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2.4. Study Assessment and Outcomes | Eligible participants completed a clinic assessment visit and faecal sample collection (for gut microbiome analysis) at the start (weeks 0 and 16) and at the end (weeks 8 and 24) of each diet intervention phase. To determine the effect of a MedDairy diet on the gut microbiota, changes to the gut microbiota between baseline of the intervention phase and at the end of the 8-week diet intervention, for the MedDairy or LFD diet, were assessed. Between-group differences at the end of the 8-week diet intervention were also assessed to determine MedDairy diet-specific effects on bacterial relative abundance. The exploratory outcomes were associations between changes in MedDairy diet-specific bacterial relative abundance and changes in clinical, anthropometric, and cognitive function measurements. Clinical measures include blood pressure (systolic and diastolic blood pressure at a clinic or self-measured), blood levels of insulin, glucose, HOMA-IR, C-reactive protein, total triglyceride, total cholesterol, HDL, LDL, and cholesterol:HDL ratio [ | PMC10459086 | ||
2.5. Dietary Adherence | Dietary adherence was assessed and reported previously [ | PMC10459086 | ||
2.6. Faecal Microbiome Analysis | EBOS | Faecal sample collection was performed in an OMNIgene GUT stool collection kit (DNA Genotek, Ottawa, ON, Canada) for sample preservation, according to instructions provided by the manufacturer, and using a disposable urine collection hat (EBOS Healthcare, Kingsgrove, NSW, Australia). Samples were returned to the laboratory within approximately 24 h of collection and stored at −80 °C until analyses. Faecal DNA extraction was performed by transferring 200 µL of the faecal slurry to a tube containing 200 µL of 1X phosphate buffered saline (PBS, pH 8.0) (Life Technologies, Waltham, MA, USA). The faecal slurry was mixed by vortexing and centrifuged at 13,000× Paired-end sequence reads were demultiplexed, and bioinformatics analysis was performed using the QIIME2 platform (release 2021) for microbiota profiling [Microbial alpha diversity measures of richness, evenness, and diversity (observed species, Pielou’s evenness, and Faith’s phylogenetic diversity, respectively), as well as weighted Unifrac distances for composition analysis, were computed using QIIME2. Raw sequence data are publicly accessible from the Sequence Read Archive repository (BioProject ID: PRJNA996323). | PMC10459086 | |
2.7. Statistical Analyses | Baseline participant demographics between dietary groups were statistically compared using an unpaired All microbiome data were checked for normality using the Shapiro–Wilks method. Changes in overall microbial alpha diversity measures were analysed using the Wilcoxon sign-rank or Mann–Whitney The association between changes in specific bacterial relative abundance and changes in clinical, anthropometric, and cognitive assessment outcomes was performed using a repeated measures correlation analysis package in R (rmcorr v.0.5.4). Similar correlations were performed to determine associations between bacterial relative abundance and adherence to the MedDiet based on the 10- and 18-point MDS. | PMC10459086 | ||
2.8. Power Calculation | The initial sample size calculation was based on the ability to detect a clinically relevant difference of 2.5 mmHg in systolic blood pressure (primary study outcome) at a power of 90% and | PMC10459086 | ||
3. Results | Of the 43 participants randomised, 41 commenced the diet schedule and 37 continued to completion ( | PMC10459086 | ||
3.1. Effects of Diet Intervention on the Overall Faecal Microbiota Structure and Composition | No significant changes in bacterial richness and evenness were evident after the MedDairy or LFD diet study arms (The potential for effects resulting from the MedDairy or LFD intervention at Phase 1 to affect baseline measures at Phase 2 (following the 8-week washout period) was investigated. Carryover effects from Phase 1 were assessed by comparing baseline measures of paired samples at Phase 1 to those at Phase 2 (corresponding to Week 0 and Week 15 of the study, respectively). Bacterial richness, evenness, and diversity did not differ significantly between the Phase 1 baseline and the Phase 2 baseline ( | PMC10459086 | ||
3.2. Differential Effects between MedDairy and Low-Fat Diets on Specific Gut Bacteria | While the broad characteristics of the faecal microbiota remained unaltered by MedDairy or LFD, changes were observed at the level of individual bacteria taxa. Following the 8-week MedDairy intervention, significant changes were observed for several bacterial taxa, including increases in the relative abundance of | PMC10459086 | ||
3.3. Gut Bacteria Changes Were Associated with Diet and Clinical Outcomes | Associations between changes in altered bacterial taxa and changes in clinical, anthropometric, and cognitive measures were determined by correlation analysis (Correlation analysis based on both interventions (MedDairy and LFD) indicates that a higher relative abundance of The changes in relative abundance of | PMC10459086 | ||
4. Discussion | CVD | This study sought to explore the effects of an 8-week Mediterranean diet enriched with dairy products (to reach the recommended Australian dietary intake of 1000–1300 mg of calcium) on the gut microbiome of Australian adults at risk of CVD. The dairy enrichment involved 3–4 daily servings of any of the following dairy foods: one serve (250 mL) of low-fat milk, 40–120 g of hard and/or semisoft to soft cheese, 200 g of low-fat Greek yoghurt, or 200 g of tzatziki dip. Participants recruited to the study recorded a MedDiet adherence score at moderate levels based on their habitual diet at baseline (average ± SD of 4.4 ± 1.8 for the 10-point score and 7.0 ± 1.4 for the 18-point score), which reflect those of an Australian population that are not following a prescribed MedDiet [Faecal microbiota analysis was performed based on paired comparisons between baseline and after 8 weeks of MedDairy or LFD intervention and between the groups at 8 weeks. Paired analysis indicated that the overall structure and composition of the faecal microbiota were not