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INTRODUCTION
auto‐HSCT in stage IV, DLBCL
LYMPHOMA
Diffuse large B‐cell lymphoma (DLBCL) is the most common (30–35%) type of B‐cell lymphoma with an incidence of about 5.6 per 100.000 men and women per year.The standard treatment of DLBCL is R‐CHOP immunochemotherapy (ICT).Upfront auto‐HSCT was studied as a way to improve outcomes as a consolidative treatment option in...
PMC10075296
MATERIALS AND METHODS
PMC10075296
Study design
Retrospective cohort single‐center trial.
PMC10075296
Patient selection
DLBCL
The main inclusion criterion was biopsy‐confirmed CD20(+) DLBCL NOS, according to the WHO 2017 criteria. All patients were from 18 to 65 years old. According to Russian legislation, a majority is reached at the age of 18 and younger patients are treated according to pediatric protocols. The peak age was selected to bet...
PMC10075296
Statistical analysis
death
DEL
The primary endpoint of this study was progression‐free survival (PFS, measured from the date of diagnosis to confirmed relapse or death from any cause). Secondary endpoints were overall survival (OS, measured from the date of diagnosis to death from any cause), response rate and relapse rate.To determine differences i...
PMC10075296
RESULTS
PMC10075296
Patients and procedures characteristic
The two trial arms were well balanced. (Table Patient and procedures characteristics.
PMC10075296
Clinical response
There were 63% (22/35) CR in patients, who further enrolled in the upfront group and 100% (70/70) in the control group. After auto‐HSCT in the upfront group, the CR rate significantly increased (Clinical response in upfront group. Inner ring—response after ICT. Outer ring—response after upfront HDCT with auto‐HSCT.
PMC10075296
Relapse rate and cause of death
A total of 3% (1/35) early (ER) and 6% (2/35) late (LR) relapses occurred in the upfront group (Figure Between‐group comparisons. Inner ring–upfront group, In the control group, 21% (15/70) ER and 6% LR (4/70) occurred (Figure There was a significantly higher early relapse rate in the control group (1/35 vs. 15/70,
PMC10075296
Survival analysis
PMC10075296
Progression‐free survival
lymphomas
LYMPHOMAS, DEL
The favor of upfront was demonstrated (Figure Progression‐free survival results. (A) PFS by treatment groups. (B) PFS by DEL. (C) PFS by lung involvement. (D) PFS by ICT.Patients with double‐expressor lymphomas (DEL) demonstrated (Figure Patients, treated by DA‐EPOCH‐R demonstrated (Figure Multivariate PFS analysis dem...
PMC10075296
Overall survival
deaths
Patients in the upfront group demonstrated significantly higher (Figure Overall survival results. (A) OS by treatment groups; (B) OS by relapse occurrence.Multivariate OS analysis confirmed the significant characteristics–upfront auto‐HSCT was associated with better 3‐year OS (HR = 0.11, 95% CI [0.02–0.63], Multivariat...
PMC10075296
DISCUSSION
metabolic tumor, tumor, high‐intermediate, toxicity, DLBCL, DEL DLBCL, lymphomas, DSHNHL
TUMOR, REMISSIONS, PROLIFERATION, DISEASE, LYMPHOMAS, DEL
The role of upfront auto‐HSCT in DLBCL remains controversial. EBMT (level of evidence 1)These statements are based on the results of RCT. The improvement of 2‐year FFS (In NCT00355199,SWOG‐S7904 trialOn the other hand, DSHNHL 2002‐1 trial demonstrated only increased toxicity in the HDCT group without survival benefit.M...
PMC10075296
CONCLUSION
DEL DLBCL, DLBCL
DEL
In this trial, upfront patients demonstrated significantly better 3‐year OS and PFS. It is a relatively small period, and further follow‐up is needed to confirm the sustainability of our result. The significant difference in early relapse rate and the same tendency in all relapse rates in favor of upfront auto‐HSCT is ...
