Distinct Clinical Features and Prognostic Factors in Hepatitis C Virus-Associated Non-Hodgkin’s Lymphoma: A Systematic Review and Meta-Analysis

Distinct Clinical Features and Prognostic Factors in Hepatitis C Virus-Associated Non-Hodgkin’s Lymphoma: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Primary research Distinct Clinical Features and Prognostic Factors in Hepatitis C Virus-Associated Non-Hodgkin’s Lymphoma: A Systematic Review and Meta-Analysis Minyue Zhang, Fei Gao, Ling Peng, Lijing Shen, Peng Zhao, Beiwen Ni, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-472650/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: Increasing evidence suggested that hepatitis C virus (HCV) infection was associated with non-Hodgkin’s lymphoma (NHL). However, no clear consensus has been reached about the clinical features and the effective treatment in HCV-associated NHL patients. We therefore performed a systematic review and meta-analysis to explore the clinical characteristics and effect of antiviral treatment or rituximab administration in NHL patients with HCV infection. Methods : PubMed, Embase, Web of Science, and OVID database were searched for eligible studies up to Feb 28, 2021. Hazard ratio (HR) or odds ratio (OR) corresponding to 95% confidence interval (CI) were calculated to estimate outcomes. Publication biases were assessed by Egger's test and Begg's test. Statistical analysis was performed by software RevMan 5.4 and Stata version 15. Results: There were 27 shortlisted articles out of a total of 13368 NHL patients included in the current meta-analysis. Our results demonstrated that NHL patients with HCV infection showed significantly shorter overall survival (OS: HR 1.89; 95% CI 1.42-2.51, P<0.0001) and progress-free survival (PFS: HR 1.58; 95% CI 1.26-1.98, P<0.0001), lower overall response rate (ORR: OR 0.58, 95% CI 0.46-0.73, P<0.00001) and higher incidence of hepatic dysfunction during chemotherapy (OR 5.96; 95% CI 2.61-13.62, P<0.0001) compared with NHL patients without HCV infection. HCV-positive NHL patients exhibited advanced disease stage, elevated level of LDH, high-intermediate and high IPI/FLIPI risk as well as higher incidence of spleen and liver involvement. Moreover, antiviral treatment could prolong survivals (OS: HR 0.38; 95% CI 0.24-0.60, P<0.0001), reduce disease progression [PFS/DFS (disease-free survival): HR 0.63; 95% CI 0.46-0.86, P=0.003] and reinforce treatment response (ORR: OR 2.62; 95% CI 1.34-5.11, P=0.005) in HCV-infected NHL patients. Finally, rituximab administration was associated with a favorable OS while liver cirrhosis and low levels of albumin were inferior prognostic factors of OS for HCV-positive NHL patients. Conclusions: The current study provided the compelling evidence about an inferior prognosis and distinct clinical characteristics in HCV-associated NHL patients. Antiviral treatment and rituximab-containing regimes were shown to be efficacious to improve clinical outcomes of NHL patients with HCV infection. Cancer Biology non-Hodgkin’s lymphoma HCV infection prognosis antiviral treatment meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Non-Hodgkin’s lymphoma (NHL) is a group of lymphoid malignancies with high heterogeneity. It can be classified into B-cell, T-cell, and natural killer (NK)-cell lymphoma. Increasing evidence has implicated that pathogen infection contributed to the pathogenesis of different subtypes of lymphoma, such as Epstein-Barr virus (EBV) in Hodgkin disease or Burkitt’s lymphoma, human T-cell leukemia virus type 1 in adult T cell leukemia and lymphoma, and Helicobacter pylori in gastric mucosa-associated lymphoid tissue [ 1 – 3 ]. According to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms, two subtypes of NHL associated with specific viral infection, EBV-positive diffuse large B-cell lymphoma (DLBCL) and human herpesvirus type-8 (HHV-8)-positive DLBCL, have been classified as separated subtypes of DLBCL [ 4 ]. These new categories strongly suggested that NHL patients with specific infection displayed distinct clinical manifestations and prognosis. Recently, hepatitis C virus (HCV) was found in peripheral blood mononuclear cells and lymph nodes [ 5 , 6 ] and hepatitis C NS3 protein could be detected in tumor cells from patients with HCV-associated B cell-lymphoma [ 7 ], hence suggesting that HCV is also lymphotropic. On the other hand, meta-analysis provided quantitative evidence that HCV infection could lead to a 2.5-fold increased risk of developing NHL [ 8 ]. Nevertheless, the clinical characteristics and prognosis of HCV-associated lymphoma is still undefined. Arising clinical attention to the association of HCV infection and clinical outcomes of NHL patients has been paid. However, the results were still inconsistent based on existing retrospective studies with small sample sizes [ 9 – 18 ]. Hosry J et al [ 17 ] found that HCV-associated DLBCL had unique clinical features and poor outcomes. However, other studies [ 14 , 18 ] had shown that HCV infection was not associated with NHL patients’ survivals. In addition, increasing studies have explored the survival benefit of antiviral treatment or rituximab-containing chemotherapy in NHL patients with HCV infection yet results were also controversial [ 15 , 19 – 22 ]. In view of the limitations of previous studies, we hereby performed a systematic review and meta-analysis aiming to evaluate the clinical features and prognostic factors in HCV-associated NHL patients. Moreover, the effect of antiviral treatment and rituximab administration on NHL patients with HCV infection was also investigated in the current study. Methods Identification of relevant studies To identify all studies that explored the impact of HCV infection on the clinical outcomes of NHL patients or the effect of antiviral treatment and rituximab administration on NHL patients with HCV infection, a literature search of four electronic databases, including PubMed, OVID, Web of Science, and Embase, up to Feb 28, 2021, was conducted. The search strategy was based on combinations of the following keywords and search terms without language limitation: (“lymphoma” [MeSH] or “Lymphoma, Non-Hodgkin” [MeSH] or “Non-Hodgkin lymphoma” or “NHL”) AND (“hepatitis C” [MeSH] or “hepatitis C virus” or “HCV” or “Hep C virus” or “Hep C”). References of the retrieved studies, meeting abstracts, relevant meta-analyses and systematic reviews were also screened. Case reports, editorials and review articles were excluded. When a publication overlapped with other publication of the same trial, only the article with more details or the most recent article was retained. Selection criteria The studies included in the meta-analysis should satisfy all the following criteria: (1) the study population was NHL patients; (2) the study consisted of two groups: NHL patients with and without HCV infection, or HCV infected NHL patients receiving and not receiving antiviral/rituximab treatment; (3) clinical features and survivals between two groups of patients were compared. Exclusion criteria were: (1) patients co-infected with human immunodeficiency virus (HIV); (2) patient with post-transplant lymphoproliferative disorder; (3) patient number less than or equal to ten in any study groups. When the relevant data was not reported in paper, we contacted the author to get the relevant information by e-mail or telephone. The primary outcomes assessed the impact of HCV infection on NHL patients’ prognoses, including overall survival (OS) and disease progression [progress-free survival (PFS) / disease-free survival (DFS)]. The other outcomes measured treatment response [overall response rate (ORR)] and clinical characteristics of NHL patients with HCV infection, including age of disease onset (< 60 years old), presence of B symptoms, advanced disease stage (Ann Arbor staging III/IV), involvement of spleen, liver and bone marrow, elevated LDH level, high-intermediate and high IPI/FLIPI risk and incidence of hepatic dysfunction during chemotherapy. Furthermore, the effect of antiviral therapy or rituximab administration as well as liver-related prognostic factors for HCV-positive NHL patients was also investigated. Since PFS and DFS were similar outcomes of disease progression, we pooled PFS and DFS as the same outcome indicators to analyze in the current study. Data extraction and study quality Two reviewers (Gao F and Peng L) independently extracted data and outcomes using an electronic standard form. The following information from each study was summarized: (1) first author, (2) year of publication, (3) country, (4) subtypes of NHL, (5) number of patients with and without HCV infection, (6) number of HCV positive NHL patients receiving and not receiving antiviral/rituximab treatment, (7) anti-lymphoma therapeutic regimens, (8) antivirus treatment regimens, (9) patient’s characteristics. Any discrepancies amongst the two reviewers were resolved by an additional investigator, Zhang M. Quality assessment Newcastle-Ottawa Quality Assessment Scale (NOS) was adopted to assess the methodological quality of the included studies [ 23 ]. The following three items were evaluated including: (1) patient selection, (2) comparability of interventions and observations group, and (3) assessment of outcome. Statistical analysis Hazard ratio (HR) corresponding to 95% confidence interval (CI) were used to assess OS and PFS/DFS. If both univariate and multivariate analyses results were reported in the included study, the latter will be used in the meta-analysis. If HRs and 95% CIs were not available from the original article, Kaplan–Meier curves of the included studies were read and re-analyzed by software Engauge digitizer. HRs and 95% CIs were indirectly calculated from Kaplan–Meier curve using Tierney’s methods [ 24 ]. Odds ratio (OR) corresponding to 95% CI were calculated to estimate other outcomes. Publication biases were assessed by Egger's test and Begg's test. When the outcome with less than five included studies, publication biases was not performed. The methods of meta-analysis and publication biases tests were detailed in our previous publications [ 25 – 28 ]. Statistical analysis was performed by software ReviewManager 5.4 (The Cochrane Collaboration, Oxford, UK) and Stata version 15 (Stata Corp, College Station, Texas, USA). All P-values were both-sided and P-value of < 0.05 was considered significance. Results Characteristics of studies After the comprehensive literature search based on the criteria above, 2599 articles were identified as potentially relevant publications. Upon further evaluation of the full-text, 17 articles were excluded from the calculations of this systematic review. Thus, 27 articles (29 studies) [ 9 – 22 , 29 – 41 ] with a total of 13368 NHL patients, including 3063 patients with HCV infection and 10305 patients without HCV infection, fulfilled the inclusion criteria and were included in current meta-analysis (Figure.1). The characteristics of the included articles were summarized in Table 1 . The articles were published between 1997 and 2020 with sample size ranging from 58 to 5586. Majority of studies were conducted in Italy (n = 11), Japan (n = 4), Egypt (n = 3), China (n = 2), French (n = 2) and the United States (n = 2). The other articles consisted of single study conducted in Russia, Korea, and Spain. Among the included articles, 14 articles focused on DLBCL, two articles on follicular lymphoma and two articles on marginal zone lymphoma. In addition to the aforementioned lymphoma subtypes, the patients in 9 articles consisted of more than two subtypes of NHL. With regards to the methodological quality, most of included articles had reliable quality as indicated by NOS scores ≥ 6 points except for 2 articles [ 30 , 38 ] with NOS scores 5 points (Table S1). Table 1 Baseline characteristics of included studies Author year Country Diagnosis Regimes of anti-lymphoma treatment Regimes of AT treatment Follow-up (m) Median (range) HCV infection R use in HCV + patients AT in HCV + patients Hazard ratio yes no yes no yes no Besson C [ 9 ] 2006 France DLBCL - - 47 (0-112) 26 5560 - - - - Extrapolated Chen TT [ 10 ] 2015 China DLBCL I-CHT - 36 (0.84–96.24) 29 139 29 0 - - Extrapolated Chen YY [ 11 ] 2015 China DLBCL I-CHT - - 22 102 15 7 - - Reported Dlouhy I [ 12 ] 2017 Spain DLBCL I-CHT - 48 (1.2-146.4) 31 290 31 0 - - Extrapolated Elbedewy TA [ 13 ] 2020 Egypt DLBCL I-CHT - - 76 277 33 43 34 42 Reported Ennishi D [ 14 ] 2010 Japan DLBCL I-CHT DAA HCV + 31 (4–42) HCV- 