The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial)

The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial) Laurent Derré, Francois Crettenand, Nuno Grilo, Kevin Stritt, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4046807/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Oct, 2024 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Introduction Cancer, malnutrition, and surgery negatively impact patient’s immune system. Despite standardized surgical technique and the development of new perioperative care protocols, morbidity after cystectomy remains a serious challenge for urologists. Most common postoperative complications, such as infections and ileus, often lead to longer length of stay and worse survival. The immune system and its interaction with the gut microbiota play a pivotal role in cancer immunosurveillance and in patient’s response to surgical stress. Malnutrition has been identified as an independent and modifiable risk factor for both mortality and morbidity. Immunonutrition (IN) may improve the nutritional status, immunological function, and clinical outcome of surgical patients. Aims of the study are 1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy, 2) to determine immune and microbiota signature that would predict IN effect. Methods This is a randomized, multicentric, controlled, pragmatic, parallel-group comparative study, supported by the Swiss National Science Foundation. A total of 232 patients is planned to be enrolled between April 2023 and June 2026. Three participating centers (Lausanne, Bern and Riviera-Chablais) have been selected. All patients undergoing elective radical and simple cystectomy will be randomly assigned to receive seven days of preoperative IN (Oral Impact ® , Nestlé, Switzerland) versus standard of care (control group) and followed for 90 days after surgery. For the exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at Lausanne. In order to determine the impact of IN on immune fitness, patients enrolled at Lausanne will be vaccinated against influenza and the establishment of the vaccine-specific immune response will be followed. Analysis of the microbiota and expression of Argininosuccinate synthetase 1 as potential biomarker will also be performed. Discussion and Conclusion Strengths of the INCyst study include the randomized, multicenter, prospective design, the large number of patients studied and the translational investigation. This study will challenge the added value of preoperative IN in patients undergoing cystectomy, assessing the clinical effect of IN on the onset of post-operative morbidity and mortality after cystectomy. Furthermore, it will provide invaluable data on the host immune response and microbiota composition. Trial registration: ClinicalTrials.gov (NCT05726786) Immunonutrition bladder cancer cystectomy infection complications microbiota immune cells Figures Figure 1 Figure 2 INTRODUCTION Radical cystectomy (RC) with extended bilateral pelvic lymph node dissection (PLND) represents the best available treatment for muscle-invasive BC [ 1 ]. Furthermore, this major surgery may be the treatment of choice for non-malignant pathologies, such as interstitial cystitis, painful bladder syndrome, neurogenic bladder, haemorrhagic radiation cystitis, infectious diseases of the bladder, endometriosis and refractory genitourinary fistulae [ 2 ] in patients who have failed previous conservative therapy. Although cystectomy is considered as an extended major surgery, it has unique features that preclude any outcomes extrapolation from other abdominal surgeries (i.e. colonic resections, gynaecologic procedures). These include lymph node resection, longer operative time, significant bleeding, urinary diversion with bowel resulting in metabolic changes and peritoneal soiling with urine [ 3 ]. Despite standardized surgical technique and the development of new perioperative care protocols, cystectomy morbidity remains a serious challenge for urologists. Postoperative complications lead to longer length of stay and worse survival. Infectious complications, including pneumonia, urinary tract infections, surgical site infections, septicaemia and shock, are relatively frequent after cystectomy, rated between 25% and 45% [ 4 , 5 ]. Patients undergoing cystectomy for a bladder cancer or a benign disease have the similar risk of complications [ 6 ]. Antibiotic prophylaxis practices are highly heterogeneous in cystectomy and there is a lack of adherence in guidelines [ 7 ]. Careful perioperative risk reduction in patients undergoing major surgery is an evolving key concept to decrease postoperative morbidity rates. Many risk factors, such as repeated radio-chemotherapy regimens, pre-existing co-morbidities and increased age can hardly be influenced. Although malnutrition has been identified as an independent risk factor for morbidity and mortality after cystectomy [ 8 – 10 ], there is no recommendation with regards to preoperative screening and/or treatment of malnutrition in guidelines for cystectomy. In most of hospitals where cystectomies are performed, there is no standardized malnutrition screening policy and malnourished patients undergoing surgery are therefore neither identified nor treated. Another major pathogenic factor leading to postoperative morbidity is the so-called surgical stress response. Nowadays, it has been clarified that surgery induces a complex cascade resulting in inflammatory response, immune suppression, altered metabolism with hypercatabolism, which altogether lead to impaired wound healing and multi-organ failure. The mediators of this endocrine-metabolic stress response are cytokines, arachidonic acid, nitric oxide, and free oxygen radicals. While the mechanisms mentioned above have been extensively studied, to date, no single intervention has been shown to eliminate postoperative morbidity and mortality. Consequently, immunosurveillance and therefore successful cancer treatment relies on maintaining an unharmed immune system. Immunonutrition (IN) aims to improve the nutritional status, immunological function, and clinical outcome of cancer patients. When applied to cancer patients treated by radiation or chemotherapy (i.e. not undergoing surgery, thus avoiding surgical stress response), IN has been shown to increase T lymphocyte counts and to decrease inflammatory and oxidative stress response [ 11 ]. Many randomized controlled trials and meta-analyses have demonstrated that IN allows for a reduction of complication rate, infections and length of stay after major abdominal surgery [ 12 ]. Unfortunately, very few data are available on the impact of IN on infectious complications after cystectomy [ 13 , 14 ]. The aims of this study are 1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy, 2) to determine immune and microbiota signature that would predict IN effect. METHODS Study design The present study (approval #2022 − 01528 version 5) is designed as a multicentre, prospective, controlled, pragmatic, parallel-group comparative study with block randomization stratified by centres (Fig. 1 and Table 1 ). Patients will be randomly assigned to 2 groups (per center randomization): intervention group (seven days of preoperative oral supplementation with an immune-enhanced oral nutrition (Oral Impact ® , Nestlé Nutrition, Switzerland)) or control group (standard of care, no preoperative IN). During an overall study duration of 4 years, a total of 232 patients (116 in each arm) will be included (Table 2 ). Allocation consignment will be generated by a dedicated research nurse at each centre, through centralized block randomization via the Interface Web Response System (IWRS) developed within the electronic Case Report Form (eCRF). Equilibrated randomization will be performed on a site-stratified basis to avoid imbalanced randomization between clinical sites where patient recruitment may differ. The