PMC10075296
AUTHOR CONTRIBUTIONS
PMC10075296
CONFLICT OF INTEREST STATEMENT
The authors have stated explicitly that there are no conflicts of interest in connection with this article.
PMC10075296
ETHICS STATEMENT
All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
PMC10075296
Supporting information
Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.
PMC10075296
ACKNOWLEDGMENTS
This trial had no financial or material support from external organizations.
PMC10075296
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
PMC10075296
REFERENCES
PMC10075296
1. Introduction
tumor, primary tumors, muscle atrophy, fatigue, Malnutrition, cancer, non-melanoma skin cancer, sarcopenia, inflammation, gastrointestinal tract, cancer deaths, Sarcopenia, cancer cachexia, reduced skeletal muscle mass, impaired muscle function, Cancer
TUMOR, PRIMARY TUMORS, MUSCLE ATROPHY, MALNUTRITION, CANCER, INFLAMMATION, SARCOPENIA, FRAGILITY, SARCOPENIA, CANCER
(1) Background: Malnutrition frequently affects patients with cancer, and it negatively impacts treatment tolerance, clinical outcomes and survival. Thus, appropriate nutritional screening and early nutrition support are extremely recommended. Currently, a significant number of oral supplements (OS) are commercially av...
PMC10302788
2. Material and Methods
PMC10302788
2.1. Patients
cancer of different origin (, weight loss
END-STAGE KIDNEY DISEASE
This study was approved by the Ethics Committee of the Reina Sofia University Hospital (Cordoba, Spain; reference number 4788), which was conducted in accordance with the Declaration of Helsinki and according to national and international guidelines. This is a prospective open-label study, wherein a written informed co...
PMC10302788
2.2. Study Design
nausea
When included in the study, all patients received general education about nutritional support, OS, Mediterranean diet and physical activity; additionally, patients received oral supplementation with calcifediol (in different doses to reach levels of sufficiency, defined with a serum 25OH vitamin D levels > 30 ng/dL) fo...
PMC10302788
2.3. Outcomes
Primary outcome was to evaluate the percentage of change in muscle mass of patients after both nutritional interventions. Secondary outcomes included other changes in body composition (lean mass, water, bone, phase angle); anthropometric parameters (calf, arm and abdominal circumference); biochemical nutritional parame...
PMC10302788
2.4. Statistical Analysis
Between-group comparisons were analyzed using the Mann–Whitney U test (nonparametric data) or the Kruskal–Wallis test (nonparametric data, when we compared more than two groups). Paired analysis was performed using Student’s
PMC10302788
3. Results
urothelial cancer, colorectal cancer, gastrointestinal neuroendocrine tumor, head–neck cancer, tumors, gastric cancer
COLORECTAL CANCER, TUMORS, GASTRIC CANCER
Forty-six patients were included. Most of them were female (54.3%), with a median age of 74 years; the patients presented with tumors of different origin, including colorectal cancer (19.6%), urothelial cancer (32.6%), head–neck cancer (13%), gastric cancer (8.7%), gastrointestinal neuroendocrine tumor (8.7%) and other...
PMC10302788
Primary and Secondary Outcomes
cancer
CANCER
The nutritional intervention in all the evaluated patients resulted in body composition maintenance assessed via bioimpedance analysis. Particularly, the BMI decreased in a non-significant manner; furthermore, the lean mass tended to increase after twelve weeks of treatment (Significantly, all patients improved their p...
PMC10302788
4. Discussion
Cancer, muscle mass, gastrointestinal symptoms, cancers, skeletal muscle mass, tumor, metabolic dysregulation, cancer, cardiac dysfunction, inflammation, tumors, head–neck cancer, skeletal muscle loss, malnutrition, muscle mass gain, ACS, anorexia,
CANCERS, TUMOR, CANCER, MALNUTRITION, INFLAMMATION, TUMORS, CHRONIC DISEASES, ADVERSE EFFECTS, TUMOR PROGRESSION, INSULIN RESISTANCE, VITAMIN D DEFICIENCY, MALNUTRITION, PRIMARY TUMOR, STAGE II COLON CANCER, CANCER
The nutritional status is severely affected in most patients with cancer; this condition affects the treatment tolerability and overall survival [Malnutrition affects patients of both the male and female sexes and all age groups. In cancer, malnutrition is a result of a combination of anorexia, gastrointestinal symptom...
