Association of depressive symptoms with quality of life and treatment efficacy in patients with intermediate or advanced hepatocellular carcinoma receiving immunotherapy: A prospective cohort study

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This prospective cohort study aims to examine the relationships between depressive symptoms and both quality of life (QoL) and treatment efficacy in patients with intermediate or advanced hepatocellular carcinoma (HCC) who are receiving immunotherapy. Methods A cohort of 156 patients with intermediate or advanced HCC who were receiving immunotherapy was included in the analysis. Depressive symptoms were evaluated utilizing the Patient Health Questionnaire-9 (PHQ-9). The primary outcome was progression-free survival (PFS), whereas the secondary outcomes were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and QoL. Results Nearly half (48.7%) of the patients exhibited depressive symptoms. Over a median follow-up period of 10 months, patients with depressive symptoms had significantly lower PFS (HR 4.31, 95% CI: 2.75–6.76) and significantly shorter OS (HR 5.39, 95% CI: 1.84–15.82). Furthermore, the ORR and DCR were notably lower in patients with depressive symptoms (ORR 10.5% compared with 37.5%; DCR 52.6% compared with 91.2%). QoL scores were significantly lower at all assessed time points for patients with depressive symptoms, indicating worse overall well-being. Conclusions Depression is significantly associated with the efficacy of immunotherapy in HCC patients and is negatively associated with both clinical outcomes and QoL. Addressing mental health is essential for optimizing treatment strategies and improving overall patient outcomes in this population. Depression Advanced liver cancer Immunotherapy Quality of life Prognosis Longitudinal study Figures Figure 1 Figure 2 Figure 3 1 Introduction Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal tumors worldwide and the second leading cause of cancer-related death 1 . In China, the incidence of HCC is particularly high, primarily due to cirrhosis caused by chronic hepatitis B virus (HBV) infection 2 . Since the early stages of HCC are often asymptomatic, most patients are diagnosed at an intermediate or advanced stage 3 . This delayed diagnosis results in missed opportunities for curative surgical treatment and poor responses to radiotherapy and chemotherapy, with a five-year survival rate of only 20% for patients with advanced-stage disease 4 , 5 . In recent years, immune checkpoint inhibitors (ICIs) have emerged as promising treatment options for intermediate to advanced HCC. ICIs work by blocking immune checkpoints, reactivating T cells, and inhibiting tumor growth 6 . This treatment approach is distinguished by its high specificity and relatively fewer side effects than conventional therapies 7 , 8 . ICIs have been shown to be effective at prolonging patient survival and reducing recurrence rates 9 . However, the objective response rate (ORR) remains between 20% and 30%, indicating that many patients do not experience significant clinical benefits from this therapy 10 . Identifying factors that influence the efficacy of ICIs is critical for optimizing HCC treatment strategies 11 . In addition to these biological factors, psychological conditions, particularly depression, have been found to impact the efficacy of immunotherapy. Depression and other negative emotions can suppress immune function, affect the immune microenvironment, and potentially reduce treatment efficacy 12 , 13 . Depression is common among HCC patients and often interferes with immune cells by activating the hypothalamic‒pituitary‒adrenal (HPA) axis, which can hinder treatment success 14 . Research on the impact of depression on immunotherapy outcomes in HCC patients is limited 15 , and most existing studies have focused on other cancers, such as lung cancer and melanoma 16 . Psychological distress can also alter circulating tumor DNA and inflammatory cytokines, impacting the immune response to ICIs 17 . Furthermore, the HPA axis-induced elevation of cortisol has been linked to worse immunotherapy outcomes 18 . Managing both mental and physical health is essential to improving overall treatment outcomes in patients receiving ICIs 19 , 20 . This study was performed to address this gap by using a prospective cohort to further explore the relationships among depression, treatment efficacy, quality of life (QoL), and prognosis. The longitudinal assessment of patient outcomes provides scientific data that can be used to support early screening and intervention strategies, with the goal of improving the effectiveness of immunotherapy and enhancing QoL in HCC patients. 2 Methods 2.1 Study design and patients This study was a prospective cohort study in which patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC who received immunotherapy at Guangxi Medical University Cancer Hospital between January 2022 and July 2023 were initially enrolled. The inclusion criteria were as follows: According to the AASLD diagnostic criteria, HCC was confirmed on the basis of preoperative imaging findings combined with alpha-fetoprotein (AFP) levels, and the patients had no prior history of immunotherapy; age between 18 and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status score of 0–1, a Child‒Pugh score ≤ 7, a Karnofsky performance score (KPS) > 60, an estimated survival time ≥ 6 months, no family history of mental illness, no history of mental disorders, no impaired consciousness, and normal cognitive function. The exclusion criteria were as follows: the presence of other malignancies; a history of tumor-related surgery within the past two months; the concurrent use of herbal medicines with antitumor effects; active or a history of autoimmune diseases with the potential for recurrence; and the discontinuation of subsequent treatments due to severe immune-related adverse events, such as immune-related myocarditis, hepatitis, or colitis. The study was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital (KY2024397) and conformed to the principles in the Declaration of Helsinki. All enrolled patients provided written informed consent. This study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 2.2 Immunotherapy regimens Treatment plans for all patients were evaluated and selected by a minimum of two attending physicians on the basis of the patient's condition. Medication could be discontinued in cases of disease progression or intolerable adverse reactions. The immune checkpoint inhibitors included PD-1 inhibitors such as sintilimab, toripalimab, camrelizumab, pembrolizumab, and nivolumab, which were all administered intravenously at a dosage of 200 mg every three weeks. Additionally, the PD-L1 inhibitor atezolizumab was administered intravenously at a dosage of 1200 mg every three weeks. 2.3 Assessment of depressive symptoms Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), which is recommended for screening for depression in cancer patients 21 . The PHQ-9 has been translated into Chinese and validated in clinical research, demonstrating good reliability and validity, with high internal consistency (Cronbach's α typically ranging from 0.86 to 0.89) and construct validity 22 . The PHQ-9 consists of 9 items, each scored from 0 to 3, resulting in a total score ranging from 0 to 27 23 . A score of 5 or higher indicates the presence of depressive symptoms. In this study, patients were classified into nondepressed (0–4) and depressed (≥ 5) groups on the basis of their PHQ-9 scores. 2.4 Assessment of outcomes and follow-up This study included 156 patients with intermediate or advanced HCC who were receiving immunotherapy. Depressive symptoms were assessed using the PHQ-9. The primary outcome was progression-free survival (PFS). The secondary outcomes were the ORR, disease control rate (DCR), overall survival (OS), and QoL. PFS was defined as the time from the initiation of ICI treatment to disease progression or death. OS was defined as the time from the initiation of ICI treatment to death from any cause. The efficacy of immunotherapy was evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) 24 as follows: complete response (CR) was defined as the disappearance of target lesion enhancement in the arterial phase; partial response (PR) was defined as a ≥ 30% reduction in the diameter of the target lesions; stable disease (SD) was defined as a reduction in target lesion size that did not meet the criterion for PR or a slight increase that did not reach the criterion for progressive disease (PD); and progressive disease (PD) was defined as a ≥ 20% increase in lesion diameter or the appearance of new lesions. The efficacy assessment indicators were as follows: ORR = (CR + PR)/total number of patients × 100%; DCR = (CR + PR + SD)/total number of patients × 100%. QoL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire 25 . The FACT-Hep includes 45 items divided into five subscales: physical well-being; social/family well-being; emotional well-being; functional well-being; and the Hepatobiliary Cancer Subscale (HepCS), which includes 18 items that specifically assess the symptoms of hepatobiliary cancer and treatment side effects. The total score ranges from 0 to 180, with higher scores on all the FACT-Hep subscales indicating better QoL. Following immunotherapy, patients were followed every two months. These follow-up assessments included routine blood tests, liver and kidney function tests, key tumor markers assessments, enhanced abdominal CT or MRI, chest CT, and survival status. QoL assessments were conducted at four time points: baseline (prior to immunotherapy), two months postimmunotherapy, four months postimmunotherapy, and six months postimmunotherapy. The study required each patient to have at least two QoL assessments. The follow-up was completed on December 31, 2023. 2.5 Covariates Baseline characteristics, including sociodemographic and imaging information before immunotherapy, were recorded in electronic case report forms. These characteristics included age, sex, drinking status, income, family history of cancer, family history of diabetes, family history of hypertension; hepatitis B surface antigen, hepatitis C antibody, liver cirrhosis, body mass index, tumor number, tumor size, extrahepatic metastasis, vascular invasion, a-fetoprotein, BCLC stage, targeted therapy regimens, immunotherapy regimens, liver resection, transarterial chemoembolization (TACE), and radiotherapy. Body mass index was calculated as the weight in kilograms divided by the height in meters squared. 2.6 Statistical analysis Continuous data are expressed as the means ± standard deviations (SDs), whereas categorical data are presented as frequencies with percentages. Baseline data were compared between groups on the basis of the presence or absence of depressive symptoms, using an independent sample t test for continuous variables and either the chi-square test or Fisher’s exact test for categorical data. The Kaplan‒Meier method was used to calculate survival rates, and the log-rank test was used for comparisons. A logistic regression model was used to examine the associations of depressive symptoms with the ORR and DCR, and the odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated. A Cox regression model was used to analyze the associations of depressive symptoms with PFS and OS, yielding hazard ratios (HRs) and corresponding 95% CIs. A generalized estimating equation model was used to assess the associations between depression and total QoL scores as well as scores in each dimension. The link function was a Gaussian equation, and the correlation matrix was unstructured. The QoL scores and every QoL dimension score measured at 2, 4, and 6 months postimmunotherapy were compared with those before immunotherapy. Three models were estimated: Model 1 was adjusted for age and sex; Model 2 was adjusted for age, sex, family history of cancer, alcohol consumption, monthly household income, hepatitis C status, diabetes status, hypertension status, hepatitis B status, cirrhosis status, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP levels, and BCLC stage; and Model 3 was adjusted for the variables in Model 2 plus previous liver resection, TACE/HAIC, treatment frequency, and radiotherapy. The data were analyzed using R 4.3.0 software (R Foundation). All hypothesis tests were two-sided, and statistical significance was defined as P < 0.05. 