significantly altered by the MedDairy or LFD groups, except for a modest decrease in microbial diversity in the LFD group. These results are consistent with other studies that assessed the gut microbiome following a MedDiet intervention, including the CARDIVEG study, which involved a 3-month low-calorie MedDiet in adults with CVD risk [The MedDairy diet did not result in broad changes to the gut microbiota but significantly altered the relative abundance of selected bacterial taxa, a result that is consistent with previous MedDiet studies [Reductions in the levels of The MedDairy diet intervention was associated with modest but significant increases in Lachnospiraceae and Higher adherence to a MedDiet diet has been previously shown to mediate protective effects on cardiometabolic risk factors, including blood pressure (lowers systolic and diastolic blood pressure), lipids (lower total cholesterol:HDL ratio, lower LDL levels, and higher HDL levels), and/or glycaemic control (lowers insulin secretion and HOMA-IR levels) when compared to the group consuming a healthy dietary guideline diet [Our study was limited to the measurement of gut microbiota levels and clinical outcomes but did not measure other factors such as changes in metabolic capacity [Taken together, our results suggest that an 8-week MedDiet supplemented with dairy foods results in relative abundance changes in bacterial taxa. Microbial changes, including an increase in | PMC10459086 | |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10459086 | ||
Author Contributions | K.J.M., J.M.H., A.T.W. and C.R.D. designed the project and secured funding. K.A.D. contributed to the project design. K.J.M., A.T.W., K.A.D. and C.R.D. conducted the trial and collected study data. K.J.M. and C.R.D. developed the diet. J.M.C. and Y.W. performed the gut microbiome analysis. J.M.C. and Y.W. developed and performed the statistical analysis of the gut microbiome. J.M.C., K.J.M., E.L.B., R.J.W. and G.B.R. prepared the manuscript. All authors have read and agreed to the published version of the manuscript. | PMC10459086 | ||
Data Availability Statement | Raw sequence data are publicly accessible from the Sequence Read Archive repository using the BioProject ID PRJNA996323 and at | PMC10459086 | ||
Conflicts of Interest | The authors declare no conflict of interest. The funding sponsor, Dairy Australia, had no role in the design of the study or the preparation of the manuscript. | PMC10459086 | ||
References | cardiovascular disease | CARDIOVASCULAR DISEASE | Flow diagram of the cross-over study involving an 8-week MedDairy and an 8-week low-fat diet intervention in adults with cardiovascular disease risk. Adapted from Wade et al., 2018 [Alpha diversity measures of (Alterations in bacterial relative abundance following 8 weeks of the MedDairy diet. ((Demographic and clinical characteristics of the study sample at week 0 (start of the study trial) by group.Values are presented as mean (SD). * Significant difference between groups at | PMC10459086 |
Background | seroma, bleeding, hernia | BLEEDING, SEROMA, POSTOPERATIVE COMPLICATION, COMPLICATIONS | Open mesh repair of incisional hernia is associated with different local complications, particularly bleeding and seroma formation. Traditionally, drains have been placed perioperatively to prevent these complications, despite the lack of scientific evidence or expert consensus. We formulated the hypothesis that the absence of drainage would reduce number of patients presenting collections or complications. The present study aimed to compare postoperative complication rates after open mesh repair for incisional hernia with or without prophylactic wound drainage. | PMC9803733 |
Methods | SECONDARY, OTHER COMPLICATION | Prospective randomized study using standardized surgical technique and drain placement. The primary endpoint was the evaluation of residual fluid collection with ultrasound on postoperative day 30. Other complications, subdivided into medical and surgical, were analyzed as secondary endpoints. | PMC9803733 | |
Results | There were 144 patients randomized (70 with drain, 74 without drain). No difference was identified between both groups for fluid collection at 30 days (60.3% vs. 62%, | PMC9803733 | ||
Conclusions | hernia | Prophylactic drainage in open incisional hernia repair does not objectively reduce the rate of postoperative fluid collections. Therefore, our results do not support the use of routine drainage in incisional hernia repair. | PMC9803733 | |
Trial registration | Trial registration on clinicaltrials.gov (NCT00478348). | PMC9803733 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00268-022-06725-4.Open access funding provided by University of Lausanne | PMC9803733 | ||
Introduction | hernia | SITE INFECTION, COMPLICATIONS | Incisional hernia formation presents a major burden of care after open abdominal surgery. It may occur in up to 20% of patients after median laparotomy [The most common complications after open mesh incisional hernia repairs are surgical site infections and collections [Indeed there are few prospective studies comparing outcomes with and without drains after incisional hernia repair [We formulated the hypothesis that the absence of drainage would not influence the number of patients presenting collections or complications after incisional hernia repair. This current prospective, randomized controlled trial aimed to determine the influence of prophylactic drainage in incisional hernia repair on postoperative fluid collections and complications. | PMC9803733 |
Material and methods | PMC9803733 | |||
Compliance with ethical standards | This prospective randomized multicentric study was conducted according to the CONSORT statement guidelines [ | PMC9803733 | ||
Patients | strangulated hernia, hernia | Patients were screened preoperatively at the outpatient clinic of the Department of visceral surgery, Lausanne University Hospital CHUV. Inclusion criteria were patients between 20 and 80 years old requiring an elective open incisional hernia repair with a physical status classification according to the American Society of Anesthesiologists (ASA) between 1 and 3. Exclusion criteria were a hernia defect of less than 2 cm, inguinal hernia, ongoing antibiotic treatment before admission, and emergency surgery for an incarcerated or strangulated hernia. In addition, we excluded laparoscopic hernia procedures and patients under immunosuppressive therapy.All included patients completed an informed consent form validated by the local ethics committee. | PMC9803733 | |
