In early 2022, the Coronavirus disease 2019 (COVID-19) remains a global challenge. COVID-19 is caused by an increasing number of variants of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we report an outbreak of SARS-CoV-2 breakthrough infections related to a student festive event with 100 mostly vaccinated guests, which took place in Northern Bavaria, Germany, in October 2021. The data were obtained by retrospective guest interviews. In total, 95 students participated in the study, with 94 being fully vaccinated and 24 reporting infection by the delta variant. Correlation analyses among 15 examined variables revealed that time spent at the event, conversation with the supposed index person, and a homologous viral vector vaccination regime were significant risk factors for infection. Non-significant observations related to higher rates of infection included time since last vaccination, shared use of drinking vessels, and number of individual person-to-person contacts at the event. Our data suggest that a high rate of breakthrough infections with the delta variant occurs if no preventive measures are practiced. To limit infection risk, high-quality testing of participants should be considered a mandatory measure at gatherings, irrespective of the participants’ vaccination status. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the betacoronaviruses, like the highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV), and the first SARS-CoV . DiscoveSafe and effective vaccines have game-changing potential against the COVID-19 pandemic. Vaccination is intended to induce B-cells that produce neutralizing antibodies against SARS-CoV-2 to prevent cellular infiltration. An additional effect is the stimulation of T-cells that provide cellular immunity and thus protect from the disease . FurtherSuper spreader events are serious drivers of the COVID-19 pandemic ,21,22 an2 and 250 m3 of airspace   based upt-tests were used to test continuously distributed variables. Logistic regression analysis was applied to test and illustrate the effect of various risk factors on the risk of infection. All reported tests were two-sided, and p-values below 0.05 were considered statistically significant. All statistical analyses in this report were performed with STATISTICA 13 , PASW 24 , or GraphPad Prism .The data were compiled in Excel and checked for consistency. Crosstabulation tables were analyzed using Pearson’s Chi-Square test, Fisher’s Exact test, and the Kruskal–Wallis test for singly ordered tables. The Mann–Whitney U test and Bootstrap The sequencing of SARS-CoV-2 isolates was performed on the Illumina platform using standard parameters. SARS-CoV-2 lineages were assigned using PANGO lineages ,27. Char2 and a connected garage  featured one or two risk factors for severe COVID-19. The participants attended the event for 60 to 510 min . At least 89 guests were at the venue simultaneously with the supposed index person. Persons reported contacts with 4–80 other guests . p < 0.05):t-test, p = 0.0002). Notably, none of the guests that stayed 210 min or less tested positive.Extended stay at the event  . For participants staying ≥3 h, we calculated risks of infection of 25% (without conversation) and 38% (with conversation).Conversation with the supposed index person. Of the 24 persons who were infected, 13 (54%) had talked to this person. This translates to a risk of infection of 36% compared to 17% without conversation .The risk of infection was significantly lower upon heterologous vaccination with AZD + BNT (23%) than with AZD + AZD (60%) :In addition, the following non-significant observations were found (p = 0.14);Risk of infection appeared decreased with BNT + BNT compared to AZD + AZD ;Risk of infection appeared decreased with AZD + BNT compared to BNT + BNT ;The time since last vaccination appeared to be inversely correlated with protection ;Infections of guests who shared drinking vessels were slightly increased .The number of contacts was slightly increased in subjects who were infected (21.6 ± 12.6) vs. subjects without infection  and infection. Three correlations were statistically significant  students, in which proximity to a teacher who was infected and occasionally read aloud to the class while unmasked resulted in an almost three-fold increased primary infection rate .Notably, among the 24 persons who were infected of our study, 10 declared no direct contact with the putative index person. Possible explanations for their infection are: (i) more than 1 index person was present (which may be supported by the finding of one other lineage among eight sequenced isolates); (ii) infectious particles spread through the air within the venue and, over time, accumulated above the infective threshold; and (iii) infection did not occur at the event.Third, a vaccination scheme with two jabs of AZD compared to heterologous vaccination (with the 1st from AZD and the the 2nd from BNT) was a risk factor. In both cases, however, breakthrough infections occurred. Some vaccines against other infectious diseases practically provide lifelong protection and almost completely eradicate the etiologic agent upon encounter by a host. One example of this “sterilizing immunity” is the vaccine against measles, mumps, and rubella. Currently approved SARS-CoV-2 vaccines do not provide sterilizing immunity against COVID-19 . This isOur study is based on a very comprehensive set of data encompassing 15 variables, which permits multifold correlation analysis and delineation of recommendations. One limitation of the study is that the participants were rather homogeneous in terms of age and social status, which limits aspects of diversity. Another limitation is that only eight SARS-CoV-2 samples were available for sequencing and phylogenetic analyses. Therefore, we cannot exclude that additional positive index persons were present at the event.This study shows that time spent at the event, conversation with the supposed index person, and a homologous viral vector vaccination regime were significant risk factors for SARS-CoV-2 breakthrough infection with the delta variant. While practicing social distancing, hand hygiene, and the use of face masks remain important measures in preventing the spread of SARS-CoV-2, high-quality testing of participants at in-person events could be considered mandatory to limit risk of infection, irrespective of the participants’ vaccination status. Further studies that include larger and more diverse cohorts and provide comprehensive datasets of several variables are required to shed further light on the interplay of risk factors for transmission of SARS-CoV-2 and its variants of concern—whether they are already known or have yet to emerge.


Background: Several studies have demonstrated that using a higher dose of statin can easily induce liver injury and myopathy. Low-density lipoprotein cholesterol (LDL-C) is a well-established modifiable risk factor for cardiovascular disease; however, the large majority of Chinese patients cannot meet the target level of LDL-C recommended by the Chinese expert consensus. Evolocumab has been demonstrated to reduce LDL-C by approximately 60% in many studies. Nevertheless, whether combined evolocumab and moderate-intensity statin is as effective in lowering LDL-C and decreasing incidence of MACE in Chinese patients presenting with the acute phase of acute coronary syndrome (ACS) remains unknown. Therefore, the “Evolocumab added to Moderate-Intensity Statin therapy on LDL-C lowering and cardiovascular adverse events in patients with Acute Coronary Syndrome” (EMSIACS) is conducted.Methods: The EMSIACS is a prospective, randomized, open-label, parallel-group, multicenter study involving analyzing the feasibility and efficacy of evolocumab added to moderate-intensity statin therapy on lowering LDL-C levels in adult Chinese patients hospitalized for acute phase ACS. The sample size calculation is based on the primary outcome, and 500 patients will be planned to recruit. Patients are randomized in evolocumab arm (evolocumab 140mg every 2weeks plus rosuvastatin 10mg/day or atorvastatin 20mg/day) and statin-only arm (rosuvastatin 10mg/day or atorvastatin 20mg/day). The primary outcome is the percentage change in LDL-C in weeks 4 and week 12 after treatment. The secondary outcome is the occurrence of MACE after 12weeks and 1year of treatment.Discussion: If the EMSIACS trial endpoints prove statistically significant, the evolocumab added to moderate-intensity statin therapy will have the potential to effectively lower subjects’ LDL-C levels, especially for the Chinese patients with acute phase ACS. However, if the risk of MACE is not significantly different between the two groups, we may extend follow-up time for secondary outcome when the clinical trial is over.Clinical trial registration: The study is registered to ClinicalTrials.gov (NCT04100434), which retrospectively registered on November 24, 2020. In recent years, acute coronary syndrome (ACS) has been among the leading causes of cardiovascular death in China . It is cExpert consensus or guidelines have recommended treatment goals of LDL-C level. The 2019 ESC/EAS Guidelines for the management of dyslipidemias  stated tStatins have been widely used as an effective LDL-C lowering agent for ASCVD patients . HoweverTo achieve the target reduction in LDL-C, combinatory therapy using non-statin agents added to statin has been developed. Several recent trials have shown that the addition of either ezetimibe or anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies to statin therapy provides a further reduction in ASCVD risk, which is positively correlated with the incrementally achieved absolute LDL-C reduction . CurrentEvolocumab is a fully human monoclonal antibody against PCSK9. To date, several studies have been investigating the efficacy of evolocumab added to statin therapy in reducing the risk of cardiovascular events . It has The overall purpose of EMSIACS study is to determine the feasibility, safety, and efficacy of the evolocumab added to moderate-intensity statin therapy, using the statin-only therapy as the control arm, on LDL-C level variability between baseline and 1-year follow-up in patients with acute phase ACS. This study was designed to address two principal research questions:We determine the effects of the evolocumab added to moderate-intensity statin therapy on MACE.We plan to identify the appropriate ACS patient population for the administration of evolocumab in combination with standard statin therapy.This is a prospective, open-label, randomized, parallel-group, and multicenter study. We are planning to include 500 patients with acute phase ACS , acute ST-segment elevation MI within 24h of onset, and unstable angina within 72h of onset). Patients will be randomly assigned in a 1:1 ratio using a computer-generated random number system (block randomization with blocks of size 4 at random) and are divided into two treatment groups: statin-only therapy and evolocumab plus statin therapy. A 48-week follow-up study will be conducted.ClinicalTrials.gov (No. NCT04100434). The dates of the study estimated from January 1, 2021, to June 1, 2023.This trial has been registered in This study will be conducted in the Tianjin Chest Hospital, China. Patients will be recruited from eight grade III Level A hospitals across the Tianjin area. The comprehensive analysis of baseline demographic characteristics, clinical examination, laboratory tests, and investigation of the forecast value will be conducted in the Tianjin Chest Hospital.The study protocol has been reviewed and approved by the Ethics Committee (IEC) of the Tianjin Chest Hospital, China (No. 2019KY-019-01).The usage and dosage of evolocumab and statins used in the present study are as follows :Statins: according to the recommendations of the 2020 edition of the Expert Consensus on Clinical Pathway of Blood Lipid Management in Patients with Acute Coronary Syndrome , all patEvolocumab (trade name: Repatha®): patients will be given evolocumab within 72h immediately after diagnosis of ACS, with subcutaneous administration of 140mg evolocumab once every 2weeks . Use a single-use prefilled auto-injector to administer evolocumab subcutaneously in areas of the abdomen, thighs, or upper arms that are not tender, bruised, red or hardened. Within 30min, three injections will be given continuously with a single-use prefilled auto injector.Patients admitted to one of the eight participating hospitals with acute