At the last follow-up, 40 patients (16.5%) had died, the median follow-up time was 51.9 months. Among them, 4 cases died from non-tumor-related diseases, containing 2 cases of cardiovascular deaths, 1 case of stroke, and 1 case of traffic accident. Taking together, there were 36 cases (14.9%) of tumor-related deaths in this study (18 cases in the Exp-group and 18 cases in the Con-group). The overall survival (OS) was calculated and shown in Fig. | PMC10589235 |
Overall Survival (OS) for laparoscopic total mesorectal excision (TME) with Denonvilliers’ fascia preservation (Exp-group) vs laparoscopic TME with Denonvilliers’ fascia resection (Con-group) at 3 years after surgery. | Kaplan–Meier method was used to estimate survival probabilities over time and the log-rank test was applied to compare survival curves between two groups. We set truncation at 36 months for restricted mean survival time (RMST). The RMST in the Exp-group was 35.50 months (95% CI, 35.05–35.94 months). Correspondingly, the restricted mean times lost (RMTL) was 0.50 months (95% CI, 0.06–0.95 months). In contrast, the RMST was 34.95 months (95% CI, 34.21–35.69 months) and the RMTL was 1.05 months (95% CI, 0.32–1.79 months) in the Con-group. The RMST ratio for L-DVF-P to L-DVF-R was 1.02 (95% CI, 0.99–1.04), suggesting that the Exp-group had a mean survival time of 2% more than that of the Con-group (The disease-free survival (DFS) was presented in Fig. | PMC10589235 | ||
Recurrence rate and pattern | RECURRENCE, RECURRENCE, METASTASIS, LUNG METASTASIS, LIVER METASTASIS | At the last follow-up, 37 patients (15.3%) were diagnosed with recurrence, containing 9 cases of local recurrence (24.3%), 12 cases of liver metastasis (32.4%), 13 cases of lung metastasis (35.1%) and 3 cases of peritoneal metastasis (8.1%). As shown in Table Recurrence rate and pattern of patients in the modified intention-to-treat populationData are analyzed using Pearson’s two-sided χ | PMC10589235 | |
Discussion | obesity, tumor, urinary dysfunction | OBESITY, TUMOR, TUMOR RECURRENCE, RECURRENCE, COMPLICATION, DYSFUNCTION, CAVITY, RECTAL CANCER | Urogenital dysfunction has become the major complication of total mesorectum excision (TME) for low-mid rectal cancer. In this study, we revealed that compared with traditional TME surgery, TME surgery with Denonvilliers’ fascia (DVF) preservation had better postoperative urogenital function, with a comparable oncological outcome, thus may be a better choice for male rectal cancer patients with specific staging.It was reported that more than 50% of patients treated for rectal cancer experienced a deterioration in sexual function, while urinary dysfunction occurred in one-third of patientsPrevious studies have proved that DVF acted as a protective sheet for PAN and thus partial resection of DVF may lead to PAN injury and postoperative urogenital dysfunctionFiguring out an appropriate surgical procedure is the key to solve this problem. There used to be two surgical procedures for anterior dissection. First, dissection 1–1.5 cm above peritoneal reflection, which helps better exposure of the anterior pelvic cavity, is especially beneficial for patients with obesity or narrow pelvic cavity. Second, dissection at the lowest level of peritoneal reflection. In clinical practice, it was difficult to dissect posterior to DVF with the first surgical procedure. However, dissection at the lowest level of peritoneal reflection sometimes helps enter the surgical plane posterior to DVF. Based on this, we performed both cadaveric study and surgical video review, finding that DVF began with a white thickened line at the lowest level of peritoneal reflection, and ended at the perineal bodySome may still doubt the general applicability of DVF preservation, especially for high BMI patients. Although the mean BMI was normal in this study, there were also some cases of overweight and obesity, while the procedure was performed smoothly regardless of the high BMI. Usually, for patients with high BMI or narrow pelvic cavity, hanging the peritoneal reflection with a suture or performing traction of the rectum with tieback will help better exposure of both the pelvic cavity and the anterior wall of rectum, and thus make surgery easier to generalize.Although previous studies have strongly indicated