allocation sequence is concealed from the investigators enrolling and assessing the patients. Table 1 Trial Registration Data Set according to World Health Organization Data category Information Primary registry and trial identifying number ClinicalTrials.gov NCT05726786 Date of registration in primary registry March 09th 2023 Secondary identifying numbers 2022 − 01528; BASEC2022-01528; SNCTP000005406 Source(s) of monetary or material support Swiss National Science Foundation Primary sponsor University Hospital of Lausanne (CHUV) Secondary sponsor(s) None Contact for public queries Dr. MD. Ilaria Lucca ( [email protected] ) Contact for scientific queries Dr. MD. Ilaria Lucca ( [email protected] ) Public title The impact of immunonutrition on postoperative complications in patients undergoing bladder removal surgery. Scientific title The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial) Countries of recruitment Switzerland Health condition(s) or problem(s) studied Determination of infectious complications rate at 30 days after surgery Intervention(s) Drug: Oral Impact®, Nestlé Health Science, Switzerland. Key inclusion and exclusion criteria Inclusion criteria: Age ≥ 18 years, patient undergoing open cystectomy (for all reasons). Exclusion criteria: Contraindications to immunonutrition (e.g. known hypersensitivity or allergy to lactose, fish oil or soy lecithin), Severe diarrhea requiring medical attention, Current treatment with any immunosuppressive drug. Study type Multicenter, prospective, controlled, pragmatic, parallel-group comparative study with block randomization stratified by centers Date of first enrolment April 2023 Target sample size 232 Recruitment status Recruiting Primary outcome(s) Determination of the Comprehensive Complication Index (CCI) at 30 and 90 days after surgery. Determination of the mortality rate at 30 and 90 days after surgery. Determination of the post-operative complication-free survival Key secondary outcome Identification of biomarkers predictive of postoperative complications studying the patient's immune and microbiome signature. Table 2 schedule of enrolment, interventions, and assessments Study periods: Screening Pre-operative Follow-up Visit V0 V1 V2 V3 V4 V5 V6 Time (day) J-30* /-8 J-1/0 J0 + 1 J0 + 5 end of hospitalization J0 + 30+/-10 J0 + 90 +/-20 Informed consent X Demographic characteristics X Medical history X In-/Exclusion criteria X Physical examination X X X X X X X Weight X X X X X X Laboratory samples (only Lausanne) Blood (50ml/sample) Urine (5 to 300 ml/sample) Stools Arginine level Tissue (ASS1 expression analysis) Fresh Tissue (oncological patients) X X X X X X X X X X X X X NRS X Eligibility and Randomization X Post-operative infectious complications X X Comprehensive Complication Index (CCI) X X EORTC-QLQ-C30 questionnaire X X X Peri-operative management X Nutritional Risk Status (NRS) Score will be performed in each patient before inclusion. Preoperative carbohydrate loading will be allowed in both groups in case of malnutrition and at discretion of the referent physician. Malnutrition status will not impact the group allocation. This trial will be conducted in accordance with the Good Clinical Practice Guidelines and applicable local regulations. Moreover, we used the SPIRIT reporting guidelines to write the protocol (Supplementary Fig. 1). Further details on the protocol are in the supplemental information. Clinical outcomes The primary endpoint is to investigate the infectious complications rate at 30 days after surgery. All type of infectious complication will be considered and graded according to the Clavien's grade. Secondary clinical outcome is Comprehensive Complication Index (CCI) evaluated at 30 and 90 days after surgery. Postoperative complications will be graded according to their severity. A validated therapy-oriented, modified Clavien-Dindo classification will be used to asses complication grade [ 15 ]: major complications are defined as grade 3–4, grade 5 corresponds to mortality. Mortality rate at 30 and 90 days after surgery, post-operative complication-free survival, treatment compliance, impact of IN on oncologic and non-oncologic patients, role of IN in patients undergoing neoadjuvant chemotherapy and quality of life after surgery will also be investigated. Exploratory outcomes For exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at the site of Lausanne. The main goal is to characterize different immune parameters to define a signature that will be predictive of the IN efficacy and that will guide to select patients likely to benefit from IN. Percentages of different immune cell subsets from the peripheral blood mononuclear cells (PBMCs) will be measured by flow cytometry. We will study the frequency of different subsets of immune cells such as CD3 + T cells, regulatory CD4 + T cells, Natural Killer (NK) cells and myeloid-derived suppressor cells. Furthermore, the expression of immune checkpoints (PD-1, TIM-3, BTLA, CTLA-4 and TIGIT) on T cells from blood will also be performed ex vivo. To determine the influence of IN on immune response generated in vivo, T-cell specific immune response against influenza will be monitored in the PBMCs before vaccination and after. It is well known that the presence of polyfunctional T cells (i.e. capacity to produce several cytokines at the same time) may be beneficial to the outcome of a disease, especially in cancer [ 16 – 18 ]. Thus, T-cell polyfunctionality assessment may provide a surrogate for potential antitumor immune response. We will stimulate blood T cells from patients in vitro either with anti-CD3 and anti-CD28 antibodies or with a pool of peptides from influenza and measure the production of TNF-α, IFN-𝛾, IL-2, IL-4, IL-10, IL-17 and CD107a by flow cytometry. We also intend to determine the concentration of inflammatory and suppressive cytokines in serum and urine using the classical Luminex assay, as we did in a previous clinical trial [ 19 ]. Furthermore, it is well known now that a disruption of the symbiosis between the microbiota and the immune system, as a result of antibiotic usage or diet alteration, may lead to the development and/or exacerbation of different diseases [ 20 ], supporting the fact that IN may impact the gut microbiota. Microbiota diversity and abundance will be thus determined by genomic sequencing and bioinformatics analysis on patient feces. Finally, Argininosuccinate synthetase 1 (ASS1) expression will be analysed by immunohistochemistry in order to evaluate whether its expression may alter the IN efficacy. Biological material will be appropriately stored in a restricted area only accessible to authorized personnel according to the regulation of the urology biobank of Lausanne University Hospital ( https://www.chuv.ch/fr/urologie/uro-home/recherche/axes-de-recherche/biobanque-durologie ). No publication or report of any kind will contain patient’s names or any identifying features of single patients. No on-line or written document or communication will refer to participant’s personal detail. Patients’ selection, antibiotic regimen, and perioperative protocol All patients undergoing radical or simple cystectomy (for all reasons) will be included. Inclusion and exclusion criteria are listed in Fig. 2 . A urine culture will be performed 10 days before surgery and all patients will receive the same prophylactic antibiotic regimen: Cefuroxime iv (single dose) and Metronidazole IV (single dose) at the time of surgery for cystectomy with ileostomy/ureterocutaneostomy and Cefuroxime iv and metronidazole IV (48h after surgery) for cystectomy with orthotopic neobladder or heterotopic pouches. Patients will receive oral Co-trimoxazole (single dose) at the time of ureteral stent removal. In case of allergies or antibiotic resistances according to the urinary culture, the antibiotic regimen will be adapted, and all changes will be recorded. Each