3 Results 3.1 Baseline characteristics At baseline, 256 patients with HCC were assessed. Of these, 52 patients were excluded because they did not receive immunotherapy, 3 declined to participate, and 45 were lost to follow-up, resulting in a final cohort of 156 patients for analysis. The selection process is detailed in Fig. 1 , while Table 1 provides the demographic and clinical characteristics of the study population. Among the 156 patients, the mean age was 50.81 years, with a standard deviation of 10.48 years. The cohort comprised 140 males (89.7%) and 16 females (10.3%). In terms of disease stage, 37 patients (23.7%) were classified as having Barcelona Clinic Liver Cancer (BCLC) stage B disease, and 119 patients (76.3%) were classified as have stage C disease. Regarding the treatment modalities, 67.9% of the patients received targeted therapy with lenvatinib, and 67.3% received immunotherapy with tislelizumab. A total of 13.5% of patients had undergone prior liver resection, 82.1% had received TACE, and 13.5% had received radiotherapy. At baseline, the mean (standard deviation) PHQ-9 score was 5.58 (3.27), with 76 patients (48.7%) exhibiting depressive symptoms (refer to eFigure 1 in the Supplement ). Table 1 Baseline characteristics of patients according to depressive symptoms status Characteristic All patients ( n = 156) Depressive symptoms a P b Yes (n = 76) No (n = 80) Age, years 50.81 ± 10.48 49.21 ± 10.20 52.34 ± 10.57 0.062 Sex 0.026 Male 140 (89.7%) 64 (84.2%) 76 (95.0%) Female 16 (10.3%) 12 (15.8%) 4 (5.0%) BMI, kg/m 2 22.09 ± 3.12 21.68 ± 2.64 22.48 ± 3.48 0.109 Drinking Status 0.001 No 89 (57.1%) 54 (71.1%) 35 (43.8%) Yes 67 (42.9%) 22 (28.9%) 45 (56.2%) Monthly Household Income,yuan 0.642 ≤ 2000 3 (1.9%) 1 (1.3%) 2 (2.5%) 2001 ~ 3999 28 (17.9%) 13 (17.1%) 15 (18.8%) 4000 ~ 5999 98 (62.8%) 46 (60.5%) 52 (65.0%) ≥ 6000 27 (17.3%) 16 (21.1%) 11 (13.8%) BCLC Stage 0.023 B 37 (23.7%) 12 (15.8%) 25 (31.2%) C 119 (76.3%) 64 (84.2%) 55 (68.8%) Liver Cirrhosis 0.764 No 49 (31.4%) 23 (30.3%) 26 (32.5%) Yes 107 (68.6%) 53 (69.7%) 54 (67.5%) Hepatitis B surface antigen 0.525 Negative 16 (10.3%) 9 (11.8%) 7 (8.8%) Positive 140 (89.7%) 67 (88.2%) 73 (91.2%) Hepatitis C antibody 0.395 Negative 151 (96.8%) 75 (98.7%) 76 (95.0%) Positive 5 (3.2%) 1 (1.3%) 4 (5.0%) Family History of Cancer 0.454 No 121 (77.6%) 57 (75.0%) 64 (80.0%) Yes 35 (22.4%) 19 (25.0%) 16 (20.0%) Diabetes 0.538 No 137 (87.8%) 68 (89.5%) 69 (86.2%) Yes 19 (12.2%) 8 (10.5%) 11 (13.8%) Hypertension 0.022 No 126 (80.8%) 67 (88.2%) 59 (73.8%) Yes 30 (19.2%) 9 (11.8%) 21 (26.2%) Tumor number 0.881 Single 28 (17.9%) 14 (18.4%) 14 (17.5%) Multiple 128 (82.1%) 62 (81.6%) 66 (82.5%) Tumor size, cm 0.079 <5 27 (17.3%) 9 (11.8%) 18 (22.5%) ≥ 5 129 (82.7%) 67 (88.2%) 62 (77.5%) Extrahepatic Metastasis 0.158 No 103 (66.0%) 46 (60.5%) 57 (71.2%) Yes 53 (34.0%) 30 (39.5%) 23 (28.7%) Vascular Invasion 0.508 No 47 (30.1%) 21 (27.6%) 26 (32.5%) Yes 109 (69.9%) 55 (72.4%) 54 (67.5%) a-Fetoprotein, ng/ml 0.505 ≤ 400 72 (46.2%) 33 (43.4%) 39 (48.8%) >400 84 (53.8%) 43 (56.6%) 41 (51.2%) Targeted Therapy Regimen 0.071 Donafenib 27 (17.3%) 11 (14.5%) 16 (20.0%) Lenvatinib 106 (67.9%) 56 (73.7%) 50 (62.5%) Regorafenib 1 (0.6%) 1 (1.3%) 0 Apatinib 7 (4.5%) 5 (6.6%) 2 (2.5%) Anlotinib 1 (0.6%) 0 1 (1.2%) Bevacizumab 14 (9.0%) 3 (3.9%) 11 (13.8%) Immunotherapy Regimen 0.033 Atezolizumab 3 (1.9%) 0 3 (3.8%) Sintilimab 13 (8.3%) 4 (5.3%) 9 (11.2%) Camrelizumab 30 (19.2%) 18 (23.7%) 12 (15.0%) Toripalimab 105 (67.3%) 49 (64.5%) 56 (70.0%) Penpulimab 3 (1.9%) 3 (3.9%) 0 Pembrolizumab 2 (1.3%) 2 (2.6%) 0 Liver Resection 0.718 No 135 (86.5%) 65 (85.5%) 70 (87.5%) Yes 21 (13.5%) 11 (14.5%) 10 (12.5%) Transarterial chemoembolization 0.571 No 28 (17.9%) 15 (19.7%) 13 (16.2%) Yes 128 (82.1%) 61 (80.3%) 67 (83.8%) Radiotherapy 0.295 No 135 (86.5%) 68 (89.5%) 67 (83.8%) Yes 21 (13.5%) 8 (10.5%) 13 (16.2%) Abbreviation: BCLC,Barcelona clinic liver cancer. Data are presented as mean ± SD or n (%), unless otherwise specified. a Patients were grouped by depression status using the PHQ-9 scale. b P value was based on independent samples t-test, Chi-square test, or Fisher's exact test where appropriate 3.2 Associations between depressive symptoms and treatment efficacy During the 6-month follow-up, 36 patients achieved an objective response. The ORR was 10.5% among patients with elevated depressive symptoms and 37.5% among patients without elevated depressive symptoms. Disease control was observed in 113 patients, with a disease DCR of 52.6% among those with elevated depressive symptoms and 91.2% among those without (e Table 1 in the Supplement ). Table 2 shows the associations of depressive symptoms with the ORR and DCR. After adjusting for potential confounders (in Model 3), the presence of elevated baseline depressive symptoms was independently associated with an 87.0% reduced likelihood of achieving an objective response (OR, 0.13; 95% CI, 0.04–0.40; P < 0.001) and a 95.0% reduced likelihood of achieving disease control (OR, 0.05; 95% CI, 0.01–0.18; P < 0.001). Table 2 Association between depressive symptoms and immunotherapy efficacy in patients with advanced hepatocellular carcinoma Item Events / Total Model 1 a Model 2 b Model 3 c OR (95% CI) P OR (95% CI) P OR (95% CI) P ORR Depressive symptoms No 30 / 80 Reference Reference Reference Yes 8 / 76 0.18 (0.07–0.43) < 0.001 0.13 (0.04–0.41) < 0.001 0.13 (0.04–0.40) < 0.001 DCR Depressive symptoms No 73 / 80 Reference Reference Reference Yes 40 / 76 0.09 (0.04–0.23) < 0.001 0.05 (0.01–0.18) < 0.001 0.05 (0.01–0.18) < 0.001 Abbreviations: ORR, objective response rate; DCR, disease control rate; OR, odds ratio; CI, confidence interval. a Adjusted for age and gender. b Adjusted for age, gender, family history of cancer, alcohol consumption, monthly household income, hepatitis C, comorbid diabetes, comorbid hypertension, hepatitis B, cirrhosis, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP, and BCLC staging. c Adjusted as model 2 plus previous liver surgery resection, TACE/HAIC and its frequency, and radiotherapy. 3.3 Association between depressive symptoms and QoL The QoL scores of the 2 groups at each time point are shown in Fig. 2 . QoL scores, along with the scores for each dimension, were significantly lower in depressed patients than in nondepressed patients at various time points (all P values < 0.05). QoL scores and every QoL dimension score measured at 2, 4, and 6 months postimmunotherapy were compared with those before immunotherapy using the generalized estimating equation model (Table 3 ). At month 6, the change in the QoL score from baseline was − 32.54 points among patients with elevated depressive symptoms and 10.04 points among patients without elevated depressive symptoms (difference, -42.59 [95% CI, -50.37 -34.80]; P < 0.001). Similar results were observed at 2 and 4 months, as well as across various dimensions. Table 3 Change from baseline in quality of life a Quality of life Depression (n = 76) No depression (n = 80) Between-group difference in change from baseline Mean (SD) Change from baseline (95% CI) Mean (SD) Change from baseline (95% CI) Mean (95% CI) P Total quality of life score Baseline 125.01 (15.08) 136.19 (10.38) 2 months 111.84 (21.71) -13.17 (-18.21 to -8.13) 132.12 (20.24) -4.06 (-8.06 to -0.07) -9.11 (-15.54 to -2.68) 0.006 4 months 109.09 (22.01) -18.43 (-23.83 to -13.02) 143.27 (12.49) 4.63(1.57 to 7.70) -23.06(-29.25 to -16.87) < 0.001 6 months 95.80 (24.39) -32.54 (-38.87 to -26.22) 148.35 (19.65) 10.04(5.41 to 14.68) -42.59(-50.37 to -34.80) < 0.001 Physical well-being Baseline 20.79 (4.74) 23.09 (3.99) 2 months 18.80 (5.78) -1.99(-3.10 to -0.87) 21.96 (4.97) -1.13(-2.02 to -0.23) -0.86(-2.29 to 0.57) 0.238 4 months 17.32 (5.13) -4.30(-5.69 to -2.90) 23.96 (3.52) 0.22(-0.57 to 1.02) -4.52(-6.12 to -2.92) < 0.001 6 months 14.76 (5.51) -6.91(-8.39 to -5.42) 24.21 (4.45) 0.61(-0.45 to 1.67) -7.52(-9.33 to -5.70) < 0.001 Social/family well-being Baseline 14.42 (2.90) 15.88 (2.78) 2 months 13.11 (3.24) -1.32(-2.07 to -0.56) 15.14 (3.56) -0.74(-1.37 to -0.10) -0.58(-1.56 to 0.41) 0.250 4 months 13.19 (3.17) -1.38(-2.15 to -0.62) 16.69 (2.81) 0.59(0.03 to 1.16) -1.98(-2.92 to -1.03) < 0.001 6 months 11.67 (3.49) -2.95(-3.80 to -2.10) 18.07 (3.21) 2.03(1.26 to 2.81) -4.99(-6.13 to -3.84) < 0.001 Emotional well-being Baseline 13.33 (2.90) 16.56 (2.46) 2 months 11.89 (3.40) -1.43(-2.16 to -0.71) 16.29 (3.72) -0.27(-1.03 to 0.48) -1.16(-2.21 to -0.11) 0.030 4 months 11.04 (3.00) -2.66(-3.45 to -1.87) 18.03 (2.81) 1.02(0.31 to 1.74) -3.69(-4.75 to -2.62) < 0.001 6 months 9.50 (2.29) -4.18(-4.94 to -3.42) 18.84 (3.29) 2.01(1.15 to 2.87) -6.19(-7.33 to -5.04) < 0.001 Functional well-being Baseline 13.04 (3.43) 15.45 (3.82) 2 months 11.57 (3.80) -1.47(-2.30 to -0.64) 16.06 (5.22) 0.61(-0.43 to 1.66) -2.09(-3.42 to -0.75) 0.002 4 months 12.34 (4.00) -0.89(-1.77 to -0.00) 18.44 (3.83) 2.66(1.69 to 3.63) -3.54(-4.85 to -2.24) < 0.001 6 months 11.48 (3.86) -1.72(-2.67 to -0.76) 19.60 (4.05) 3.93(2.94 to 4.92) -5.65(-7.02 to -4.28) < 0.001 Disease-specific hepatobiliary cancer subscale Baseline 63.43 (8.47) 65.21 (5.44) 2 months 56.47 (10.54) -6.96(-9.58 to -4.35) 62.67 (7.88) -2.54(-4.27 to -0.81) -4.42(-7.56 to -1.29) 0.006 4 months 55.19 (10.62) -9.45(-12.26 to -6.63) 66.15 (4.63) -0.07(-1.54 to 1.39) -9.37(-12.53 to -6.21) < 0.001 6 months 48.39 (12.33) -16.53(-19.91 to -13.15) 67.75 (7.59) 1.69(-0.36 to 3.73) -18.22(-22.14 to -14.29) < 0.001 Abbreviations: SD, standard deviation; CI, confidence interval. a All models were adjusted for age, gender, family history of cancer, alcohol consumption, monthly household income, hepatitis C, comorbid diabetes, comorbid hypertension, hepatitis B, cirrhosis, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP, BCLC stage, previous liver surgery resection, TACE/HAIC and its frequency, and radiotherapy. 3.4 Associations of depressive symptoms with PFS and OS During a median follow-up of 10 months, 31 patients died, and 124 patients experienced recurrence. The median PFS was 4.0 months (95% CI, 3.0 to 5.0 months), with a 1-year PFS rate of 16.8% ( eFigure 2A in the Supplement ). The median OS was not reached, but the 1-year OS rate was 81.8% ( eFigure 2B in the Supplement ). Patients with depressive symptoms had significantly worse PFS (Fig. 3 A) and OS (Fig. 3 B) than those without depressive symptoms. Table 4 shows the associations of depressive symptoms with PFS, OS and RFS. After adjusting for potential confounders (in Model 3), elevated depressive symptoms at baseline were independently associated with an increased risk of recurrence (HR, 4.31; 95% CI, 2.75–6.67) and death (HR, 5.39; 95% CI, 1.84–15.82). Table 4 Association of depressive symptoms with PFS and OS in patients with advanced hepatocellular carcinoma Item Events / Total Model 1 a Model 2 b Model 3 c HR (95% CI) P HR (95% CI) P HR (95% CI) P PFS Depressive symptoms No 52/80 Reference Reference Reference Yes 72/76 3.46(2.36–5.07) < 0.001 3.66(2.41–5.57) < 0.001 4.31(2.75–6.76) < 0.001 OS Depressive symptoms No 7/80 Reference Reference Reference Yes 24/76 4.09(1.75–9.60) 0.001 4.76(1.77–12.80) 0.02 5.39(1.84–15.82) 0.02 Abbreviations: PFS, progression-free survival; OS, overall survival; CI, confidence interval. a Adjusted for age and gender. b Adjusted for age, gender, family history of cancer, alcohol consumption, monthly household income, hepatitis C, comorbid diabetes, comorbid hypertension, hepatitis B, cirrhosis, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP, and BCLC staging. c Adjusted as model 2 plus previous liver surgery resection, TACE/HAIC and its frequency, and radiotherapy. 