that DVF resection may be the reason for PAN injury, there is still a lack of clinical trial studies to prove the effect of DVF preservation on urogenital function protection and confirm the oncological safety. Based on this, we conducted the PUF-01 study with two aims. First, to evaluate the advantage of preserving DVF during laparoscopic TME on protecting postoperative urogenital function in male patients with rectal cancer. Both the initial resultsIn this study, cases of APR or Non-RConsidering that tumor location and T stage may have an impact on DVF preservation and tumor recurrence, we performed a univariate analysis of 3-year DFS and OS based on variables containing tumor location and T stage. The results revealed no differences in either OS or DFS of TNeoadjuvant radiotherapy or chemoradiotherapy was believed to help control local recurrence of locally advanced rectal cancerThis study had several limitations. First, patients with neoadjuvant radiotherapy were not included in this trial. Further studies should be performed to investigate whether laparoscopic TME with DVF preservation is also feasible, as well as of better postoperative urogenital function and comparable oncological outcome for them. Second, some cases in this study did not reach the follow-up of 60 months. Thus, the 5-year OS, DFS, and recurrence rate should be furthered follow-up to get a more convincing result of oncological safety. Third, for rectal cancer located in the anterior wall, only TIn conclusion, the PUF-01 trial revealed that laparoscopic TME with DVF preservation was feasible and safe, had the advantage on postoperative urogenital function, as well as comparable 3-year OS and DFS oncological results, thus may be a better choice for male rectal cancer patients with specific staging. | PMC10589235 |
Methods | PMC10589235 | |||
Study design | The PUF-01 trial is an open-label, multicenter, randomized clinical trial conducted at 11 centers in China. The trial was registered on ClinicalTrials.gov on April 26, 2015 ( | PMC10589235 | ||
Participants | MAY | Patients were enrolled from August 26, 2015, through May 6, 2020. Eligibility criteria were listed in (Supplementary Table There were two reasons why only male patients were enrolled in this study. First, the structure of DVF was more complicated and multiple-morphologic for females, thus the feasibility of DVF preservation for females was still unclear. Second, the assessment method of sexual function for females was relatively insufficient. | PMC10589235 | |
Randomization and blinding | This study is an open-label and a single-blind design is adopted in this study. Stratified blocked randomization was used, the stratification factor was center, and the block size was 4. The random allocation sequence was generated by a statistician who was independent of the research, using the SAS 9.3 software (SAS Institute, Cary, NC). Participants were randomly assigned using random envelopes in a 1:1 ratio to groups that underwent laparoscopic TME with DVF preservation (L-DVF-P, Exp-group) or DVF resection (L-DVF-R, Con-group), respectively. The surgeons were informed of grouping information preoperatively, while the participants and research assistants enrolling in patient follow-up and functional evaluation were blinded. | PMC10589235 | ||
Interventions | tumor, pain | TUMOR | Following randomization, laparoscopic TME surgery was performed. In the Con-group, dissection of the anterior rectum was performed anterior to DVF, and the fascia was resected by an “inverted U-shaped” incision ≥2 cm beneath the tumor. In contrast, for the Exp-group, dissection was performed posterior to DVF and thus DVF was preserved entirelyTo ensure the surgical homogeneity and quality, video recordings of each procedure were stored for reference, and mandatory intraoperative photographs of specific fields to verify PAN protection were obtained illustrating: (1) the area of ligation of the inferior mesenteric artery, (2) the area of bilateral hypogastric nerve, (3) bilateral rectal ligament area, (4) the anterior rectal wall and DVF area. The integrity of the gross specimen and histopathological examination for TME grading classification were evaluatedPostoperative prophylactic antibiotics and pain medications, fluid therapy, and nutritional support were administered in accordance with routine medical practice. Adjuvant chemotherapy was arranged if needed, using capecitabine, CapeOX, or mFOLFOX6 regimen. | PMC10589235 |