Sample size calculation | hernia, hematoma, seroma | RECURRENCE, SURGICAL SITE INFECTION, COMPLICATION, SEROMA, HEMATOMA, COMPLICATIONS | The complication rate in the drainage group was estimated to reach 20%. No prospective study comparing drainage and without drainage was available in the literature when the study was started. Rates of complications were estimated according to a consensus between surgeons participating to the study. We hypothesized that the absence of drainage would decrease the occurrence of either surgical site infection, seroma, hematoma, or early hernia recurrence by 50% within 30 days after surgery. The sample size was calculated with an 80% power; and a significance level with a | PMC9803733 |
Surgical techniques and randomization | BLIND | Patients were electronically randomized on the day before surgery. They were allocated to the treatment group (with drainage) or the control group (without drainage). A clinical nurse performed the randomization through a web-based service (This study was not blinded due to technical limitations. Indeed, it would have been difficult to blind the operators placing a drain and to blind the patients due to the presence of dressings and drain bottles.The surgical technique was standardized in both groups. All patients underwent an open repair according to the Rives-Stoppa procedure [ | PMC9803733 | |
Endpoints | Seroma, hematoma, seroma, abscess | ABSCESS, SEROMA, HEMATOMA, SEROMA, COMPLICATIONS | The endpoints were registered during a follow up period of thirty days. The primary endpoint was the presence of a fluid collection on postoperative day 30 (POD 30). All patients underwent an ultrasound to objectively assess the presence or absence of a collection. Collections were subdivided into seroma, hematoma and abscess. Seroma was defined as a subcutaneous fluid collection without a solid component. The hematoma was characterized by the presence of debris, and abscess was confirmed by the presence of pus on a puncture.Secondary endpoints were complications, classified according to Clavien-Dindo classification [ | PMC9803733 |
Statistical analysis | COMPLICATIONS | The null hypothesis was the absence of difference between both groups and the alternative hypothesis was a decrease of complications without drain. The normal distribution of the variables was assessed with a Kolmogorov–Smirnov test. Continuous variables were analyzed with a Student’s t-test and categorial binary variables with a Pearson’s chi-square test or a Fisher’s exact test. A | PMC9803733 | |
Results | PMC9803733 | |||
Endpoints | SITE INFECTION, DISEASE | The rate of fluid collection at POD 30, which was defined as the primary endpoint, was high in both groups, but the difference between both groups (60.3% drain group vs. 62.0% no drain group, Operative and postoperative characteristicsSurgical site infection according to Center for Disease Control and Prevention (CDC) criteria, | PMC9803733 | |
Follow up | The follow up was complete for all patients, with a clinical and radiological control at POD 30. | PMC9803733 | ||
Discussion | seroma, hernia | MINOR, SURGICAL SITE INFECTION, RECRUITMENT, COMPLICATION, SECONDARY, SURGICAL COMPLICATIONS, SEROMA, COMPLICATIONS | This prospective randomized study assessed the role of intraoperatively placed drains to avoid postoperative fluid collection after open incisional hernia repair. Postoperative fluid collections were observed in both groups in up to 65% of patients, and drain placement could not decrease the incidence of that particular complication at POD 30. This rate of collection seems important; however, only a small amount was clinically relevant. Although the trial was negative on the primary endpoint, the secondary endpoints highlighted significant results in terms of morbidity. There were significantly fewer overall complications on POD 30 in the drain group and a lower rate of surgical complications. These findings will be discussed in more detail below.There is no clear evidence in the current literature regarding the prophylactic use of drains. In a prospective study including 42 patients in 2015, Westphalen et al. reported a similar rate of seroma in patients with drains (52.4%) versus quilting sutures (42.9%) on POD 30. A retrospective study of Krpata et al. in 2017 analyzed complications after drainage in incisional hernia repair with a retromuscular mesh [The high complication rate in our study (29% in the drainage group; 50.7% in the control group) is explained by a compulsory and institutionally-organized system of complication recording, including minor complications graded I and II according to Clavien-Dindo classification. The higher rate of surgical complications in the group without drainage might suggest that drainage could prevent complications other than fluid collection, and therefore positively influence postoperative outcomes. Although drainage was predictive of a lower CCI, it did not reflect on hospital stay or readmission rate. In addition, the severity of complications graded by Clavien-Dindo classification was similar in both groups.We investigated which subtype of complication was most present in each group. The surgical site infection rate was comparable in both groups (5.9% vs. 9.3%, The strength of the present study relies on its high-standard prospective, randomized design and also on the recording of objective and quantifiable endpoints. External validity is high since inclusion criteria did not select the type of initial surgery or patient comorbidities. The sample represents a standard population making it easily reproducible for further investigation. The 10-year recruitment period is a drawback since laparoscopic surgeries have become widely popular. These minimally-invasive procedures competed with our study and limited recruitment. After careful evaluation of this situation with our ethical committee, the study had to be terminated prematurely and the number of participants estimated by the initial power calculation has not been reached. In our opinion, the value of the present study remains strong, as these novel approaches are still not widely accepted or implemented, and open surgery remains the gold standard for the majority of surgeons. In addition, the 144 included patients represent a large population when compared to other series. Since this study was terminated prematurely due to the expansion of minimally invasive techniques, it would be interesting to repeat this research with other techniques, such as minimal invasive approaches or onlay mesh placement. Finally, according to our primary endpoint, the study was negative. However, a clinically relevant conclusion is in our view appropriate. | PMC9803733 |