32 (5–51) 131 422 131 0 7 124 Reported Hosry J [ 17 ] 2016 USA DLBCL I-CHT IFN, Rib, DAA > 6 76 228 76 0 26 40 Extrapolated Nishikawa H [ 29 ] 2012 Japan DLBCL I-CHT - HCV + 40.8 (3.6–92.4) HCV-31.2 (2.4–94.8) 28 220 28 0 0 28 Extrapolated Park BB [ 16 ] 2008 Korea DLBCL I-CHT - 37.8 32 371 - - - - Extrapolated Shimono J [ 18 ] 2019 Japan ps-DLBCL I-CHT - HCV + 46.9(4.0–94.3) HCV- 36.8 (0.8–133.5) 12 46 10 2- - - Extrapolated Ordinary DLBCL I-CHT - HCV + 27.8 (1.9–122.1) HCV- 35.9 (0.1–90.1) 25 120 - - - - Extrapolated Arcaini L [ 30 ] 2007 Italy Non-gastric MALToma CHT, RT, surgery - - 60 112 - - - - Extrapolated Arcaini L[ 31 ] 2006 Italy SMZL splenectomy, IFN - 37.2 49 206 - - - - - Hosry J [ 32 ] 2020 USA FL I-CHT, RT IFN, Rib, DAA - 19 57 - - 13 6 - Nesterova E [ 33 ] 2020 Russia FL I-CHT DAA - 11 105 11 0 11 0 - De Vita S [ 34 ] 1997 Italy B-NHL - - - 35 122 - - - - - Luppi M [ 35 ] 1998 Italy B-NHL IFN, CHT - 72 35 122 0 35 - - Extrapolated La Mura V [ 36 ] 2008 Italy NHL CHT IFN, Rib - 69 274 0 69 25 44 Extrapolated Strianese D [ 37 ] 2010 Italy OA lymphoma I-CHT, RT - mean 75 (12–185) 23 106 - - - - Extrapolated Tajima K [ 38 ] 2017 Japan NHL - - - 66 1316 - - - - - Vallisa D [ 39 ] 1999 Italy NHL CHT, surgery - 30 (1–68) 65 110 0 65 - - - Arcaini L [ 19 ] 2014 Italy indolent NHL surgery, I-CHT, RT IFN, Rib 42 (6-204) 704 0 126 578 134 570 Reported Merli M [ 15 ] 2014 Italy DLBCL surgery, I-CHT, RT IFN, Rib 24 (12–168) 535 0 255 280 23 512 Reported Michot JM [ 20 ] 2015 French NHL surgery, I-CHT, RT IFN, Rib 31(19–71) 116 0 - - 70 46 Reported Persico M [ 40 ] 2018 Italy DLBCL I-CHT DAA 12 121 0 70 51 20 101 Extrapolated Rattotti S [ 21 ] 2019 Italy Indolent NHL I-CHT, antibiotics IFN, Rib 36 (1-84) 138 0 - - 36 102 Extrapolated Aggressive NHL 112 0 - - 17 95 Salah-Eldin MA [ 41 ] 2014 Egypt DLBCL I-CHT - 41 (38.6–43.4) 280 0 200 80 0 0 Reported Zaky AH [ 22 ] 2014 Egypt DLBCL I-CHT - 36 (5–42) 137 0 68 69 - - Extrapolated Abbreviation AT: antiviral treatment; CHT: chemotherapy; DAA: direct-acting antiviral; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; I-CHT: immunochemotherapy; IFN: interferon; MALToma: mucosa-associated lymphoid tissue lymphoma; NHL: non-Hodgkin’s lymphoma; OA: ocular adnexal; ps-DLBCL: primary splenic diffuse large B-cell lymphoma; SMZL: splenic marginal zone lymphoma; R: rituximab; RT: radiotherapy; Rib: Ribavirin The impact of HCV infection on NHL patients’ prognosis Among all 27 studies, 15 studies were available for analyses of OS. Due to obvious heterogeneity among these studies (I 2 = 47%, P heterogeneity =0.02), a random-effects model was employed to pool all of HRs and their 95% CIs. Meta-analysis revealed that HCV positive patients had significantly worse OS than HCV negative patients (HR 1.89; 95% CI 1.42–2.51, P < 0.0001; Figure. 2a). A total of 8 studies were eligible for the assessment of PFS. The fixed-effects model was used to calculate the result as there was no heterogeneity among the included studies (I 2 = 0%, P heterogeneity =0.59). Similarly, the result demonstrated that patients with HCV infection showed significantly shortened PFS compared with the patients without HCV infection (HR 1.58; 95% CI 1.26–1.98, P < 0.0001; Figure. 2b). HCV infection and treatment response Eleven studies were identified to assess ORR between NHL patients with and without HCV infection. The OR and 95% CI of ORR was pooled by using fixed-effects model as the heterogeneity tests suggested no significant heterogeneity (I 2 = 28%, P heterogeneity =0.18). The combined results showed that ORR of HCV-positive NHL patients was significantly lower than that of HCV-negative NHL patients (OR 0.58, 95% CI 0.46–0.73, P < 0.00001, Figure. 3). HCV infection and hepatic dysfunction during chemotherapy Totally, 7 studies including 2095 participants (DLBCL patients) were eligible to analyze this outcome by the random-effects mode (I 2 = 78%, P heterogeneity =0.0001). As shown in Figure. 4, higher incidence of hepatic dysfunction during chemotherapy was observed in HCV infected patients in comparison to HCV non-infected patients (OR 5.96; 95% CI 2.61–13.62, P < 0.0001). HCV infection and clinical characteristics Clinical features of NHL patients were also comprehensively compared between HCV positive and negative NHL patients. The results indicated that HCV infection was associated with advanced disease stage (OR 1.42, 95% CI 1.14–1.76, P = 0.001, Figure. S1), elevated level of LDH (OR 1.44; 95% CI 1.17–1.79, P = 0.0008, Figure. S2), high-intermediate and high IPI/FLIPI risk (OR 1.29; 95% CI 1.07–1.56, P = 0.008, Figure. S3), as well as higher incidence of spleen involvement (OR 2.95; 95% CI 2.17–4.02, P < 0.00001, Figure. S4) and liver involvement (OR 2.01; 95% CI 1.46–2.78, P < 0.0001, Figure. S5). However, there was no significant difference in age of disease onset (Figure. S6), presence of B symptoms (Figure. S7) and incidence of involvement of bone marrow (Figure. S8) between two groups of patients. Effect of antiviral treatment and rituximab administration on HCV-associated NHL patients Since NHL patients with HCV infection were found to have disadvantages of survivals and treatment response, whether antiviral treatment may improve clinical outcomes of HCV-associated NHL patients was also investigated. Of all the studies reviewed, 9 studies including 1838 HCV infected NHL patients were included to evaluate the impact of antiviral treatment on OS, PFS/DFS and ORR. As shown in Fig. 5 , antiviral treatment was associated with improved OS (HR 0.38; 95% CI 0.24–0.60, P < 0.0001; Figure. 5a) and PFS/DFS (HR 0.63; 95% CI 0.46–0.86, P = 0.003; Figure. 5b), as well as higher ORR (OR 2.62; 95% CI 1.34–5.11, P = 0.005, Figure. 5c) in comparison with patients without antiviral treatment. In addition, we also explored whether rituximab-containing regimes could improve the clinical prognosis of HCV positive NHL patients. Four studies comprising of 688 participants (DLBCL patients) were evaluated. The results demonstrated that patients treated with rituximab-containing chemotherapy exhibited favorable OS compared with those receiving rituximab-free chemotherapy (HR 0.68; 95% CI 0.54–0.86, P = 0.001; Figure. 6a). However, no difference in PFS was observed between these two groups of patients (HR 0.97; 95% CI 0.70–1.36, P = 0.88; Figure. 6b). Liver-related survival factors in HCV-associated NHL patients We subsequently evaluated liver-related survival factors in HCV-associated NHL patients, including liver cirrhosis, liver involvement, low level of albumin (< 3.5 g/dl) and elevated alanine transaminase (ALT). As shown in Figure. 7a-d, low level of albumin (HR 2.61; 95% CI 1.71–3.97, P < 0.00001; Figure. 7a) and liver cirrhosis (HR 2.91; 95% CI 1.44–5.88, P = 0.003; Figure. 7b) were significantly associated with inferior OS. There was a trend for an association between liver involvement and short OS (HR 1.27; 95% CI 0.96–1.67, P = 0.09; Figure. 7c). However, no association was found between elevated ALT and OS (HR 1.09; 95% CI 0.86–1.37, P = 0.50; Figure. 7d). Subgroup analysis Firstly, subgroup analysis was conducted based on prevalence of HCV infection. According to the report of prevalence of HCV infection form global hepatitis report 2017 from WHO [ 42 ], the countries of included studies were divided into high prevalence of HCV infection, including Italy, Spain, French, Russia and Egypt, and low prevalence of HCV infection, including the United States, Japan, Korea, and China (cut-off value of HCV infection prevalence as 1.5%). The results of subgroup analysis were shown in Table 2 (high prevenance) and Table 3 (low prevenance). Compared with the results from overall population, similar results could be observed from subgroup analysis. NHL patients with HCV infection had inferior prognosis, lower treatment response and high incidence of hepatic dysfunction in both sub-populations. With regards to clinical features, HCV infection had no effect on the IPI/FLIPI risk in neither of subgroups of patients, which was inconsistent with this outcome in overall population. In addition, HCV-associated NHL patient had an early age of disease onset among the countries with lower prevalence of HCV infection. For the outcomes of the effect of antiviral and rituximab treatment as well as survival factors in HCV-positive NHL patients, all the included studies were performed in the countries with high prevalence of HCV infection except one study [ 17 ]. Therefore, subgroup analysis was not performed. Table 2 Subgroup analysis in countries with high prevalence of HCV infection Outcome Studies HR/OR (95%CI) P value Heterogeneity I 2 % P value Impact of HCV infection Overall survival 7 2.07 (1.37–3.14) 0.0006 61 0.02 Progress-free survival 2 1.89 (1.27–2.82) 0.002 0 0.66 Overall response rate 6 0.51 (0.38–0.68) < 0.00001 46 0.10 Hepatic dysfunction 2 30.13 (1.75-517.77) 0.02 84 0.01 Age of onset 5 1.04 (0.50–2.16) 0.92 79 0.0009 Advanced disease stage 11 1.53 (1.22–1.91) 0.0002 44 0.06 Presence of B symptom 6 0.99 (0.53–1.84) 0.97 63 0.02 Elevated LDH level 5 1.33 (0.96–1.84) 0.09 49 0.10 H-I/H risk 6 1.53 (0.96–2.44) 0.07 60 0.03 Spleen involvement 4 3.74 (2.32–6.02) < 0.00001 0 0.52 Liver involvement 5 1.98 (1.23–3.20) 0.005 41 0.15 Bone marrow involvement 6 1.39 (0.97-2.00) 0.07 46 0.10 Abbreviation: H-I/H high-intermediate and high Table 3 Subgroup analysis in countries with low prevalence of HCV infection Outcome Studies HR/OR (95%CI) P value Heterogeneity I 2 % P value Impact of HCV infection Overall survival 8 1.59 (1.16–2.17) 0.004 16 0.31 Progress-free survival 6 1.45 (1.10–1.90) 0.008 0 0.52 Overall response rate 5 0.70 (0.49-1.00) 0.05 0 0.59 Hepatic dysfunction 5 3.87 (1.60–9.36) 0.003 76 0.002 Age of onset 4 1.97 (1.18–3.28) 0.01 4 0.37 Advanced disease stage 10 1.22 (0.98–1.52) 0.07 28 0.18 Presence of B symptom 4 0.80 (0.53–1.21) 0.30 47 0.13 Elevated LDH level 6 1.54 (1.16–2.04) 0.003 26 0.24 H-I/H risk 8 1.16 (0.89–1.51) 0.26 0 0.52 Spleen involvement 5 2.48 (1.65–3.74) < 0.0001 0 0.63 Liver involvement 7 2.04 (1.32–3.15) 0.001 17 0.30 Bone marrow involvement 8 0.98 (0.72–1.34) 0.90 0 0.46 Abbreviation: H-I/H high-intermediate and high Since NHL is a group of heterogenous diseases, we performed subgroup analysis based on pathological types of NHL. In the current study, majority of the included studies focused on DLBCL hence subgroup analysis was conducted in DLBCL patients. Similar to overall patients, DLBCL patients with HCV infection had shorter OS and PFS, lower ORR and distinct clinical features in comparison to DLBCL patients without HCV infection. Moreover, HCV-associated DLBCL patients receiving antiviral treatment shared a better OS and PFS/DFS than patients without antiviral treatment. Due to small sample size, subgroup analysis was not performed in terms of the outcomes of liver-related survival factors. The results of subgroup analysis in DLBCL patients were summarized in Table 4 . Table 4 Subgroup analysis in DLBCL patients Outcome Studies HR/OR (95%CI) P value Heterogeneity I 2 % P value Impact of HCV infection Overall survival 11 2.29 (1.85–2.84) < 0.00001 46 0.05 Progress-free survival 7 1.55 (1.23–1.95) 0.0002 0 0.54 Overall response rate 8 0.55 (0.42–0.72) < 0.00001 23 0.24 Hepatic dysfunction 6 5.89 (2.31–15.01) 0.0002 82 < 0.0001 Age of onset 7 1.31 (0.67–2.57) 0.43 70 0.003 Advanced disease stage 11 1.20 (0.98–1.48) 0.08 14 0.31 Presence of B symptom 6 1.16 (0.70–1.94) 0.56 59 0.03 Elevated LDH level 9 1.47 (1.17–1.85) 0.0009 46 0.06 H-I/H risk 10 1.34 (1.07–1.67) 0.01 0 0.48 Spleen involvement 5 2.75 (1.92–3.95) < 0.00001 0 0.55 Liver involvement 7 1.87 (1.22–2.85) 0.004 0 0.60 Bone marrow involvement 6 1.03 (0.71–1.50) 0.86 17 0.31 Impact of anti-viral treatment Overall survival 5 0.40 (0.24–0.66) 0.0003 37 0.18 Progress-free survival 4 0.60 (0.39–0.92) 0.02 41 0.17 Abbreviation: H-I/H high-intermediate and high In terms of antiviral treatment, subgroup analysis was performed based on the regimes of antiviral treatment. Among the 9 included studies, patients in most studies (n = 6) received interferon (IFN) +/- ribavirin as antiviral treatment. Only two study [ 13 , 40 ] focused on new direct-acting antiviral (DAA) treatments of HCV and another study [ 17 ] consisted of different types of antiviral treatment. Therefore, subgroup analysis was conducted in patients receiving IFN +/- ribavirin. The results suggested that patients receiving IFN +/- ribavirin had obvious improved OS (HR 0.25; 95% CI 0.12–0.52, P = 0.0002, figure