4 Discussion This study investigated the impact of depression on the efficacy of immunotherapy, QoL, and prognosis in patients with advanced HCC. The results showed that depression is common among HCC patients and significantly affects treatment outcomes and QoL. Patients in the depressed group had a significantly lower ORR and DCR than did those in the nondepressed group, along with a continuous decline in QoL. These findings underscore the importance of mental health, highlighting the need for the early identification of and intervention in depressive symptoms to optimize treatment outcomes. Multiple studies have shown that depression is prevalent at various stages of cancer treatment. This study revealed a 48.7% incidence of depression in patients with advanced HCC, which is consistent with previous reports ranging from 28.3–64.4% 26,27 . The high incidence of depression can be attributed to disease complexity, poor prognosis, and heavy treatment burden 28 . In China, where HCC is often caused by hepatitis B infection, patients frequently face social stigma, increasing the risk of depression 29 . The efficacy of immunotherapy is influenced by various factors, including the tumor immune microenvironment, PD-L1 expression levels, DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) 30 – 32 . These factors, to some extent, determine the strength of a patient’s response to immunotherapy and the treatment outcomes. However, in recent years, psychological factors, particularly depression, have increasingly been recognized as important nonbiological factors affecting immunotherapy efficacy 33 . Depression not only impacts a patient's psychological state but also disrupts the normal function of the immune system through complex biological mechanisms 34 . In this study, we observed that the ORR and DCR were 87% and 95% lower, respectively, in the depressed group than in the nondepressed group. These findings align with those of other cancer studies 35 , indicating a close relationship between depression and cancer treatment outcomes, particularly suggesting that the efficacy of immunotherapy can be significantly reduced by depression. Depression alters the tumor immune microenvironment in various ways. Specifically, it can reduce the activity of immune cells, especially T cells and natural killer (NK) cells, which play crucial roles in identifying and eliminating cancer cells. When patients are in a depressed state, this immune defense ability is weakened, giving tumor cells a greater chance of evading immune surveillance. Additionally, depression increases inflammatory responses and the secretion of stress hormones such as cortisol, further weakening the immune response. These hormones can inhibit T-cell proliferation and function, reducing their ability to recognize and attack cancer cells 36 . Moreover, depression may lead to an increased proportion of regulatory T cells (Tregs), which suppress immune responses in the tumor microenvironment, further promoting immune evasion by tumors. In this study, we revealed the negative impact of depression on immunotherapy efficacy. The underlying mechanisms include reduced immune cell activity, increased inflammatory responses, and overall suppression of the immune system. All of these changes work together to significantly diminish the effectiveness of immunotherapy. The findings of this study are also consistent with those performed with other cancer types, further supporting the close relationship between depression and immunotherapy efficacy. Therefore, this study highlights the profound impact of depression on immunotherapy outcomes. For patients with advanced HCC, immunotherapy is a promising treatment option, but if patients also experience depression, the treatment efficacy may be greatly compromised. Given the negative impact of depression on immunotherapy efficacy, early identification of and proactive intervention in depressive symptoms can not only improve patients' QoL but also potentially enhance the effectiveness of immunotherapy and ultimately prolong patient survival. This study also revealed that QoL in the depressed group declined continuously during immunotherapy, whereas that in the nondepressed group initially decreased but then gradually improved. Depression affects patients’ physical, psychological, and social functions, reducing treatment compliance and worsening QoL 37 , 38 . Compared with nondepressed patients, those with depression are more susceptible to negative emotions, further exacerbating the decline in QoL. Given the adverse effects of depression on immunotherapy efficacy and QoL, early screening for and intervention in depression should be a priority in managing patients with advanced HCC 39 . Clinical healthcare providers can use psychological counseling, cognitive‒behavioral therapy, and other approaches to improve patients' mental health and enhance treatment outcomes 40 . For high-risk patients, individualized intervention strategies and family and social support should be encouraged to help maintain a positive mindset 41 . Depression is closely associated with worse survival outcomes. In this study, the risks of disease progression and death in the depressed group were 4.31 times and 5.39 times greater, respectively, than those in the nondepressed group 42 . This findings aligns with those of other cancer studies, indicating that depression weakens the immune system, delays recovery, and even promotes tumor metastasis 43 . The early identification of and intervention in depressive symptoms can improve the survival of HCC patients 44 . This study has several notable strengths. First, as a prospective cohort study, it is well suited for the accurate assessment of the impact of depressive symptoms on the efficacy of immunotherapy in patients with advanced HCC. By longitudinally following patients, we were able to observe the dynamic changes in depressive symptoms in relation to the treatment outcomes, QoL, and prognosis. Second, the study utilized validated tools for depression screening (PHQ-9) and QoL assessment in cancer patients (FACT-Hep), ensuring the reliability and validity of the mental health and QoL data. Furthermore, the study included multiple clinical outcome measures, such as the ORR, DCR, PFS, and OS, providing a solid foundation for the comprehensive evaluation of the impact of depression on immunotherapy. Despite providing valuable insights, this study has several limitations. First, while the sample size was sufficient for the primary analysis, it may not fully represent the diversity of patients with advanced HCC, especially with regard to genetic and cultural factors 45 . Second, the study relied on self-reported measures of depression and QoL, which, despite the use of standardized tools, may introduce bias when the study involves patients with advanced disease 46 . Third, although adjustments were made for several confounding factors, unmeasured variables such as genetic susceptibility or environmental influences may still exist 47 . Future research should aim to validate these findings through larger, multicenter studies and explore the biological mechanisms linking depression and immunotherapy outcomes to identify potential therapeutic targets 48 . Additionally, depression intervention trials are needed specifically for cancer patients receiving immunotherapy to determine the best strategies for alleviating psychological distress and improving treatment outcomes and QoL 49 , 50 . 5 Conclusions This study revealed significant associations among depression, the effectiveness of immunotherapy, and QoL in patients with advanced liver cancer, with depressed patients having worse treatment outcomes. This research emphasizes the importance of regular depression screening and psychological interventions to improve treatment efficacy. A multidisciplinary approach that addresses both physical and mental health is crucial, and further research is needed to develop effective mental health interventions. Declarations Conflict of interest disclosures All the authors have nothing to disclose. Declaration of conflicts of interest The authors have no conflicts of interest to declare that are relevant to the content of this article. Funding This work was supported by the National Natural Science Foundation of China (81960308). Author Contribution Fei-Chen Lu designed the study and developed the research protocol. Fan-Rong Li and Feng-Juan Zhao conducted data collection and performed statistical analyses. Rong-Rui Huo interpreted the results and provided critical revisions to the manuscript. Fei-Chen Lu and Fan-Rong Li wrote the main manuscript text, and Feng-Juan Zhao prepared figures 1-3 and tables 1-2. All authors reviewed and approved the final version of the manuscript.Corresponding Author: Xue-Mei You supervised the overall study and reviewed and approved the final version of the manuscript. For any inquiries, please contact Xue-Mei You (email: [email protected] ). Data availability statement The data are available upon request due to privacy/ethical restrictions. References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Measuring health-related quality of life in patients with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol. 2002;20(9):2229–39. 10.1200/JCO.2002.07.093 . Peng JK, Hepgul N, Higginson IJ, Gao W. Symptom prevalence and quality of life of patients with end-stage liver disease: A systematic review and meta-analysis. Palliat Med. 2019;33(1):24–36. 10.1177/0269216318807051 . Kim DW, Talati C, Kim R. Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J Gastrointest Oncol. 2017;8(2):256–65. 10.21037/jgo.2016.09.07 . Lieber SR, Jones AR, Jiang Y, et al. Psychiatric diagnoses are common after liver transplantation and are associated with increased health care utilization and patient financial burden. Liver Transpl Published online June. 2024;25. 10.1097/LVT.0000000000000390 . Le TV, Vu TTM, Mai HT, et al. Social Determinants of Stigma and Discrimination in Vietnamese Patients with Chronic Hepatitis B. Int J Environ Res Public Health. 2019;16(3):398. 10.3390/ijerph16030398 . Busato D, Mossenta M, Baboci L, Di Cintio F, Toffoli G, Dal Bo M. Novel immunotherapeutic approaches for hepatocellular carcinoma treatment. Expert Rev Clin Pharmacol. 2019;12(5):453–70. 10.1080/17512433.2019.1598859 . Hong WF, Gu YJ, Wang N, et al. Integrative Characterization of Immune-relevant Genes in Hepatocellular Carcinoma. J Clin Transl Hepatol. 2021;9(3):301–14. 10.14218/JCTH.2020.00132 . Mukai S, Kanzaki H, Ogasawara S, et al. Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment. JGH Open. 2021;5(11):1266–74. 10.1002/jgh3.12660 . McFarland DC. New lung cancer treatments (immunotherapy and targeted therapies) and their associations with depression and other psychological side effects as compared to chemotherapy. Gen Hosp Psychiatry. 2019;60:148–55. 10.1016/j.genhosppsych.2019.04.001 . Young K, Singh G. Biological Mechanisms of Cancer-Induced Depression. Front Psychiatry. 2018;9:299. Published 2018 Jul 10. 10.3389/fpsyt.2018.00299 Ahmed E. Antidepressants in Patients With Advanced Cancer: When They're Warranted and How to Choose Therapy. Oncol (Williston Park). 2019;33(2):62–8. Lee CH, Giuliani F. The Role of Inflammation in Depression and Fatigue. Front Immunol. 2019;10:1696. 10.3389/fimmu.2019.01696 . Published 2019 Jul 19. Caldirola D, Grassi M, Riva A, et al. Self-reported quality of life and clinician-rated functioning in mood and anxiety disorders: relationships and neuropsychological correlates. Compr Psychiatry. 