Conclusion | hernia | Prophylactic drainage in open incisional hernia repair does not objectively reduce the rate of postoperative fluid collections. Therefore, our results do not support the use of routine drainage in incisional hernia repair. | PMC9803733 | |
Acknowledgements | RECRUITMENT | The authors would like to thanks Dr Paroz A., Dr Vuilleumier H. and Dr Donadini A. for their respective contribution to the study, regarding the design, the implementation and patient’s recruitment. The authors declare that they have no conflict of interest. Abdominal wall ultrasound carried out systematically on post-operative day 30 were supported by the research fund of the Visceral Surgery Department of Lausanne University Hospital CHUV, Lausanne, Switzerland. | PMC9803733 | |
Funding | Open access funding provided by University of Lausanne. | PMC9803733 | ||
Declarations | PMC9803733 | |||
Conflict of interest | The authors declare no conflict of interest. | PMC9803733 | ||
Ethical approval | Abdominal wall ultrasounds carried out systematically on post-operative day 30 were supported by the research fund of the Visceral Surgery Department of Lausanne University Hospital CHUV, Lausanne, Switzerland. The study was approved by the local ethics committee (CER-VD 31/07, DP-2007-CHV-UNIL) and was registered as a prospective randomized clinical trial on clinicaltrials.gov (NCT00478348). | PMC9803733 | ||
Informed consent | Informed consent was obtained from all individual participants included in the study. | PMC9803733 | ||
References | PMC9803733 | |||
Objective | hypotension | Academic Editor: V. E. Sathishkumar The aim of the study is to explore the clinical effect of dexmedetomidine combined with low-dose norepinephrine (NE) continuous pumping in preventing supine hypotension. | PMC9922180 | |
Methods | A total of 160 puerperaes who underwent elective cesarean section were selected. The puerperaes were equally divided into | PMC9922180 | ||
Results | bleeding | BLEEDING | There were no statistically significant differences in the age, gestational age, body mass index, bleeding volume, fluid supplement volume, Apgar scores of new borns at the 1st and 5th minute, the blood gas values of umbilical cord arterial and venous in the four groups ( | PMC9922180 |
Conclusion | hypotension | ADVERSE REACTIONS, ADVERSE EFFECTS | Dexmedetomidine combined with continuous pumping of low-dose norepinephrine can effectively prevent the occurrence of supine hypotension, reduce the occurrence of other adverse reactions, and have no obvious adverse effects on neonates. | PMC9922180 |
1. Introduction | SUPINE HYPOTENSION SYNDROME, UTERUS | Intraspinal anesthesia has always been the first choice for cesarean section. However, after the full-term parturient is anesthetized in spinal canal, the foil effect of abdominal muscles on the uterus is eliminated. In supine position, the enlarged uterus oppresses the inferior vena cava and abdominal aorta. At the same time, anesthesia can dilate the blood vessels in the plane, resulting in supine hypotension syndrome [ | PMC9922180 | |
2. Materials and Methods | PMC9922180 | |||
2.1. General Information | congenital malformations, fetal distress | PRETERM DELIVERY, CARDIOVASCULAR DISEASE, FETAL DISTRESS | This study selected 160 healthy singleton mothers aged 20–35 who underwent elective cesarean section in Wuhu Second People's Hospital from August, 2019, to August, 2021. Participants with cardiovascular disease, fetal congenital malformations, fetal distress and preterm delivery, and participants who have intraspinal anesthesia contradictions were excluded from this study. According to the method of random number table, the patients were equally divided into | PMC9922180 |
2.2. Study Protocol and Intervention | hypotension | After all the eligible parturients entered the operating room, venous passage of the upper limb was established, and the left radial artery catheterization was performed under local anesthesia, and BP, HR, EKG and SpOAfter intrathecal injection of 10 min, the maternal sensory block level was measured by acupuncture method. If the level did not reach T6, 2% lidocaine 5–10 ml was injected through the epidural catheter and exclude the case; if T6 was reached or exceeded, the operation would be started. BP and HR were recorded every minute from immediately after intrathecal injection to 20 minutes after spinal anesthesia. If the maternal SBP decreased by more than 20% or less than 90 mmHg at a single time, it was defined as hypotension and 5 | PMC9922180 | |
2.3. Outcome Measures | bleeding, nausea, chest tightness, hypotension, shivering | ADVERSE REACTIONS, REACTIVE HYPERTENSION, SECONDARY, BLEEDING | The primary outcome was defined as the additional dose of NE and the secondary outcome was defined as other indicators of puerperaes and neonates, including the incidence of maternal hypotension. General condition of parturient: age, gestational age, body mass index, volume of bleeding and fluid replacement; intervention dose of norepinephrine and atropine; incidence of maternal hypotension and adverse reactions (reactive hypertension, chest tightness, nausea, shivering, oxytocin reaction); neonatal 1-minute and 5-minute Apgar score [ | PMC9922180 |
2.4. Statistical Analysis | Statistical analysis was performed using SPSS 25.0 software. All data were tested by | PMC9922180 | ||
