Research On The Association Between Depression And Occurrence And Recurrence Of Hepatocellular Carcinoma

Background:Depression is a mental disorder clinically characterized by recurrent and persistent depressing mood accompanied with physical symptoms.It has been estimated that there are currently 350 million patients with depression worldwide.There were more than 40 million patients with depression in China.The majority of patients are inaccessible to timely medical treatment in time,leading to severe impaired physical and mental health.In recent years,more and more studies have shown that depression is associated with a variety of chronic diseases,including cancer,diabetes,coronary heart disease,stroke,Alzheimer's disease,osteoarthritis,acquired immune deficiency syndrome and etc.The study concerning the correlation between depression and cancer is mainly manifested as:on the one hand,depression increases the risk of certain types of cancers;on the other hand,the accompanied mental disorders,such as depression in cancer patients would generally accelerate disease progression,seriously affecting the life quality of patients.Primary liver cancer,especially hepatocelluar carcinoma(HCC),remains the third leading cause of cancer-related death worldwide,with an extremely high incidence in Asia(including China),certain African countries and regions.Due to the insidious course,long incubation period and rapid growth of HCC,there is great difficulty in early diagnosis,along with poor prognosis following conventional treatment,thereby leading to greatly poor life quality of HCC patients.At present,HCC is considered as a consequence of long-term comprehensive effects of various factors,not only related to viral infection,environmental factors and lifestyle,but also associated with emotional,mental and psychological factors.Of note,the relationship of depression with the progression and prognosis of HCC has gradually become a research hotspot.Therefore,in-depth study and clarification of the relationship of depression with the pathogenesis and recurrence of HCC contribute to the prevention and treatment as well as nursing of HCC.In this study,we would focus on the relationship of depression with the pathogenesis and recurrence of HCC.Firstly,based on evidence-based nursing theory and meta-analysis,we comprehensively explored whether depression affected the risk of HCC.Secondly,we carried out clinical investigation of HCC patients to establish a model for depression risk in HCC patients for clinical psychological nursing work,followed by the utilization of nomogram method for visual prediction.Thirdly,HCC patients were divided into depression and non-depression cohorts,who were followed-up for one year in order to analyze the relationship between depression and recurrence of HCC.Finally,based on the theory of neuroimmunoendocrine system dysfunction of depression and HCC pathogenesis,we intended to detect serum levels of glucocorticoid and cytokine in HCC patients with depression,to further explore the role of glucocorticoids and cytokines in depression and HCC recurrence.Methods:This study has been registered in Clinical Trial Registry:ID#ChiCTR1800016674.The relationship between depression and risk of cancer.Based on the evidence-based nursing theory,the inclusion and exclusion criteria were established according to the principles of PICOS.The Newcastle Ottawa scale was used for quality assessment.Cochrane Library,Web of Science,MEDLINE,PsycINFO,CINAHL and PubMed were used.Articles were published from 1 January 1990 to 30September 2016.The random-effects model was used to calculate the combined effect size.Forest plots,funnel plots,sensitivity analysis,Trim-and-Fill method and Egger regression were used in this meta-analysis.Risk prediction model for depression in HCC patients.Cross-sectional study design was adopted.Patients were diagnosed as a patient with HCC from the First Hospital,the Second Hospital and the Third Hospital of Jilin University.Recruitment,questionnaire survey,medical record information collection and management were completed by doctors and nurses.HAMD,BAI,SSRS,PSQI and NRS were used to evaluate depression,anxiety,social support,sleep quality and pain,respectively.The t test,non-parametric mann-whitney U test,Chi-squared test,Fisher's exact probability test,Logistic regression,nomogram,Bootstrap method,ROC analysis,multiple interpolation method were used in this study.The relationship between depression and HCC recurrence.A prospective cohort study design was