centre will follow the same perioperative protocol according to the ERAS protocol for cystectomy [ 21 ]. The surgical procedure will be undertaken in a standardized technique among the three centres. As the robotic access is not routinely performed in Switzerland, only open cystectomies will be included. Bilateral PLND will be performed only in bladder cancer patients as an extended template. The mode of diversion/reconstruction will be left at the surgeon’s discretion but will be nevertheless documented. In case of orthotopic or heterotopic urinary diversion, the Studer technique will be performed. A dedicated questionnaire (EORTC QLQ-C30) will be distributed to patients assessing patients’ health status. The questionnaire will be discussed with each patient at visit V1 (inclusion), V5 (30 days after surgery) and V6 (90 days after surgery). Choice of comparators and protocol adherence Oral Impact® (IN) is an immune-modulating nutritional supplement containing arginine, omega-3 polyunsaturated fatty acids and ribonucleic acid. Arginine is a key amino acid involved in multiple cellular processes as well as in lymphocyte function and its deficiency results in impaired adaptive immune response. It plays an active role in wound healing, muscle repair (by protein translation) and thrombosis prevention. The present design raises the issue of supplementing patients that are not at nutritional risk with Oral Impact®, resulting in overnutrition with potentially deleterious clinical consequences. However, this hypothesis has not been confirmed by others [ 22 ] and the product’s brochure stipulates that the administration of Oral Impact® in the preoperative phase is also indicated in well-nourished patients [ 23 ]. Moreover, surgery induces arginine deficiency and many patients with normal preoperative arginine concentrations cannot endogenously satisfy the metabolic demand after surgery. Patients will be randomly assigned to receive seven days of preoperative IN, three times a day (Oral Impact®) or will not receive oral IN supplements. Carbohydrate loading and protein drinks will be allowed in both groups. In the interventional group, patient’s compliance to the allocated treatment will be recorded by asking the patient how many nutritional supplements she/he has ingested preoperatively (ranging from 0 to 21 bags). Compliant patients will be defined by having drunk at least 14 of the 21 allocated nutritional supplements. To objectively verify and validate these subjective data, serum arginine levels will be assessed at enrolment (between Day − 30 and Day − 8) and at preoperative admission after intake of the allocated nutrition (Day − 1). Statistical analysis The literature review showed a postoperative infectious rate between 25% and 45% among patients treated with cystectomy. Assuming a normal distribution for infectious complications after cystectomy and a common standard deviation in both study arms, desired probabilities of type I error (α) of 5% and of type II error (β) of 20% (i.e. 80% statistical power) and applying a two-sided test, 110 informative patients per arm (i.e. a total of 220) would be needed to decrease the rate of infectious complications by 17% in the IN group (37% infections at 30 days after surgery in the control group vs 20% in the IN group). Since we anticipate a possible dropout rate of up to 5%, a total of 232 patients are intended for enrolment in the study (116 patients per group). To achieve adequate participant enrolment, three Swiss hospitals participate to this study (University hospital of Lausanne, University Hospital of Bern, and Hospital of Riviera-Chablais). No imputations will be done on missing data. Ordinal and continuous data will be presented by study group in the form of descriptive statistics, as number of patients, mean, standard deviation, minimum, median, maximum. Categorical data will be presented by study group using contingency tables with absolute and relative frequencies. Complications rate will be presented using contingency tables with absolute and relative frequencies, overall and then by study group. The complication rate will be compared between groups using a Chi2 test. Mortality after surgery and post-operative complication-free survival will be analyzed using Kaplan-Meier curves. The study groups will be compared with a log-rank test. CONCLUSION There is an urgent need of improvement in the perioperative management of cystectomy patients. The INCyst trial will challenge the added-value of preoperative IN in patients undergoing cystectomy, possibly reducing the post-operative morbidity and mortality. It might bring breakthrough changes in the daily urology clinical practice, that would also be relevant in other medical disciplines practicing heavy surgeries. Plus, it will provide invaluable data on the host immune response and microbiota composition. Declarations TRAIL STATUS The INCyst trial has received governance approval (version 5 dated 06.06.2023) and is registered at ClinicalTrials.gov (NCT05726786). Patient recruitment has started in April 2023 and the study will presumably end in June 2026. First results from this study are expected in the last quarter 2026. ETHICS APPROVAL AND CONSENT TO PARTICIPATE All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent (containing an additional consent for collection and use of participant data and biological specimens in ancillary studies) will be obtained from all study participants by urologists involved in the study. The study was approved by the lead ethics committee in Lausanne, Switzerland on March 2023 and subsequently by the ethic committee of Bern, Switzerland (approval #2022 − 01528 version 5). CONSENT FOR PUBLICATION Not applicable. COMPETING INTERESTS The authors declare that they have no competing interests. FUNDING The INCyst Trial is supported by the Swiss National Science Foundation (#32003B_207837). AUTHORS’ CONTRIBUTIONS LD, YC and IL conceived the study, wrote the initial study protocol, and applied for funding. FC, BR, NG, KS, SDP participated in finalizing the study protocol and the statistical analysis plan. SDP and IL coordinate the study. LD, FC, NG, KS, BK, TT, SDP, BR, YC, IL participate in the execution of the study. LD, SDP, BR, and IL drafted the first manuscript. All authors contributed to the manuscript and all authors read and approved the final version. ACKNOWLEDGEMENTS The authors thank all study nurses and investigators participating in this study. We thank also the Swiss National Science Foundation for the financial support (#32003B_207837). AVAILABILITY OF DATA AND MATERIALS Datasets generated during the study will be kept by the corresponding author and made available upon request. References Witjes JA, Bruins HM, Cathomas R, Comperat EM, Cowan NC, Gakis G, Hernandez V, Linares Espinos E, Lorch A, Neuzillet Y, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol. 2021;79(1):82–104. Chong JT, Dolat MT, Klausner AP, Dragoescu E, Hampton LJ. The role of cystectomy for non-malignant bladder conditions: a review. Can J Urol. 2014;21(5):7433–41. 