2014;55(4):979–88. 10.1016/j.comppsych.2013.12.007 . Akechi T. Psychotherapy for depression among patients with advanced cancer. Jpn J Clin Oncol. 2012;42(12):1113–9. 10.1093/jjco/hys152 . Santos GG, Gonçalves LC, Buzzo N et al. Quality of life, depression, and psychosocial characteristics of patients awaiting liver transplants. Transplant Proc. 2012;44(8):2413–2415. 10.1016/j.transproceed.2012.07.046 Chong Guan N, Mohamed S, Kian Tiah L, Kar Mun T, Sulaiman AH, Zainal NZ. Psychotherapy for cancer patients. Int J Psychiatry Med. 2016;51(5):414–30. 10.1177/0091217416680197 . Klafke N, Bossert J, Boltenhagen U, et al. Counseling lifestyle medicine in oncology: A qualitative analysis of interprofessional patient-nurse-physician interactions. Patient Educ Couns. 2024;127:108352. 10.1016/j.pec.2024.108352 . Boyajian R. Depression's impact on survival in patients with cancer. Clin J Oncol Nurs. 2010;14(5):649–52. 10.1188/10.CJON.649-652 . Panjwani AA, Li M. Recent trends in the management of depression in persons with cancer. Curr Opin Psychiatry. 2021;34(5):448–59. 10.1097/YCO.0000000000000727 . Vita G, Compri B, Matcham F, Barbui C, Ostuzzi G. Antidepressants for the treatment of depression in people with cancer. Cochrane Database Syst Rev. 2023;3(3):CD011006. 10.1002/14651858.CD011006.pub4 . Montagnese S, Bajaj JS. Impact of Hepatic Encephalopathy in Cirrhosis on Quality-of-Life Issues. Drugs. 2019;79(Suppl 1):11–6. 10.1007/s40265-018-1019-y . Schulte L, Scheiner B, Voigtländer T, et al. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int. 2019;39(4):714–26. 10.1111/liv.14048 . Deshayes E, Guiu B. Liver function: homogenous or not? HPB (Oxford). 2016;18(11):871. 10.1016/j.hpb.2016.07.017 . Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. Eur Neuropsychopharmacol. 2015;25(10):1532–43. 10.1016/j.euroneuro.2015.06.007 . Adzic M, Brkic Z, Mitic M, et al. Therapeutic Strategies for Treatment of Inflammation-related Depression. Curr Neuropharmacol. 2018;16(2):176–209. 10.2174/1570159X15666170828163048 . Branchi I, Poggini S, Capuron L, et al. Brain-immune crosstalk in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2021;45:89–107. 10.1016/j.euroneuro.2020.11.016 . Additional Declarations No competing interests reported. Supplementary Files etable1.docx eFigure1.tif eFigure2A2B.tif Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5768098","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":398283092,"identity":"f2ffc2f8-a181-475f-b869-5919a100f485","order_by":0,"name":"Fei-Chen Lu","email":"","orcid":"","institution":"Guangxi Medical University Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fei-Chen","middleName":"","lastName":"Lu","suffix":""},{"id":398283093,"identity":"b530a76b-a9a7-46d6-b65a-f637b0eb1621","order_by":1,"name":"Fan-Rong Li","email":"","orcid":"","institution":"Guangxi Medical University Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fan-Rong","middleName":"","lastName":"Li","suffix":""},{"id":398283094,"identity":"225d333f-ebcf-4491-86de-fa33a2c4d413","order_by":2,"name":"Feng-Juan Zhao","email":"","orcid":"","institution":"Guangxi Medical University Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Feng-Juan","middleName":"","lastName":"Zhao","suffix":""},{"id":398283095,"identity":"36729153-8317-42a5-8c13-ddc908858127","order_by":3,"name":"Rong-Rui Huo","email":"","orcid":"","institution":"Guangxi Medical University Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rong-Rui","middleName":"","lastName":"Huo","suffix":""},{"id":398283096,"identity":"637656ac-83a7-41dc-8310-d76a646fb40c","order_by":4,"name":"Xue-Mei You","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYDADNvYGJB4PUVp4DjAiNBGlhUEigUgtBsd7zKR5KrbJ8Uk+f/6Yh6E2ce2MBMYHb9sY5M1xaTlzxtiY58xtYzbpHMNmHobjxmY3EpgN57YxGO5swKHlRo7hY96224lt0jmMQC3H5IBa2KR52xgSDA7g1GJwmPff7fo2yeMPQVp4gFrYfxPQArSl4XYCmwQDyGE1YFuY8WmRPHOs2HDOsduGbTw5hjPnGBwwNjvzsFlyzjkJww04tPAdb94m8abmtrx8+/EHH95U1CVuO5588MObMht5XLYooIobHAYS4PiRwK4eCOQbUPl1OFWOglEwCkbByAUAcFdarWCpRawAAAAASUVORK5CYII=","orcid":"","institution":"Guangxi Medical University Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xue-Mei","middleName":"","lastName":"You","suffix":""}],"badges":[],"createdAt":"2025-01-05 13:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5768098/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5768098/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73267696,"identity":"7c187b22-e5a8-4178-8746-84df53168944","added_by":"auto","created_at":"2025-01-08 10:38:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2756287,"visible":true,"origin":"","legend":"\u003cp\u003eConsort diagram of patient population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e QOL, quality of life.\u003c/p\u003e","description":"","filename":"Figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/c1bebb0a3b0ea412c8b98699.jpg"},{"id":73267692,"identity":"2f213607-bc72-4c0f-9842-5abed312f413","added_by":"auto","created_at":"2025-01-08 10:38:04","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":443155,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal changes in quality of life in patients with advanced hepatocellular carcinoma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe graphs show the mean scores for the total QoL score (A), physical well-being dimension (B), social/family well-being dimension (C), emotional well-being dimension (D), functional well-being dimension (E), and hepatobiliary cancer-specific condition (F). Higher scores indicate better quality of life. \u003csup\u003e** \u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01, \u003csup\u003e*** \u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001 by t test. \u003cstrong\u003eAbbreviations: \u003c/strong\u003eT0: before immunotherapy; T1: 2 months after immunotherapy; T2: 4 months after immunotherapy; T3: 6 months after immunotherapy.\u003c/p\u003e","description":"","filename":"Figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/7630c7bd53dfea56c40a8066.jpg"},{"id":73267695,"identity":"4c15a314-47c9-4d9c-bb23-d5e7d7de2d0b","added_by":"auto","created_at":"2025-01-08 10:38:04","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":238310,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan‒Meier curves for survival in patients with hepatocellular carcinoma according to depressive symptom status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe graphs show the Kaplan‒Meier estimates for recurrence-free survival (A) and overall survival (B). The vertical lines indicate censored data.\u003c/p\u003e","description":"","filename":"Figure3A3B.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/038b1f9384d75b4da2a002c8.jpg"},{"id":101847301,"identity":"c07f0cea-83bd-4018-a598-abc2b6a2f2f2","added_by":"auto","created_at":"2026-02-04 09:28:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5211379,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/a23c5410-fba9-48e3-abca-8809dfd03ccd.pdf"},{"id":73267691,"identity":"d605a057-b23f-4db7-92ce-5011d9bf9cfb","added_by":"auto","created_at":"2025-01-08 10:38:04","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18714,"visible":true,"origin":"","legend":"","description":"","filename":"etable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/44442cc9d73374d8d3ba68be.docx"},{"id":73269862,"identity":"36f44229-7ba9-4bd1-8685-05d1c6e34c14","added_by":"auto","created_at":"2025-01-08 10:46:04","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":446324,"visible":true,"origin":"","legend":"","description":"","filename":"eFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/4cada917e569da76fd984e32.tif"},{"id":73267703,"identity":"443a436e-fba6-4767-8321-dd918ed29adf","added_by":"auto","created_at":"2025-01-08 10:38:05","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":388100,"visible":true,"origin":"","legend":"","description":"","filename":"eFigure2A2B.tif","url":"https://assets-eu.researchsquare.com/files/rs-5768098/v1/76b20cc4935901141a67a868.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of depressive symptoms with quality of life and treatment efficacy in patients with intermediate or advanced hepatocellular carcinoma receiving immunotherapy: A prospective cohort study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is one of the most common gastrointestinal tumors worldwide and the second leading cause of cancer-related death\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In China, the incidence of HCC is particularly high, primarily due to cirrhosis caused by chronic hepatitis B virus (HBV) infection\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Since the early stages of HCC are often asymptomatic, most patients are diagnosed at an intermediate or advanced stage\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. This delayed diagnosis results in missed opportunities for curative surgical treatment and poor responses to radiotherapy and chemotherapy, with a five-year survival rate of only 20% for patients with advanced-stage disease \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn recent years, immune checkpoint inhibitors (ICIs) have emerged as promising treatment options for intermediate to advanced HCC. ICIs work by blocking immune checkpoints, reactivating T cells, and inhibiting tumor growth\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. This treatment approach is distinguished by its high specificity and relatively fewer side effects than conventional therapies\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. ICIs have been shown to be effective at prolonging patient survival and reducing recurrence rates\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. However, the objective response rate (ORR) remains between 20% and 30%, indicating that many patients do not experience significant clinical benefits from this therapy\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Identifying factors that influence the efficacy of ICIs is critical for optimizing HCC treatment strategies\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn addition to these biological factors, psychological conditions, particularly depression, have been found to impact the efficacy of immunotherapy. Depression and other negative emotions can suppress immune function, affect the immune microenvironment, and potentially reduce treatment efficacy\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Depression is common among HCC patients and often interferes with immune cells by activating the hypothalamic‒pituitary‒adrenal (HPA) axis, which can hinder treatment success\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eResearch on the impact of depression on immunotherapy outcomes in HCC patients is limited \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, and most existing studies have focused on other cancers, such as lung cancer and melanoma\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Psychological distress can also alter circulating tumor DNA and inflammatory cytokines, impacting the immune response to ICIs\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Furthermore, the HPA axis-induced elevation of cortisol has been linked to worse immunotherapy outcomes\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Managing both mental and physical health is essential to improving overall treatment outcomes in patients receiving ICIs\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study was performed to address this gap by using a prospective cohort to further explore the relationships among depression, treatment efficacy, quality of life (QoL), and prognosis. The longitudinal assessment of patient outcomes provides scientific data that can be used to support early screening and intervention strategies, with the goal of improving the effectiveness of immunotherapy and enhancing QoL in HCC patients.