Outcome measures | death, Prostate | RETROGRADE EJACULATION, RECURRENCE, ANEJACULATION, EVENT, PROSTATE, DISEASES | The patients’ urinary function was evaluated by RUV (mL, by ultrasonography), maximum flow rate (MFR, mL/s, by urodynamics), and International Prostate Symptom Score (IPSS). Erectile function and ejaculation function were evaluated by IIEF-5 and ejaculation function grading (Grade I: normal ejaculation; Grade II: retrograde ejaculation; Grade III: anejaculation), respectively. The initial results of postoperative urogenital function have been published in the previous paperThe oncological data included the 3-year overall survival (OS) and disease-free survival (DFS), and recurrence rate. Postoperative follow-up was performed every 3 months within 2 years, and every 6 months 3–5 years postoperatively. Comprehensive hematology, chest and abdomen spiral CT, and colonoscopy were used to evaluate the patient’s postoperative survival status. OS was calculated from the day of randomization until the day of death (event) or the day of the last follow-up examination (censored), while DFS was calculated from the day of randomization until the day of recurrence or death (event) or the day of the last follow-up examination (censored). Data were censored for patients with no evidence of diseases at the last follow-up examination or for patients who died from other diseases or reasons without evidence of recurrence. The last follow-up was on October 24, 2022. | PMC10589235 |
Sample size calculation | sexual dysfunction, urinary dysfunction | DYSFUNCTION | In this study, the incidences of urinary dysfunction 2 weeks postoperatively and sexual dysfunction 12 months postoperatively were the primary endpoints and dominant evaluation indicators. In our previous study, the incidence of urinary dysfunction and sexual dysfunction were 24.39% and 9.76%, respectively, for DVF-preserving procedures; the corresponding incidences for DVF-resecting procedures were 44.68% and 42.55% | PMC10589235 |
Statistical analysis | REGRESSION | DFS and OS were evaluated by the Kaplan–Meier method and compared by the log-rank test. The Cox proportional hazards regression model was used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the effect of surgical approach on DFS and OS. The “survminer” package in R was used to provide various functions for survival analysis, including testing for differences in OS between groups. The median follow-up time was calculated using the reverse Kaplan–Meier method. Restricted mean survival time (RMST) was used to quantify the survival time, and the RMST ratio and 95% CI were obtained by survRM2 package in R software | PMC10589235 | |
Reporting summary | Further information on research design is available in the | PMC10589235 | ||
Supplementary information |
Supplementary InformationReporting SummaryPeer Review File | PMC10589235 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-42367-3. | PMC10589235 | ||
Acknowledgements | We thank Professor R.J. Heald for his guidance and generous help during the study. We thank Hao Chen (Nanfang Hospital of Southern Medical University, China) for the consultation. We thank Dr. Yang Shuo and Dr. Luo Hao (Department of Epidemiology and Biostatistics, School of Public Health; Sun Yat-Sen University), Xiaohua Li (the Third Affiliated Hospital of Sun Yat-sen University, China) for the statistical consultation. This study was supported by grants from the Sun Yat-Sen University Clinical Medicine Research 5010 Program (No. 2015016), the National Natural Science Foundation of China (No. 81971378, No. 81901471) and the Natural Science Foundation of Guangdong Province (No. 2021A1515010577, No. 2022A1515012653). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10589235 | ||
Author contributions | C.H., G.W. | J.F. and H.W. contributed to design and writing. B.W., Z.Z., J.Z., J.L. X.Y., T.C., Y.H., J.H., and J.L. contributed acquisition, analysis, and interpretation of data. J.X., F.H., M.H., Q.X., X.W., C.H., G.W., Y.J., G.S., and H.D. contributed surgical support. | PMC10589235 |
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