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Supplementary Files Supplementalinformation.docx SupplementaryTable1.docx Cite Share Download PDF Status: Published Journal Publication published 17 Oct, 2024 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 11 Jul, 2024 Reviewers agreed at journal 06 Jul, 2024 Reviewers invited by journal 06 Jul, 2024 Editor assigned by journal 15 Apr, 2024 First submitted to journal 20 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Vaudois","correspondingAuthor":false,"prefix":"","firstName":"Francois","middleName":"","lastName":"Crettenand","suffix":""},{"id":323454817,"identity":"b9507da7-0803-4532-9ba8-10a928f154da","order_by":2,"name":"Nuno Grilo","email":"","orcid":"","institution":"CHUV: Centre Hospitalier Universitaire Vaudois","correspondingAuthor":false,"prefix":"","firstName":"Nuno","middleName":"","lastName":"Grilo","suffix":""},{"id":323454818,"identity":"36f13b66-0d62-4553-a5fc-aa4672ce0999","order_by":3,"name":"Kevin Stritt","email":"","orcid":"","institution":"CHUV: Centre Hospitalier Universitaire Vaudois","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Stritt","suffix":""},{"id":323454819,"identity":"0d6c3a33-943e-4970-829e-3641a1eaafc2","order_by":4,"name":"Bernhard Kiss","email":"","orcid":"","institution":"Inselspital University Hospital Bern: Inselspital Universitatsspital 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Bern","correspondingAuthor":false,"prefix":"","firstName":"Beat","middleName":"","lastName":"Roth","suffix":""},{"id":323454823,"identity":"7573efbc-b828-4c51-8307-850c14bf8378","order_by":8,"name":"Yannick Cerantola","email":"","orcid":"","institution":"CHUV: Centre Hospitalier Universitaire Vaudois","correspondingAuthor":false,"prefix":"","firstName":"Yannick","middleName":"","lastName":"Cerantola","suffix":""},{"id":323454824,"identity":"32c8cbe6-f6c5-40fa-a2d6-1aa341463ac2","order_by":9,"name":"Ilaria Lucca","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACNnYgkcDAIAPmfWA4ABbEr4UZooUHxGGcQYwWBmYIBdbCzEOMFj5m5mcfHtQw8BgcP/zws03NncQNB5ifPcDvMDbjGQnHgFrOpBlL5xx7BtTCZm5AwC/GDAlsQC03eBikcxsOJ85s4GGTwK+F/TNDwj+wFubflsRp4TFmSGwDa2GTZgRq6WcgrKWYIbFPgkfyTJqZZc+xw8b9zGxmeLXIt7dvZvzxzUaO7/jhxzd+1ByWbWNvfoZXCxQgq2EmQv0oGAWjYBSMAvwAAJXQPTIJBE/bAAAAAElFTkSuQmCC","orcid":"","institution":"CHUV: Centre Hospitalier Universitaire Vaudois","correspondingAuthor":true,"prefix":"","firstName":"Ilaria","middleName":"","lastName":"Lucca","suffix":""}],"badges":[],"createdAt":"2024-03-08 16:23:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4046807/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4046807/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08536-5","type":"published","date":"2024-10-17T15:57:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62133271,"identity":"451ad5bc-709d-46b4-8597-bb2e0e391707","added_by":"auto","created_at":"2024-08-09 15:55:52","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":204277,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design\u003c/p\u003e","description":"","filename":"Figure1HQ.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4046807/v1/c9b9e9b7357e7bbd95229787.jpeg"},{"id":62132460,"identity":"25b9502f-0e40-48f5-9e82-6af8e0f7750a","added_by":"auto","created_at":"2024-08-09 15:47:52","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":263777,"visible":true,"origin":"","legend":"\u003cp\u003eInclusion and exclusion criteria\u003c/p\u003e","description":"","filename":"Figure2HQ.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4046807/v1/16024c27562cba22e3ff05eb.jpeg"},{"id":67148972,"identity":"8b284937-c27a-4bac-adcd-7a6201d85b7d","added_by":"auto","created_at":"2024-10-21 16:10:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":990541,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4046807/v1/c090917c-8cf7-42a5-9b42-ab1f69cf8d9d.pdf"},{"id":62132458,"identity":"2ba593c5-0356-4b5e-ba81-6ff9f7ea20af","added_by":"auto","created_at":"2024-08-09 15:47:52","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":30883,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4046807/v1/093d15bf6bc90de1f7ffe987.docx"},{"id":62133270,"identity":"10e35dd3-4232-4497-b0cd-e21dae3da211","added_by":"auto","created_at":"2024-08-09 15:55:52","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":42101,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4046807/v1/1cfde2da71d884bc7fe27d6f.docx"}],"financialInterests":"","formattedTitle":"The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eRadical cystectomy (RC) with extended bilateral pelvic lymph node dissection (PLND) represents the best available treatment for muscle-invasive BC [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, this major surgery may be the treatment of choice for non-malignant pathologies, such as interstitial cystitis, painful bladder syndrome, neurogenic bladder, haemorrhagic radiation cystitis, infectious diseases of the bladder, endometriosis and refractory genitourinary fistulae [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] in patients who have failed previous conservative therapy.\u003c/p\u003e \u003cp\u003eAlthough cystectomy is considered as an extended major surgery, it has unique features that preclude any outcomes extrapolation from other abdominal surgeries (i.e. colonic resections, gynaecologic procedures). These include lymph node resection, longer operative time, significant bleeding, urinary diversion with bowel resulting in metabolic changes and peritoneal soiling with urine [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite standardized surgical technique and the development of new perioperative care protocols, cystectomy morbidity remains a serious challenge for urologists. Postoperative complications lead to longer length of stay and worse survival. Infectious complications, including pneumonia, urinary tract infections, surgical site infections, septicaemia and shock, are relatively frequent after cystectomy, rated between 25% and 45% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Patients undergoing cystectomy for a bladder cancer or a benign disease have the similar risk of complications [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Antibiotic prophylaxis practices are highly heterogeneous in cystectomy and there is a lack of adherence in guidelines [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCareful perioperative risk reduction in patients undergoing major surgery is an evolving key concept to decrease postoperative morbidity rates. Many risk factors, such as repeated radio-chemotherapy regimens, pre-existing co-morbidities and increased age can hardly be influenced. Although malnutrition has been identified as an independent risk factor for morbidity and mortality after cystectomy [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], there is no recommendation with regards to preoperative screening and/or treatment of malnutrition in guidelines for cystectomy. In most of hospitals where cystectomies are performed, there is no standardized malnutrition screening policy and malnourished patients undergoing surgery are therefore neither identified nor treated.\u003c/p\u003e \u003cp\u003eAnother major pathogenic factor leading to postoperative morbidity is the so-called surgical stress response. Nowadays, it has been clarified that surgery induces a complex cascade resulting in inflammatory response, immune suppression, altered metabolism with hypercatabolism, which altogether lead to impaired wound healing and multi-organ failure. The mediators of this endocrine-metabolic stress response are cytokines, arachidonic acid, nitric oxide, and free oxygen radicals. While the mechanisms mentioned above have been extensively studied, to date, no single intervention has been shown to eliminate postoperative morbidity and mortality. Consequently, immunosurveillance and therefore successful cancer treatment relies on maintaining an unharmed immune system.\u003c/p\u003e \u003cp\u003eImmunonutrition (IN) aims to improve the nutritional status, immunological function, and clinical outcome of cancer patients. When applied to cancer patients treated by radiation or chemotherapy (i.e. not undergoing surgery, thus avoiding surgical stress response), IN has been shown to increase T lymphocyte counts and to decrease inflammatory and oxidative stress response [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Many randomized controlled trials and meta-analyses have demonstrated that IN allows for a reduction of complication rate, infections and length of stay after major abdominal surgery [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Unfortunately, very few data are available on the impact of IN on infectious complications after cystectomy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aims of this study are 1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy, 2) to determine immune and microbiota signature that would predict IN effect.