ACS are selected, and the recruitment process is as follows: (1) for patients who are going to receive the lipid-lowering therapy, assess whether they are suitable for the trial according to the inclusion and exclusion criteria; (2) for patients who fulfill the trial criteria, introduce and explain the study; patients will be enrolled only after they agree to participate and provide signed informed consent; (3) for patients who refuse to sign the informed consent form, withdraw them from this trial, and perform conventional clinical practice.Patients aged ≥18 and ≤85 with recent hospitalization for acute phase ACS are eligible for inclusion in this study. The diagnosis for ACS in this study is defined as non-ST-segment elevation myocardial infarction (MI) within 24h of onset, acute ST-segment elevation MI within 24h of onset, or unstable angina within 72h of onset. Additional inclusion criteria are based on patients with elevated LDL-C levels who meet one of the following three conditions: (1) prior to the study, patients who received intensive statins for more than 4weeks (the same dose of statin therapy has been sustained for the past 4weeks), having LDL-C levels ≥70mg/dl (≥1.8mmol/L) or non-HDL-C≥100mg/dl (≥2.6mmol/L); (2) prior to the study, patients who received moderate-intensity statin therapy for more than 4weeks (the same dose of statin therapy has been sustained for the past 4weeks), having LDL-C levels ≥90mg/dl (≥2.3mmol/L) or non-HDL-C≥120mg/dl (≥3.1mmol/L); (3) prior to the study, patients who do not receive any statin therapy or discontinue statin therapy, having LDL-C≥125mg/dl (≥3.2mmol/L) or non-HDL-C≥155mg/dl (≥4.0mmol/L); and (4) prior to the study, patients who do not receive any statin therapy or discontinue statin therapy, having LDL-C L125 mg/dL (≤3.2mmol/L).2; (5) patients with active liver diseases or liver dysfunction, either recorded in the patient’s medical record or defined as an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 3 times above the upper limit of normal range; (6) patients with intolerance to rosuvastatin (any dose) or to other statins; (7) patients with known allergies to contrast agents, heparin, aspirin, ticagrelor, or clopidogrel; (8) patients with known allergies to supplements required for the use of the drug; (9) patients who have been treated with evolocumab or other PCSK9 inhibitors; (10) patients who have received cholesterol ester transfer protein inhibitors treatment 12months prior to screening; (11) patients who have received systemic steroid or cyclosporine treatment in the past 3months; (12) patients with known infections, hemorrhages, metabolic or endocrine disorders as determined by the researchers; (13) patients who have been included in other studies; (14) patients with active malignant tumor in need of treatment; and (15) women who are fertile  and have not received tubal ligation, oophorectomy, or hysterectomy.Patients with the following conditions are excluded: (1) patients unable to understand the research requirements or refuse to sign the informed consent form; (2) patients with unstable clinical status ; (3) patients with uncontrolled arrhythmia, defined as recurrent or symptomatic ventricular tachycardia and atrial fibrillation with rapid ventricular reaction that the drug cannot control within 3months prior to screening; (4) patients with severe renal insufficiency, defined as the estimated glomerular filtration rate (eGFR)<30ml/min/1.73mData will be recorded in Case Report Forms (CRFs) and entered into the clinical trial center by an electronic data capture system. Baseline data and data of different follow-up time points will be recorded. The schedule for the baseline assessment and subsequent assessments at different follow-up time points is shown in At baseline, the following characteristics are assessed: (1) demographic characteristics , (2) physical status , (3) medical history , (4) treatment history , (5) family history , (6) life style , (7) current medical history, (8) echocardiography , and (9) laboratory examinations.The laboratory examinations will be performed at baseline and at weeks 1, 4, 12, 24 and 48 post-treatment and will include the following: routine blood tests , kidney function panel ]; serum lipids panel ; myocardial damage markers ; and quality of life assessment using the PROMIS 10 scale , coronary artery bypass (CABG) or thrombolytic therapy for revascularization, coronary angiography of the diseased vessels , stent implantation factors ; and postoperative lesions  grade flow).Subjects of the present study will receive 24 treatments after being enrolled, and data of laboratory examinations will be evaluated at 72h and weeks 1, 4, 8, 12, 24, and 48 after intervention .The primary outcome of the present study will be the mean percentage change of the LDL-C level between baseline and weeks 4 and 12 post-treatment . The secvia regular medical examination and laboratory tests. For analyses of clinical endpoints, incidence of AEs and/or serious adverse events (SAEs) will be summarized for each randomized treatment group. Serious adverse events include cardiovascular events , muscle-related adverse events, neurocognitive impairments, incident diabetes; adverse events of special interest include allergies, injection-site reactions, or any other clinical abnormalities. If unexpected or SAE occur, the researchers or staff will fill out the SAE Report Form and notify the Ethics Committee and the State Food and Drug Administration (SFDA) as well as the pharmacological authorities.For safety outcome analysis, missing data will not be imputed. Adverse events (AEs) will be recorded and summarized using descriptive statistics. Tolerability of study drug will be monitored and evaluated throughout the study period Possible intervention-related complications will be recorded at 72h, and weeks 1, 4, 8, 12, 24, and 48 after intervention, including: dissection, acute thrombosis, coronary perforation, puncture site complications, allergic reactions, vasovagal response, perioperative myocardial infarction, cerebrovascular events, and hypotension.Patients have the right to withdraw from the proposed study at any time without reason. Such withdrawal will not affect the patients’ rights to receive appropriate medical management in the future. However, researchers will terminate the study for patients having the following situations: poor adherence to the treatments; serious adverse drug reactions; pregnancy; patients refusing to continue participating in the study; lost to follow-up; or other safety reasons.Excessively high withdrawal rates may lead to unexplained results. Therefore, unnecessary withdrawal should be avoided. Withdrawal reasons should be clarified and registered on the CRF. Researchers should evaluate, judge, and follow up on adverse events that lead to patient withdrawal. Study medications that have been assigned to withdrawing patients cannot be reassigned to other patients. Subjects who quit cannot be replaced. If a subject withdraws before the end of the study, related assessments should be performed for the subject at the end of the study.This is a superiority trial, and the sample size calculation is based on the primary efficacy endpoint, namely the percentage of change in LDL-C levels from baseline to week 4 after randomization. In order to have 90% power to detect clinically meaningful differences in treatment effects with a one-sided significance level of 5% (α=0.05), a sample size of 193 patients is required for each treatment arm. Assuming that the drop-out rate is 20%, this study aims to enroll approximately 484 patients, with 242 patients in the evolocumab plus statin arm and 242 in the statin-only arm. Therefore, the proposed study is expected to enroll a total of 500 patients with acute phase ACS, with 250 patients in each treatment arm.The number of patients enrolled from each hospital is based on the bed size of each hospital. The Tianjin Chest Hospital plans to enroll 220 patients, and the remaining seven hospitals each will enroll 40 patients.The primary efficacy analysis will be based on the time from randomization assignment to the first occurrence of any component of MACE. Data will be analyzed using intention-to-treat analysis (ITT) and per protocol (PP) to assess the efficacy and safety of evolocumab in combination with moderate-intensity statin therapy. The superiority of evolocumab will be assessed for all efficacy endpoint. Continuous variables with an approximately normal distribution will be reported with mean±standard deviation (mean±SD), and differences between the two treatment arms will be tested using independent sample t-test. For continuous variables that are not normally distributed, the median and interquartile range (IQR) will be given, and the nonparametric Mann–Whiney U test will be conducted to test for differences between treatment arms. Discrete variables will be reported with counts and percentage for each arm, and differences between arms will be examined using Fisher’s exact test. In order to compare MACE differences, Kaplan–Meier survival curve analysis will be performed, and hazard ratio (HR) and 95% CI will be calculated. Log-rank tests will also be performed to evaluate the differences in significance and verify treatment efficacy.The ITT population will include all randomized patients and the PP population will include all randomized patients who complete the entire study. Subjects with missing data will be excluded from the corresponding analysis. Logistic regression will be used to analyze differences in the central effect sizes.p<0.05.Results of the proposed study will be analyzed using SAS 9.2 or higher version  software. All statistical tests will be two-tailed unless otherwise indicated or presented with a 95% confidence interval (CI), and statistical significance will be established as The EMSIACS is the first randomized, multicenter trial to investigate the feasibility, safety and efficacy of evolocumab added to moderate-intensity statin therapy specifically for Chinese patients with acute phase ACS. Patients with ACS are at very high risk of recurrent cardiovascular diseases, namely death from cardiovascular causes, MI, repeated coronary revascularization, ischemic stroke, or unstable angina requiring hospitalization . It has Monoclonal antibodies target to PCSK9 are relatively novel lipid-lowering agents that have benefits in reducing the risk of cardiovascular disease . To dateNevertheless, compared to the results of FOURIER, EVOPACS and ODYSSEY OUTCOMES studies, the evolocumab added to moderate-intensity statin therapy is expected to reduce the LDL-C level considerably in Chinese ACS patients and to achieve the LDL-C goal recommended by the China expert consensus/advice 2020; . In addiThis study is the first to evaluate the efficacy of evolocumab added to moderate-intensity statin therapy in lowering LDL-C specifically for the Chinese patients with acute phase ACS. The outcomes of the EMSIACS study will provide insights into the ability of evolocumab to reduce LDL-C over time in Chinese patients who recently experienced with ACS and who, despite high-dosage statin therapy, fail to achieve LDL-C target levels.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.YL and JG were the principal investigators for managing the protocol and developed the protocol for this project. J-YX and M-DG were responsible for data collection and management. J-YL and P-JL were responsible for epidemiological investigations and laboratory testing. C-PL and ZC performed all statistical analysis. YL, JG, J-YL, and P-JL were involved in the initial draft of the manuscript writing. The manuscript was amended based on comments from all authors. All authors contributed to the article and approved the submitted version.This research project was funded by the Key Project of Scientific and Technological Support Plan of Tianjin in 2020 (No. 20YFZCSY00820).