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and patients\u003c/h2\u003e \u003cp\u003eThis study was a prospective cohort study in which patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC who received immunotherapy at Guangxi Medical University Cancer Hospital between January 2022 and July 2023 were initially enrolled. The inclusion criteria were as follows: According to the AASLD diagnostic criteria, HCC was confirmed on the basis of preoperative imaging findings combined with alpha-fetoprotein (AFP) levels, and the patients had no prior history of immunotherapy; age between 18 and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status score of 0\u0026ndash;1, a Child‒Pugh score\u0026thinsp;\u0026le;\u0026thinsp;7, a Karnofsky performance score (KPS)\u0026thinsp;\u0026gt;\u0026thinsp;60, an estimated survival time\u0026thinsp;\u0026ge;\u0026thinsp;6 months, no family history of mental illness, no history of mental disorders, no impaired consciousness, and normal cognitive function.\u003c/p\u003e \u003cp\u003eThe exclusion criteria were as follows: the presence of other malignancies; a history of tumor-related surgery within the past two months; the concurrent use of herbal medicines with antitumor effects; active or a history of autoimmune diseases with the potential for recurrence; and the discontinuation of subsequent treatments due to severe immune-related adverse events, such as immune-related myocarditis, hepatitis, or colitis.\u003c/p\u003e \u003cp\u003e The study was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital (KY2024397) and conformed to the principles in the Declaration of Helsinki. All enrolled patients provided written informed consent. This study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Immunotherapy regimens\u003c/h2\u003e \u003cp\u003eTreatment plans for all patients were evaluated and selected by a minimum of two attending physicians on the basis of the patient's condition. Medication could be discontinued in cases of disease progression or intolerable adverse reactions. The immune checkpoint inhibitors included PD-1 inhibitors such as sintilimab, toripalimab, camrelizumab, pembrolizumab, and nivolumab, which were all administered intravenously at a dosage of 200 mg every three weeks. Additionally, the PD-L1 inhibitor atezolizumab was administered intravenously at a dosage of 1200 mg every three weeks.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Assessment of depressive symptoms\u003c/h2\u003e \u003cp\u003eDepressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), which is recommended for screening for depression in cancer patients\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The PHQ-9 has been translated into Chinese and validated in clinical research, demonstrating good reliability and validity, with high internal consistency (Cronbach's α typically ranging from 0.86 to 0.89) and construct validity\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The PHQ-9 consists of 9 items, each scored from 0 to 3, resulting in a total score ranging from 0 to 27\u003csup\u003e23\u003c/sup\u003e. A score of 5 or higher indicates the presence of depressive symptoms. In this study, patients were classified into nondepressed (0\u0026ndash;4) and depressed (\u0026ge;\u0026thinsp;5) groups on the basis of their PHQ-9 scores.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Assessment of outcomes and follow-up\u003c/h2\u003e \u003cp\u003eThis study included 156 patients with intermediate or advanced HCC who were receiving immunotherapy. Depressive symptoms were assessed using the PHQ-9. The primary outcome was progression-free survival (PFS). The secondary outcomes were the ORR, disease control rate (DCR), overall survival (OS), and QoL.\u003c/p\u003e \u003cp\u003ePFS was defined as the time from the initiation of ICI treatment to disease progression or death. OS was defined as the time from the initiation of ICI treatment to death from any cause.\u003c/p\u003e \u003cp\u003eThe efficacy of immunotherapy was evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST)\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e as follows: complete response (CR) was defined as the disappearance of target lesion enhancement in the arterial phase; partial response (PR) was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;30% reduction in the diameter of the target lesions; stable disease (SD) was defined as a reduction in target lesion size that did not meet the criterion for PR or a slight increase that did not reach the criterion for progressive disease (PD); and progressive disease (PD) was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;20% increase in lesion diameter or the appearance of new lesions. The efficacy assessment indicators were as follows: ORR = (CR\u0026thinsp;+\u0026thinsp;PR)/total number of patients \u0026times; 100%; DCR = (CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD)/total number of patients \u0026times; 100%.\u003c/p\u003e \u003cp\u003eQoL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The FACT-Hep includes 45 items divided into five subscales:\u003c/p\u003e \u003cp\u003ephysical well-being; social/family well-being; emotional well-being; functional well-being; and the Hepatobiliary Cancer Subscale (HepCS), which includes 18 items that specifically assess the symptoms of hepatobiliary cancer and treatment side effects. The total score ranges from 0 to 180, with higher scores on all the FACT-Hep subscales indicating better QoL.\u003c/p\u003e \u003cp\u003eFollowing immunotherapy, patients were followed every two months. These follow-up assessments included routine blood tests, liver and kidney function tests, key tumor markers assessments, enhanced abdominal CT or MRI, chest CT, and survival status. QoL assessments were conducted at four time points: baseline (prior to immunotherapy), two months postimmunotherapy, four months postimmunotherapy, and six months postimmunotherapy. The study required each patient to have at least two QoL assessments. The follow-up was completed on December 31, 2023.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Covariates\u003c/h2\u003e \u003cp\u003eBaseline characteristics, including sociodemographic and imaging information before immunotherapy, were recorded in electronic case report forms. These characteristics included age, sex, drinking status, income, family history of cancer, family history of diabetes, family history of hypertension; hepatitis B surface antigen, hepatitis C antibody, liver cirrhosis, body mass index, tumor number, tumor size, extrahepatic metastasis, vascular invasion, a-fetoprotein, BCLC stage, targeted therapy regimens, immunotherapy regimens, liver resection, transarterial chemoembolization (TACE), and radiotherapy. Body mass index was calculated as the weight in kilograms divided by the height in meters squared.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistical analysis\u003c/h2\u003e \u003cp\u003eContinuous data are expressed as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SDs), whereas categorical data are presented as frequencies with percentages. Baseline data were compared between groups on the basis of the presence or absence of depressive symptoms, using an independent sample t test for continuous variables and either the chi-square test or Fisher\u0026rsquo;s exact test for categorical data. The Kaplan‒Meier method was used to calculate survival rates, and the log-rank test was used for comparisons.\u003c/p\u003e \u003cp\u003eA logistic regression model was used to examine the associations of depressive symptoms with the ORR and DCR, and the odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated. A Cox regression model was used to analyze the associations of depressive symptoms with PFS and OS, yielding hazard ratios (HRs) and corresponding 95% CIs. A generalized estimating equation model was used to assess the associations between depression and total QoL scores as well as scores in each dimension. The link function was a Gaussian equation, and the correlation matrix was unstructured. The QoL scores and every QoL dimension score measured at 2, 4, and 6 months postimmunotherapy were compared with those before immunotherapy. Three models were estimated: Model 1 was adjusted for age and sex; Model 2 was adjusted for age, sex, family history of cancer, alcohol consumption, monthly household income, hepatitis C status, diabetes status, hypertension status, hepatitis B status, cirrhosis status, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP levels, and BCLC stage; and Model 3 was adjusted for the variables in Model 2 plus previous liver resection, TACE/HAIC, treatment frequency, and radiotherapy.\u003c/p\u003e \u003cp\u003eThe data were analyzed using R 4.3.0 software (R Foundation). All hypothesis tests were two-sided, and statistical significance was defined as \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline characteristics\u003c/h2\u003e \u003cp\u003eAt baseline, 256 patients with HCC were assessed. Of these, 52 patients were excluded because they did not receive immunotherapy, 3 declined to participate, and 45 were lost to follow-up, resulting in a final cohort of 156 patients for analysis. The selection process is detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, while Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides the demographic and clinical characteristics of the study population. Among the 156 patients, the mean age was 50.81 years, with a standard deviation of 10.48 years. The cohort comprised 140 males (89.7%) and 16 females (10.3%). In terms of disease stage, 37 patients (23.7%) were classified as having Barcelona Clinic Liver Cancer (BCLC) stage B disease, and 119 patients (76.3%) were classified as have stage C disease. Regarding the treatment modalities, 67.9% of the patients received targeted therapy with lenvatinib, and 67.3% received immunotherapy with tislelizumab. A total of 13.5% of patients had undergone prior liver resection, 82.1% had received TACE, and 13.5% had received radiotherapy. At baseline, the mean (standard deviation) PHQ-9 score was 5.58 (3.27), with 76 patients (48.7%) exhibiting depressive symptoms (refer to \u003cb\u003eeFigure 1 in the Supplement\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of patients according to depressive symptoms status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;156)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eDepressive symptoms \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes (n\u0026thinsp;=\u0026thinsp;76)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo (n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.81\u0026thinsp;\u0026plusmn;\u0026thinsp;10.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.21\u0026thinsp;\u0026plusmn;\u0026thinsp;10.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.34\u0026thinsp;\u0026plusmn;\u0026thinsp;10.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e140 (89.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (84.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 (95.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (15.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.09\u0026thinsp;\u0026plusmn;\u0026thinsp;3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.48\u0026thinsp;\u0026plusmn;\u0026thinsp;3.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrinking Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89 (57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (71.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (43.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (42.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (28.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (56.