3. Results | PMC9922180 | |||
3.1. Baseline Information and Indicators | The combination of Apgar score and fetal umbilical artery blood gas analysis is considered to be the criterion for judging the state of newborns [ | PMC9922180 | ||
3.2. Incidence of Hypotension, Additional NE, and Adverse Events | ADVERSE REACTIONS, REACTIVE HYPERTENSION | Compared with group As shown in The incidence of adverse reactions in the dexmedetomidine group, noradrenalin group, and dexmedetomidine combined with noradrenalin group was significantly lower than that in the saline group, and the incidence of adverse reactions in dexmedetomidine combined with noradrenalin group was the lowest among all groups (2.5%), with only one case of reactive hypertension ( | PMC9922180 | |
4. Discussion | bradycardia, postoperative chills, anxiety, nausea and vomiting, pain, hypotension | ADVERSE EFFECTS, MUSCLE RELAXATION, COMPLICATIONS | Cesarean section is an important procedure in modern obstetrics. It is of great significance to relieve the anxiety and tension of parturient and reduce the pain and complications of cesarean section patients during perioperative period. Because of the particularity of cesarean section, in order to avoid adverse effects on the fetus, it is particularly important to choose appropriate anesthesia methods and drugs. A meta-analysis found that dexmedetomidine can significantly reduce postoperative chills, while not increasing the incidence of nausea and vomiting during surgery, and there is no obvious bradycardia, and it can enhance sedation [Spinal anesthesia is more and more favored by obstetricians because of its quick effect, good muscle relaxation effect, completed block, and little effect on the fetus. However, maternal hypotension after spinal anesthesia is a common problem in clinical anesthesia, and its incidence is as high as 80% without any preventive measures [Hasanin et al. [According to the previous findings, continuous infusion of norepinephrine 0.04∼0.10 Lankadeva et al. [ | PMC9922180 |
5. Limitation | Although this study has a certain clinical significance, it has certain limitations, and the follow-up needs to be further confirmed by a large-sample, multicenter randomized controlled trial. | PMC9922180 | ||
6. Conclusion | hypotension | ADVERSE REACTIONS, ADVERSE EFFECT | To sum up, in the healthy women who underwent elective cesarean section, continuous infusion of dexmedetomidine combined with low-dose norepinephrine can effectively maintain the circulatory stability of patients during operation, effectively prevent hypotension in the supine position, and reduce the incidence of other adverse reactions, without adverse effect on newborns. When dexmedetomidine combined with low-dose norepinephrine is continuously pumped, attention should be paid to the pump dose of norepinephrine to avoid the corresponding adverse consequences caused by excessive dose. | PMC9922180 |
Data Availability | The datasets used or analyzed during the current study are available from the corresponding author on reasonable request. | PMC9922180 | ||
Ethical Approval | This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of our hospital. | PMC9922180 | ||
Consent | All participants had signed the informed consent. | PMC9922180 | ||
Conflicts of Interest | The authors declare that they have no conflicts of interest. | PMC9922180 | ||
Authors' Contributions | blood loss, hypotension | ADVERSE REACTIONS, BLOOD LOSS | Conception and design of the research was done by WSL, ZJ, and CJ. Acquisition of data was done by ZJ, SY, ZF, and CJ. Analysis and interpretation of the data were done by ZJ, SY, and WQF. Statistical analysis was done by ZJ, SY, and WSL. ZJ and SY wrote the manuscript. Critical revision of the manuscript for the intellectual content was done by WSL. Jin Zhang and Jun Chen contributed equally to this study.Comparison of additional NE cases, atropine intervention cases, and incidence of hypotension in the four maternal groups. Group Additional NE measurement in four maternal groups. Group Comparison of adverse reactions in the four maternal groups. Group Comparison of maternal age, gestational age, body mass index, blood loss, and fluid infusion.Group Comparison of umbilical cord drive and venous blood gas values among four groups of fetuses.Group Comparison of the incidence of maternal hypotension, the dose of additional NE, and the number of atropine and NE intervention cases.Compared with Comparison of the number of adverse reactions among the four groups of parturients.Compared with group | PMC9922180 |
Aim | Cancer | METASTATIC GASTRIC CANCER, CANCER | Edited by: Yuming Jiang, Wake Forest University, United StatesReviewed by: Zibing Wang, Henan Provincial Cancer Hospital, China; Lu Han, Henan Provincial Cancer Hospital, ChinaTo evaluate the safety and initial efficacy of autologous cytokine-induced killer (CIK) cells combined with S-1+oxaliplatin (SOX) as the first-line treatment for locally advanced or metastatic gastric cancer (GC). | PMC10646377 |
Materials and methods | ADVERSE EVENTS, DISEASE, SECONDARY | In this two-arm, single-center exploratory trial, patients with locally advanced or metastatic GC were randomly assigned (1:1) to receive autologous CIK cells in combination with SOX (CIK-SOX) or SOX alone. The primary endpoint was the incidence of adverse events (AEs). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) served as the secondary endpoints. | PMC10646377 | |
Results | gastrointestinal reaction, anemia, leucopenia, neutropenia | NEUTROPENIA, THROMBOCYTOPENIA, ANEMIA, LEUCOPENIA, HYPERBILIRUBINEMIA | Fifty-nine patients were enrolled in the study between November 20, 2014 and September 6, 2017. A total of 31 patients received CIK-SOX and 28 patients received SOX. The most common AEs in both groups were gastrointestinal reaction, leucopenia, neutropenia, anemia, thrombocytopenia, hyperbilirubinemia, and elevated aspartate transaminase concentration, with a higher incidence of these conditions in the SOX group. The median PFS for the CIK-SOX and SOX groups was 6.9 and 4.9 months, respectively (hazard ratio (HR) 0.80, | PMC10646377 |