not shown) and PFS (HR 0.63; 95% CI 0.44–0.90, P = 0.01, figure not shown) in comparison with patients without antiviral treatment. Sensitivity analysis Sensitivity analysis was performed by a sequential exclusion of individual studies to find the origin of the heterogeneity and verify the sensitivity of results. The origin of the heterogeneity and overall effect after removal of origin of the heterogeneity for each outcome were summarized in Table 5 . The results showed that removal of the origin of the heterogeneity did not affect the effect size for each outcome, suggesting the stability of the result of meta-analysis. However, for the outcomes of age of disease onset, hepatic dysfunction during chemotherapy and liver cirrhosis, the heterogeneity still existed even though studies were excluded one by one. Table 5 Results of sensitivity analysis Outcome Origin of heterogeneity Overall effect P value Overall survival Dlouhy I 2017 [ 12 ] 1.78 (1.45–2.18) < 0.00001 Advanced disease stage Vallisa D 1999 [ 39 ] 1.28 (1.09–1.51) 0.003 Presence of B symptoms Arcaini L 2006 [ 31 ] 1.09 (0.84–1.41) 0.51 Liver cirrhosis Hosry J 2016 [ 17 ] 1.84 (1.26–2.69) 0.002 Publication bias Begg’s test and Egger’s test were performed to assess the publication bias. As was shown in Table 6 , no significant publication bias was observed for all the outcomes. Table 6 Results of Begg’s test and Egger’s test Outcome P Begg’s test P Egger’s test Impact of HCV infection Overall survival 1.000 0.619 Progress-free survival 0.386 0.871 Overall response rate 0.276 0.373 Hepatic dysfunction 0.452 0.236 Age of onset 1.000 0.499 Advanced disease stage 0.162 0.468 Presence of B symptom 0.074 0.065 Elevated LDH level 0.533 0.639 H-I/H risk 0.125 0.379 Spleen involvement 0.386 0.878 Liver involvement 1.000 0.895 Bone marrow involvement 0.100 0.167 Impact of antiviral treatment Overall survival 0.917 0.407 Progress-free survival 0.260 0.070 Liver-related survival factors Liver cirrhosis 0.707 0.262 Abbreviation: H-I/H high-intermediate and high Discussion Over the past two decades, considerable studies have been investigated the contribution of HCV infection to lymphomagenesis. However, the mechanisms of HCV-associated lymphoma remained elusive. Experimental data implicated that HCV-induced lymphoma development may act through multistep processes, resulting from a variety of oncogenic mechanisms, such as HCV-induced chronic B-cell immune-stimulation, genetic damages, dysregulation of signaling pathways (NF-kB, JNF, ERK and NOTCH signaling pathways), etc. [ 43 – 48 ]. A prognostic evaluation of clinical outcomes and therapeutic responses in HCV-associated lymphoma is essential to antitumor treatment. Herein, we performed a systematic review and meta-analysis to assess the impact of HCV infection on NHL patients. Furthermore, subgroup analysis was also performed based on the prevenance of HCV infection and pathological types of lymphoma. The results of current study collectively indicated that HCV-positive NHL patients had significantly inferior survival, earlier disease progression, poorer treatment response and distinct clinical characters. In addition to recognized survival factors of NHL, our study also demonstrated that liver cirrhosis and low level of albumin were inferior prognostic factors of OS for HCV-associated NHL patients. Furthermore, this study implicated the anti-lymphoma efficacy of antiviral treatment, especially IFN+/- ribavirin regimes, in HCV-associated NHL patients, which was similar to the recent meta-analysis conducted by Peveling-Oberhag, et al [ 49 ]. The authors found the good overall lymphoma response rate through the application of antiviral treatment in HCV-infected NHL patients. However, their meta-analysis was based on small studies, mostly case reports or small cohorts with less than 20 cases. Nevertheless, DAA treatments are radically changing the landscape of anti-HCV therapy. In the current study, whether HCV-associated NHL patients can benefit from DAA treatment couldn’t be expounded due to small patient sample size. In the era of DAA, future studies should illuminate the anti-lymphoma activity of DAA treatment in NHL patients with HCV infection. On the other hand, rituximab-containing regimes have been proven to be associated with better treatment response and clinical prognosis in DLBCL over the past two decades. In the current study, we also found that rituximab administration could improve OS in DLBCL patients with HCV infection. However, the association between PFS and rituximab administration couldn’t be observed in this specific subtype of DLBCL patients, which might be due to small samples size. Whether rituximab-containing regimes can improve treatment response and PFS warrants further study with large cohorts. To the best of our knowledge, this is the first meta-analysis that systematically assessed the clinical outcomes and treatment of HCV-associated NHL patients. We are confident that our results were reliable, which was supported by large sample size, moderate to high methodological quality of included studies, low heterogeneity, and no publication bias. However, there were several limitations in this study. Firstly, when evaluating OS or PFS/DFS, HR and 95% CI in some of individual studies were not available from the original articles, hence they were indirectly calculated from Kaplan-Meier curve. Secondly, our study implicated that higher incidence of hepatic dysfunction was observed in HCV infected NHL patients, probably leading to delay or termination of chemotherapy or even death. However, the direct cause-and-effect relationship between hepatic dysfunction and inferior prognosis remained unknown. On the other hand, it was still unclear whether survival benefit of antiviral treatment attributed to restoring hepatic dysfunction and reducing chance of termination or delay of chemotherapy caused by HCV-induced hepatotoxicity so far. Third, our study indicated that HCV infection was associated with poor survivals in NHL patients. Despite we attempted to further perform prognostic evaluation of HCV viral loading (HCV-RNA) in HCV infected NHL patients. However, only two articles investigated prognostic value of HCV-RNA and the results were contradictory. Fourthly, it should be noted that when analyzing some outcomes, such as prognostic factors and effect of rituximab administration in HCV-associated NHL patients, only a few studies with small sample size could be included. Therefore, the results of these outcomes need to be interpreted with caution. Lastly, patients in most of included studies were DLBCL. There were only a few studies focusing on indolent lymphoma, such as follicular lymphoma and marginal zone lymphoma hence subgroup analysis could not be carried out in indolent lymphoma patients. In view of the limitations of the current study, well-designed perspective studies with large cohorts should be performed in different subtypes of NHL, especially indolent lymphoma, to address the issues mentioned above in the future. Conclusions This meta-analysis confirmed the inferior prognosis and distinct clinical characteristics in HCV-associated NHL patients, especially in DLBCL. Patients with HCV infection were prone to undergoing hepatic dysfunction during the chemotherapy. Moreover, our data provided the compelling evidence that antiviral treatment combined with immunochemotherapy may represent an effective approach for HCV-positive NHL patients Abbreviations ALT alanine transaminase CI confidence interval DAA direct-acting antiviral DFS disease-free survival DLBCL diffuse large B-cell lymphoma HCV hepatitis C virus HR hazard ratio IFN interferon NHL non-Hodgkin’s lymphoma NOS Newcastle-Ottawa Quality Assessment Scale PFS progress-free survival OR Odds ratio ORR overall response rate OS overall survival WHO World Health Organization Declarations Availability of data and materials The datasets used in this study are available from the corresponding author upon reasonable request. Acknowledgements We would like to thank Dr. Lok Hay Yim for her guidance on this article and for her editing and proofreading of this English manuscript. Funding This work was supported by Science and Technology Development Foundation of Shanghai Pudong New Area health and Family Planning Commission (PW2015E-1) and National Natural Science Foundation of China (81903811). Author information Affiliations Division of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China; Division of Chinese Medicine, M.D. Prefectural People’s Hospital, Chuxiong Yi Autonomous Prefecture, 675500, China. Minyue Zhang State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611730, China. Fei Gao Division of Chinese Medicine, M.D. Prefectural People’s Hospital, Chuxiong Yi Autonomous Prefecture, 675500, China. Ling Peng Division of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China. Lijing Shen State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611730, China. Peng Zhao Division of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China. Beiwen Ni Division of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China. Jian Hou Division of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China. Honghui Huang Authors’ contributions Ni B and Zhao P performed literature research. Zhang M, Gao F and Peng L extracted and analyzed the data. Zhang M, Gao F and Shen L wrote the manuscript; Huang H and Hou J conceived and designed this study. All authors reviewed and approved the final manuscript. Corresponding authors Correspondence to Honghui Hu ang or Jian Hou. 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Meta-analysis of the association between status of HCV and advanced disease stage (Ann Arbor staging III/IV) of NHL patients. FigureS2LDH.jpg Figure S2. Meta-analysis of the association between status of HCV and elevated LDH level of NHL patients. FigureS3IPI.jpg Figure S3. Meta-analysis of the association between status of HCV and intermediate-high and high IPI/FLIPI risk of NHL patients. FigureS4spleen.jpg Figure S4. Meta-analysis of the association between status of HCV and spleen involvement in NHL patients. FigureS5liver.jpg Figure S5. Meta-analysis of the association between status of HCV and liver involvement in NHL patients. FigureS6age.jpg Figure S6. Meta-analysis of the association between status of HCV and age of disease onset in NHL patients. FigureS7Bsymptom.jpg Figure S7. Meta-analysis of the association between status of HCV and presence of B symptom in NHL patients. FigureS8BM.jpg Figure S8. Meta-analysis of the association between status of HCV and bone marrow involvement in NHL patients. TableS1.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 12 Jul, 2021 Reviews received at journal 03 Jun, 2021 Reviewers invited by journal 03 Jun, 2021 Editor assigned by journal 06 May, 2021 Submission checks completed at journal 06 May, 2021 Editor invited by journal 06 May, 2021 First submitted to journal 27 Apr, 2021 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. 