used.The patients in this part comes from patients diagnosed with HCC in Chapter 3.Considering the consistency and compliance of treatment regimen.The included patients were received the transcatheter arterial chemoembolization in these hospitals.The recruitment and postoperative treatment were conducted from December 2016 to June 2017.After treatment,patients were followed up regularly every 1 month.The follow-up was performed by a clinician and a nurse.Outcome measures were relapse-free survival and progression-free survival.The data were analyzed by the t test,non-parametric Mann-Whitney U test,Chi-squared test,Fisher's exact probability test,Kaplan-Meier test,Log-rank test,Cox proportional risk model.The role of glucocorticoids and cytokines in depression and HCC recurrence.The research on the levels and diagnostic value of glucocorticoid and cytokines in patients with depression was designed using a cross-sectional study.A total of 89male participants were recruited from June 15,2017 to September 31,2017.Patients with depression and volunteers without depression were recruited at the Changchun Mental Hospital and the Second Hospital of Jilin University.Clinical evaluation and serum sample collection were performed simultaneously.The research on the levels of diagnostic value of serum glucocorticoid and cytokines in the relationship between depression and HCC recurrence was designed using a cohort design.Blood samples were collected by the hospital nurses at 8:00 am.Peripheral blood samples were collected 5 ml.Liquid phase equilibrium competitive radioimmunoassay was used to detect serum glucocorticoids concentrations.Serum cytokines were detected by ELISA.Logistic regression,ROC analysis,nonparametric Bootstrap,nonparametric Kruskal-Wallis variance analysis,Bonferroni post hoc test,and Spearman rho correlation were used for statistical analysis.Results:The relationship between depression and risk of cancer.Based on the theory of evidence-based medicine,a total of 25 articles were finally included through meta-analysis.The average score of assessment of literature quality was 7.56.There was a low but positive correlation between depression and the overall risk of cancer(RR=1.15,95%CI:1.09-1.22).Heterogeneity analysis showed moderate heterogeneity among different studies(I~2=60.8%,p=0.000).In terms of tumor types,the risk of developing HCC in depressed population was 1.20 times higher than that in patients without depression(RR=1.20,95%CI:1.01-1.43;I~2=0.00%).Risk prediction model for depression in HCC patients.In total,269 patients with primary HCC diagnosed from December 2016 to June 2017 were investigated.The assessment of the severity of depression in HCC patients revealed that 134(49.82%)were burdened with depression(HAMD-17?8 points).Multivariate analysis showed that higher education was a protective factor for depression in HCC patients(OR=0.72,95%CI:0.52-0.99).Being aware of having HCC(OR=4.80,95%CI:2.60-8.89),low social support(OR:1.79,95%CI:1.07-2.99),anxiety(OR=2.22,95%CI:1.27-3.89),poor sleep quality(OR=1.05,95%CI:1.00-1.09),pain(OR=1.69,95%CI:1.18-3.15)and liver function score,Child-Pugh(OR=2.09,95%CI:1.39-3.15)might increase the risk of depression in HCC patients.The AUC of the prediction model was 0.828(95%CI:0.78-0.88),with sensitivity,specificity,positive predictive value,negative predictive value being 0.76(95%CI:0.76-0.76),0.81(95%CI:0.81-0.81),0.80(95%CI:0.80-0.70)and 0.77(95%CI:0.77-0.77),respectively.The model showed good discrimination and clinical utility.The relationship between depression and HCC recurrence.A total of 175HCC patients undergoing TACE were enrolled.Among them,92 HCC patients were accompanied with depression,with a detection rate of 52.57%and an average age of57.56±9.53 years old.Male patients accounted for a higher proportion(80.6%).The1-year RFS and PFS were 53.0%and 39.0%,respectively,in the depression group,and 75.0%and 61.3%,respectively,in the control group(p=0.001).Kaplan-Meier curve showed that the survival time in the depression group was significantly shorter than that of the non-depression group(HR=2.52,95%CI:1.38-4.59,p=0.001;HR=2.18,95%CI:1.36-3.49,p=0.001).The mean RFS was 9.15 months(95%CI:8.29-10.61)in the depression group and 11.04 months(95%CI:10.50-11.59)in the control group.The mean PFS was 8.18 months(95%CI:7.30-9.07)in the depression group and 10.39 months in the control group(95%CI:9.72-11.06).Multivariate analysis revealed that depression(HR=1.82,95%CI:1.07-3.12,p=0.028),tumor size(HR=2.50,95%CI:1.30-4.81,p=0.006),liver fibrosis(HR=2.11,95%CI:1.14-3.89,p=0.017)and ALT concentrations(HR=1.01,95%CI:1.00-1.02,p=0.032)were independent risk factors for HCC recurrence.Subgroup analysis showed that in patients in subgroups of younger than 58 years old,male,no history of drinking,hepatitis B positivity,more than three tumors,portal vein embolization,AFP<400 ng/ml,liver function grade A,and C,depression could increase the risk of recurrence.There were statistical differences in subgroup of tumor size.The role of glucocorticoids and cytokines in depression and HCC recurrence.