PMC10302788
Supplementary Materials
The following supporting information can be downloaded at: Click here for additional data file.
PMC10302788
Author Contributions
Conceptualization, A.D.H.-M. and M.J.M.P.; data curation, S.L.I., S.C.P., A.S.S., R.A.E., C.M.J. and R.R.-A.; funding acquisition, A.D.H.-M.; practical performance, S.L.I., S.C.P., A.S.S., R.A.E., C.M.J., R.R.-A., G.M.G. and M.Á.G.M.; formal and data analysis, A.D.H.-M.; preparation of manuscript, A.D.H.-M., M.J.M.P. a...
PMC10302788
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Reina Sofia University Hospital (Cordoba, Spain) (4788, 28 October 2020).
PMC10302788
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
PMC10302788
Data Availability Statement
All data was included in the article.
PMC10302788
Conflicts of Interest
The authors declare no conflict of interest.
PMC10302788
References
cancer
CANCER, NEUROENDOCRINE TUMOR
Study design.Biochemical comparison in patients with cancer and systemic treatment receiving nutritional supplements with standard hypercaloric, hyperproteic oral supplements versus leucine-enriched oral supplements. Legend: C-RP—c-reactive protein; ns—non-significative; * Clinical comparison in patients with cancer an...
PMC10302788
Background
hernia, hernias
COMPLICATION
Incisional hernia is a frequent complication following loop ileostomy reversal. Incisional hernias are associated with morbidity, loss of health-related quality of life and costs and warrant the investigation of prophylactic measures. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be...
PMC9890770
Methods
postoperative pain, hematomas, hernias, seromas
SITE INFECTION, HEMATOMAS, POSTOPERATIVE COMPLICATIONS, SEROMAS
P.E.L.I.O.N. is a multicentre, patient- and observer-blind RCT. Patients undergoing loop ileostomy closure will undergo intraoperative 1:1 randomisation into either abdominal wall closure with a continuous slowly absorbable suture in small-stitch technique without mesh reinforcement (control group) or abdominal wall cl...
PMC9890770
Discussion
Depending on the results of the P.E.L.I.O.N. trial, prophylactic mesh implantation could become the new standard for loop ileostomy reversal.
PMC9890770
Trial registration
DRKS00027921, U1111-1273-4657
PMC9890770
Supplementary Information
The online version contains supplementary material available at 10.1186/s13063-023-07089-3.
PMC9890770
Keywords
Open Access funding enabled and organized by Projekt DEAL.
PMC9890770
Administrative information
26121
Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see Sven Müller, Helios Klinikum Gifhorn, Campus 6, 38518 Gifhorn, GermanyDirk Weyhe, Klinik für Allgemein- und Viszeralchirurgie, Universitätsmedizin Oldenburg, ...
PMC9890770
Introduction
PMC9890770
Background and rationale {6a}
loop ileostomies, abdominal pain, hernia, infections, SSI
SITE INFECTION, INFECTIONS, LEAKAGE
Diverting loop ileostomy is used in colorectal surgery to reduce the consequences of leakage of a bowel anastomosis. According to the Federal Statistical Office of Germany, approximately 15,000 diverting loop ileostomies and 11,500 loop ileostomy closures are performed annually in Germany [Multiple studies have shown t...
PMC9890770
Objectives {7}
hernia
The high rate of IH after loop ileostomy closure with its associated morbidity, loss of health-related quality of life and costs (hernia repair, loss of workforce) warrants the investigation of prophylactic measures. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and s...