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e The present study (approval #2022\u0026thinsp;\u0026minus;\u0026thinsp;01528 version 5) is designed as a multicentre, prospective, controlled, pragmatic, parallel-group comparative study with block randomization stratified by centres (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients will be randomly assigned to 2 groups (per center randomization): intervention group (seven days of preoperative oral supplementation with an immune-enhanced oral nutrition (Oral Impact\u003csup\u003e\u0026reg;\u003c/sup\u003e, Nestl\u0026eacute; Nutrition, Switzerland)) or control group (standard of care, no preoperative IN). During an overall study duration of 4 years, a total of 232 patients (116 in each arm) will be included (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Allocation consignment will be generated by a dedicated research nurse at each centre, through centralized block randomization via the Interface Web Response System (IWRS) developed within the electronic Case Report Form (eCRF). Equilibrated randomization will be performed on a site-stratified basis to avoid imbalanced randomization between clinical sites where patient recruitment may differ. The allocation sequence is concealed from the investigators enrolling and assessing the patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTrial Registration Data Set according to World Health Organization\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eData category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInformation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary registry and trial identifying number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinicalTrials.gov NCT05726786\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate of registration in primary registry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarch 09th 2023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary identifying numbers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2022\u0026thinsp;\u0026minus;\u0026thinsp;01528; BASEC2022-01528; SNCTP000005406\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource(s) of monetary or material support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSwiss National Science Foundation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary sponsor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUniversity Hospital of Lausanne (CHUV)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary sponsor(s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContact for public queries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDr. MD. Ilaria Lucca ([email protected])\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContact for scientific queries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDr. MD. Ilaria Lucca ([email protected])\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePublic title\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe impact of immunonutrition on postoperative complications in patients undergoing bladder removal surgery.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScientific title\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCountries of recruitment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSwitzerland\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealth condition(s) or problem(s) studied\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDetermination of infectious complications rate at 30 days after surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntervention(s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug: Oral Impact\u0026reg;, Nestl\u0026eacute; Health Science, Switzerland.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKey inclusion and exclusion criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInclusion criteria: Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, patient undergoing open cystectomy (for all reasons).\u003c/p\u003e \u003cp\u003eExclusion criteria: Contraindications to immunonutrition (e.g. known hypersensitivity or allergy to lactose, fish oil or soy lecithin), Severe diarrhea requiring medical attention, Current treatment with any immunosuppressive drug.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMulticenter, prospective, controlled, pragmatic, parallel-group comparative study with block randomization stratified by centers\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate of first enrolment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eApril 2023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTarget sample size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e232\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecruitment status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecruiting\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary outcome(s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDetermination of the Comprehensive Complication Index (CCI) at 30 and 90 days after surgery.\u003c/p\u003e \u003cp\u003eDetermination of the mortality rate at 30 and 90 days after surgery.\u003c/p\u003e \u003cp\u003eDetermination of the post-operative complication-free survival\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKey secondary outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIdentification of biomarkers predictive of postoperative complications studying the patient's immune and microbiome signature.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eschedule of enrolment, interventions, and assessments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy periods:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eScreening\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePre-operative\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c8\" namest=\"c4\"\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eV0\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eV1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eV2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eV4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eV6\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime (day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJ-30* /-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJ-1/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJ0\u0026thinsp;+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJ0\u0026thinsp;+\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eend of hospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eJ0\u0026thinsp;+\u0026thinsp;30+/-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eJ0\u0026thinsp;+\u0026thinsp;90 +/-20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn-/Exclusion criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical examination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory samples (only Lausanne)\u003c/p\u003e \u003cp\u003eBlood (50ml/sample)\u003c/p\u003e \u003cp\u003eUrine (5 to 300 ml/sample)\u003c/p\u003e \u003cp\u003eStools\u003c/p\u003e \u003cp\u003eArginine level\u003c/p\u003e \u003cp\u003eTissue (ASS1 expression analysis)\u003c/p\u003e \u003cp\u003eFresh Tissue (oncological patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEligibility and Randomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-operative infectious complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComprehensive Complication Index (CCI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEORTC-QLQ-C30 questionnaire\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeri-operative management\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNutritional Risk Status (NRS) Score will be performed in each patient before inclusion. Preoperative carbohydrate loading will be allowed in both groups in case of malnutrition and at discretion of the referent physician. Malnutrition status will not impact the group allocation. This trial will be conducted in accordance with the Good Clinical Practice Guidelines and applicable local regulations. Moreover, we used the SPIRIT reporting guidelines to write the protocol (Supplementary Fig.