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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-472650","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Primary research","associatedPublications":[],"authors":[{"id":25776649,"identity":"8373cbc6-1203-4dad-87e8-21209a01f6d7","order_by":0,"name":"Minyue Zhang","email":"","orcid":"https://orcid.org/0000-0002-2730-4288","institution":"Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Minyue","middleName":"","lastName":"Zhang","suffix":""},{"id":25776650,"identity":"b8ea043f-308d-4e1e-b4c0-62e92e51a145","order_by":1,"name":"Fei Gao","email":"","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Gao","suffix":""},{"id":25776651,"identity":"4d76a7ad-b959-4256-b86d-408894f60242","order_by":2,"name":"Ling Peng","email":"","orcid":"","institution":"Mouding Prefectural People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Peng","suffix":""},{"id":25776652,"identity":"cdb707ff-20c1-4c7e-b57e-cb9681680171","order_by":3,"name":"Lijing Shen","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lijing","middleName":"","lastName":"Shen","suffix":""},{"id":25776653,"identity":"73a2e29e-543f-4f0c-9153-0b16802aaca3","order_by":4,"name":"Peng Zhao","email":"","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Zhao","suffix":""},{"id":25776654,"identity":"1d89a45a-9268-4633-a4e2-d20d953d472a","order_by":5,"name":"Beiwen Ni","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Beiwen","middleName":"","lastName":"Ni","suffix":""},{"id":25776655,"identity":"45edd1fe-c5c2-47ab-a81a-29be01997e00","order_by":6,"name":"Jian Hou","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Hou","suffix":""},{"id":25776656,"identity":"f8fcea93-36a5-44de-bb03-0578cc524b1f","order_by":7,"name":"Honghui Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYBACAxDB2AAkJBgYDnwAcZpJ0XJwBslamHmIcZi5RPKzh1932OTJR/cYHrbdY5PH3M7A+OFjDm4tljPSzI1lz6QVG945Y3A451laMdBhzJIzt+Fx2I0EM2nJtsOJG2fkALUcOJzY2MzAxsyLV0v6N4QWiwP/idGSYyb5EahlvgRQC8OBA0RoOfOmTJqxLS1xg0RawcGeA8lALYzN+P1yPH2b5M82m8T5M5I3f/hxwC5xY//hgx8+4tECAuDoMDgA5Rk2gKMJP2D8ASTkYerkCaofBaNgFIyCkQYAn+NZzN0pYMUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6748-8798","institution":"Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Honghui","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2021-04-28 18:31:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-472650/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-472650/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":9041782,"identity":"3c338106-2317-462e-bf89-64d5be103cf4","added_by":"auto","created_at":"2021-05-11 13:25:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":308881,"visible":true,"origin":"","legend":"Literature search and selection.","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/a9b631579ffea6ad54515a95.png"},{"id":9041788,"identity":"1496256e-8e5d-4ca0-9aff-9baae80f6f17","added_by":"auto","created_at":"2021-05-11 13:25:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":409155,"visible":true,"origin":"","legend":"Meta-analysis of the association between status of HCV and prognosis of NHL patients. 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(a) liver cirrhosis; (b) low level of albumin; (c) liver involvement; (d) elevated alanine transaminase (ALT)","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/15b6f5b3082a3546d24d4df0.png"},{"id":13692188,"identity":"21b9ea17-d62e-438a-a133-4da2efb0e33d","added_by":"auto","created_at":"2021-09-17 12:42:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2196821,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/a4f868ac-1b60-48a9-b4e5-df264cc15316.pdf"},{"id":9042885,"identity":"a58d6da0-ca11-4bbc-87ea-0379ce75a5c5","added_by":"auto","created_at":"2021-05-11 13:31:05","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":477448,"visible":true,"origin":"","legend":"Figure S1. Meta-analysis of the association between status of HCV and advanced disease stage (Ann Arbor staging III/IV) of NHL patients.","description":"","filename":"FigureS1stage.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/b52d482c9f130a9bf6ad6359.jpg"},{"id":9043393,"identity":"33866f92-b339-4925-a480-f67f16141517","added_by":"auto","created_at":"2021-05-11 13:34:05","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":316320,"visible":true,"origin":"","legend":"Figure S2. Meta-analysis of the association between status of HCV and elevated LDH level of NHL patients.","description":"","filename":"FigureS2LDH.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/f08291c8a7b8d45d3c0c0830.jpg"},{"id":9042123,"identity":"a0ad3291-58bb-435b-bd18-7423e82181ff","added_by":"auto","created_at":"2021-05-11 13:28:05","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":362009,"visible":true,"origin":"","legend":"Figure S3. Meta-analysis of the association between status of HCV and intermediate-high and high IPI/FLIPI risk of NHL patients.","description":"","filename":"FigureS3IPI.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/f374153aacad356e8401c559.jpg"},{"id":9043397,"identity":"3bf3691b-6fb4-45f5-bcb9-a3c37d09fffe","added_by":"auto","created_at":"2021-05-11 13:34:05","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":276678,"visible":true,"origin":"","legend":"Figure S4. Meta-analysis of the association between status of HCV and spleen involvement in NHL patients.","description":"","filename":"FigureS4spleen.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/d5f9b529042570892dd6b98a.jpg"},{"id":9043658,"identity":"df5fba4e-db2b-489e-a13c-5acbf956f640","added_by":"auto","created_at":"2021-05-11 13:37:05","extension":"jpg","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":320443,"visible":true,"origin":"","legend":"Figure S5. Meta-analysis of the association between status of HCV and liver involvement in NHL patients.","description":"","filename":"FigureS5liver.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/be1365017a6a62629efd0ab7.jpg"},{"id":9042129,"identity":"91a6d6d1-04d9-4d17-87e4-9355042cd99c","added_by":"auto","created_at":"2021-05-11 13:28:05","extension":"jpg","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":289479,"visible":true,"origin":"","legend":"Figure S6. Meta-analysis of the association between status of HCV and age of disease onset in NHL patients.","description":"","filename":"FigureS6age.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/2e993574632602c8c3b95b19.jpg"},{"id":9041796,"identity":"467f09e3-f9c4-456a-ad08-1e6b884126b0","added_by":"auto","created_at":"2021-05-11 13:25:05","extension":"jpg","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":288670,"visible":true,"origin":"","legend":"Figure S7. Meta-analysis of the association between status of HCV and presence of B symptom in NHL patients.","description":"","filename":"FigureS7Bsymptom.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/eaa64ceee3818bf6060b2601.jpg"},{"id":9042893,"identity":"e4df127c-4d10-4497-9a58-31567d41873d","added_by":"auto","created_at":"2021-05-11 13:31:05","extension":"jpg","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":368070,"visible":true,"origin":"","legend":"Figure S8. Meta-analysis of the association between status of HCV and bone marrow involvement in NHL patients.","description":"","filename":"FigureS8BM.jpg","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/f272f3895eb424a574a45c13.jpg"},{"id":9043396,"identity":"a12a84ae-944b-409b-ab77-35b1b334aaf7","added_by":"auto","created_at":"2021-05-11 13:34:05","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":11182,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-472650/v1/30ad54f08be2b840c1995e80.xlsx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eDistinct Clinical Features and Prognostic Factors in Hepatitis C Virus-Associated Non-Hodgkin’s Lymphoma: A Systematic Review and Meta-Analysis\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eNon-Hodgkin\u0026rsquo;s lymphoma (NHL) is a group of lymphoid malignancies with high heterogeneity. It can be classified into B-cell, T-cell, and natural killer (NK)-cell lymphoma. Increasing evidence has implicated that pathogen infection contributed to the pathogenesis of different subtypes of lymphoma, such as Epstein-Barr virus (EBV) in Hodgkin disease or Burkitt\u0026rsquo;s lymphoma, human T-cell leukemia virus type 1 in adult T cell leukemia and lymphoma, and Helicobacter pylori in gastric mucosa-associated lymphoid tissue [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. According to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms, two subtypes of NHL associated with specific viral infection, EBV-positive diffuse large B-cell lymphoma (DLBCL) and human herpesvirus type-8 (HHV-8)-positive DLBCL, have been classified as separated subtypes of DLBCL [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These new categories strongly suggested that NHL patients with specific infection displayed distinct clinical manifestations and prognosis.\u003c/p\u003e \u003cp\u003eRecently, hepatitis C virus (HCV) was found in peripheral blood mononuclear cells and lymph nodes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and hepatitis C NS3 protein could be detected in tumor cells from patients with HCV-associated B cell-lymphoma [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], hence suggesting that HCV is also lymphotropic. On the other hand, meta-analysis provided quantitative evidence that HCV infection could lead to a 2.5-fold increased risk of developing NHL [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Nevertheless, the clinical characteristics and prognosis of HCV-associated lymphoma is still undefined.\u003c/p\u003e \u003cp\u003eArising clinical attention to the association of HCV infection and clinical outcomes of NHL patients has been paid. However, the results were still inconsistent based on existing retrospective studies with small sample sizes [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Hosry J et al [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] found that HCV-associated DLBCL had unique clinical features and poor outcomes. However, other studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] had shown that HCV infection was not associated with NHL patients\u0026rsquo; survivals. In addition, increasing studies have explored the survival benefit of antiviral treatment or rituximab-containing chemotherapy in NHL patients with HCV infection yet results were also controversial [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In view of the limitations of previous studies, we hereby performed a systematic review and meta-analysis aiming to evaluate the clinical features and prognostic factors in HCV-associated NHL patients. Moreover, the effect of antiviral treatment and rituximab administration on NHL patients with HCV infection was also investigated in the current study.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eIdentification of relevant studies\u003c/h2\u003e \u003cp\u003eTo identify all studies that explored the impact of HCV infection on the clinical outcomes of NHL patients or the effect of antiviral treatment and rituximab administration on NHL patients with HCV infection, a literature search of four electronic databases, including PubMed, OVID, Web of Science, and Embase, up to Feb 28, 2021, was conducted. The search strategy was based on combinations of the following keywords and search terms without language limitation: (\u0026ldquo;lymphoma\u0026rdquo; [MeSH] or \u0026ldquo;Lymphoma, Non-Hodgkin\u0026rdquo; [MeSH] or \u0026ldquo;Non-Hodgkin lymphoma\u0026rdquo; or \u0026ldquo;NHL\u0026rdquo;) AND (\u0026ldquo;hepatitis C\u0026rdquo; [MeSH] or \u0026ldquo;hepatitis C virus\u0026rdquo; or \u0026ldquo;HCV\u0026rdquo; or \u0026ldquo;Hep C virus\u0026rdquo; or \u0026ldquo;Hep C\u0026rdquo;). References of the retrieved studies, meeting abstracts, relevant meta-analyses and systematic reviews were also screened. Case reports, editorials and review articles were excluded. When a publication overlapped with other publication of the same trial, only the article with more details or the most recent article was retained.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSelection criteria\u003c/h2\u003e \u003cp\u003eThe studies included in the meta-analysis should satisfy all the following criteria: (1) the study population was NHL patients; (2) the study consisted of two groups: NHL patients with and without HCV infection, or HCV infected NHL patients receiving and not receiving antiviral/rituximab treatment; (3) clinical features and survivals between two groups of patients were compared. Exclusion criteria were: (1) patients co-infected with human immunodeficiency virus (HIV); (2) patient with post-transplant lymphoproliferative disorder; (3) patient number less than or equal to ten in any study groups. When the relevant data was not reported in paper, we contacted the author to get the relevant information by e-mail or telephone.\u003c/p\u003e \u003cp\u003eThe primary outcomes assessed the impact of HCV infection on NHL patients\u0026rsquo; prognoses, including overall survival (OS) and disease progression [progress-free survival (PFS) / disease-free survival (DFS)]. The other outcomes measured treatment response [overall response rate (ORR)] and clinical characteristics of NHL patients with HCV infection, including age of disease onset (\u0026lt;\u0026thinsp;60 years old), presence of B symptoms, advanced disease stage (Ann Arbor staging III/IV), involvement of spleen, liver and bone marrow, elevated LDH level, high-intermediate and high IPI/FLIPI risk and incidence of hepatic dysfunction during chemotherapy. Furthermore, the effect of antiviral therapy or rituximab administration as well as liver-related prognostic factors for HCV-positive NHL patients was also investigated. Since PFS and DFS were similar outcomes of disease progression, we pooled PFS and DFS as the same outcome indicators to analyze in the current study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and study quality\u003c/h2\u003e \u003cp\u003eTwo reviewers (Gao F and Peng L) independently extracted data and outcomes using an electronic standard form. The following information from each study was summarized: (1) first author, (2) year of publication, (3) country, (4) subtypes of NHL, (5) number of patients with and without HCV infection, (6) number of HCV positive NHL patients receiving and not receiving antiviral/rituximab treatment, (7) anti-lymphoma therapeutic regimens, (8) antivirus treatment regimens, (9) patient\u0026rsquo;s characteristics. Any discrepancies amongst the two reviewers were resolved by an additional investigator, Zhang M.