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Neoadjuvant chemotherapy (NAC) is widely accepted as a potential treatment for advancedgastric cancer (AGC). Laparoscopic gastrectomy (LG) has recently been performed for advancedgastric cancer and could lead to improved adherence to multimodal treatment. In the presentstudy, we compared the feasibility and outcomes of LG in patients with or without NAC in ourinstitution.We assessed patients who underwent LG with (n=185) or without (n=1204) NAC between1997 and 2013. We used propensity score matching to evaluate perioperative short-term outcomesand long-term outcome.We used propensity score matching by patient background and treatment-reratedfactors to establish two groups of 157 patients with or without NAC. There were no significantdifferences in perioperative short-term outcomes or long-term outcome between the groups.LG for selected patients with NAC is feasible and safe but has no long-termsurvival benefit. However,surgery alone for advanced gastric cancer (AGC) has a limited beneficial effect on long-termoutcomes.2 Therefore, multimodal approachesto treatment of AGC have been tried to improve patients’ survival. In the last 20 years, largerandomized trials have demonstrated the efficacy of adjuvant chemoradiotherapy ,3 adjuvant single-drug chemotherapy,4 and perioperative three-drugcombination chemotherapy .5 Afterpublication of the results of these trials, surgery alone was no longer considered to be thestandard treatment for AGC. Adjuvant chemotherapy after D2 lymphadenectomy is currentlyconsidered the standard treatment for GC.5 However, the prognosis for AGC remains poor comparedwith that of early-stage GC, with 5-year survival rates >95%,6 and there is no established method to increase survival.6 Neoadjuvant chemotherapy (NAC) might improve theprognosis of AGC because it can reduce tumor size, decrease clinical stage, and increasecurative resection rate.5 S-1, which is a promising oralanticancer drug for GC,8 plus cisplatin therapy had a 54% response rate for AGC in a phase IIItrial. Although there were no treatment-related deaths in this trial, many grade 3 or 4 adverseevents were reported. Severe adverse events in the NAC setting could lead to incompletetreatment or delayed surgery, and the ideal timing of surgery may be missed. Therefore, comparedwith laparotomy, laparoscopic gastrectomy (LG) is expected to improve adherence to multimodaltreatment.11Gastric cancer (GC) is one of the most frequent cancers,In the present study, we evaluated the feasibility and outcomes of LG following NACby propensity score matching (PSM)-based comparison of patients with or without NAC in ourinstitution.12This was a single-center retrospective cohort study of patients who underwent LGfor GC between 1997 and 2013 at Fujita Health University, Toyoake, Japan. We divided thepatients into two groups: 185 with NAC and 1204 without NAC. We collected the followingbackground data on the patients: sex, age, American Society of Anesthesiologists (ASA) status,body mass index (BMI), and clinical stage according to Japanese Classification of GastricCarcinoma (JCGC) before treatment. We also collected data on the following treatment-relatedfactors: surgical procedures ; extent of lymphadenectomy ; combinedresection of other organs; adjuvant chemotherapy; perioperative short-term outcomes ; andlong-term outcome [Kaplan–Meier overall survival (OS) after surgery].We compared these factors between the NAC(–) and NAC(+) groups  and 2. PThe data obtained through review of medical records were managed according to theprivacy policy and ethical code of our institution.11 Distal gastrectomy was used for tumors that were localized to middle and/orlower areas, whereas total gastrectomy was used for tumors that infiltrated the upper, middleand lower areas. Distal and total gastrectomy were both performed with lymphadenectomy.Proximal gastrectomy was used for tumors that were localized in upper areas.Pancreaticoduodenectomy was performed when the tumor invaded the pancreas.13The techniques and perioperative management of LG have been reportedpreviously.14 GC stage was determined by contrast-enhancedcomputed tomography, gastrography, endoscopy, and endosonography. Postoperative complicationswere defined as those that required surgical, endoscopic or radiological intervention, and thatcorresponded to Clavien–Dindo classification grade III or higher.15The GC stage was described according to JCGC, 3rd English edition.2 test was used for between-group comparison ofnumerical data, and the Mann–Whitney U test was performed for analysis of ordinal data . Data areexpressed as median and range or odds ratio and 95% confidence interval, unless otherwisenoted. A p value <0.05 (two-tailed) was considered statistically significant.All analyses were conducted using IBM SPSS Statistics 23 .Univariate analysis using the χPatient background and treatment-related factors of the entire cohort are shown inThe perioperative short-term outcomes before matching were shown in Two groups of 157 patients with or without NAC were established by PSM of patientbackground and treatment-related factors. There was no significant difference between thegroups in patient background factors  or treatment-relatedfactors  patients according to the Response Evaluation Criteria in SolidTumors version 1.1, and we were able to perform the operation smoothly. We investigated patientbackground, treatment-related factors, perioperative short-term outcomes and long-term outcomein patients with or without NAC who underwent LG between 1997 and 2013. NAC mainly comprisedS1+cisplatin, as in the SPIRITS trial,9 or S1regimens, as in the ACTS-GC trial.4 We alsoexamined the perioperative short-term outcomes and long-term outcome in patients with or withoutNAC after PSM. There were no significant differences in perioperative short-term outcomesbetween patients with or without NAC after PSM. This shows that LG after NAC had similar safetyto LG without NAC in these selected patients at our institution. However, there were also nosignificant differences in long-term outcome (OS) between the groups after PSM. We failed toshow any survival advantage of our strategy with LG after NAC.The selected treatment strategy was based on AGC ) and surgeonsfollowing discussion of the disease and treatment and obtaining informed consent. Gastrectomyfor AGC after NAC is a demanding a precise procedure and can lead to higher incidence ofpostoperative morbidity.The main limitation of the present study was that it was a single-centerretrospective cohort study with a long study period. Our study had a wide range of cases,including stage I and stage IV GC. For patients with stage IV GC, we performed palliativeresection. The aim of the present study was to perform LG in patients with NAC to minimizepostoperative complications. Our ultimate goal is to start postoperative adjuvant chemotherapyas soon as possible and improve the prognosis of AGC. Nevertheless, this study showed that LGcould be performed safely, even in patients with AGC and NAC.Although a further prospective study is needed to evaluate the long-term outcome ofour treatment strategy for AGC, the present study shows that LG is feasible after NAC inpatients with AGC .


Childhood obesity has increased worldwide, and many clinical and public interventions have attempted to reduce morbidity. We aimed to determine the metabolomic signatures associated with weight control interventions in children with obesity. Forty children from the “Intervention for Children and Adolescent Obesity via Activity and Nutrition (ICAAN)” cohort were selected according to intervention responses. Based on changes in body mass index z-scores, 20 were responders and the remaining non-responders. Their serum metabolites were quantitatively analyzed using capillary electrophoresis time-of-flight mass spectrometry at baseline and after 6 and 18 months of intervention. After 18 months of intervention, the metabolite cluster changes in the responders and non-responders showed a difference on the heatmap, but significant metabolites were not clear. However, regardless of the responses, 13 and 49 metabolites were significant in the group of children with obesity intervention at 6 months and 18 months post-intervention compared to baseline. In addition, the top five metabolic pathways ; valine, leucine, and isoleucine biosynthesis) including several amino acids in the metabolites of obese children after 18 months were significantly changed. Our study showed significantly different metabolomic profiles based on time post obesity-related intervention. Through this study, we can better understand and predict childhood obesity through metabolite analysis and monitoring. The prevalence of childhood obesity has increased worldwide . In someObesity is caused by various complex factors, of which genetic and epigenetic factors are the major causes. These factors affect the lipidome, metabolome, and proteome, and various omics studies have investigated the causes of obesity . KnowingAs obesity rates increase, metabolic studies that reveal metabolomic signatures of patients with obesity and study metabolic changes such as inflammation or oxidative stress associated with obesity are increasing . HoweverThis study analyzed metabolites at different intervention intervals by selecting responders and non-responders and identifying metabolites that were significantly different. We also identified significant metabolite changes associated with long-term childhood obesity weight intervention. In addition, we checked whether clinical indicators have significant results with these metabolite changes. The metabolomic information from this study can be used to identify biomarkers related to childhood obesity and to develop future personalized treatmentsOf the 242 patients of the ICAAN cohort, we finally included 40 obese patients in this study. In detail, 163 and 111 were followed up at 6 and 18 months after the weight control intervention, respectively. A total of 131 participants dropped out during the intervention, mainly because of busy schedules, no response, lack of willingness, or busy schedule of parents.The clinical characteristics of the study population are presented in p-value < 0.05, fold change > 1.2) at 6 months and 18 months post-intervention compared to baseline, respectively  measurement on the basis of Human Metabolome Technologies (HMT)’s standard library and Known-Unknown peak library. First, we investigated metabolomic profiles of the study population according to responsiveness . A scorep < 0.05), and other metabolite sets including alanine, aspartate, and glutamate metabolism, tricarboxylic acid (TCA) cycle, and valine, leucine, and isoleucine biosynthesis were also enriched . We also constructed chemical and biochemical networks using these significant metabolites  metabolic pathways. Several studies have already shown that glutamate is increased in obese children and glutamine is decreased in obese patients without weight interventions ,21. ThesObesity is essentially a change due to an inflammation mechanism, and thus changes in various immune cells are affected. In obese and diabetic patients, changes in macrophage polarization can induce decreased α-ketoglutarate production and increased succinate in the TCA cycle, and glutamine metabolism is essential for the process . SuccinaArginine, aspartate, and ornithine are associated with urea cycle metabolism and play an important role in ammonia detoxification. Our study showed that decreased urea cycle intermediates including aspartate, ornithine, and arginine in plasma, which implies downregulated production of ammonia by weight-loss intervention. Aspartate, like pyruvic acid, is an amino acid associated with the TCA cycle. The metabolic shift in pyruvic acid decreased after weight control intervention in overweight pre-adolescent and obese women ,25. ZhenDysregulation of these various metabolic pathways and insulin resistance are associated with metabolic changes in childhood obesity, which may also be affected by pubertal development and the gut microbiome. During the pubertal stage, insulin sensitivity decreases by 50% and is associated with increased total body lipolysis and decreased glucose oxidation . These aTaken together, these metabolic changes by weight-loss intervention might become phenotypic characteristics of metabolically healthy obesity (MHO). Some obese patients show a healthier phenotype than other obese patients, which is often observed in young and physically active patients with good nutritional status . AlthougThis study was limited by the availability of subjects for longitudinal studies owing to many dropouts from the childhood obesity intervention cohort. In addition, there was a possibility of selection bias in the results. Lower family functioning, exercise group, lower initial attendance rate, and non-self-referral pathways were significantly associated with early dropouts, and lower family functioning and lower initial attendance rates were associated with late