Conclusion | The safety of CIK-SOX as the first-line treatment for patients with locally advanced or metastatic GC was good. Although the PFS and OS in the CIK-SOX group were not statistically significantly different compared to the values in the SOX alone group, this treatment increased the PFS and OS duration, with the absolute improvement in OS of about 8.05 months. Continuous benefit from the CIK-SOX treatment was observed during long-term follow-up. | PMC10646377 | ||
Clinical trial registration | PMC10646377 | |||
Introduction | Gastric cancer, death | MALIGNANT TUMORS, GASTRIC CANCER | Gastric cancer (GC) is one of the most common malignant tumors. Its incidence ranks fifth in the world, while death rate ranks second, representing a serious threat to people’s life and health (Adoptive cell therapy (ACT) aims to collect human autoimmune cells, expand their number after cultivation At present, a variety of ACTs combined with chemotherapy have been confirmed to be effective and safe in the treatment of locally advanced or metastatic GC, but no consensus has been reached ( | PMC10646377 |
Patients and methods | PMC10646377 | |||
Study design | toxicity, PD, Cancer | DISEASE, METASTASIS, CANCER | This randomized, open-label, exploratory study was conducted at a single center. Since the main purpose of the study was exploratory, no statistical assumptions were made about the sample size. Patients were randomly assigned (1:1) to receive CIK-SOX or SOX alone using the central randomization system. Randomized grouping was stratified according to the Eastern Cancer Cooperation Group (ECOG) performance status (PS) score of 0 or 1 and the current disease stage (locally advanced or metastasis). Six cycles of the SOX treatment were administered. Patients without progressive disease (PD) received autologous CIK cells combined with S-1 or S-1 as the maintenance treatment until PD or unacceptable toxicity level was achieved, or out of the group. No crossing between the two groups is allowed.The present study (ChiCTR-IPR-15005923; NCT02504229, | PMC10646377 |
Patients | Tumors, gastric adenocarcinoma | TUMORS, GASTRIC ADENOCARCINOMA | Patients with histologically confirmed gastric adenocarcinoma and radiographic diagnosis of locally advanced or metastatic GC were eligible for inclusion. Other inclusion criteria included age of ≥ 18 years old, measurable and/or evaluable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1, ECOG PS score of < 2, ability to take medications orally, no previous palliative chemotherapy (adjuvant chemotherapy or neoadjuvant chemotherapy with interval of ≥ 6 months was allowed), time since last radiotherapy treatment of ≥ 3 weeks, expected survival period of ≥ 3 months, and no severe lung, heart, or any other comorbidities. The following conditions for blood test examinations had to be satisfied within 14 days before enrollment to verify proper organ function: white blood cell count of (3.0–10.0) × 10 | PMC10646377 |
Preparation of autologous CIK cells | CIK cells were derived from the patient’s own peripheral blood. Peripheral blood mononuclear cells were isolated using Ficoll-Hypaque density gradient centrifugation. Mononuclear cells (lymphocytes) were adjusted to a concentration of 2×10 | PMC10646377 | ||
Cell infusion | After 14 days of cultivation, the proportion of obtained CD4, CD8, and NKT cells was as follows: CD3+: 85–98.3%, with an average of 92.6%; CD3+CD8+: 49.6–81.8%, with an average of 68.2%; CD3+CD4+: 9.7–43.5%, with an average of 22.7%; CD3-CD56+: 1–15%, with an average of 6.0%; and CD3+CD56+(NKT): 3.4–27.4%, with an average of 13.4%. The final cell products in all patients were highly viable (95%) and uncontaminated. After completing quality testing, all qualified immune cells were infused back into the patients. All patients in the CIK group completed at least one cycle of immune cell infusion containing an average of 8.6×10 | PMC10646377 | ||
Therapeutic regimen | Patients received SOX alone or in combination with autologous CIK cells every 3 weeks. SOX regimen included oxaliplatin (130 mg/m | PMC10646377 | ||
Assessment | PD, tumor, death | ADVERSE EVENTS, TUMOR, ADVERSE EVENT | Clinical examination and laboratory evaluation were required before each treatment cycle. After baseline assessment, tumor status was assessed using computed tomography scanning and tumor markers every 6 weeks until achieving PD according to the RECIST guideline version 1.1 (Safety was evaluated based on adverse event (AE) reports, laboratory test results, and vital sign measurements. AE evaluation was classified according to the common terminology criteria for adverse events (CTCAE) version 4.0, where level 1 indicates a mild AE, level 2 indicates a moderate AE, level 3 indicates a serious AE or one that is medically significant but not immediately life-threatening, level 4 indicates a life-threatening AE, and level 5 indicates death. | PMC10646377 |
Statistical analysis | PD, death, SD, tumor | DISEASE, SECONDARY, REMISSION, TUMOR | The purpose of the present study was to explore the safety and effectiveness of the CIK-SOX regimen. The primary end point was the incidence of AEs. The AE evaluation was calculated and classified according to CTCAE v4.0. The secondary end points were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). PFS was defined as the earliest evidence from randomization to PD (according to RECIST v1.1) or the time of death from any cause, whichever occurred first. OS was defined as the time from randomization to death for any reason. Patients who survived and did not progress at the last disease assessment were reviewed. ORR was defined as the proportion of patients with complete remission (CR) or partial remission (PR). DCR was defined as the proportion of patients with CR, PR, or stable disease (SD). The safety endpoint was based on the safety set (SS), in which the patient received at least one protocol treatment and one safety evaluation. The efficacy end point was based on the full analysis set (FAS), in which the population received at least one protocol treatment and had one tumor evaluation. The median follow-up period of the entire study cohort was calculated according to the reverse Kaplan-Meier method. Kaplan-Meier survival curve was used to estimate OS and PFS and log-rank test was used to evaluate the differences between treatment groups. The Cox proportional hazards model was used to estimate the risk ratio. All statistical tests were bidirectional, and | PMC10646377 |