PMC9890770
Trial design {8}
P.E.L.I.O.N is a randomised controlled observer- and patient-blinded multicentre surgical superiority trial with two parallel study groups.
PMC9890770
Methods: participants, interventions and outcomes
PMC9890770
Study setting {9}
The study will be carried out in 10 high-volume academic hospitals in Germany. A list of study sites can be found in Supplement
PMC9890770
Eligibility criteria {10}
PMC9890770
Inclusion criteria for patients
To obtain a homogenous but still representative patient population for analysis and high-external validity, all patients with primary loop ileostomy closure and without further interventions or conditions to the abdominal wall, which might interfere with the primary outcome measure and reduce the reproducibility and in...
PMC9890770
Exclusion criteria for patients
hernia, ileostomyChronic renal failure, necrosis
NECROSIS
American Society of Anesthesiologist (ASA) physical status class ≥ 4Infected/septic surgical site (risk for surgical site occurrences (SSO) of grade 4 according to Ventral Hernia Working Group (VHWG) classification) (see Supplement Presence of parastomal hernia in loop ileostomy site with fascia defect > 8cm (Table Pr...
PMC9890770
Eligibility criteria for trial sites and surgeons
Only high-volume To ensure standardisation of the procedure and to minimise training effects, all Furthermore, all
PMC9890770
Who will take informed consent? {26a}
Patients scheduled for elective loop ileostomy closure are screened preoperatively. An authorised physician with a GCP training will inform the patient about the trial (visit 1). Patients are enrolled given their ability to understand the extent and nature of the trial as well as their written informed consent after de...
PMC9890770
Additional consent provisions for collection and use of participant data and biological specimens {26b}
No biological samples will be collected during the trial.
PMC9890770
Interventions
PMC9890770
Explanation for the choice of comparators {6b}
Patients in both groups will receive ileostomy closure according to the current standard of care, i.e. direct fascia closure according to the small-stitch technique with a slowly absorbable suture. In addition, in the intervention group, the abdominal wall closure will be augmented with a non-absorbable, macro-pore lig...
PMC9890770
Intervention description {11a}
PMC9890770
Experimental intervention
stoma
STERILE, CAVITY
The re-establishment of intestinal continuity will be achieved by either stapled or by hand-sewn anastomosis, according to the surgeon’s preference, and the bowel will be positioned back into the peritoneal cavity.Changing of surgical gloves must be performed before mesh implantation. Either after surgical stoma closu...
PMC9890770
Control intervention
stoma
CAVITY
The re-establishment of intestinal continuity will be achieved either by staples or by hand-sewn anastomosis, according to the surgeon’s preference, and the bowel will be positioned back into the peritoneal cavity.Changing of surgical gloves.The posterior rectus sheath (if the stoma is within the rectus sheath) will b...
PMC9890770
Criteria for discontinuing or modifying allocated interventions {11b}
As P.E.L.I.ON. is investigating two surgical interventions, no criteria for discontinuing or modifying the allocated intervention are applicable.
PMC9890770
Strategies to improve adherence to interventions {11c}
As P.E.L.I.ON. is investigating two surgical interventions, strategies to improve adherence to the intervention are unnecessary as the patient cannot “withdraw” from the intervention during surgery.
PMC9890770
Relevant concomitant care permitted or prohibited during the trial {11d}
Further perioperative and postoperative treatment will be according to the local standard of care. This also includes the use of abdominal belts which is at the discretion of the operating surgeon. There will be no restrictions for additional treatments during the trial.
PMC9890770
Provisions for post-trial care {30}
DER
For trials that are conducted according to the Medical Association’s professional code (Berufsordnung der Bundesärztekammer) § 15, there is no obligation for a specific trial liability insurance. However, patients will be insured against travel accidents for their follow-up visits (
PMC9890770
Outcomes {12}
PMC9890770
Primary outcome measure
hernia
RECURRENCE
An Patients will be assessed for the primary endpoint at 12 and 24 months after the trial intervention. At these dates, patients will be examined by a clinician blinded for the trial intervention and by a radiologic examination performed by a blinded assessor. Radiologic exams allowed for assessment in the trial are fo...