\u0026nbsp;1). Further details on the protocol are in the supplemental information.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical outcomes\u003c/h2\u003e \u003cp\u003eThe primary endpoint is to investigate the infectious complications rate at 30 days after surgery. All type of infectious complication will be considered and graded according to the Clavien's grade.\u003c/p\u003e \u003cp\u003eSecondary clinical outcome is Comprehensive Complication Index (CCI) evaluated at 30 and 90 days after surgery. Postoperative complications will be graded according to their severity. A validated therapy-oriented, modified Clavien-Dindo classification will be used to asses complication grade [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]: major complications are defined as grade 3\u0026ndash;4, grade 5 corresponds to mortality.\u003c/p\u003e \u003cp\u003eMortality rate at 30 and 90 days after surgery, post-operative complication-free survival, treatment compliance, impact of IN on oncologic and non-oncologic patients, role of IN in patients undergoing neoadjuvant chemotherapy and quality of life after surgery will also be investigated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eExploratory outcomes\u003c/h2\u003e \u003cp\u003eFor exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at the site of Lausanne. The main goal is to characterize different immune parameters to define a signature that will be predictive of the IN efficacy and that will guide to select patients likely to benefit from IN.\u003c/p\u003e \u003cp\u003ePercentages of different immune cell subsets from the peripheral blood mononuclear cells (PBMCs) will be measured by flow cytometry. We will study the frequency of different subsets of immune cells such as CD3\u003csup\u003e+\u003c/sup\u003e T cells, regulatory CD4\u003csup\u003e+\u003c/sup\u003e T cells, Natural Killer (NK) cells and myeloid-derived suppressor cells. Furthermore, the expression of immune checkpoints (PD-1, TIM-3, BTLA, CTLA-4 and TIGIT) on T cells from blood will also be performed ex vivo.\u003c/p\u003e \u003cp\u003eTo determine the influence of IN on immune response generated in vivo, T-cell specific immune response against influenza will be monitored in the PBMCs before vaccination and after. It is well known that the presence of polyfunctional T cells (i.e. capacity to produce several cytokines at the same time) may be beneficial to the outcome of a disease, especially in cancer [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Thus, T-cell polyfunctionality assessment may provide a surrogate for potential antitumor immune response. We will stimulate blood T cells from patients in vitro either with anti-CD3 and anti-CD28 antibodies or with a pool of peptides from influenza and measure the production of TNF-α, IFN-\u0026#120574;, IL-2, IL-4, IL-10, IL-17 and CD107a by flow cytometry. We also intend to determine the concentration of inflammatory and suppressive cytokines in serum and urine using the classical Luminex assay, as we did in a previous clinical trial [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, it is well known now that a disruption of the symbiosis between the microbiota and the immune system, as a result of antibiotic usage or diet alteration, may lead to the development and/or exacerbation of different diseases [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], supporting the fact that IN may impact the gut microbiota. Microbiota diversity and abundance will be thus determined by genomic sequencing and bioinformatics analysis on patient feces. Finally, Argininosuccinate synthetase 1 (ASS1) expression will be analysed by immunohistochemistry in order to evaluate whether its expression may alter the IN efficacy.\u003c/p\u003e \u003cp\u003eBiological material will be appropriately stored in a restricted area only accessible to authorized personnel according to the regulation of the urology biobank of Lausanne University Hospital (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.chuv.ch/fr/urologie/uro-home/recherche/axes-de-recherche/biobanque-durologie\u003c/span\u003e\u003cspan address=\"https://www.chuv.ch/fr/urologie/uro-home/recherche/axes-de-recherche/biobanque-durologie\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). No publication or report of any kind will contain patient\u0026rsquo;s names or any identifying features of single patients. No on-line or written document or communication will refer to participant\u0026rsquo;s personal detail.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; selection, antibiotic regimen, and perioperative protocol\u003c/h2\u003e \u003cp\u003eAll patients undergoing radical or simple cystectomy (for all reasons) will be included. Inclusion and exclusion criteria are listed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A urine culture will be performed 10 days before surgery and all patients will receive the same prophylactic antibiotic regimen: Cefuroxime iv (single dose) and Metronidazole IV (single dose) at the time of surgery for cystectomy with ileostomy/ureterocutaneostomy and Cefuroxime iv and metronidazole IV (48h after surgery) for cystectomy with orthotopic neobladder or heterotopic pouches. Patients will receive oral Co-trimoxazole (single dose) at the time of ureteral stent removal. In case of allergies or antibiotic resistances according to the urinary culture, the antibiotic regimen will be adapted, and all changes will be recorded.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEach centre will follow the same perioperative protocol according to the ERAS protocol for cystectomy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The surgical procedure will be undertaken in a standardized technique among the three centres. As the robotic access is not routinely performed in Switzerland, only open cystectomies will be included. Bilateral PLND will be performed only in bladder cancer patients as an extended template. The mode of diversion/reconstruction will be left at the surgeon\u0026rsquo;s discretion but will be nevertheless documented. In case of orthotopic or heterotopic urinary diversion, the Studer technique will be performed.\u003c/p\u003e \u003cp\u003eA dedicated questionnaire (EORTC QLQ-C30) will be distributed to patients assessing patients\u0026rsquo; health status. The questionnaire will be discussed with each patient at visit V1 (inclusion), V5 (30 days after surgery) and V6 (90 days after surgery).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eChoice of comparators and protocol adherence\u003c/h2\u003e \u003cp\u003eOral Impact\u0026reg; (IN) is an immune-modulating nutritional supplement containing arginine, omega-3 polyunsaturated fatty acids and ribonucleic acid. Arginine is a key amino acid involved in multiple cellular processes as well as in lymphocyte function and its deficiency results in impaired adaptive immune response. It plays an active role in wound healing, muscle repair (by protein translation) and thrombosis prevention. The present design raises the issue of supplementing patients that are not at nutritional risk with Oral Impact\u0026reg;, resulting in overnutrition with potentially deleterious clinical consequences. However, this hypothesis has not been confirmed by others [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and the product\u0026rsquo;s brochure stipulates that the administration of Oral Impact\u0026reg; in the preoperative phase is also indicated in well-nourished patients [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Moreover, surgery induces arginine deficiency and many patients with normal preoperative arginine concentrations cannot endogenously satisfy the metabolic demand after surgery.