Results | PMC10646377 | |||
Patient disposition and characteristics | Tumors | TUMORS, DISEASE, ONCOLOGY | Between November 20, 2014 and September 6, 2017, 62 patients were randomly assigned to receive treatment with CIK-SOX (n=31) or SOX alone (n=31). Three patients in the SOX group withdrew their informed consent and did not start the study treatment. Thus, SS and FAS included 31 patients in the CIK-SOX group and 28 patients in the SOX group (A flow diagram for the study. 62 patients were randomly assigned to receive autologous CIK cells in combination with SOX or SOX alone. 3 patients in SOX group withdrew their informed consent and did not start the study treatment. 31 patients in CIK-SOX group and 28 patients in SOX group were evaluated for safety and efficacy. 29 patients in the CIK-SOX group and 25 patients in the SOX group had measurable lesions, and assessed ORR and DCR. CIK, cytokine-induced killer; SOX, S-1 + oxaliplatin; CIK-SOX, autologous CIK cells in combination with SOX; RECIST, Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; DCR, disease control rate.Baseline characteristics.*The initial diagnosis was unresectable. SOX, S-1+oxaliplatin; CIK-SOX, CIK cells in combination with SOX; ECOG, Eastern Oncology Collaboration Group; PS, performance status. | PMC10646377 |
Treatment exposure | PD | As of December 6, 2017, all 59 patients ceased study therapy, most of them due to PD. Furthermore, 61.3% (19/31) of patients in the CIK-SOX group and 53.5% (15/28) of patients in the SOX group received follow-up chemotherapy, while 12.9% (4/31) and 7.1% (2/28) of patients, respectively, received radical gastrectomy. | PMC10646377 | |
Safety | ADVERSE EVENT |
Adverse events.
SOX, S-1+oxaliplatin; CIK-SOX, CIK cells in combination with SOX; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL total bilirubin; DBIL direct bilirubin; CREA, creatinine.Bold represents P-values with statistical differences. | PMC10646377 | |
PFS and OS | PD | EVENTS | As of December 6, 2019, 46 patients experienced endpoint events (PD) and 10 were censored (six patients received surgical treatment and four were lost to follow-up). Median PFS values were 6.9 months [95% confidence interval (CI), 4.3–8.8] in the CIK-SOX group and 4.9 months [95% CI, 3.6–7.7] in the SOX group (hazard ratio (HR) 0.80, Progression-free survival. As of December 6, 2019, six patients in the CIK-SOX group and four patients in the SOX groups survived, and their median follow-up time was 47.3 and 41.2 months, respectively. Median OS for the CIK-SOX and SOX groups was 17.8 months (95% CI, 10.2–24.3) and 9.75 months (95% CI, 6.4–16.5; HR 0.76, Overall survival. The median number of cell therapy cycle in the CIK-SOX group was 5. Twenty-eight patients with no fewer than 3 cell therapy cycles and twenty-five patients with no fewer than 4 cell therapy cycles. In terms of PFS (PFS of the number of cell therapy cycle. OS of the number of cell therapy cycle. | PMC10646377 |
ORR and DCR | PD | DISEASE, REMISSION, BEST | In the efficacy analysis, the investigators determined that 29 patients in the CIK-SOX group and 25 patients in the SOX group had measurable lesions. No patients in the CIK-SOX group achieved CR, while 16 patients achieved PR, and 11 patients achieved SD. The ORR was 55.2% (95% CI, 35.7–73.6%) and DCR was 93.1% (95% CI, 77.2–99.2%). In the SOX group, eight patients achieved PR and 14 patients achieved SD. The ORR and DCR were 32.0% (95% CI, 14.9–53.5%) and 88.0% (95% CI, 68.8–97.5%), respectively. The efficacy analysis results for all eligible patients are shown in Best overall response (Patients with measurable lesions).N: The total number of subjects in the treatment group. It is the denominator for percentage (%) calculation. n: Number of subjects who are at the corresponding category. The exact 95% CI for the frequency distribution of each variable were computed using Clopper and Pearson method.CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate; CI, confidence interval. | PMC10646377 |
Discussion | tumor | TUMOR, INFILTRATION, METASTASIS | With the development of ICIs, a number of large phase III clinical studies have established the role of ICI combined with chemotherapy in the treatment of locally advanced or metastatic GC patients, but the population-wide data showed limited benefits. It has been hypothesized that one of the reasons for the poor efficacy of anti-PD-1/anti-PD-L1 therapy is the limited T lymphocyte infiltration in the tumor mcroenvironment (The present exploratory, random, open-label study investigated the use of autologous CIK cells combined with SOX versus SOX alone. Adding autologous CIK cells to SOX reduced the incidence of AEs. Previous studies have shown that activated CIK cells In previous studies, patients with a higher tumor load had a higher number of immunosuppressive cells, such as tumor-associated macrophages, regulatory T cells, or myeloid-derived suppressor cells, which promoted immune evasion while impeding immune monitoring (The present study results suggest that patients who received no fewer than three cycles of autologous CIK cells benefited the most from combination therapy. The timing of administration of the enhanced CIK cell preparation and favorable auto-lymphocyte characteristics may account for the improved OS and immune response. Treatment compliance in the study was satisfactory, which may be due to the low rate of serious AEs and well-tolerated characteristics, suggesting the feasibility of using autologous CIK cells in combination with chemotherapy. Subgroup analysis further suggested that the effect of autologous CIK cells may be more pronounced in patients with no fewer than two metastatic organs. This suggests that for patients with more extensive metastasis, improving the immune status of the body is more beneficial than chemotherapy alone, which needs to be confirmed by larger studies.The present study had several limitations. This was an exploratory study with a relatively small sample size and