dropouts in our cohort study . Thus, iIn conclusion, weight-loss intervention induced serial changes in specific amino acid metabolites and a metabolic pathway regardless of response to interventions in childhood obesity. Long-term follow-up results of weight intervention and metabolite changes are more important than responses to weight-loss interventions, which may inform clear mechanisms of obesity. This is why it is important to regularly visit a clinic for treatment of obesity, and tracking changes in metabolites will be helpful in monitoring the individual. Therefore, this study can be utilized for the development of metabolite biomarkers related to childhood obesity treatment through a long-term follow-up study. It is also expected to contribute to large-scale research for the prediction and prevention of personal childhood obesity using metabolites in the future.n = 84, 34.7%; exercise group ; nutrition feedback group ), and all groups received five category interventions . The exercise group included the contents of the usual care group and added weekly exercise class and activity feedback. The nutrition feedback group received additional individual nutrition feedback including the usual care group contents.We selected 40 obese subjects (BMI > 97th percentile for age and sex) from 242 patients in the ICAAN study cohort based on intervention responses. This 24-month post-intervention follow-up study was designed as a multidisciplinary intervention test to prevent excessive weight gain and to improve several health indices in children and adolescents (aged 6–17 years) with obesity in Korea ,37,38. Pn = 20). In the responder and non-responder groups, the changes in BMI z-scores were <−0.45 and >−0.1 in the responder and non-responder groups, respectively. Random sampling was not possible owing to the limited sample size; therefore, the portion and number of samples in each intervention group were considered. As no patients gained weight because of the intervention, patients with the least weight change were selected as the non-responder group based on total responders. A flowchart of the participant selection is provided in Participants were categorized into two groups based on changes in BMI z-scores after 18 months. Twenty subjects presenting significant intervention effects were assigned to the target (responder) group and those with minimal weight loss to the non-responder group , with Anion Buffer Solution  as the electrolyte. The sample was injected at a pressure of 50 mbar for 10 s. The applied voltage was set at 30 kV. ESI-MS was conducted in the negative ion mode, and the capillary voltage was set at 3500 V. The spectrometer was scanned from m/z 50 to 1000. To guarantee analytical reproducibility, we monitored the relative standard deviation of internal standards which are added in the sample (less than 10%).The 120 plasma samples were transported from Seoul National University (SNU) to HMT via Young-In Frontier Co., Ltd. The samples were stored in a deep freezer below −80 °C. To each 50 μL of sample, 200 μL of methanol containing internal standards  was added, diluted with 150 μL of distilled water and mixed thoroughly. Each mixture (300 μL) was filtered through a 5-kDa cut-off filter  to remove macromolecules. The filtrate was centrifugally concentrated and resuspended in 50 μL of distilled water immediately before analysis. The compounds were measured in the cation and anion modes using an Agilent CE-TOFMS system  and a fused silica capillary i.d. 50 μm × 80 cm. Cationic metabolites were analyzed with a fused silica capillary , with Cation Buffer Solution  as the electrolyte. The sample was injected at a pressure of 50 mbar for 5 s. The applied voltage was set at 30 kV. Electrospray ionization-mass spectrometry (ESI-MS) was conducted in the positive ion mode, and the capillary voltage was set at 4000 V. The spectrometer was scanned from m/z values, migration time (MT), and peak area. The peak area was then converted and normalized to a relative peak area by dividing by sample amount and internal standard peak area. The peak detection limit was determined based on a signal-to-noise ratio of 3. Relative peak areas under the peak detection limit were imputed by K-nearest neighbor method. Putative metabolites were then assigned from HMT’s standard library and the Known-Unknown peak library based on m/z and MT with tolerances of ±10 ppm and ±0.5 min, respectively. If several peaks were assigned to the same candidate, the candidate was assigned a branch number.Peaks detected by CE-TOFMS analysis were extracted using an automatic integration software  to obtain peak information, including p-value < 0.05, fold change > 1.2). Significant metabolites between baseline and 6 months post-intervention or baseline and 18 months post-intervention were determined by paired t-test . With the significant metabolites, we identified enriched metabolite sets based on KEGG supported by MetaboAnalyst 5.0 and mapped the metabolites according to chemical and biochemical relationships by MetaMapp [We compared clinical characteristics between responder and non-responder groups by chi-squared test for categorical variables. To explore metabolome distribution by groups, we performed principal component analysis with Pareto-scaled data using MetaboAnalyst 5.0 . Then, mMetaMapp . MetabolMetaMapp .


The value of cytokines as epithelial ovarian cancer (EOC) prognostic factors has been widely investigated. This study aimed to determine the role of single cytokine as a biomarker prognosis in EOC. We conducted a systematic review and meta-analysis of studies reporting cytokine as the prognostic predictor in EOC based on PRISMA guideline. We included English articles investigating associations of preoperative cytokines level in tissue, blood or ascites with overall survival (OS) or disease-free survival (DFS) from PUBMED and EBSCO. Summary hazard ratios (HRs) and confidence intervals (CIs) were calculated.  Fifty studies investigating twenty types of cytokines in tumor tissue, serum, and ascites from 5,376 patients were included. Pre-operative high VEGF level was associated with poor OS  and DFS  in serum and OS  in tissue. IL-6 level in blood was associated with DFS . There was no single cytokine which investigated by at least 2 studies reporting hazard ratio in ascites, so we did not conduct the meta-analysis. Other cytokines  associated with the poorer prognosis, could not be pooled due to lack of studies.  Pre-operative VEGF level in serum and tissue specimen seem to be the potential candidate of an unfavorable prognostic biomarker for EOC. The evidence was lacking to support the other cytokines investigated in blood, tissue and ascites as prognostic biomarkers for EOC. Ovarian cancer known as a ‘silent lady killer’ due to high mortality and lack of early screening resulting in delayed diagnosis. In the United States, the mortality of ovarian cancer was 6.7 per 100,000 in 2015 . Various strategies in early detection, diagnosis, treatment and prognosis of ovarian cancer have been investigated. Existing treatments of epithelial ovarian cancer (EOC) include surgery and chemotherapy . However, the prognosis of patients who undergo those treatments are poor. The 5-year cause-specific survival of EOC for all stages is 47% . There are many factors affecting survival in EOC, for instance, cancer stage, age at diagnosis, histopathological type, pathological grade, surgical status, residual disease, performance status, and biological factors such as proteins and gene expressions . Prognostic factors may help clinicians in deciding on types of surgery and adjuvant therapies according to individual risks. The role of immunology in ovarian cancer has been investigated in many studies. The competence to predict ovarian cancer cells’ behavior in molecular levels either in blood, tissue or ascites would be beneficial for patients and clinicians in the decision-making process.The tumor micro-environment of ovarian cancer consists of various cells and molecules that promote or suppress tumor cells. In addition to cancer cells, in the microenvironment of ovarian cancer, there are various types of immune and stromal cells, extracellular matrix molecules, cytokines and chemokines . Cytokines are low molecular weight proteins that mediate intracellular communications. Cytokines are produced by tumor cells, immune cells, and stromal cells like fibroblasts and endothelial cells that might be able to regulate proliferation, survival, differentiation, migration and death. The role of cytokines in ovarian cancer pathogenesis has been investigated in many studies. Most cytokines are found in normal ovarian tissue and are also found associated with malignancy in different functions. Cytokines could be anti-tumor cells but on the other hand, they could be tumor promotors. In some studies, several cytokines were found increasing in patients with EOC including Vascular Endothelial Growth Factor (VEGF), Interleukin 6 (IL 6), IL 8, and IL 10. There are many variations in existing studies in terms of the types of cytokines, cut-off level, methods of measurement, and type of specimens used. Many studies regarding the role of cytokines in survival of EOC have been conducted, but there is no systematic review discussing what kind of cytokines in EOCs that affect survival, from what specimens the sample is collected  and what are the most widely used methods.In this study, we conducted a systematic review and meta-analysis of the prognostic roles of cytokines in EOC from published studies. This study was aimed to determine the roles of cytokines in overall survival (OS) and disease-free survival (DFS) of patients with EOC. The secondary aim was to identify the specimens and methodological characteristics used among the studies that may describe variations.Search strategyThis study was conducted based on PRISMA guidelines. We used search terms [(ovary or ovarian) and ] or [“ovarian neoplasms” (MESH)], [“cytokines” or “proinflammatory cytokines” or “anti-inflammatory cytokines” or “chemotactic cytokines” or “proangiogenic cytokines”]. We searched literatures from PUBMED and EBSCO from 1988 up to 2018 as shown in Selection criteriaTypes of studyWe included the following characteristics of studies: full-text original articles published in English, prospective or retrospective cohort or case control studies, investigated association individual cytokines in tissue, blood or ascites with OS or DFS of patients with EOC. We excluded the following studies: letters to the editor, reviews or systematic reviews or meta-analysis, case reports or case series, using cell lines, and those that did not report estimation of the effects .Types of participantWe included patients who undergone primary surgery for EOC. We excluded patients with history of chemotherapy and previous surgery, and patients with co-existing primary malignancy in other organs.Data extraction and study selectionWe independently scanned the titles of articles that we searched to exclude irrelevant studies. We reviewed abstracts of the remaining articles to find the potentially relevant studies and excluded duplicated study. Full-texts of potentially relevant studies were reviewed to be included in this study based on eligibility criteria. We resolved disagreements by discussion and, if required, we involved a third reviewer to make the final decision. The data was extracted from included studies including: first author, year of publication, country, study design, types of cytokines, measurement test methods, sample specimens, sample size, cut-off measurements, methods for determining cut-off, times of follow-up and estimation effect. The endpoints of this study were OS and DFS. Quality assessmentStudy quality was reviewed by two authors. To assess the quality of included study, we used Quality in Prognosis Study (QUIPS) tools. We placed each included study into ‘low’, ‘moderate’ and ‘high’ risk of bias in six domains  as shown in Statistical analysis2>50%. A random effect model was used when significant heterogeneity was observed. Otherwise, a fixed effect model was performed. Publication bias was visually evaluated by using Egger’s and Begg’s tests. The STATA software of version 14.2 was performed by clinical epidemiologist and biostatistician in meta-analysis to get the value of pooled hazard ratio of cytokine level in EOC. There were pooled hazard ratio with 95% confidence intervals. Significant heterogeneity was indicated by IA total of 11,369 