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment\u003c/h2\u003e \u003cp\u003eNewcastle-Ottawa Quality Assessment Scale (NOS) was adopted to assess the methodological quality of the included studies [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The following three items were evaluated including: (1) patient selection, (2) comparability of interventions and observations group, and (3) assessment of outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eHazard ratio (HR) corresponding to 95% confidence interval (CI) were used to assess OS and PFS/DFS. If both univariate and multivariate analyses results were reported in the included study, the latter will be used in the meta-analysis. If HRs and 95% CIs were not available from the original article, Kaplan\u0026ndash;Meier curves of the included studies were read and re-analyzed by software Engauge digitizer. HRs and 95% CIs were indirectly calculated from Kaplan\u0026ndash;Meier curve using Tierney\u0026rsquo;s methods [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Odds ratio (OR) corresponding to 95% CI were calculated to estimate other outcomes. Publication biases were assessed by Egger's test and Begg's test. When the outcome with less than five included studies, publication biases was not performed. The methods of meta-analysis and publication biases tests were detailed in our previous publications [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Statistical analysis was performed by software ReviewManager 5.4 (The Cochrane Collaboration, Oxford, UK) and Stata version 15 (Stata Corp, College Station, Texas, USA). All P-values were both-sided and P-value of \u0026lt;\u0026thinsp;0.05 was considered significance.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of studies\u003c/h2\u003e \u003cp\u003eAfter the comprehensive literature search based on the criteria above, 2599 articles were identified as potentially relevant publications. Upon further evaluation of the full-text, 17 articles were excluded from the calculations of this systematic review. Thus, 27 articles (29 studies) [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] with a total of 13368 NHL patients, including 3063 patients with HCV infection and 10305 patients without HCV infection, fulfilled the inclusion criteria and were included in current meta-analysis (Figure.1). The characteristics of the included articles were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The articles were published between 1997 and 2020 with sample size ranging from 58 to 5586. Majority of studies were conducted in Italy (n\u0026thinsp;=\u0026thinsp;11), Japan (n\u0026thinsp;=\u0026thinsp;4), Egypt (n\u0026thinsp;=\u0026thinsp;3), China (n\u0026thinsp;=\u0026thinsp;2), French (n\u0026thinsp;=\u0026thinsp;2) and the United States (n\u0026thinsp;=\u0026thinsp;2). The other articles consisted of single study conducted in Russia, Korea, and Spain. Among the included articles, 14 articles focused on DLBCL, two articles on follicular lymphoma and two articles on marginal zone lymphoma. In addition to the aforementioned lymphoma subtypes, the patients in 9 articles consisted of more than two subtypes of NHL. With regards to the methodological quality, most of included articles had reliable quality as indicated by NOS scores\u0026thinsp;\u0026ge;\u0026thinsp;6 points except for 2 articles [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] with NOS scores 5 points (Table S1).\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 included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eyear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRegimes of\u003c/p\u003e \u003cp\u003eanti-lymphoma treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRegimes of\u003c/p\u003e \u003cp\u003eAT treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFollow-up (m)\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eHCV infection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eR use in\u003c/p\u003e \u003cp\u003eHCV\u0026thinsp;+\u0026thinsp;patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e \u003cp\u003eAT in\u003c/p\u003e \u003cp\u003eHCV\u0026thinsp;+\u0026thinsp;patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBesson C [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47 (0-112)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChen TT [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36 (0.84\u0026ndash;96.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChen YY [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDlouhy I [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e48 (1.2-146.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElbedewy TA [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e277\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnnishi D [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHCV\u0026thinsp;+\u0026thinsp;31 (4\u0026ndash;42)\u003c/p\u003e \u003cp\u003eHCV- 32 (5\u0026ndash;51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e422\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHosry J [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIFN, Rib, DAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNishikawa H [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHCV\u0026thinsp;+\u0026thinsp;40.8 (3.6\u0026ndash;92.4) HCV-31.2 (2.4\u0026ndash;94.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePark BB [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e37.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eShimono J [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eps-DLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHCV\u0026thinsp;+\u0026thinsp;46.9(4.0\u0026ndash;94.3)\u003c/p\u003e \u003cp\u003eHCV- 36.8 (0.8\u0026ndash;133.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOrdinary DLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHCV\u0026thinsp;+\u0026thinsp;27.8 (1.9\u0026ndash;122.1) HCV- 35.9 (0.1\u0026ndash;90.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArcaini L [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-gastric MALToma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCHT, RT, surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArcaini L[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSMZL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esplenectomy, IFN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e37.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHosry J [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIFN, Rib, DAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNesterova E [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRussia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDe Vita S [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1997\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB-NHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuppi M [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eB-NHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIFN, CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLa Mura V [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIFN, Rib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStrianese D [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOA lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003emean 75 (12\u0026ndash;185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTajima K [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVallisa D [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCHT, surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30 (1\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArcaini L [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eindolent NHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esurgery, I-CHT, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIFN, Rib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42 (6-204)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e578\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e570\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMerli M [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esurgery, I-CHT, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIFN, Rib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24 (12\u0026ndash;168)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e535\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e512\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMichot JM [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrench\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esurgery, I-CHT, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIFN, Rib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31(19\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersico M [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRattotti S [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndolent NHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eI-CHT, antibiotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIFN, Rib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e36 (1-84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAggressive NHL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalah-Eldin MA [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e41 (38.6\u0026ndash;43.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eReported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZaky AH [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI-CHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36 (5\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eExtrapolated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003cb\u003eAbbreviation\u003c/b\u003e AT: antiviral treatment; CHT: chemotherapy; DAA: direct-acting antiviral; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; I-CHT: immunochemotherapy; IFN: interferon; MALToma: mucosa-associated lymphoid tissue lymphoma; NHL: non-Hodgkin\u0026rsquo;s lymphoma; OA: ocular adnexal; ps-DLBCL: primary splenic diffuse large B-cell lymphoma; SMZL: splenic marginal zone lymphoma; R: rituximab; RT: radiotherapy; Rib: Ribavirin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eThe impact of HCV infection on NHL patients\u0026rsquo; prognosis\u003c/h2\u003e \u003cp\u003eAmong all 27 studies, 15 studies were available for analyses of OS. Due to obvious heterogeneity among these studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;47%, P \u003csub\u003eheterogeneity\u003c/sub\u003e=0.02), a random-effects model was employed to pool all of HRs and their 95% CIs. Meta-analysis revealed that HCV positive patients had significantly worse OS than HCV negative patients (HR 1.89; 95% CI 1.42\u0026ndash;2.51, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Figure. 2a).\u003c/p\u003e \u003cp\u003eA total of 8 studies were eligible for the assessment of PFS. The fixed-effects model was used to calculate the result as there was no heterogeneity among the included studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, P \u003csub\u003eheterogeneity\u003c/sub\u003e=0.59). Similarly, the result demonstrated that patients with HCV infection showed significantly shortened PFS compared with the patients without HCV infection (HR 1.58; 95% CI 1.26\u0026ndash;1.98, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Figure. 2b).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eHCV infection and treatment response\u003c/h2\u003e \u003cp\u003eEleven studies were identified to assess ORR between NHL patients with and without HCV infection. The OR and 95% CI of ORR was pooled by using fixed-effects model as the heterogeneity tests suggested no significant heterogeneity (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;28%, P \u003csub\u003eheterogeneity\u003c/sub\u003e =0.18). The combined results showed that ORR of HCV-positive NHL patients was significantly lower than that of HCV-negative NHL patients (OR 0.58, 95% CI 0.46\u0026ndash;0.73, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, Figure. 