\u003c/p\u003e \u003cp\u003ePatients will be randomly assigned to receive seven days of preoperative IN, three times a day (Oral Impact\u0026reg;) or will not receive oral IN supplements. Carbohydrate loading and protein drinks will be allowed in both groups. In the interventional group, patient\u0026rsquo;s compliance to the allocated treatment will be recorded by asking the patient how many nutritional supplements she/he has ingested preoperatively (ranging from 0 to 21 bags). Compliant patients will be defined by having drunk at least 14 of the 21 allocated nutritional supplements. To objectively verify and validate these subjective data, serum arginine levels will be assessed at enrolment (between Day \u0026minus;\u0026thinsp;30 and Day \u0026minus;\u0026thinsp;8) and at preoperative admission after intake of the allocated nutrition (Day \u0026minus;\u0026thinsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe literature review showed a postoperative infectious rate between 25% and 45% among patients treated with cystectomy. Assuming a normal distribution for infectious complications after cystectomy and a common standard deviation in both study arms, desired probabilities of type I error (α) of 5% and of type II error (β) of 20% (i.e. 80% statistical power) and applying a two-sided test, 110 informative patients per arm (i.e. a total of 220) would be needed to decrease the rate of infectious complications by 17% in the IN group (37% infections at 30 days after surgery in the control group vs 20% in the IN group). Since we anticipate a possible dropout rate of up to 5%, a total of 232 patients are intended for enrolment in the study (116 patients per group). To achieve adequate participant enrolment, three Swiss hospitals participate to this study (University hospital of Lausanne, University Hospital of Bern, and Hospital of Riviera-Chablais). No imputations will be done on missing data.\u003c/p\u003e \u003cp\u003eOrdinal and continuous data will be presented by study group in the form of descriptive statistics, as number of patients, mean, standard deviation, minimum, median, maximum. Categorical data will be presented by study group using contingency tables with absolute and relative frequencies.\u003c/p\u003e \u003cp\u003eComplications rate will be presented using contingency tables with absolute and relative frequencies, overall and then by study group. The complication rate will be compared between groups using a Chi2 test. Mortality after surgery and post-operative complication-free survival will be analyzed using Kaplan-Meier curves. The study groups will be compared with a log-rank test.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThere is an urgent need of improvement in the perioperative management of cystectomy patients. The INCyst trial will challenge the added-value of preoperative IN in patients undergoing cystectomy, possibly reducing the post-operative morbidity and mortality. It might bring breakthrough changes in the daily urology clinical practice, that would also be relevant in other medical disciplines practicing heavy surgeries. Plus, it will provide invaluable data on the host immune response and microbiota composition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eTRAIL STATUS\u003c/h2\u003e \u003cp\u003eThe INCyst trial has received governance approval (version 5 dated 06.06.2023) and is registered at ClinicalTrials.gov (NCT05726786). Patient recruitment has started in April 2023 and the study will presumably end in June 2026. First results from this study are expected in the last quarter 2026.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/h2\u003e \u003cp\u003e All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent (containing an additional consent for collection and use of participant data and biological specimens in ancillary studies) will be obtained from all study participants by urologists involved in the study. The study was approved by the lead ethics committee in Lausanne, Switzerland on March 2023 and subsequently by the ethic committee of Bern, Switzerland (approval #2022\u0026thinsp;\u0026minus;\u0026thinsp;01528 version 5).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFUNDING\u003c/h2\u003e \u003cp\u003eThe INCyst Trial is supported by the Swiss National Science Foundation (#32003B_207837).\u003c/p\u003e\u003ch2\u003eAUTHORS\u0026rsquo; CONTRIBUTIONS\u003c/h2\u003e \u003cp\u003eLD, YC and IL conceived the study, wrote the initial study protocol, and applied for funding. FC, BR, NG, KS, SDP participated in finalizing the study protocol and the statistical analysis plan. SDP and IL coordinate the study. LD, FC, NG, KS, BK, TT, SDP, BR, YC, IL participate in the execution of the study. LD, SDP, BR, and IL drafted the first manuscript. All authors contributed to the manuscript and all authors read and approved the final version.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e \u003cp\u003eThe authors thank all study nurses and investigators participating in this study. We thank also the Swiss National Science Foundation for the financial support (#32003B_207837).\u003c/p\u003e\u003ch2\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/h2\u003e \u003cp\u003eDatasets generated during the study will be kept by the corresponding author and made available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWitjes JA, Bruins HM, Cathomas R, Comperat EM, Cowan NC, Gakis G, Hernandez V, Linares Espinos E, Lorch A, Neuzillet Y, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol. 2021;79(1):82\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChong JT, Dolat MT, Klausner AP, Dragoescu E, Hampton LJ. The role of cystectomy for non-malignant bladder conditions: a review. Can J Urol. 2014;21(5):7433\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVidal A, Arnold N, Vartolomei MD, Kiss B, Burkhard F, Thalmann GN, Roth B. Oncological and functional outcomes of postoperative total parenteral nutrition after radical cystectomy in bladder cancer patients: A single-center randomized trial. Int J Urol. 2016;23(12):992\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDjaladat H, Katebian B, Bazargani ST, Miranda G, Cai J, Schuckman AK, Daneshmand S. 90-Day complication rate in patients undergoing radical cystectomy with enhanced recovery protocol: a prospective cohort study. World J Urol. 2017;35(6):907\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaibom SL, Joensen UN, Poulsen AM, Kehlet H, Brasso K, Roder MA. Short-term morbidity and mortality following radical cystectomy: a systematic review. BMJ Open. 2021;11(4):e043266.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eErpelding SG, Dugan A, Isharwal S, Strup S, James A, Gupta S. Cystectomy for benign disease: readmission, morbidity, and complications. Can J Urol. 2018;25(5):9473\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntonelli L, Sebro K, Lahmar A, Black PC, Ghodoussipour S, Hamilton-Reeves JM, Shah J, Bente Thoft J, Lerner SP, Llorente C, et al. Association Between Antibiotic Prophylaxis Before Cystectomy or Stent Removal and Infection Complications: A Systematic Review. Eur Urol Focus. 