publications were obtained from PUBMED and EBSCO using our search method. After reviewing the titles and abstracts, we excluded 11,120 citations for several reasons including study design , non-English languages, and inappropriate topics. From the number of citations, we reviewed the full text and finally included 249 studies that investigated the prognostic role of cytokines as biomarkers for ovarian cancer. After a deep review, 199 full text studies were excluded for some reasons including patients with mixed epithelial and non-epithelial types, did not have survival analysis and investigated mixed with recurrent ovarian cancer. There were 50 studies which matched the inclusion and exclusion criteria of this study (Suppl 1).Fifty studies analyzed the role of various cytokines as prognostic factors of epithelial ovarian cancer. The studies were conducted in European countries (24 studies), and Asian countries (15 studies). One study was a multicenter study with subjects collected in United States, Japan, and United Kingdom . Fifteen studies investigated serum cytokines’ level (Suppl 2), 28 studies sought for cytokines’ expression in ovarian tissues (Suppl 3), while 9 studies measured cytokines’ level in ascites fluid (Suppl 4).Study designFifty studies investigated more than 20 types of cytokines , TGF-β1, Colony Stimulating Factor-1 (CSF-1), Interferon-alpha (IFN-α), IFN- γ and Tumor Growth Factor-alpha (TNF-α). All of the studies used cohort design to assess the prognostic values of each of the cytokines, and 16 of them were retrospective study. Only five studies focused on advanced stage ovarian cancer . We know that some study groups shared the same sample, but it was difficult to determine whether a number of samples were taken from the same sample banks or from the fresh subjects. Sample sizeSample size was varied from 37 up to 320 participants among studies. The total number of participants in this review were 5,376. Twelve studies did not include control groups. The rest of them involved either normal or benign, or borderline ovarian tumor as control groups.Measurement methodsImmunohistochemistry staining on paraffin-embedded was the most commonly used method in tissue. To evaluate the staining of epithelial cells, the studies used quantitative, qualitative, or semi-quantitative scoring methods. The scoring system was varied among studies.Nine studies in serum used Enzyme-linked immunosorbent assays (ELISA) as measurement tools. Two studies utilized sandwich enzyme immune-assay technique to quantify serum VEGF-C levels . One study uses western blot method to measure VEGF-A, VEGF-D, and VEGF-C level in serum . Two studies used commercially available multiple panel cytokines assay which was based on sandwich immunoassay to simultaneously investigate various cytokines in a single sample . Studies measuring cytokine level in ascites commonly utilized ELISA method, while four study used sandwich immunoassay  and commercially available multiple panel cytokines assay . Cytokines level in serum and prognosis of EOC2 = <50%) showed a variation of homogeneous research. There were wide ranges of cut-off value, from 171 pg/mL  up to 10.200 pg/mL . Most of the cut-off values were defined from median values, and the remaining were based on 95% percentile , 75% quartile , and taken from previous studies . There were two cytokines commonly investigated in serum, VEGF and IL-6. Nine studies reviewed the association between serum VEGF and EOC prognosis. Two studies investigated VEGF-C , one study researched about VEGF-165 , an another six studies reviewed VEGF (VEGF-A). All of those study consistently showed that higher levels of VEGF were associated with poor OS, except for one study which stated that preoperative VEGF levels were not associated with OS . All of the four studies assessing DFS or recurrence-free survival (RFS) showed that higher VEGF level was associated with poor prognosis. In this meta-analysis, high VEGF level was associated with poor OS  and DFS  as shown in 2 = <50%) showed a variation of homogeneous research. Three of those studies , showed significant association between high level of IL-6 and poor OS, while one of them  showed no significant association. Two studies revealed significant association between higher blood IL-6 with shorter progression and DFS, while one study showed no significant association . Cut-off value was varied from 0.7 pg/mL  to 24 pg/mL . One study investigated the association of serum IL-8 level and OS and found that more than 59 pg/mL serum IL-8 level was related to worse OS . Five studies investigated blood IL-6 level as a prognostic factor of EOC. There was an association between IL-6 level in blood for DFS  as shown in Cytokines expression in tissue and prognosis of EOC2 = >50%) showed a variation of heterogeneous research. Eleven studies (58%) found that higher expression of VEGF was correlated with shorter OS . One study found that expression of VEGF-C and VEGF-R2 were associated with poor OS while VEGF-A and VEGF-R3 expressions were not significantly associated . The study performed by Yokoyama found that positive VEGF-D was associated with reduced 10-years survival rates, while positive VEGF-C and VEGFR-3 were not significantly associated with 10-years survival . Another five studies showed no significant effect of VEGF expression on OS. In contrast, only two studies showed that higher VEGF expression were associated with prolonged OS . Fourteen studies investigated PFS of the patients with VEGF expression of ovarian tissue. Six of them found that positive VEGF expression significantly reduced PFS . Two studies showed improvement of PFS in tissue with positive VEGF expression . Another six studies showed no significant association between VEGF expression with prognosis related to PFS.Twenty-four studies reviewed VEGF and the isoforms . Twenty studies investigated VEGF (VEGF-A), while the rest of them studied VEGF-B (1 study), VEGF-C (4 studies), and VEGF-D (1 study). Nineteen of them analyzed their effect on OS, while 14 of them analyzed the DFS or progression free survival (PFS). As shown in Another five studies investigating six different cytokines found expression of some cytokines were correlated with prognosis. Expressions of IL-17 and TGF-β were correlated with better RFS . Expressions of TGF-β1 and CSF-1 were associated with poor OS and DFS, respectively . Expressions of IL-10 and IL-6 in ovarian tissue were not significantly correlated to OS .Cytokines level in ascites and prognosis of EOCFourteen studies assessed the association between cytokines level in ascites and prognosis of EOC. Four of them were studies of IL-6, three studies of IL-10, three studies of VEGF, one study of IFN-γ, two studies of TNF-α, and one study of IL-8.We did not conduct a meta-analysis in ascites due to there was no cytokine that investigated by at least 2 studies reporting hazard ratio. Two studies investigating IL-6 showed shortened PFS in patients with higher IL-6 levels . Kolomeyevskaya et al. found that Il-6 level in ascites level was not independently correlated to PFS and OS . Meanwhile, if high IL-6 level (>4741.6 pg/ml) was combined with higher TNF-α (>38.5 pg/m), they give shorter PFS . Only one study investigating IL-10 found that higher level of ascites IL-10 serum was associated with poor PFS, while another two studies showed no significant correlation. Two studies reviewed the correlation of VEGF (VEGF-A) and prognosis, while one study reviewed VEGF-C. VEGF level in ascites fluid consistently correlated to poor prognosis. One of three studies reviewing ascites’ VEGF found that increasing level of VEGF-C was associated with shorter OS , while the other study showed that high VEGF-A level was associated with shorter PFS . Another study showed that VEGF level higher than 2575 pg/mL was associated with significantly shorter OS and PFS . Some studies analyzed the correlation between VEGF expression and tumor stage, which showed that positive or high VEGF expression was correlated with advanced stage tumor, however, this correlation was not consistently significant.Study about IFN-γ in ascites found that higher IFN-γ was correlated with reduction of both OS and PFS . The same correlation was found in IL-8 and TNF-α .Publication BiasAs shown in In this study, we conducted a systematic review and meta-analysis of the cytokines as prognostic biomarkers in EOC. We found that significant association between high VEGF level in serum with poor OS and DFS. In tissue high VEGF level was correlated with OS but not in DFS. This finding indicates that VEGF has a role in carcinogenesis and progression of disease in EOC. High VEGF level in serum could be a potential biomarker of prognosis. VEGF family consists of seven isoforms; VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and Placental Growth Factor (PIGF) . The main isoform which is important for angiogenesis is VEGF-A and is simply referred to as VEGF .Preclinical experiments have shown that overexpression of VEGF can convert normal ovarian epithelium into neoplastic tissue which produces ascites. VEGF expression in omental metastases, cysts fluid, ascitic fluids and blood of EOC patients indicate the role of VEGF in the process of carcinogenesis. In addition, overexpression of VEGF receptors and co-receptors has been found in ovarian cancer . VEGF and Platelet Derived Growth Factor (PDGF) are secreted by cancer cells. These factors activate endothelial cells, thus causing the formation of new blood vessels to initiate angiogenesis . The newly formed vessels infiltrate tumor mass in the local tumor microenvironment and promote tumor mass expansion, and subsequent hematogenous metastasis spread, thereby contributing to cancer progression . VEGF ligands bind various tyrosine kinases and non-tyrosine kinase receptors involved in cancer development . Binding of the ligand to the receptor induces receptor dimerization that leads to the initiation of intracellular signaling .VEGF derived from ovarian cancer cells increases the regulation of angiopoietin 2 in host endothelial cells and induces paracrine remodeling of the host blood vessels to support angiogenesis during tumor growth. VEGF secretion can activate the Akt1 and Akt3 pathways, two downstream effectors of PI3K signaling pathways. Akt1 and Akt3 have their important role in ovarian carcinogenesis. In ovarian cancer there is an increase in tumor growth through the autocrine loop mechanism by the expression of VEGFR-2 in cancer cells along with VEGF .VEGF has an important role in the aggressiveness and metastasis by directly stimulating proliferation, survival, and/or migration of tumor cells, producing blood vessels, forming ascitic fluid and producing matrix which are important for tumor blood supply. The role of VEGF-VEGFR in invasion and migration of ovarian cancer is proven in vitro through the secretion and activation of Matrix Metalloproteinase-2 (MMP-2), MMP-7, MMP-9 and urokinase type plasminogen activators. VEGF contributes to intraperitoneal spread of ovarian cancer by promoting neovascularization and increasing vascular permeability leading to subsequent growth of intraperitoneal tumors, development of peritoneal carcinomatosis, and formation of malignant ascites. The role of VEGF in peritoneal metastasis of ovarian cancer has been explored by different researchers. Increased ascites accumulation is not only caused by tumor growth through stimulation of angiogenesis but also directly through its ability to increase permeability of peritoneal blood vessels. Intraperitoneal carcinomatosis has components that depend on the presence of the angiogenesis process needed by solid tumors for neovascularization to grow larger and have components that do not depend on angiogenesis such as thin layers of tumors and some small solid tumors that survive through passive diffusion of nutrients from the host blood vessels and fluid in the peritoneum around it .The wide range of cut-off values of VEGF levels among the studies can be caused by various factors, such as host factors , samples collection, methods and duration of storage, and measurement tools. In tissue specimens, eleven studies found that high VEGF expressions were associated with poor OS. Expression of VEGF in cancer tissue was not consistently correlated to PFS. While 22 studies revealed tissue VEGF expression as a poor prognostic factor for survival, two studies found the contrasting results. Ogawa showed correlation between higher VEGF expression