PMC9890770
Sample size {14}
death
REGRESSION, EVENT
Sample size calculation is based on the rate of the primary endpoint (IH rate) within 24 months after surgery. Based on the assumption that the percentage of patients developing an IH in the control group is 30% (4–7), we hypothesise a reduction to 15% in the intervention arm (conservative reduction rate below that rep...
PMC9890770
Recruitment {15}
RECRUITMENT
To enrol the required number of patients in the planned recruitment period, 13 trial sites will participate in this trial. The trial will be performed by the Clinical Trial Network of the German Society of Surgery (CHIR-Net, In order to minimise loss to follow-up, the following measures are being implemented:A pragmati...
PMC9890770
Assignment of interventions: allocation
PMC9890770
Sequence generation {16a}
To ensure equal distribution of patient characteristics, randomisation will be used. Allocation of treatments will be performed using a web-based randomisation tool (
PMC9890770
Concealment mechanism {16b}
Allocation concealment will be ensured as the result of the randomisation will be unknown to the study team until the patient has been randomised through the web-based tool. Block size will be kept confidential to the study team. Randomisation will be performed in the operation theatre, after the closure of the posteri...
PMC9890770
Implementation {16c}
Randomisation will be performed by a study team in the operation theatre. Names of this team member and the operating surgeon are noted as these team members are unblinded. They will not be involved in the outcome assessment of the trial.
PMC9890770
Assignment of interventions: blinding
PMC9890770
Who will be blinded {17a}
Blinding will be performed according to the evidence-based guidelines published by Probst et al. [Patients are blinded as they are under general anaesthesia during the trial intervention. Neither the discharge letter nor the operation report will contain any information regarding group allocation. This will be monitore...
PMC9890770
Procedure for unblinding if needed {17b}
Unblinding can be performed if medically indicated by the treating surgeon with the help of an unblinded study team member. Unblinding will be documented and reported to the steering group of the trial.
PMC9890770
Data collection and management
PMC9890770
Plans for assessment and collection of outcomes {18a}
The trial will be performed by the Clinical Trial Network of the German Society of Surgery (CHIR-Net,
PMC9890770
Plans to promote participant retention and complete follow-up {18b}
In order to minimise loss to follow-up, the following measures have been implemented:A pragmatic trial design with high-external validity, meaning that trial sites will have little problems to adapt their standard clinical workflow to the follow-up visitsFinancial reimbursement of travel costs for patients covering add...
PMC9890770
Data management {19}
All protocol-required information collected during the trial must be entered by the investigator, or designated representative, in the eCRF. The investigator, or designated representative, should complete the eCRF pages as soon as possible after information is collected, preferably on the same day that a trial subject ...
PMC9890770
Confidentiality {27}
The data protection concept stipulates that patients are only included in the study after they have been informed and after having signed the informed consent form (ICF). They will be informed as to the strict confidentiality of their data, but that their medical records may be reviewed for trial purposes by authorised...
PMC9890770
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
No plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis are implemented in the P.E.L.I.O.N. trial.
PMC9890770
Statistical methods
PMC9890770
Interim analyses {21b}
Due to the long observation period for the primary endpoint, an interim analysis would only be possible using a short-term endpoint as a surrogate. However, no reliable short-term endpoint is available. Therefore, no interim analyses are planned for the present trial. However, the DSMB will oversee unblinded data on a ...
PMC9890770
Methods for additional analyses (e.g. subgroup analyses) {20b}
hernia/hernia, diabetes mellitus, hernia, non-COPD, abdominal aortic aneurysm, SSI, seroma, hematoma, COPD
CARDIOVASCULAR DISEASE, DIABETES MELLITUS, POSTOPERATIVE COMPLICATION, COPD, RENAL DISEASE, SEROMA, REGRESSION, HEMATOMA, COMPLICATIONS
Pre-specified subgroup analysis will be performed in the FAS population for the rate of IH in the following subgroups: (a) body mass index (< 27 vs. ≥ 27), (b) neoadjuvant therapy (yes/no), (c) COPD vs. non-COPD, (d) previous laparotomy vs. previous minimal invasive surgery and (e) history of hernia/hernia repair vs. n...