3).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eHCV infection and hepatic dysfunction during chemotherapy\u003c/h2\u003e \u003cp\u003eTotally, 7 studies including 2095 participants (DLBCL patients) were eligible to analyze this outcome by the random-effects mode (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;78%, P \u003csub\u003eheterogeneity\u003c/sub\u003e=0.0001). As shown in Figure. 4, higher incidence of hepatic dysfunction during chemotherapy was observed in HCV infected patients in comparison to HCV non-infected patients (OR 5.96; 95% CI 2.61\u0026ndash;13.62, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eHCV infection and clinical characteristics\u003c/h2\u003e \u003cp\u003eClinical features of NHL patients were also comprehensively compared between HCV positive and negative NHL patients. The results indicated that HCV infection was associated with advanced disease stage (OR 1.42, 95% CI 1.14\u0026ndash;1.76, P\u0026thinsp;=\u0026thinsp;0.001, Figure. S1), elevated level of LDH (OR 1.44; 95% CI 1.17\u0026ndash;1.79, P\u0026thinsp;=\u0026thinsp;0.0008, Figure. S2), high-intermediate and high IPI/FLIPI risk (OR 1.29; 95% CI 1.07\u0026ndash;1.56, P\u0026thinsp;=\u0026thinsp;0.008, Figure. S3), as well as higher incidence of spleen involvement (OR 2.95; 95% CI 2.17\u0026ndash;4.02, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, Figure. S4) and liver involvement (OR 2.01; 95% CI 1.46\u0026ndash;2.78, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Figure. S5). However, there was no significant difference in age of disease onset (Figure. S6), presence of B symptoms (Figure. S7) and incidence of involvement of bone marrow (Figure. S8) between two groups of patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEffect of antiviral treatment and rituximab administration on HCV-associated NHL patients\u003c/h2\u003e \u003cp\u003eSince NHL patients with HCV infection were found to have disadvantages of survivals and treatment response, whether antiviral treatment may improve clinical outcomes of HCV-associated NHL patients was also investigated. Of all the studies reviewed, 9 studies including 1838 HCV infected NHL patients were included to evaluate the impact of antiviral treatment on OS, PFS/DFS and ORR. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, antiviral treatment was associated with improved OS (HR 0.38; 95% CI 0.24\u0026ndash;0.60, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Figure. 5a) and PFS/DFS (HR 0.63; 95% CI 0.46\u0026ndash;0.86, P\u0026thinsp;=\u0026thinsp;0.003; Figure. 5b), as well as higher ORR (OR 2.62; 95% CI 1.34\u0026ndash;5.11, P\u0026thinsp;=\u0026thinsp;0.005, Figure. 5c) in comparison with patients without antiviral treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn addition, we also explored whether rituximab-containing regimes could improve the clinical prognosis of HCV positive NHL patients. Four studies comprising of 688 participants (DLBCL patients) were evaluated. The results demonstrated that patients treated with rituximab-containing chemotherapy exhibited favorable OS compared with those receiving rituximab-free chemotherapy (HR 0.68; 95% CI 0.54\u0026ndash;0.86, P\u0026thinsp;=\u0026thinsp;0.001; Figure. 6a). However, no difference in PFS was observed between these two groups of patients (HR 0.97; 95% CI 0.70\u0026ndash;1.36, P\u0026thinsp;=\u0026thinsp;0.88; Figure. 6b).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLiver-related survival factors in HCV-associated NHL patients\u003c/h2\u003e \u003cp\u003eWe subsequently evaluated liver-related survival factors in HCV-associated NHL patients, including liver cirrhosis, liver involvement, low level of albumin (\u0026lt;\u0026thinsp;3.5 g/dl) and elevated alanine transaminase (ALT). As shown in Figure. 7a-d, low level of albumin (HR 2.61; 95% CI 1.71\u0026ndash;3.97, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; Figure. 7a) and liver cirrhosis (HR 2.91; 95% CI 1.44\u0026ndash;5.88, P\u0026thinsp;=\u0026thinsp;0.003; Figure. 7b) were significantly associated with inferior OS. There was a trend for an association between liver involvement and short OS (HR 1.27; 95% CI 0.96\u0026ndash;1.67, P\u0026thinsp;=\u0026thinsp;0.09; Figure. 7c). However, no association was found between elevated ALT and OS (HR 1.09; 95% CI 0.86\u0026ndash;1.37, P\u0026thinsp;=\u0026thinsp;0.50; Figure. 7d).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis\u003c/h2\u003e \u003cp\u003eFirstly, subgroup analysis was conducted based on prevalence of HCV infection. According to the report of prevalence of HCV infection form global hepatitis report 2017 from WHO [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], the countries of included studies were divided into high prevalence of HCV infection, including Italy, Spain, French, Russia and Egypt, and low prevalence of HCV infection, including the United States, Japan, Korea, and China (cut-off value of HCV infection prevalence as 1.5%). The results of subgroup analysis were shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (high prevenance) and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e (low prevenance). Compared with the results from overall population, similar results could be observed from subgroup analysis. NHL patients with HCV infection had inferior prognosis, lower treatment response and high incidence of hepatic dysfunction in both sub-populations. With regards to clinical features, HCV infection had no effect on the IPI/FLIPI risk in neither of subgroups of patients, which was inconsistent with this outcome in overall population. In addition, HCV-associated NHL patient had an early age of disease onset among the countries with lower prevalence of HCV infection. For the outcomes of the effect of antiviral and rituximab treatment as well as survival factors in HCV-positive NHL patients, all the included studies were performed in the countries with high prevalence of HCV infection except one study [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, subgroup analysis was not performed.\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\u003eSubgroup analysis in countries with high prevalence of HCV infection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eStudies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHR/OR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eI\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e%\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpact of HCV infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.07 (1.37\u0026ndash;3.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress-free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.89 (1.27\u0026ndash;2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall response rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51 (0.38\u0026ndash;0.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.13 (1.75-517.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.04 (0.50\u0026ndash;2.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced disease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.53 (1.22\u0026ndash;1.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of B symptom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 (0.53\u0026ndash;1.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated LDH level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.33 (0.96\u0026ndash;1.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH-I/H risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.53 (0.96\u0026ndash;2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpleen involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.74 (2.32\u0026ndash;6.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.98 (1.23\u0026ndash;3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.39 (0.97-2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviation: H-I/H high-intermediate and high\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\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\u003eSubgroup analysis in countries with low prevalence of HCV infection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eStudies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHR/OR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eI\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e%\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpact of HCV infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.59 (1.16\u0026ndash;2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress-free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.45 (1.10\u0026ndash;1.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall response rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.70 (0.49-1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.87 (1.60\u0026ndash;9.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.97 (1.18\u0026ndash;3.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced disease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.22 (0.98\u0026ndash;1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of B symptom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.80 (0.53\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated LDH level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.54 (1.16\u0026ndash;2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH-I/H risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.16 (0.89\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpleen involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.48 (1.65\u0026ndash;3.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.04 (1.32\u0026ndash;3.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.98 (0.72\u0026ndash;1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviation: H-I/H high-intermediate and high\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSince NHL is a group of heterogenous diseases, we performed subgroup analysis based on pathological types of NHL. In the current study, majority of the included studies focused on DLBCL hence subgroup analysis was conducted in DLBCL patients. Similar to overall patients, DLBCL patients with HCV infection had shorter OS and PFS, lower ORR and distinct clinical features in comparison to DLBCL patients without HCV infection. Moreover, HCV-associated DLBCL patients receiving antiviral treatment shared a better OS and PFS/DFS than patients without antiviral treatment. Due to small sample size, subgroup analysis was not performed in terms of the outcomes of liver-related survival factors. The results of subgroup analysis in DLBCL patients were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\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\u003eSubgroup analysis in DLBCL patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eStudies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHR/OR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eI\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e%\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpact of HCV infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.29 (1.85\u0026ndash;2.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress-free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.55 (1.23\u0026ndash;1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall response rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.55 (0.42\u0026ndash;0.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.89 (2.31\u0026ndash;15.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31 (0.67\u0026ndash;2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced disease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.20 (0.98\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of B symptom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.16 (0.70\u0026ndash;1.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated LDH level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.47 (1.17\u0026ndash;1.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH-I/H risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.34 (1.07\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpleen involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.75 (1.92\u0026ndash;3.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.87 (1.22\u0026ndash;2.