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonthly Household Income,yuan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.642\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2001\u0026thinsp;~\u0026thinsp;3999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (17.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (18.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4000\u0026thinsp;~\u0026thinsp;5999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98 (62.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (60.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (65.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;6000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (17.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCLC Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (15.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (31.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (76.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (84.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (68.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver Cirrhosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.764\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (30.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (32.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (69.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (67.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis B surface antigen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e140 (89.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (88.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (91.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis C antibody\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e151 (96.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 (98.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 (95.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily History of Cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121 (77.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (75.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64 (80.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (22.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137 (87.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (89.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69 (86.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126 (80.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (88.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59 (73.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (19.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.881\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (17.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e128 (82.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (81.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (82.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (17.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (22.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (82.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (88.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (77.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrahepatic Metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.158\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103 (66.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (60.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (71.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (34.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (39.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (28.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular Invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.508\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (30.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (32.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109 (69.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (72.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (67.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ea-Fetoprotein, ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (43.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (48.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84 (53.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (56.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (51.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTargeted Therapy Regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonafenib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (17.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (14.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLenvatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106 (67.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (73.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegorafenib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnlotinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (9.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunotherapy Regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtezolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSintilimab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (11.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCamrelizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (19.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToripalimab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e105 (67.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (64.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (70.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePenpulimab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePembrolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver Resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.718\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (86.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (85.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (87.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (14.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransarterial chemoembolization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.571\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (17.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (19.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e128 (82.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (80.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (83.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.295\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (86.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (89.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (83.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviation: BCLC,Barcelona clinic liver cancer.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or n (%), unless otherwise specified.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e Patients were grouped by depression status using the PHQ-9 scale.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e P value was based on independent samples t-test, Chi-square test, or Fisher's exact test where appropriate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Associations between depressive symptoms and treatment efficacy\u003c/h2\u003e \u003cp\u003eDuring the 6-month follow-up, 36 patients achieved an objective response. The ORR was 10.5% among patients with elevated depressive symptoms and 37.5% among patients without elevated depressive symptoms. Disease control was observed in 113 patients, with a disease DCR of 52.6% among those with elevated depressive symptoms and 91.2% among those without (e\u003cb\u003eTable 1 in the Supplement\u003c/b\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the associations of depressive symptoms with the ORR and DCR. After adjusting for potential confounders (in Model 3), the presence of elevated baseline depressive symptoms was independently associated with an 87.0% reduced likelihood of achieving an objective response (OR, 0.13; 95% CI, 0.04\u0026ndash;0.40; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a 95.0% reduced likelihood of achieving disease control (OR, 0.05; 95% CI, 0.01\u0026ndash;0.18; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation between depressive symptoms and immunotherapy efficacy in patients with advanced hepatocellular carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eItem\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEvents / Total\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eModel 1 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eModel 2 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eModel 3 \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 / 80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 / 76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.18 (0.07\u0026ndash;0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.13 (0.04\u0026ndash;0.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.13 (0.04\u0026ndash;0.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 / 80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 / 76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09 (0.04\u0026ndash;0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.05 (0.01\u0026ndash;0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.05 (0.01\u0026ndash;0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eAbbreviations: ORR, objective response rate; DCR, disease control rate; OR, odds ratio; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ea\u003c/sup\u003e Adjusted for age and gender.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003eb\u003c/sup\u003e Adjusted for age, gender, family history of cancer, alcohol consumption, monthly household income, hepatitis C, comorbid diabetes, comorbid hypertension, hepatitis B, cirrhosis, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP, and BCLC staging.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ec\u003c/sup\u003e Adjusted as model 2 plus previous liver surgery resection, TACE/HAIC and its frequency, and radiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Association between depressive symptoms and QoL\u003c/h2\u003e \u003cp\u003eThe QoL scores of the 2 groups at each time point are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. QoL scores, along with the scores for each dimension, were significantly lower in depressed patients than in nondepressed patients at various time points (all \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05). QoL scores and every QoL dimension score measured at 2, 4, and 6 months postimmunotherapy were compared with those before immunotherapy using the generalized estimating equation model (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). At month 6, the change in the QoL score from baseline was \u0026minus;\u0026thinsp;32.54 points among patients with elevated depressive symptoms and 10.04 points among patients without elevated depressive symptoms (difference, -42.59 [95% CI, -50.37 -34.80]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similar results were observed at 2 and 4 months, as well as across various dimensions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange from baseline in quality of life \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eQuality of life\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eDepression (n\u0026thinsp;=\u0026thinsp;76)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eNo depression (n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eBetween-group difference\u003c/p\u003e \u003cp\u003ein change from baseline\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChange from baseline\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChange from baseline\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal quality of life score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e125.01 (15.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e136.19 (10.