and improvement of PFS, but it was only significant for early stage cancer. The author explained that heterogeneity in most of the slides was the reason for this paradoxical result . Engel said that positive correlation between positive VEGF and prolonged PFS was due to increased vessel permeability effect of VEGF, thus improving drug delivery to tumor tissue . However, there is no scientific evidence of such mechanisms.Although there were three studies investigating the significant correlation between high VEGF level and poor prognosis, but could not be analyzed in meta-analysis because only one study reporting the hazard ratio. Some studies in ascites specimen analyzed the correlation between VEGF expression and tumor stage, which showed that positive or high VEGF expression was correlated with advanced stage tumor, however, this correlation was not consistently significant. In this systematic review, the other cytokine that was most commonly studied, in addition to VEGF, is IL-6. In meta-analysis, two studies showed that serum IL-6 were associated with DFS. More studies with larger sample size and multivariate analysis are required to determine the role of IL-6 in EOC prognosis.We found that some other cytokines such as serum IL-8, ascites fluid IFN-γ and TNF-α; and ovarian tissue TGF-α, CSF-1, and TGF-β1 were associated with poorer prognosis of EOC, but only seven studies investigated those correlations. Therefore, we can conclude that, the evidence was limited and not sufficient to determine the prognostic value of those biomarkers.Based on this systematic review and meta-analysis, we conclude that VEGF level could be potential candidate biomarkers of OS and DFS in serum and OS in tissue. We recommend that a multicenter, high quality study of serum VEGF with larger sample sizes should be conducted. It should involve a uniform, standardized method of cytokine measurement and include adequate follow-up duration to determine the cut-off value of VEGF to differentiate EOC patients with good or bad prognosis. Another study is expected to find out whether serum VEGF is useful in chemotherapy response follow-up, like the widely-used Ca-125, and in measuring patient response to targeted therapy such as bevacizumab.In conclusion, pre-operative serum VEGF level in serum and tissue specimen seem to be a potential candidate of an unfavorable prognostic biomarker for epithelial ovarian cancer. The evidence was lacking to support the other cytokines investigated in blood, tissue and ascites as prognostic biomarkers for epithelial ovarian cancer.


Number of ASMs at the time of CC and post-VNS were significantly associated with responders in univariate analyses , whereas age, sex, seizure frequency, and addition of novel ASMs were not. In multivariate analysis, the presence of VNS procedures after CC was the only factor favorably associated with responder status . Conclusions: VNS therapy after CC may increase the proportion of responders independent of the addition of novel ASMs.Objective: The effectiveness of vagus nerve stimulation (VNS) for residual seizures after corpus callosotomy (CC) has not yet been fully investigated. We hypothesized that seizure control would be improved by VNS after CC. The purpose of this study was to compare seizure frequency between patients with implantation of a VNS generator (post-VNS group) or without VNS (non-post-VNS group) following CC. Methods: We retrospectively reviewed patients who underwent CC between January 2009 and May 2019 in our institution. We evaluated proportions of ≥50% reduction in seizure frequency (responders) and seizure reduction rate 1 and 2 years after VNS. To investigate factors related to responders, uni- and multivariate logistic regression analyses were performed regarding age, number of anti-seizure medications (ASMs), addition of novel ASMs , and post-VNS or non-post-VNS status. Results: Thirteen post-VNS patients and 24 non-post-VNS patients were analyzed in this study. Responder rate at 1 year after VNS differed significantly between the post-VNS group (53.9%) and non-post-VNS group (12.5%,  Palliative techniques such as corpus callosotomy (CC) and vagus nerve stimulation (VNS) can be considered for patients with drug-resistant epilepsy who are not candidates for resective surgery. Satisfactory efficacy of both techniques for drug-resistant epilepsy has been demonstrated, with the proportion of a ≥50% reduction in seizure frequency reported as 40–70% for VNS ,3,4,5,6 Patients may undergo CC first and achieve no favorable improvement of seizures, but may then receive VNS as additional surgery. However, only two reports have described outcomes of additional VNS therapy after CC, suggesting that the implantation of VNS after CC for patients with Lennox-Gastaut syndrome (LGS) induced a ≥50% reduction in seizure frequency in 57–60% of patients .However, no case-control studies appear to have compared patients who received VNS implantation after CC with those who underwent CC alone. Since novel anti-seizure medications (ASMs) have appeared one after another over the last two decades, the effects of novel ASMs need to be taken into account to more accurately compare the outcomes of VNS and CC. In Japan, levetiracetam (LEV), perampanel (PER), and lacosamide (LCM) became available clinically from September 2010, May 2016, and July 2016, respectively. Case-control studies comparing outcomes from patients with VNS to those for patients without VNS after CC without bias from these new ASMs appear to be required.The present study retrospectively reviewed patients who did and did not receive implantation of VNS after CC, investigating the efficacy of additional VNS after CC as the purpose of this study. We hypothesized that the addition of VNS therapy after CC could induce more favorable improvement of seizures than CC without addition.This study was a single-site, retrospective investigation conducted in Japan. The Ethics Committee of Seirei Hamamatsu General Hospital approved the protocol for this study , which was performed in accordance with the principles of the Declaration of Helsinki. Participants in this study were identified via a retrospective study of patients treated at the Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital. Written informed consent was obtained from all patients. Written informed consent for publication of data pertaining to participants under the age of 19 years was obtained from the patients’ guardians.We reviewed the data for patients with refractory epilepsy who underwent CC between January 2009 and May 2019 in our institution. We then compared patients implanted with a VNS generator after CC (post-VNS group) to patients not implanted with a VNS generator after CC (non-post-VNS group). The inclusion criterion was patients with poor outcomes after CC {International League Against Epilepsy (ILAE) classification 4–6} . ExclusiAs demographic data, we reviewed age at epilepsy onset and at the time of CC, sex, epilepsy syndromes such as West syndrome or LGS, number and type of ASMs at the time of CC and VNS therapy, seizure type at the time of CC, seizure frequency at the time of CC, extent of CC , and model of VNS generator implanted. We divided seizure frequency into daily (≥1 seizure/day), weekly (≥1 seizure/week but <1 seizure/day), monthly (≥1 seizure/month but <1 seizure/week), and yearly (≥1 seizure/year but <1 seizure/month).® System; Cyberonics, Houston, TX, USA) until August 2014 and also using the 105 Aspire HC  after August 2014 and the 106 Aspire SR  after August 2018. The device was activated 2–3 weeks after implantation of VNS. We increased the current output (0.25 mA at once) or duty cycle (<10% at once) at each visit until optimal seizure reduction was obtained.We performed VNS therapies using only a 103 Demipulse VNS generator  from start point to outcome point, and post-VNS or non-post-VNS group. To investigate the presence or absence of addition of novel ASMs, we reviewed the number and type of ASMs at both start and outcome points.χ2 test to compare categorical variables, or Fisher’s exact test when the sample size was small. Student’s t-test or the Mann–Whitney U test was used to compare continuous variables. Two-sided p-values < 0.05 were considered statistically significant.We used the To show factors associated with responder status, we used logistic regression analysis with adjustment for age, sex, number of ASMs, addition of novel ASMs from start point to outcome point, and post-VNS or non-post-VNS group.In this study, VNS treatment affected prognosis in both uni- and multivariate analyses. However, since the sample size was not sufficiently large, statistical power was lacking for multivariate analysis.All statistical analyses were performed using Stata/SE 14.0 .We performed CC for 84 patients in our institution between January 2009 and May 2019. We identified 16 patients who had undergone VNS therapy following CC in our institution and 68 patients who had not undergone VNS therapy after CC. Among these, 13 patients in the post-VNS group and 24 patients in the non-post-VNS group met the criteria. The mean interval from CC to VNS in the post-VNS group was 26.9 ± 34.9 months.p = 0.04).Eleven of 13 patients (84.6%) in the post-VNS group and 13 of 24 patients (54.2%) in the non-post-VNS group were male. Median age at onset of epilepsy was 2 years in the post-VNS group and 1.5 years in the non-post-VNS group. Median age at the time of CC was 8 years in the post-VNS group and 18 years in the non-post-VNS group. The number of ASMs just before CC was significantly lower in the post-VNS group (3.0 ± 0.20) than in the non-post-VNS group , but seizure frequency at the start point differed significantly between groups .Seizure frequency before CC did not differ significantly between post-VNS and non-post-VNS groups . The proportion of responders from start point to 2 years after the start point was similar between groups .The proportion of responders from start point to 1 year after the start point differed significantly between the post-VNS and non-post-VNS groups . The seizure reduction rate in the non-post-VNS group increased significantly from 1 year to 2 years after start point  at 2 years after start point, p = 0.0268).The seizure reduction rate in the post-VNS group decreased from 1 year to 2 years after VNS, but this difference was not significant . Age at time of CC, sex, seizure frequency at start point, and addition of novel ASMs were not significantly associated with responder status. In multivariate analysis, the presence or absence of post-VNS was the only factor significantly correlated with responders .Preoperative predictors related to responders were analyzed using uni- and multivariate logistic regression analyses . The numThis study investigated the effects of additional VNS after CC, comparing patients who received VNS after CC with those who did not. This study revealed that additional VNS after CC significantly increased the proportion of patients showing a ≥50% reduction in seizure frequency at 1 year after VNS regardless of the addition of novel ASMs. The results of this retrospective case-control study supported our hypothesis that the addition of VNS therapy after CC could induce more favorable improvement of seizures than CC without additional VNS.Two non-comparative studies have investigated the outcomes of VNS after CC for patients with LGS showed favorable results with a responder rate at 1 year after VNS of 57–60% . Similarp = 0.033), although responder rates at 1 and 2 years after VNS were similar in both groups. The efficacy of VNS may not improve over time for patients who have already undergone other epilepsy surgeries, including CC, and thus may not obtain favorable improvement of seizures, because such patients are likely to have more refractory epilepsy.In this study, the responder rate at 2 years after VNS was less than at 1 year after VNS, although some authors have documented VNS efficacy improving over time ,8,19. KaWe compared patients who underwent VNS after CC (post-VNS) with those who did not (non-post-VNS) and used multivariate analysis to eliminate the seizure-reducing effects of novel ASMs. Many reports have examined the efficacy of novel ASMs for refractory epilepsy. The ≥50% reduction rate was reported as 39–58% with LEV ,21, 35.7On the other hand, the responder rate at 1 year after VNS in the post-VNS group was 53.85%, significantly higher than that in the non-post VNS group. In both groups, we had prescribed optimal ASMs for each outpatient. Furthermore, multivariate logistic regression analysis revealed that the addition of VNS after CC was the only factor significantly correlating with responder status, whereas addition of novel ASMs was not. The present study therefore revealed that VNS therapy for patients who had no favorable improvement of seizures after CC could significantly increase the frequency of achieving responder status, independent of the addition of novel ASMs such as LEV, LCM, or PER.Several limitations to the present study must be acknowledged. First, this study was a retrospective observational study at a single facility. Patients with more refractory epilepsy might have been included in the non-post-VNS group rather than the post-VNS group, although patient characteristics other than seizure frequency at the start point were similar between groups. Second, this study included only a small sample. The small number of patients with addition of novel ASMs may have been associated with the result that the addition of novel ASMs could not significantly increase the frequency of responders according to logistic regression analysis. Third, half of the non-post VNS group had already received VNS therapy before CC. This may have led to an increase in patients with more intractable epilepsy in non-post VNS. To address these potential sources of bias, prospective registry studies or larger population-based studies across multiple institutions are needed to increase the generalizability of the study results.Addition of VNS therapy to patients who could not obtain adequate seizure control after CC may increase the proportion of responders showing a ≥50% reduction in seizure frequency independent of the addition of novel ASMs. Given the present results, prospective and multicenter studies appear warranted.