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03 (0.71\u0026ndash;1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpact of anti-viral treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40 (0.24\u0026ndash;0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress-free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.60 (0.39\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviation: H-I/H high-intermediate and high\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn terms of antiviral treatment, subgroup analysis was performed based on the regimes of antiviral treatment. Among the 9 included studies, patients in most studies (n\u0026thinsp;=\u0026thinsp;6) received interferon (IFN) +/- ribavirin as antiviral treatment. Only two study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] focused on new direct-acting antiviral (DAA) treatments of HCV and another study [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] consisted of different types of antiviral treatment. Therefore, subgroup analysis was conducted in patients receiving IFN +/- ribavirin. The results suggested that patients receiving IFN +/- ribavirin had obvious improved OS (HR 0.25; 95% CI 0.12\u0026ndash;0.52, P\u0026thinsp;=\u0026thinsp;0.0002, figure not shown) and PFS (HR 0.63; 95% CI 0.44\u0026ndash;0.90, P\u0026thinsp;=\u0026thinsp;0.01, figure not shown) in comparison with patients without antiviral treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eSensitivity analysis was performed by a sequential exclusion of individual studies to find the origin of the heterogeneity and verify the sensitivity of results. The origin of the heterogeneity and overall effect after removal of origin of the heterogeneity for each outcome were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The results showed that removal of the origin of the heterogeneity did not affect the effect size for each outcome, suggesting the stability of the result of meta-analysis. However, for the outcomes of age of disease onset, hepatic dysfunction during chemotherapy and liver cirrhosis, the heterogeneity still existed even though studies were excluded one by one.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of sensitivity analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOrigin of heterogeneity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOverall effect\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDlouhy I 2017 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.78 (1.45\u0026ndash;2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.00001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced disease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVallisa D 1999 [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.28 (1.09\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of B symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArcaini L 2006 [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.09 (0.84\u0026ndash;1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.51\u003c/p\u003e \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 \u003cp\u003eHosry J 2016 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.84 (1.26\u0026ndash;2.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003ePublication bias\u003c/h2\u003e \u003cp\u003eBegg\u0026rsquo;s test and Egger\u0026rsquo;s test were performed to assess the publication bias. As was shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, no significant publication bias was observed for all the outcomes.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of Begg\u0026rsquo;s test and Egger\u0026rsquo;s test\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP \u003csub\u003eBegg\u0026rsquo;s test\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP \u003csub\u003eEgger\u0026rsquo;s test\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpact of HCV infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.619\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress-free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall response rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.373\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.236\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.499\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced disease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.468\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of B symptom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated LDH level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.533\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.639\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH-I/H risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.379\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpleen involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.878\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.895\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpact of antiviral treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.917\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.407\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress-free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver-related survival factors\u003c/b\u003e\u003c/p\u003e \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 \u003cp\u003e0.707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviation: H-I/H high-intermediate and high\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eOver the past two decades, considerable studies have been investigated the contribution of HCV infection to lymphomagenesis. However, the mechanisms of HCV-associated lymphoma remained elusive. Experimental data implicated that HCV-induced lymphoma development may act through multistep processes, resulting from a variety of oncogenic mechanisms, such as HCV-induced chronic B-cell immune-stimulation, genetic damages, dysregulation of signaling pathways (NF-kB, JNF, ERK and NOTCH signaling pathways), etc. [\u003cspan additionalcitationids=\"CR44 CR45 CR46 CR47\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. A prognostic evaluation of clinical outcomes and therapeutic responses in HCV-associated lymphoma is essential to antitumor treatment. Herein, we performed a systematic review and meta-analysis to assess the impact of HCV infection on NHL patients. Furthermore, subgroup analysis was also performed based on the prevenance of HCV infection and pathological types of lymphoma. The results of current study collectively indicated that HCV-positive NHL patients had significantly inferior survival, earlier disease progression, poorer treatment response and distinct clinical characters. In addition to recognized survival factors of NHL, our study also demonstrated that liver cirrhosis and low level of albumin were inferior prognostic factors of OS for HCV-associated NHL patients.\u003c/p\u003e \u003cp\u003eFurthermore, this study implicated the anti-lymphoma efficacy of antiviral treatment, especially IFN+/- ribavirin regimes, in HCV-associated NHL patients, which was similar to the recent meta-analysis conducted by Peveling-Oberhag, et al [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The authors found the good overall lymphoma response rate through the application of antiviral treatment in HCV-infected NHL patients. However, their meta-analysis was based on small studies, mostly case reports or small cohorts with less than 20 cases. Nevertheless, DAA treatments are radically changing the landscape of anti-HCV therapy. In the current study, whether HCV-associated NHL patients can benefit from DAA treatment couldn\u0026rsquo;t be expounded due to small patient sample size. In the era of DAA, future studies should illuminate the anti-lymphoma activity of DAA treatment in NHL patients with HCV infection. On the other hand, rituximab-containing regimes have been proven to be associated with better treatment response and clinical prognosis in DLBCL over the past two decades. In the current study, we also found that rituximab administration could improve OS in DLBCL patients with HCV infection. However, the association between PFS and rituximab administration couldn\u0026rsquo;t be observed in this specific subtype of DLBCL patients, which might be due to small samples size. Whether rituximab-containing regimes can improve treatment response and PFS warrants further study with large cohorts.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first meta-analysis that systematically assessed the clinical outcomes and treatment of HCV-associated NHL patients. We are confident that our results were reliable, which was supported by large sample size, moderate to high methodological quality of included studies, low heterogeneity, and no publication bias. However, there were several limitations in this study. Firstly, when evaluating OS or PFS/DFS, HR and 95% CI in some of individual studies were not available from the original articles, hence they were indirectly calculated from Kaplan-Meier curve. Secondly, our study implicated that higher incidence of hepatic dysfunction was observed in HCV infected NHL patients, probably leading to delay or termination of chemotherapy or even death. However, the direct cause-and-effect relationship between hepatic dysfunction and inferior prognosis remained unknown. On the other hand, it was still unclear whether survival benefit of antiviral treatment attributed to restoring hepatic dysfunction and reducing chance of termination or delay of chemotherapy caused by HCV-induced hepatotoxicity so far. Third, our study indicated that HCV infection was associated with poor survivals in NHL patients. Despite we attempted to further perform prognostic evaluation of HCV viral loading (HCV-RNA) in HCV infected NHL patients. However, only two articles investigated prognostic value of HCV-RNA and the results were contradictory. Fourthly, it should be noted that when analyzing some outcomes, such as prognostic factors and effect of rituximab administration in HCV-associated NHL patients, only a few studies with small sample size could be included. Therefore, the results of these outcomes need to be interpreted with caution. Lastly, patients in most of included studies were DLBCL. There were only a few studies focusing on indolent lymphoma, such as follicular lymphoma and marginal zone lymphoma hence subgroup analysis could not be carried out in indolent lymphoma patients. In view of the limitations of the current study, well-designed perspective studies with large cohorts should be performed in different subtypes of NHL, especially indolent lymphoma, to address the issues mentioned above in the future.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eThis meta-analysis confirmed the inferior prognosis and distinct clinical characteristics in HCV-associated NHL patients, especially in DLBCL. Patients with HCV infection were prone to undergoing hepatic dysfunction during the chemotherapy. Moreover, our data provided the compelling evidence that antiviral treatment combined with immunochemotherapy may represent an effective approach for HCV-positive NHL patients\u003c/p\u003e "},{"header":"Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eALT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealanine transaminase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDAA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edirect-acting antiviral\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDFS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edisease-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDLBCL\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediffuse large B-cell lymphoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eHCV\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehepatitis C virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eHR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eIFN\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterferon\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNHL\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-Hodgkin\u0026rsquo;s lymphoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNOS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNewcastle-Ottawa Quality Assessment Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePFS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogress-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eOR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOdds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eORR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eOS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eWHO\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld Health Organization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used in this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Dr. Lok Hay Yim for her guidance on this article and for her editing and proofreading of this English manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Science and Technology Development Foundation of Shanghai Pudong New Area health and Family Planning Commission (PW2015E-1) and National Natural Science Foundation of China (81903811).