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e111.84 (21.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-13.17 (-18.21 to -8.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e132.12 (20.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-4.06 (-8.06 to -0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-9.11 (-15.54 to -2.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e109.09 (22.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-18.43 (-23.83 to -13.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e143.27 (12.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.63(1.57 to 7.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-23.06(-29.25 to -16.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95.80 (24.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-32.54 (-38.87 to -26.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e148.35 (19.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.04(5.41 to 14.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-42.59(-50.37 to -34.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical well-being\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.79 (4.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23.09 (3.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.80 (5.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.99(-3.10 to -0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21.96 (4.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.13(-2.02 to -0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.86(-2.29 to 0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.238\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17.32 (5.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4.30(-5.69 to -2.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23.96 (3.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.22(-0.57 to 1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-4.52(-6.12 to -2.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.76 (5.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-6.91(-8.39 to -5.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e24.21 (4.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.61(-0.45 to 1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-7.52(-9.33 to -5.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSocial/family well-being\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.42 (2.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.88 (2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.11 (3.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.32(-2.07 to -0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.14 (3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.74(-1.37 to -0.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.58(-1.56 to 0.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.19 (3.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.38(-2.15 to -0.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.69 (2.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.59(0.03 to 1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-1.98(-2.92 to -1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.67 (3.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2.95(-3.80 to -2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.07 (3.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.03(1.26 to 2.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-4.99(-6.13 to -3.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmotional well-being\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.33 (2.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.56 (2.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.89 (3.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.43(-2.16 to -0.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.29 (3.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.27(-1.03 to 0.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-1.16(-2.21 to -0.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.04 (3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2.66(-3.45 to -1.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.03 (2.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.02(0.31 to 1.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-3.69(-4.75 to -2.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.50 (2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4.18(-4.94 to -3.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.84 (3.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.01(1.15 to 2.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-6.19(-7.33 to -5.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFunctional well-being\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.04 (3.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.45 (3.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.57 (3.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.47(-2.30 to -0.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.06 (5.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.61(-0.43 to 1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-2.09(-3.42 to -0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.34 (4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.89(-1.77 to -0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.44 (3.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.66(1.69 to 3.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-3.54(-4.85 to -2.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.48 (3.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.72(-2.67 to -0.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.60 (4.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.93(2.94 to 4.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-5.65(-7.02 to -4.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease-specific\u003c/p\u003e \u003cp\u003ehepatobiliary cancer subscale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63.43 (8.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e65.21 (5.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56.47 (10.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-6.96(-9.58 to -4.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e62.67 (7.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.54(-4.27 to -0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-4.42(-7.56 to -1.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55.19 (10.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-9.45(-12.26 to -6.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e66.15 (4.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.07(-1.54 to 1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-9.37(-12.53 to -6.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48.39 (12.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-16.53(-19.91 to -13.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e67.75 (7.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.69(-0.36 to 3.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-18.22(-22.14 to -14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: SD, standard deviation; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003ea\u003c/sup\u003e All models were adjusted for age, gender, family history of cancer, alcohol consumption, monthly household income, hepatitis C, comorbid diabetes, comorbid hypertension, hepatitis B, cirrhosis, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP, BCLC stage, previous liver surgery resection, TACE/HAIC and its frequency, and radiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Associations of depressive symptoms with PFS and OS\u003c/h2\u003e \u003cp\u003eDuring a median follow-up of 10 months, 31 patients died, and 124 patients experienced recurrence. The median PFS was 4.0 months (95% CI, 3.0 to 5.0 months), with a 1-year PFS rate of 16.8% (\u003cb\u003eeFigure 2A in the Supplement\u003c/b\u003e). The median OS was not reached, but the 1-year OS rate was 81.8% (\u003cb\u003eeFigure 2B in the Supplement\u003c/b\u003e). Patients with depressive symptoms had significantly worse PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) and OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) than those without depressive symptoms.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the associations of depressive symptoms with PFS, OS and RFS. After adjusting for potential confounders (in Model 3), elevated depressive symptoms at baseline were independently associated with an increased risk of recurrence (HR, 4.31; 95% CI, 2.75\u0026ndash;6.67) and death (HR, 5.39; 95% CI, 1.84\u0026ndash;15.82).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation of depressive symptoms with PFS and OS in patients with advanced hepatocellular carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eItem\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEvents / Total\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eModel 1 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eModel 2 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eModel 3 \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52/80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72/76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.46(2.36\u0026ndash;5.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.66(2.41\u0026ndash;5.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.31(2.75\u0026ndash;6.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24/76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.09(1.75\u0026ndash;9.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.76(1.77\u0026ndash;12.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.39(1.84\u0026ndash;15.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eAbbreviations: PFS, progression-free survival; OS, overall survival; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ea\u003c/sup\u003e Adjusted for age and gender.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003eb\u003c/sup\u003e Adjusted for age, gender, family history of cancer, alcohol consumption, monthly household income, hepatitis C, comorbid diabetes, comorbid hypertension, hepatitis B, cirrhosis, BMI, number of tumors, tumor diameter, extrahepatic metastasis, major vascular invasion, AFP, and BCLC staging.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003ec\u003c/sup\u003e Adjusted as model 2 plus previous liver surgery resection, TACE/HAIC and its frequency, and radiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThis study investigated the impact of depression on the efficacy of immunotherapy, QoL, and prognosis in patients with advanced HCC. The results showed that depression is common among HCC patients and significantly affects treatment outcomes and QoL. Patients in the depressed group had a significantly lower ORR and DCR than did those in the nondepressed group, along with a continuous decline in QoL. These findings underscore the importance of mental health, highlighting the need for the early identification of and intervention in depressive symptoms to optimize treatment outcomes.