(1)The levels and diagnostic value of glucocorticoid and cytokines in patients with depression.A total of 89 subjects(55 of whom were diagnosed with depression and 34 were not)were enrolled from a psychology hospital and general hospital,followed by evaluation of depression severity and determination of serum glucocorticoid and cytokine levels.As a result,the serum glucocorticoid concentration was higher in the depression group than that in the non-depression group(p?0.05).Meanwhile,all patients were divided into four groups,according to the following criteria:no depression(score less than 8),mild depression(score ranging from 8 to16),moderate depression(score ranging from 17 to 23),and severe depression(score ranging from 17 to 23).Afterwards,the serum concentration of glucocorticoid was analyzed in patients with different degree of depression.As a result,there was statistical significance among the four groups(p?0.001).Hamilton depression rating score(HDRS)was positively correlated with serum glucocorticoid concentration(p?0.001),suggesting a possible association between glucocorticoids and depression.A combined diagnosis of serum glucocorticoid ROC curve analysis showed AUC was(95%CI:0.77-0.94,p?0.01),while the AUC in serum glucocorticoid was 0.82(95%CI:0.73-0.92,p?0.01).The cutoff value was 147?g/dl,indicating that serum glucocorticoid could significantly distinguish between depression and non-depression populations.(2)The levels of diagnostic value of serum glucocorticoid and cytokines in the relationship between depression and HCC recurrence.Glucocorticoid,TNF-?,and IL-6 were statistically different among the four groups(HCC patients without depression or recurrence,HCC patients with recurrence,HCC patients with depression,and HCC patients with both depression and recurrence).By pair-wise comparison,the serum glucocorticoid levels were significantly higher in HCC patients with both depression and recurrence than other three groups.Meanwhile,the serum glucocorticoid levels were significantly decreased in HCC patients without depression or recurrence compared to the other three groups,indicating that serum glucocorticoid elevation may be associated with depression and recurrence of HCC patients.ROC curve analysis revealed that serum GC,TNF-?and IL-6 combined with depression prediction(AUC=0.788)and serum GC(AUC=0.736)showed certain clinical diagnostic value in predicting recurrence in HCC patients.Conclusions:1.Depression may increase the risk of cancer,and depression may increase the risk of HCC,however,with a low degree of association.Multicenter,large-scale,randomized controlled trials and cohort studies are still needed to further confirm the causal association between them.2.In this study,we established an individualized,visualized prediction model for the risk of depression in HCC patients.The model has good clinical application value.Additionally,we demonstrate that this model may help clinicians to conduct psychological assessments and improve patient satisfaction.3.Depression may accelerate the progression and recurrence of HCC.And depression shortens the recurrence time of HCC patients.Further large samples and longer follow-up periods are required to clarify the relationship between depression and cancer development and death.4.Serum glucocorticoids are higher in depression populations than in non-depression populations,with certain diagnostic value.Meanwhile,serum glucocorticoids are positively correlated with the severity of depression.5.Serum glucocorticoids,TNF-?,IL-6 might be intermediates between depression and HCC.Meanwhile,a combination of serum glucocorticoids,TNF-?,IL-6 or serum GC alone is of certain clinical diagnostic value in predicting recurrence of HCC patients.6.Clarifying the association between depression and HCC,and the analysis of the relationship between with the risk factors should be conducive to the effectiveness of nursing staff's psychological care for cancer patients.