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAffiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDivision of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China; Division of Chinese Medicine, M.D. Prefectural People\u0026rsquo;s Hospital, Chuxiong Yi Autonomous Prefecture, 675500, China.\u003c/p\u003e\n\u003cp\u003eMinyue Zhang\u003c/p\u003e\n\u003cp\u003eState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611730, China.\u003c/p\u003e\n\u003cp\u003eFei Gao\u003c/p\u003e\n\u003cp\u003eDivision of Chinese Medicine, M.D. Prefectural People\u0026rsquo;s Hospital, Chuxiong Yi Autonomous Prefecture, 675500, China.\u003c/p\u003e\n\u003cp\u003eLing Peng\u003c/p\u003e\n\u003cp\u003eDivision of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China.\u003c/p\u003e\n\u003cp\u003eLijing Shen\u003c/p\u003e\n\u003cp\u003eState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611730, China.\u003c/p\u003e\n\u003cp\u003ePeng Zhao\u003c/p\u003e\n\u003cp\u003eDivision of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China.\u003c/p\u003e\n\u003cp\u003eBeiwen Ni\u003c/p\u003e\n\u003cp\u003eDivision of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China.\u003c/p\u003e\n\u003cp\u003eJian Hou\u003c/p\u003e\n\u003cp\u003eDivision of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pu Jian Road, Shanghai, 200127, China.\u003c/p\u003e\n\u003cp\u003eHonghui Huang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNi B and Zhao P performed literature research. Zhang M, Gao F and Peng L extracted and analyzed the data. Zhang M, Gao F and Shen L wrote the manuscript; Huang H and Hou J conceived and designed this study. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to\u0026nbsp;\u003ca href=\"https://cancerci.biomedcentral.com/articles/10.1186/s12935-020-01590-4/email/correspondent/c1/new\"\u003eHonghui Hu\u003c/a\u003eang\u0026nbsp;or\u0026nbsp;Jian Hou.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ede The G. Viruses and human cancers: challenges for preventive strategies. Environmental health perspectives. 1995; 103 Suppl 8:269 \u0026ndash; 73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParsonnet J, Isaacson PG. Bacterial infection and MALT lymphoma. N Engl J Med. 2004;350(3):213\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaderer M, Kiesewetter B, Ferreri AJ. Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). CA Cancer J Clin. 2016;66(2):153\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePal S, Sullivan DG, Kim S, Lai KK, Kae J, Cotler SJ, et al. 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Neuroscience research. 2010;68(2):142\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang MY, Zhu GQ, Shi KQ, Zheng JN, Cheng Z, Zou ZL, et al. Systematic review with network meta-analysis: Comparative efficacy of oral nucleos(t)ide analogues for the prevention of chemotherapy-induced hepatitis B virus reactivation. Oncotarget. 2016;7(21):30642\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang MY, Zhu GQ, Zheng JN, Cheng Z, Van Poucke S, Shi KQ, et al. Nucleos(t)ide analogues for preventing HBV reactivation in immunosuppressed patients with hematological malignancies: a network meta-analysis. Expert review of anti-infective therapy. 2017;15(5):503\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishikawa H, Tsudo M, Osaki Y. Clinical outcome in diffuse large B-cell lymphoma with hepatitis C virus infection in the rituximab era: a single center experience. Oncol Rep. 2012;28(3):835\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArcaini L, Burcheri S, Rossi A, Paulli M, Bruno R, Passamonti F, et al. Prevalence of HCV infection in nongastric marginal zone B-cell lymphoma of MALT. Ann Oncol. 2007;18(2):346\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArcaini L, Lazzarino M, Colombo N, Burcheri S, Boveri E, Paulli M, et al. Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood. 2006;107(12):4643\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosry J, Miranda RN, Samaniego F, Angelidakis G, Torres HA. Clinicopathologic characteristics of follicular lymphoma in hepatitis C virus-infected patients. Hematol Oncol. 2020;38(3):301\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNesterova E, Tanaschuk E, Abdurakhmanov D, Gemdzhian E, Kravchenko S, Mangasarova Y, et al. Safe and effective treatment of follicular lymphoma in patients with HCV-infection. Hematol Oncol. 2020;38(4):604\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Vita S, Sacco C, Sansonno D, Gloghini A, Dammacco F, Crovatto M, et al. Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood. 1997;90(2):776\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuppi M, Longo G, Ferrari MG, Barozzi P, Marasca R, Morselli M, et al. Clinico-pathological characterization of hepatitis C virus-related B-cell non-Hodgkin's lymphomas without symptomatic cryoglobulinemia. Ann Oncol. 1998;9(5):495\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLa Mura V, De Renzo A, Perna F, D'Agostino D, Masarone M, Romano M, et al. Antiviral therapy after complete response to chemotherapy could be efficacious in HCV-positive non-Hodgkin's lymphoma. J Hepatol. 2008;49(4):557\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrianese D, Tranfa F, Finelli M, De Renzo A, Staibano S, Schiemer R, et al. Hepatitis C virus infection in ocular adnexal lymphomas. Arch Ophthalmol. 2010;128(10):1295\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTajima K, Takahashi N, Ishizawa K, Murai K, Akagi T, Noji H, et al. Clinicopathological characteristics of malignant lymphoma in patients with hepatitis C virus infection in the Tohoku district in Eastern Japan. Leuk Lymphoma. 2017;58(6):1509\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVallisa D, Bert\u0026egrave; R, Rocca A, Civardi G, Giangregorio F, Ferrari B, et al. Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of viral infection on histologic subtype and clinical course. Am J Med. 1999;106(5):556\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePersico M, Aglitti A, Caruso R, De Renzo A, Selleri C, Califano C, et al. Efficacy and safety of new direct antiviral agents in hepatitis C virus-infected patients with diffuse large B-cell non-Hodgkin's lymphoma. Hepatology. 2018;67(1):48\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalah-Eldin MA, Ebrahim MA, El-Sadda W. Clinical outcome of HCV-positive patients with diffuse large B-cell lymphoma treated with rituximab-based chemotherapy. Ann Hematol. 2014;93(11):1903\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlobal Hepatitis Report. 2017. In. Geneva: World Health Organization; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarcucci F, Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood. 2011;117(6):1792\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeng WK, Levy S. Hepatitis C virus (HCV) and lymphomagenesis. Leuk Lymphoma. 2003;44(7):1113\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK\u0026uuml;ppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001;20(40):5580\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerri C, Sebastiani M, Giuggioli D, Colaci M, Fallahi P, Piluso A, et al. Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin's lymphoma, and cancer. World J Hepatol. 2015;7(3):327\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForghieri F, Luppi M, Barozzi P, Maffei R, Potenza L, Narni F, et al. Pathogenetic mechanisms of hepatitis C virus-induced B-cell lymphomagenesis. Clin Dev Immunol. 2012; 2012:807351.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol. 2013;59(1):169\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeveling-Oberhag J, Arcaini L, Bankov K, Zeuzem S, Herrmann E. The anti-lymphoma activity of antiviral therapy in HCV-associated B-cell non-Hodgkin lymphomas: a meta-analysis. J Viral Hepat. 2016;23(7):536\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"non-Hodgkin’s lymphoma, HCV infection, prognosis, antiviral treatment, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-472650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-472650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Increasing evidence suggested that hepatitis C virus (HCV) infection was associated with non-Hodgkin’s lymphoma (NHL). However, no clear consensus has been reached about the clinical features and the effective treatment in HCV-associated NHL patients. We therefore performed a systematic review and meta-analysis to explore the clinical characteristics and effect of antiviral treatment or rituximab administration in NHL patients with HCV infection.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: \u0026nbsp;PubMed, Embase, Web of Science, and OVID database were searched for eligible studies up to Feb 28, 2021. Hazard ratio (HR) or odds ratio (OR) corresponding to 95% confidence interval (CI) were calculated to estimate outcomes. Publication biases were assessed by Egger's test and Begg's test. Statistical analysis was performed by software RevMan 5.4 and Stata version 15.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThere were 27 shortlisted articles out of a total of 13368 NHL patients included in the current meta-analysis. Our results demonstrated that NHL patients with HCV infection showed significantly shorter overall survival (OS: HR 1.89; 95% CI 1.42-2.51, P\u0026lt;0.0001) and progress-free survival (PFS: HR 1.58; 95% CI 1.26-1.98, P\u0026lt;0.0001), lower overall response rate (ORR: OR 0.58, 95% CI 0.46-0.73, P\u0026lt;0.00001) and higher incidence of hepatic dysfunction during chemotherapy (OR 5.96; 95% CI 2.61-13.62, P\u0026lt;0.0001) compared with NHL patients without HCV infection. HCV-positive NHL patients exhibited advanced disease stage, elevated level of LDH, high-intermediate and high IPI/FLIPI risk as well as higher incidence of spleen and liver involvement. Moreover, antiviral treatment could prolong survivals (OS: HR 0.38; 95% CI 0.24-0.60, P\u0026lt;0.0001), reduce disease progression [PFS/DFS (disease-free survival): HR 0.63; 95% CI 0.46-0.86, P=0.003] and reinforce treatment response (ORR: OR 2.62; 95% CI 1.34-5.11, P=0.005) in HCV-infected NHL patients. Finally, rituximab administration was associated with a favorable OS while liver cirrhosis and low levels of albumin were inferior prognostic factors of OS for HCV-positive NHL patients. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e The current study provided the compelling evidence about an inferior prognosis and distinct clinical characteristics in HCV-associated NHL patients. Antiviral treatment and rituximab-containing regimes were shown to be efficacious to improve clinical outcomes of NHL patients with HCV infection.\u003c/p\u003e","manuscriptTitle":"Distinct Clinical Features and Prognostic Factors in Hepatitis C Virus-Associated Non-Hodgkin’s Lymphoma: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-05-11 13:25:02","doi":"10.21203/rs.3.rs-472650/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-07-12T15:31:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-06-03T16:47:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-06-03T16:46:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-05-07T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-05-06T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-05-06T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Cell International","date":"2021-04-28T00:42:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8c71268c-7767-4c9a-8ffb-3f7458f96c09","owner":[],"postedDate":"May 11th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":4227569,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-08-11T16:08:17+00:00","versionOfRecord":[],"versionCreatedAt":"2021-05-11 13:25:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-472650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-472650","identity":"rs-472650","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}