A substantial reduction in self-harm recorded in primary care occurred during the first wave of COVID-19 but effects on primary care management of self-harm are unknown. Our objectives were to examine the impact of COVID-19 on clinical management within 3 months of an episode of self-harm.Retrospective cohort study.UK primary care.4238 patients with an index episode of self-harm recorded in UK primary care during the COVID-19 first-wave period (10 March 2020–10 June 2020) compared with 48 739 patients in a prepandemic comparison period .Using data from the UK Clinical Practice Research Datalink, we compared cohorts of patients with an index self-harm episode recorded during the prepandemic period versus the COVID-19 first-wave period. Patients were followed up for 3 months to capture subsequent general practitioner (GP)/practice nurse consultation, referral to mental health services and psychotropic medication prescribing. We examined differences by gender, age group and Index of Multiple Deprivation quintile.Likelihood of having at least one GP/practice nurse consultation was broadly similar (83.2% vs 80.3% in the COVID-19 cohort). The proportion of patients referred to mental health services in the COVID-19 cohort (4.2%) was around two-thirds of that in the prepandemic cohort (6.1%). Similar proportions were prescribed psychotropic medication within 3 months in the prepandemic (54.0%) and COVID-19 first-wave (54.9%) cohorts.Despite the challenges experienced by primary healthcare teams during the initial COVID-19 wave, prescribing and consultation patterns following self-harm were broadly similar to prepandemic levels. We found no evidence of widening of digital exclusion in terms of access to remote consultations. However, the reduced likelihood of referral to mental health services warrants attention. Accessible outpatient and community services for people who have self-harmed are required as the COVID-19 crisis recedes and the population faces new challenges to mental health. First study examining effects of COVID-19 on primary care management following self-harm in the UK.Findings are based on a large number of general practices across the UK, using data from the Clinical Practice Research Datalink.Data broadly representative of geographical coverage, area-level deprivation, age and sex in England.Data accuracy is determined by the quality of the information inputted by contributing practices.Prompt clinical intervention and follow-up is recommended for people who have recently self-harmed, in part due to their increased risks of suicide.In April 2020, during the first UK COVID-19 lockdown, rates of primary care-recorded incident self-harm in the UK were 38% lower than expected based on trends that occurred during the previous 10 years.9Primary care settings provide vital support for people who have self-harmed. A recent study found that 26% of people sought help from their general practitioner (GP) in the week prior to suicide, with self-harm a common reason for contact.13It is unknown how clinical management following self-harm has been affected by the COVID-19 pandemic. Although GPs continued to offer consultations to patients throughout the first wave in the spring of 2020, with most consultations taking place remotely,16In the UK, a nationwide lockdown was imposed on 23 March 2020, with public health messaging to encourage people to avoid contact with others announced the week before this.Identify two cohorts of patients presenting with an index episode of self-harm, comprising prepandemic versus COVID-19 first-wave time periods.Estimate the probabilities (%) of receiving a new psychotropic medication prescription (by drug type), frequency of subsequent GP or practice nurse consultations, and referral to mental health services within 3 months of the index self-harm episode.Estimate ratios comparing probabilities of psychotropic medication prescribing, referral to mental health services and GP or practice nurse consultation (by face to face and telephone) within 3 months of the index episode, between the COVID-19 and prepandemic comparison cohorts.We conducted a cohort study using anonymised primary care data from the Clinical Practice Research Datalink (CPRD) Aurum and GOLD databases.Analysis was conducted on pooled Aurum and GOLD data. We compared two cohorts of patients: (1) those with an index self-harm episode recorded in a prepandemic comparison period  and those with an index self-harm episode recorded in the COVID-19 first-wave period (10 March 2020–10 June 2020). Patients in each cohort were followed up for 3 months to capture psychotropic medication prescribing, referral to mental health services and GP or practice nurse consultations. To be included in either of the two study cohorts, patients must have been aged 10 years or older and registered with a contributing practice, deemed by the CPRD as providing up-to-standard data, for at least 1 year prior to the date of the index self-harm episode. Patients with less than 3 months of follow-up time in the CPRD were excluded from our analyses. The cohorts were restricted to patients with records that were deemed acceptable by the CPRD for research purposes, which excluded patients with missing data on sex or age. IMD data were missing for 9.2% of the prepandemic comparison cohort and 10.3% of the COVID-19 first-wave cohort . In termhttps://clinicalcodes.rss.mhs.man.ac.uk/medcodes/article/173/). Mode of consultation was grouped into face-to-face and video/telephone consultations, with a GP or practice nurse. Information on referral to mental health services were identified using two CPRD fields: a ‘psychiatry’ code in the Family Health Services Authority (FHSA) specialty variable and codes of ‘mental illness’, ‘child and adolescent psychiatry’, ‘forensic psychiatry’, ‘psychotherapy’, ‘old age psychiatry’, ‘clinical psychology’, ‘adult psychiatry’ and ‘community psychiatric nurse’ in the NHS specialty field.https://clinicalcodes.rss.mhs.man.ac.uk/medcodes/article/173/). We examined frequencies and rate ratios between the prepandemic and COVID-19 first-wave cohorts by the following covariates: gender, age group  and practice-level IMD quintile. Subgroup categories were derived to avoid reporting cell counts less than 10; if cell counts were found to be less than 10, subgroups were collapsed.Index episodes of self-harm were identified from Read, SNOMED and EMIS codes: SNOMED CTFrequencies and probabilities of GP/nurse consultation, referral to mental health services and psychotropic medication prescribing during the antecedent period were estimated and compared with observed values during the COVID-19 first-wave period. The modelling was conducted using modified Poisson regression in a generalised linear modelling framework with a log-link function and a robust variance estimator with analyses stratified by gender, age group and practice-level IMD quintile. This study was conducted in accordance with REporting of studies Conducted using Observational Routinely collected health Data guidance  than in the prepandemic comparison cohort  . AlthougOverall, 4.2% of patients (179/4238) were referred to mental health services in the COVID-19 first-wave cohort, a significant reduction vs the probability observed in the prepandemic comparison cohort  . The redJust over half of patients in the prepandemic (54.0%) and COVID-19 first-wave (54.9%) cohorts were prescribed psychotropic medication within 3 months of the index self-harm episode . The likPrepandemic and COVID-19 first-wave cohorts of patients with an index episode of self-harm recorded in primary care had similar gender, age and deprivation profiles. Similar proportions were prescribed psychotropic medication within 3 months of their index self-harm episode—just over half in both the prepandemic and COVID-19 first-wave cohorts. However, patients aged 10–24 years in the COVID-19 first-wave cohort were more likely to be prescribed psychotropic medication than in the preceding years. Overall, the likelihood of having at least one GP/practice nurse consultation was slightly lower in the COVID-19 first-wave cohort, although there was no such difference observed among men, patients aged 65 years and over, and those registered with practices located in more deprived areas. Patients in more deprived practice populations who had harmed themselves were just as likely to consult face to face or remotely with a GP or a practice nurse than those in less deprived populations. The proportion of patients referred to mental health services in the COVID-19 first-wave cohort was around two-thirds of that in the prepandemic comparison cohort.The main strength of our study is the broadly representative data source that included a large number of general practices across the UK. CPRD Aurum is broadly representative of geographical coverage, area-level deprivation, age and sex in EnglandPrevious research found that reductions in help-seeking were greatest among patients registered at practices located in more deprived areas.Likelihood of referral to NHS mental health services was lower during the first wave of COVID-19 than during the prepandemic comparison period, particularly for patients aged under 65 years. Younger people have been found to have been particularly negatively affected by the pandemic. Individuals aged 18–29 years reported greater increases in suicidal ideation over the first 6 weeks of the UK’s lockdown than other groups,4Evidence shows the number of people seeking mental health help, including for self-harm, from non-NHS services such as via digital platforms and helplines increased during the second quarter of 2020.Data from NHS DigitalDespite the challenges experienced by GPs in delivering healthcare during the 3 months of the initial wave of COVID-19 in the UK, the management of self-harm was broadly similar to the prepandemic comparison period in terms of psychotropic prescribing and GP/nurse consultations. We found no evidence of digital exclusion due to socioeconomic influences during the pandemic, in terms of likelihood of remote consultation. However, the reduced likelihood of referral to mental health services during March–June 2020 warrants close attention, particularly in the context of increasing prevalence of mental distress in the population. Our findings suggest that COVID-19 may have increased the likelihood that adolescents and young people do not receive psychosocial interventions, with pharmacological intervention alone becoming more likely during the early phase of the crisis. Accessible outpatient and community services that people who have self-harmed can be referred to by their GPs are required.