\u003c/p\u003e \u003cp\u003eMultiple studies have shown that depression is prevalent at various stages of cancer treatment. This study revealed a 48.7% incidence of depression in patients with advanced HCC, which is consistent with previous reports ranging from 28.3\u0026ndash;64.4%\u003csup\u003e26,27\u003c/sup\u003e. The high incidence of depression can be attributed to disease complexity, poor prognosis, and heavy treatment burden\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In China, where HCC is often caused by hepatitis B infection, patients frequently face social stigma, increasing the risk of depression\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe efficacy of immunotherapy is influenced by various factors, including the tumor immune microenvironment, PD-L1 expression levels, DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and circulating tumor DNA (ctDNA)\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. These factors, to some extent, determine the strength of a patient\u0026rsquo;s response to immunotherapy and the treatment outcomes. However, in recent years, psychological factors, particularly depression, have increasingly been recognized as important nonbiological factors affecting immunotherapy efficacy\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Depression not only impacts a patient's psychological state but also disrupts the normal function of the immune system through complex biological mechanisms\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. In this study, we observed that the ORR and DCR were 87% and 95% lower, respectively, in the depressed group than in the nondepressed group. These findings align with those of other cancer studies\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, indicating a close relationship between depression and cancer treatment outcomes, particularly suggesting that the efficacy of immunotherapy can be significantly reduced by depression.\u003c/p\u003e \u003cp\u003eDepression alters the tumor immune microenvironment in various ways. Specifically, it can reduce the activity of immune cells, especially T cells and natural killer (NK) cells, which play crucial roles in identifying and eliminating cancer cells. When patients are in a depressed state, this immune defense ability is weakened, giving tumor cells a greater chance of evading immune surveillance. Additionally, depression increases inflammatory responses and the secretion of stress hormones such as cortisol, further weakening the immune response. These hormones can inhibit T-cell proliferation and function, reducing their ability to recognize and attack cancer cells\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Moreover, depression may lead to an increased proportion of regulatory T cells (Tregs), which suppress immune responses in the tumor microenvironment, further promoting immune evasion by tumors. In this study, we revealed the negative impact of depression on immunotherapy efficacy. The underlying mechanisms include reduced immune cell activity, increased inflammatory responses, and overall suppression of the immune system. All of these changes work together to significantly diminish the effectiveness of immunotherapy. The findings of this study are also consistent with those performed with other cancer types, further supporting the close relationship between depression and immunotherapy efficacy. Therefore, this study highlights the profound impact of depression on immunotherapy outcomes. For patients with advanced HCC, immunotherapy is a promising treatment option, but if patients also experience depression, the treatment efficacy may be greatly compromised. Given the negative impact of depression on immunotherapy efficacy, early identification of and proactive intervention in depressive symptoms can not only improve patients' QoL but also potentially enhance the effectiveness of immunotherapy and ultimately prolong patient survival.\u003c/p\u003e \u003cp\u003eThis study also revealed that QoL in the depressed group declined continuously during immunotherapy, whereas that in the nondepressed group initially decreased but then gradually improved. Depression affects patients\u0026rsquo; physical, psychological, and social functions, reducing treatment compliance and worsening QoL\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Compared with nondepressed patients, those with depression are more susceptible to negative emotions, further exacerbating the decline in QoL. Given the adverse effects of depression on immunotherapy efficacy and QoL, early screening for and intervention in depression should be a priority in managing patients with advanced HCC\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Clinical healthcare providers can use psychological counseling, cognitive‒behavioral therapy, and other approaches to improve patients' mental health and enhance treatment outcomes\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. For high-risk patients, individualized intervention strategies and family and social support should be encouraged to help maintain a positive mindset\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDepression is closely associated with worse survival outcomes. In this study, the risks of disease progression and death in the depressed group were 4.31 times and 5.39 times greater, respectively, than those in the nondepressed group\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. This findings aligns with those of other cancer studies, indicating that depression weakens the immune system, delays recovery, and even promotes tumor metastasis\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The early identification of and intervention in depressive symptoms can improve the survival of HCC patients\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study has several notable strengths. First, as a prospective cohort study, it is well suited for the accurate assessment of the impact of depressive symptoms on the efficacy of immunotherapy in patients with advanced HCC. By longitudinally following patients, we were able to observe the dynamic changes in depressive symptoms in relation to the treatment outcomes, QoL, and prognosis. Second, the study utilized validated tools for depression screening (PHQ-9) and QoL assessment in cancer patients (FACT-Hep), ensuring the reliability and validity of the mental health and QoL data. Furthermore, the study included multiple clinical outcome measures, such as the ORR, DCR, PFS, and OS, providing a solid foundation for the comprehensive evaluation of the impact of depression on immunotherapy. Despite providing valuable insights, this study has several limitations. First, while the sample size was sufficient for the primary analysis, it may not fully represent the diversity of patients with advanced HCC, especially with regard to genetic and cultural factors\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Second, the study relied on self-reported measures of depression and QoL, which, despite the use of standardized tools, may introduce bias when the study involves patients with advanced disease\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Third, although adjustments were made for several confounding factors, unmeasured variables such as genetic susceptibility or environmental influences may still exist\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Future research should aim to validate these findings through larger, multicenter studies and explore the biological mechanisms linking depression and immunotherapy outcomes to identify potential therapeutic targets\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. Additionally, depression intervention trials are needed specifically for cancer patients receiving immunotherapy to determine the best strategies for alleviating psychological distress and improving treatment outcomes and QoL\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"5 Conclusions","content":"\u003cp\u003eThis study revealed significant associations among depression, the effectiveness of immunotherapy, and QoL in patients with advanced liver cancer, with depressed patients having worse treatment outcomes. This research emphasizes the importance of regular depression screening and psychological interventions to improve treatment efficacy. A multidisciplinary approach that addresses both physical and mental health is crucial, and further research is needed to develop effective mental health interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest disclosures\u003c/h2\u003e \u003cp\u003eAll the authors have nothing to disclose.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDeclaration of conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare that are relevant to the content of this article.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Natural Science Foundation of China (81960308).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eFei-Chen Lu designed the study and developed the research protocol. Fan-Rong Li and Feng-Juan Zhao conducted data collection and performed statistical analyses. Rong-Rui Huo interpreted the results and provided critical revisions to the manuscript. Fei-Chen Lu and Fan-Rong Li wrote the main manuscript text, and Feng-Juan Zhao prepared figures 1-3 and tables 1-2. All authors reviewed and approved the final version of the manuscript.Corresponding Author: Xue-Mei You supervised the overall study and reviewed and approved the final version of the manuscript. For any inquiries, please contact Xue-Mei You (email: [email protected]).\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eThe data are available upon request due to privacy/ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Eur Neuropsychopharmacol. 2021;45:89\u0026ndash;107. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.euroneuro.2020.11.016\u003c/span\u003e\u003cspan address=\"10.1016/j.euroneuro.2020.11.016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Depression, Advanced liver cancer, Immunotherapy, Quality of life, Prognosis, Longitudinal study","lastPublishedDoi":"10.21203/rs.3.rs-5768098/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5768098/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDepression is prevalent among individuals with cancer. This prospective cohort study aims to examine the relationships between depressive symptoms and both quality of life (QoL) and treatment efficacy in patients with intermediate or advanced hepatocellular carcinoma (HCC) who are receiving immunotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA cohort of 156 patients with intermediate or advanced HCC who were receiving immunotherapy was included in the analysis. Depressive symptoms were evaluated utilizing the Patient Health Questionnaire-9 (PHQ-9). The primary outcome was progression-free survival (PFS), whereas the secondary outcomes were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and QoL.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNearly half (48.7%) of the patients exhibited depressive symptoms. Over a median follow-up period of 10 months, patients with depressive symptoms had significantly lower PFS (HR 4.31, 95% CI: 2.75\u0026ndash;6.76) and significantly shorter OS (HR 5.39, 95% CI: 1.84\u0026ndash;15.82). Furthermore, the ORR and DCR were notably lower in patients with depressive symptoms (ORR 10.5% compared with 37.5%; DCR 52.6% compared with 91.2%). QoL scores were significantly lower at all assessed time points for patients with depressive symptoms, indicating worse overall well-being.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDepression is significantly associated with the efficacy of immunotherapy in HCC patients and is negatively associated with both clinical outcomes and QoL. Addressing mental health is essential for optimizing treatment strategies and improving overall patient outcomes in this population.\u003c/p\u003e","manuscriptTitle":"Association of depressive symptoms with quality of life and treatment efficacy in patients with intermediate or advanced hepatocellular carcinoma receiving immunotherapy: A prospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-08 10:37:59","doi":"10.21203/rs.3.rs-5768098/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f54fe16-16e7-424f-aca7-0a94c812d1a9","owner":[],"postedDate":"January 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-04T09:27:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-08 10:37:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5768098","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5768098","identity":"rs-5768098","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}