2023;9(4):631\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCerantola Y, Valerio M, Hubner M, Iglesias K, Vaucher L, Jichlinski P. Are patients at nutritional risk more prone to complications after major urological surgery? J Urol. 2013;190(6):2126\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGregg JR, Cookson MS, Phillips S, Salem S, Chang SS, Clark PE, Davis R, Stimson CJ Jr, Aghazadeh M, Smith JA, editors. Jr. : Effect of preoperative nutritional deficiency on mortality after radical cystectomy for bladder cancer. \u003cem\u003eJ Urol\u003c/em\u003e 2011, 185(1):90\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarl A, Staehler M, Bauer R, Tritschler S, Hocaoglu Y, Buchner A, Hoffmann J, Kuppinger D, Stief C, Rittler P. Malnutrition and clinical outcome in urological patients. Eur J Med Res. 2011;16(10):469\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHegazi RA, Hustead DS, Evans DC. Preoperative standard oral nutrition supplements vs immunonutrition: results of a systematic review and meta-analysis. J Am Coll Surg. 2014;219(5):1078\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTobert CM, Hamilton-Reeves JM, Norian LA, Hung C, Brooks NA, Holzbeierlein JM, Downs TM, Robertson DP, Grossman R, Nepple KG. Emerging Impact of Malnutrition on Surgical Patients: Literature Review and Potential Implications for Cystectomy in Bladder Cancer. J Urol. 2017;198(3):511\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamilton-Reeves JM, Bechtel MD, Hand LK, Schleper A, Yankee TM, Chalise P, Lee EK, Mirza M, Wyre H, Griffin J, et al. Effects of Immunonutrition for Cystectomy on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. Eur Urol. 2016;69(3):389\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyon TD, Turner IIR, McBride D, Wang L, Gingrich JR, Hrebinko RL, Jacobs BL, Davies BJ, Tarin TV. Preoperative immunonutrition prior to radical cystectomy: a pilot study. Can J Urol. 2017;24(4):8895\u0026ndash;901.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraefen M. The modified Clavien system: a plea for a standardized reporting system for surgical complications. Eur Urol. 2010;57(3):387\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImai N, Ikeda H, Tawara I, Shiku H. Tumor progression inhibits the induction of multifunctionality in adoptively transferred tumor-specific CD8\u0026thinsp;+\u0026thinsp;T cells. Eur J Immunol. 2009;39(1):241\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRizzuto GA, Merghoub T, Hirschhorn-Cymerman D, Liu C, Lesokhin AM, Sahawneh D, Zhong H, Panageas KS, Perales MA, Altan-Bonnet G, et al. Self-antigen-specific CD8\u0026thinsp;+\u0026thinsp;T cell precursor frequency determines the quality of the antitumor immune response. J Exp Med. 2009;206(4):849\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan J, Gnjatic S, Li H, Powel S, Gallardo HF, Ritter E, Ku GY, Jungbluth AA, Segal NH, Rasalan TS, et al. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci U S A. 2008;105(51):20410\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDerre L, Cesson V, Lucca I, Cerantola Y, Valerio M, Fritschi U, Vlamopoulos Y, Burruni R, Legris AS, Dartiguenave F, et al. Intravesical Bacillus Calmette Guerin Combined with a Cancer Vaccine Increases Local T-Cell Responses in Non-muscle-Invasive Bladder Cancer Patients. Clin Cancer Res. 2017;23(3):717\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012;148(6):1258\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCerantola Y, Valerio M, Persson B, Jichlinski P, Ljungqvist O, Hubner M, Kassouf W, Muller S, Baldini G, Carli F, et al. Guidelines for perioperative care after radical cystectomy for bladder cancer: Enhanced Recovery After Surgery (ERAS((R))) society recommendations. Clin Nutr. 2013;32(6):879\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorgan TM, Tang D, Stratton KL, Barocas DA, Anderson CB, Gregg JR, Chang SS, Cookson MS, Herrell SD, Smith JA Jr., et al. Preoperative nutritional status is an important predictor of survival in patients undergoing surgery for renal cell carcinoma. Eur Urol. 2011;59(6):923\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrieto I, Montemuino S, Luna J, de Torres MV, Amaya E. The role of immunonutritional support in cancer treatment: Current evidence. Clin Nutr. 2017;36(6):1457\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Immunonutrition, bladder cancer, cystectomy, infection, complications, microbiota, immune cells","lastPublishedDoi":"10.21203/rs.3.rs-4046807/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4046807/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCancer, malnutrition, and surgery negatively impact patient’s immune system. Despite standardized surgical technique and the development of new perioperative care protocols, morbidity after cystectomy remains a serious challenge for urologists. Most common postoperative complications, such as infections and ileus, often lead to longer length of stay and worse survival. The immune system and its interaction with the gut microbiota play a pivotal role in cancer immunosurveillance and in patient’s response to surgical stress. Malnutrition has been identified as an independent and modifiable risk factor for both mortality and morbidity. Immunonutrition (IN) may improve the nutritional status, immunological function, and clinical outcome of surgical patients. Aims of the study are 1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy, 2) to determine immune and microbiota signature that would predict IN effect.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a randomized, multicentric, controlled, pragmatic, parallel-group comparative study, supported by the Swiss National Science Foundation. A total of 232 patients is planned to be enrolled between April 2023 and June 2026. Three participating centers (Lausanne, Bern and Riviera-Chablais) have been selected. All patients undergoing elective radical and simple cystectomy will be randomly assigned to receive seven days of preoperative IN (Oral Impact\u003csup\u003e®\u003c/sup\u003e, Nestlé, Switzerland) versus standard of care (control group) and followed for 90 days after surgery. For the exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at Lausanne. In order to determine the impact of IN on immune fitness, patients enrolled at Lausanne will be vaccinated against influenza and the establishment of the vaccine-specific immune response will be followed. Analysis of the microbiota and expression of Argininosuccinate synthetase 1 as potential biomarker will also be performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion and Conclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStrengths of the INCyst study include the randomized, multicenter, prospective design, the large number of patients studied and the translational investigation. This study will challenge the added value of preoperative IN in patients undergoing cystectomy, assessing the clinical effect of IN on the onset of post-operative morbidity and mortality after cystectomy. Furthermore, it will provide invaluable data on the host immune response and microbiota composition.\u003c/p\u003e\n\u003cp\u003eTrial registration: ClinicalTrials.gov (NCT05726786)\u003c/p\u003e","manuscriptTitle":"The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 15:47:47","doi":"10.21203/rs.3.rs-4046807/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-07-11T06:25:15+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-07-06T11:14:25+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-06T10:29:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-15T11:08:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-03-20T07:55:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"48404942-6a89-43fd-8ab6-4f248d014ff1","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-21T16:01:42+00:00","versionOfRecord":{"articleIdentity":"rs-4046807","link":"https://doi.org/10.1186/s13063-024-08536-5","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2024-10-17 15:57:27","publishedOnDateReadable":"October 17th, 2024"},"versionCreatedAt":"2024-08-09 15:47:47","video":"","vorDoi":"10.1186/s13063-024-08536-5","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08536-5","workflowStages":[]},"version":"v1","identity":"rs-4046807","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4046807","identity":"rs-4046807","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}