safety serving as the primary endpoint. Moreover, the single-center study lacked sufficient universality, making it difficult to generalize its findings. Due to the early start year of the study, biomarkers, such as TMB and PD-L1, have not been stratified, and partial immunohistochemical results, including those for HER2, are missing. Different marker states may affect the final results. In addition, the level of lymphocytes represents the state of immune function in the body, and further analysis of the number of lymphocyte subsets in patients was not available in the present investigation. Multicenter randomized controlled trials in larger cohorts are needed to further validate the efficacy and safety of the combination regimen and to further screen the population for benefit analysis.Future research should include determining the optimal number of cell therapy cycle and the interval between CIK cell treatments. In addition, population screening can be performed based on different markers, such as microsatellite status or PD-L1 expression, in order to explore the treatment efficacy in different types of patients receiving cell therapy. | PMC10646377 |
Conclusions | Autologous CIK cells in combination with SOX demonstrated a good safety profile as the first-line therapy in locally advanced or metastatic GC patients. Although the PFS and OS in the CIK-SOX group were not statistically significantly different compared to those in the SOX alone group, the treatment prolonged the PFS and OS duration, with the absolute improvement in OS duration of about 8.05 months. Continuous benefit of autologous CIK cells in combination with SOX was observed during long-term follow-up. | PMC10646377 | ||
Data availability statement | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author. | PMC10646377 | ||
Ethics statement | Cancer Center/Cancer | The studies involving humans were approved by The Ethics Committee of the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences and Peking Union Medical College. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. | PMC10646377 | |
Author contributions | XM: Conceptualization, Data curation, Writing – original draft, Formal Analysis, Methodology, Project administration. LP: Data curation, Formal Analysis, Writing – original draft. JW: Data curation, Formal Analysis, Writing – original draft. LG: Investigation, Writing – original draft. WZ: Investigation, Writing – original draft. XL: Methodology, Project administration, Writing – original draft. JL: Methodology, Project administration, Writing – original draft. LY: Project administration, Writing – review & editing. | PMC10646377 | ||
Acknowledgments | SESSION | The paper was selected by 2023 ASCO Annual Meeting for presentation in a ‘Poster Session’. | PMC10646377 | |
Conflict of interest | Authors XL and JL were employed by the company Beijing Biohealthcare Biotechnology Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10646377 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10646377 | ||
References | PMC10646377 | |||
Background | LAGC, gastric cancer | GASTRIC CANCER | Gastrectomy with D2 dissection and adjuvant chemotherapy is the standard treatment for locally advanced gastric cancer (LAGC) in Asia. However, administering chemotherapy with sufficient intensity after gastrectomy is challenging. Several trials demonstrated the efficacy of neoadjuvant chemotherapy (NAC). However, limited studies explored the feasibility of NAC-SOX for older patients with LAGC. This phase II study (KSCC1801) evaluated the safety and efficacy of NAC-SOX in patients with LAGC aged ≥ 70 years. | PMC10468941 |
Methods | Patients received three cycles of SOX | PMC10468941 | ||
Results | The median age of 26 enrolled patients was 74.5 years. The median DI in NAC-SOX | PMC10468941 | ||
Conclusions | NAC-SOX | PMC10468941 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s10147-023-02373-3. | PMC10468941 | ||
Keywords | PMC10468941 | |||
Introduction | gastric cancer, cancer, Cancer | GASTRIC CANCER, CANCER, CANCER | According to the 2020 Global Cancer Observatory Data, gastric cancer (GC) is the 4th most deadly cancer in the world, and most common in East Asia [Gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy is currently the standard treatment for locally advanced GC (LAGC) in Asian countries [The current phase II study, named KSCC1801, was conducted to investigate the safety and efficacy of SOX | PMC10468941 |
Patients and methods | MAY | This multicenter, open-label, single-arm, prospective phase II clinical trial was conducted from June 2018 to May 2020 at 11 institutions in Japan. The study protocol was approved by the Clinical Research Network Fukuoka Certified Review Board. The study was conducted according to the tenets of the Declaration of Helsinki and the Clinical Trials Act. Written informed consent was obtained from all eligible patients prior to registration. The study protocol was registered in the Japan Registry of Clinical Trials ( | PMC10468941 | |
Eligibility criteria | neurologic or psychiatric disorders, cancer, liver cirrhosis, hepatitis, esophageal infiltration, gastric adenocarcinoma | CARDIOVASCULAR DISEASE, DRUG HYPERSENSITIVITY, CANCER, LIVER CIRRHOSIS, GASTRIC CANCER, ONCOLOGY, HEPATITIS, GASTRIC ADENOCARCINOMA | All patients had histologically confirmed untreated gastric adenocarcinoma based on an endoscopic biopsy of the primary lesion. The major inclusion criteria were diagnoses of cT3–4, N1–3, and M0 (according to the Japanese Gastric Cancer Classification: 3rd English edition) based on image findings (endoscopy, abdominal CT), and laparoscopically proven H0, P0, CY0. In addition, patients who were capable of oral intake were Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤ 1 and over 70 years of age. Exclusion criteria included an esophageal infiltration distance of 3 cm or more, presence of liver cirrhosis or active hepatitis, history of neurologic or psychiatric disorders, cardiovascular disease, drug hypersensitivity, or another cancer diagnosis within the past five years. Detailed inclusion and exclusion criteria are listed in Online Resource 1. | PMC10468941 |
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