This systematic review compares clinical outcomes between platelet-rich plasma (PRP) and corticosteroid injections for the treatment of lumbar spondylosis and sacroiliac arthropathy. A systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the Pubmed, SCOPUS, and Ovid MEDLINE databases. All level I-III evidence comparative studies published in the English language investigating the clinical outcomes between PRP and corticosteroid injections for the treatment of lumbar spondylosis and sacroiliac arthropathy were included. Five studies  were analyzed. One randomized study was level I evidence, two randomized studies were level II, and two non-randomized studies were level III. Final follow-up ranged from six weeks to six months. Four studies found that both PRP and corticosteroid treatment led to a statistically significant reduction in the visual analog scale (VAS). One found that only the PRP group led to a statistically significant reduction in VAS. Three studies found more significant improvements in one or more clinical outcome scores among PRP patients as compared with corticosteroid patients at the three- to six-month follow-up. Two studies found no difference in outcome score improvements between the two groups at six- to 12-week follow-up. There were no reports of major complications. There were no significant differences in minor complication rates between the two groups. In conclusion, both PRP and corticosteroid injections are safe and effective options for the treatment of lumbar spondylosis and sacroiliac arthropathy. There is some evidence that PRP injection is a more effective option at long-term follow-up compared with corticosteroid injection. Further randomized controlled trials with longer-term follow-up are necessary to compare its long-term efficacy. One of the leading causes of disability in the United States is chronic low back pain (CLBP), with nearly an 80% lifetime prevalence -3. Low bIt is important to understand the biology and underpinnings of lumbar spondylosis in order to avoid only temporal, symptomatic relief, i.e., with NSAIDs and steroid injections. Various factors, including apoptosis, collagen abnormalities, ingrowth of the vasculature, and upregulation of matrix collagenases, have been associated with the disc degeneration seen in lumbar spondylosis ,19. In bPlatelet-rich plasma (PRP) is autologous blood that contains platelet concentrations above normal physiological levels, and the injectable solution is obtained by using centrifugation to separate solid and liquid blood components -21. PRP MethodsThis systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 1/11/2020 (Registration ID: CRD42021230383). The authors were unable to identify any similar prior systematic reviews or meta-analyses within the PROSPERO. The search was conducted and reported using the protocol described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines .Two authors conducted separate searches using the following medical databases on January 12, 2020: PubMed (1966-present), SCOPUS (1966-present), and Ovid MEDLINE (1946-present). To ensure a stringent search strategy of relevant literature, keywords including “platelet-rich plasma,” “corticosteroid,” “sacroiliac,” and “spine” were combined with Boolean operators to develop a search protocol. A hand search of the included references was also performed to further minimize the unintentional exclusion of relevant studies.All Level I, II, and III evidence (as defined by the Oxford Centre for Evidence-Based Medicine (CEBM)) therapeutic studies published in the English language that investigated clinical outcomes between PRP and corticosteroid injections for spinal pathologies were included .Studies were excluded if they were studies of non-spinal pathology, non-comparative studies (i.e. only one treatment method studied), cadaveric studies, basic science studies, animal studies, diagnostic studies, economic studies, prognostic studies, letters to editors, review articles, editorials, and surveys. In the situation of duplicate studies from the same author(s) and/or institution(s) reporting on the same or overlapping subjects, only one study was retained: the highest level of evidence, the largest number of subjects, the longest follow-up, and the most pertinent primary outcome score (or relevant secondary). The others were excluded Figure .https://automeris.io/WebPlotDigitizer) was utilized to best estimate the reported data using prior described methods [Two authors independently reviewed all studies using the previously recommended methodology . If two  methods -32. If t methods .Data analysis was performed using the Statistical Package for the Social Sciences (SPSS) statistical software . A two-tailed student t-test was used to analyze continuous data and the chi-square test was used to analyze categorical data. A p-value of ≤0.05 was considered statistically significant.Two authors used the Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2) and the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) assessment tool to perform a risk-of-bias assessment of each included study -35.ResultsThree-hundred and thirty-four studies were identified during the preliminary search, with 47 found to be duplicates. Of the remaining 287 studies, five met all inclusion and exclusion criteria Figure .One randomized study was level I evidence, two randomized studies were level II, and two non-randomized studies were level III. According to MCMS, two studies were rated as good (scores between 70 and 84) and three studies were rated as fair (scores between 55 and 69) . The ovePRP was obtained in all studies by centrifugation of 30 to 200 mL of autologous blood to perform image-guided injections of 0.5 to 16.5 mL of PRP into the target site (Table Five studies containing 112 PRP patients (98.2%) and 125 corticosteroid patients (97.7%) were available at a final follow-up range of six weeks to six months Table . All fivThere were no major complications across all five studies Table . Three sDiscussionThe authors hypothesized that PRP injection is more effective than corticosteroid injection for the treatment of lumbar spondylosis and sacroiliac arthropathy with a similar safety profile. The first hypothesis was partially disproven as two of the five analyzed studies reported equal effectiveness between PRP and corticosteroid injections in treating pain related to lumbar spondylosis and sacroiliac arthropathy. However, three of the five studies reported more significant improvements in several pain and functional scores among patients receiving PRP as compared to corticosteroid injections at long-term follow-ups. The second hypothesis was confirmed, as both PRP and corticosteroid injections were both noted to be safe with no significant difference in major or minor complication rates between the groups.To our knowledge, this is the first systematic review in the current literature assessing clinical outcomes between PRP and corticosteroid injections for the treatment of lumbar spondylosis and sacroiliac arthropathy. Although prior systematic reviews and meta-analyses have measured the potency of PRP for pain treatment in lumbar spondylosis and sacroiliac arthropathy, the majority of articles included in these studies were non-comparative in nature -24,41. IPRP has previously been shown as an effective treatment in tendinopathies, including patellar, Achilles, and humeral epicondyle conditions, as well as degenerative disc disease (DDD) . In a reAll five studies reported VAS as an outcome score, and three of these five studies reported a significant improvement in VAS among the PRP groups compared with the corticosteroid group showing significant improvements in VAS scores at long-term follow-up -38. The The study by Hagg et al., using a cohort of 289 patients with chronic low back pain, suggests the MCID for VAS to be at least greater than 2.0 . An addiWhen considering the treatment of lumbar spondylosis and sacroiliac arthropathy, treatments can be categorized into non-operative and operative. Non-operative treatments for clinical pain syndromes related to CLBP include exercise-based therapy and are often used in conjunction with NSAIDs as part of a treatment strategy; however, these options often may not lead to clinically significant benefits and there are renal, cardiac, and gastrointestinal side effects reported with NSAID usage ,12,13,47This systematic review has several limitations. First, the included studies analyzed a variety of spinal pathologies including sacroiliac arthropathy. However, to our knowledge, this is the first systematic review that comprehensively assesses all comparative studies that analyze PRP versus corticosteroid injection in the spine. Additionally, although we used high-quality comparative studies in this review, only one was of level I evidence. Lastly, it is possible that our stringent search protocol and limiters may have excluded other relevant studies on this topic, including those published in the non-English language.Both PRP and corticosteroid injections are safe and effective options for the treatment of lumbar spondylosis and sacroiliac arthropathy. There is some evidence that PRP injection is a more effective option at long-term follow-up as compared with corticosteroid injection. Further randomized controlled trials with longer-term follow-up are necessary to compare its long-term efficacy.