PMC9890770
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
SECONDARY
For patients with incomplete follow-up, missing data will be shown as missing on appropriate tables and listings. Imputation of main secondary outcomes will be performed.
PMC9890770
Plans to give access to the full protocol, participant-level data and statistical code {31c}
The full protocol is accessible with this publication. Participant-level data will be available anonymised after the publication of the final results of the study.
PMC9890770
Oversight and monitoring
PMC9890770
Composition of the coordinating centre and trial steering committee {5d}
The trial will have a steering committee consisting of the trial statistician (AS), three clinical experts (AM, SM, DW) and a patient representative (EG). The steering committee will supervise the conduct of the trial and will issue recommendations for early termination, modifications or continuation of the trial, if n...
PMC9890770
Composition of the data monitoring committee, its role and reporting structure {21a}
hernia
SECONDARY, RECRUITMENT, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS
The trial’s Data Safety and Monitoring Board (DSMB) will be composed of two independent clinical experts in the field of hernia surgery. Furthermore, an independent statistician will be part of the DSMB. The DSMB members will receive a written report twice a year and should advise whether to continue, modify or stop th...
PMC9890770
Adverse event reporting and harms {22}
hematomas, seromas
HEMATOMAS, ADVERSE EVENTS, POSTOPERATIVE COMPLICATION, SECONDARY, ADVERSE EVENT, SITE INFECTION, SEROMAS, DER, COMPLICATIONS
Since trial interventions in P.E.L.I.O.N are medical routine, and the trial is conducted under the Medical Association’s professional code (Berufsordnung der Bundesärztekammer) §15, there is no need to record every adverse event. Instead of documenting serious adverse events (SAE), the following secondary endpoints wil...
PMC9890770
Frequency and plans for auditing trial conduct {23}
RECRUITMENT, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS
Clinical monitoring will be performed regularly by the independent monitoring department of the Furthermore, for a specific number of long-term postoperative visits (12 and 24 months postoperative), monitoring will confirm that primary outcome assessment is performed by blinded outcome assessors. For other items, the p...
PMC9890770
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any amendment to the protocol will be communicated to the participating trial sites immediately by email. Furthermore, regular investigator meetings will be held during the twice yearly CHIR-Net meetings to resolve questions and discuss the progress of the trial. Trial registries, REC/IRBs, will be contacted by the pro...
PMC9890770
Dissemination plans {31a}
Trial results will be communicated to participating trial sites prior to publication. The final report will be reviewed by all trial sites. Results will be made available in an open access journal. Results will be communicated to appropriate patient organisations like the ILCO e.V. Trial results will be presented at an...
PMC9890770
Discussion
RECRUITMENT
Given the high rate of IH after loop ileostomy closure with its associated morbidity, loss of health-related quality of life and costs, prophylactic measures after ostomy closure are urgently needed. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and safe method to pre...
PMC9890770
Trial status
MAY
The current protocol number is 1.1, May 12, 2022.Recruitment has started in October 2022.Recruitment is planned to be completed at the beginning of 2024.
PMC9890770
Acknowledgements
N/A
PMC9890770
Authors’ contributions {31b}
CDH
SM: substantial contributions to the conception and design of the work and analysis methods and draft of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of th...
PMC9890770
Authors’ information
N/A
PMC9890770
Funding {4}
Open Access funding enabled and organized by Projekt DEAL. The P.E.L.I.O.N trial is financed by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung BMBF, Förderkennzeichen 01KG2023). The funding body has no influence on study design and conduct, analysis and interpretation of dat...
PMC9890770