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A total of 127 patients diagnosed with aggressive B cell lymphomas at Chongqing Cancer Institute/Hospital between January 2014 and December 2015 were enrolled in this retrospective study. Informed consent was obtained from all patients, and the study was approved by the Ethics Committee of Chongqing Cancer Institute/Hospital. All cases were reviewed by two experienced pathologists according to the criteria of the World Health Organization classification. Patients' medical history review, physical examination, WBC-DC, renal and liver function tests, such as serum albumin, globulin, β2MG, and bone marrow biopsy, and imaging examinations (ultrasound and radiological examinations of the brain, chest, abdomen, and pelvis) were carried out, and the results were reviewed. Patients were staged according to the Ann Arbor classification, and a risk stratification was performed according to the IPI, R-IPI, and NCCN-IPI scoring systems[16-18].
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Slides of formalin-fixed, paraffin-embedded tissues were stained with primary monoclonal antibodies to anti-CD4 (clone SP35, rabbit monoclonal; Abcam, Cambridge, MA, USA), anti-Foxp3 (clone 236A/E7, mouse monoclonal; Abcam), anti-CD8 (clone SP16, rabbit monoclonal; Abcam), anti-CD68 (clone KP-1, mouse monoclonal; Abcam), anti-CD163 (clone 10D6, mouse monoclonal; Abcam), anti-PD-1 (clone MRQ22, mouse monoclonal; ORIGENE, Rockville, MD, USA), and anti-PD-L1 (clone SP142, rabbit monoclonal; ORIGENE) using the GTVision Ⅲ detection system (DAKO, Carpinteria, CA USA) according to the manufacturer's instructions. Tumor-infiltrating immune cell subsets were quantified as total counts of CD3, CD4, CD8, Foxp3, CD68, and CD163 positive cells per high power field (0.2 mm2) by manual inspection of stained sections with at least 10 fields of high staining density. Membranous immunostaining for PD-1 and PD-L1 was considered as positive and scored by a staining density ranging from 0 to 3 (0 = no staining, 1 = weak, 2 = moderate, 3 = strong).
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All data were analyzed with SPSS 18.0 software (IBM Corp., Armonk, NY, USA). Categorical variables were compared using the chi-square test. The difference between continuous variables was assessed using analysis of variance (ANOVA). All P-values < 0.05 were considered significant. A multinomial logistic regression model was developed and probability was estimated in a single model using a maximum likelihood technique. The three scoring models (IPI, R-IPI, and NCCN-IPI) were used as the dependent variable in the multinominal logistic regression. Significant factors selected from the ANOVA and chi-square test were used as control variables. Concordance rates for methods using these factors with or without the Ann Arbor stage data were analyzed with paired t-tests.
The predicted probabilities from the model were calculated with the following Equations:
$$ \begin{array}{l} p1 = p\left( {y \le 1\left| {{x_1}, {x_2}, \cdots {x_{\rm{K}}}} \right.} \right) = \frac{{\exp \left( {{\rm{a + }}{{\rm{b}}_1}{{\rm{x}}_1} + {{\rm{b}}_2}{{\rm{x}}_2} + \cdots {{\rm{b}}_{\rm{k}}}{{\rm{x}}_{\rm{k}}}} \right)}}{{1 + \exp \left( {{{\rm{a}}_1} + {{\rm{b}}_1}{{\rm{x}}_1} + {{\rm{b}}_2}{{\rm{x}}_2} + \cdots + {{\rm{b}}_{\rm{k}}}{{\rm{x}}_{\rm{k}}}} \right)}}\\ p2 = p\left( {y \le 2\left| {{x_1}, {x_2}, \cdots {x_{\rm{K}}}} \right.} \right) = \frac{{\exp \left( {{{\rm{a}}_2}{\rm{ + }}{{\rm{b}}_1}{{\rm{x}}_1} + {{\rm{b}}_2}{{\rm{x}}_2} + \cdots {{\rm{b}}_{\rm{k}}}{{\rm{x}}_{\rm{k}}}} \right)}}{{1 + \exp \left( {{{\rm{a}}_2} + {{\rm{b}}_1}{{\rm{x}}_1} + {{\rm{b}}_2}{{\rm{x}}_2} + \cdots + {{\rm{b}}_{\rm{k}}}{{\rm{x}}_{\rm{k}}}} \right)}}\\ p3 = p\left( {y \le 3\left| {{x_1}, {x_2}, \cdots {x_{\rm{K}}}} \right.} \right) = \frac{{\exp \left( {{{\rm{a}}_3}{\rm{ + }}{{\rm{b}}_1}{{\rm{x}}_1} + {{\rm{b}}_2}{{\rm{x}}_2} + \cdots {{\rm{b}}_{\rm{k}}}{{\rm{x}}_{\rm{k}}}} \right)}}{{1 + \exp \left( {{{\rm{a}}_3} + {{\rm{b}}_1}{{\rm{x}}_1} + {{\rm{b}}_2}{{\rm{x}}_2} + \cdots + {{\rm{b}}_{\rm{k}}}{{\rm{x}}_{\rm{k}}}} \right)}}\\ p4 = p\left( {y \le 4\left| {{x_1}, {x_2}, \cdots {x_{\rm{K}}}} \right.} \right) = 1-p1-p2-p3 \end{array} $$ Where, p is the predicted probability for different scores, and xnis the control variable selected from the ANOVA or chi-square test.
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The clinicopathological characteristics of all 127 patients with aggressive B cell lymphomas are summarized in Supplementary Tables 1-3 (available in www.besjournal.com). Figure 1 demonstrated immunohistochemical staining of tumor-infiltrating immune cell subsets, PD1 and PD-L1 in DLBCL and mantle cell lymphoma, in which CD4, CD8 presented membrane positivity, and Foxp3 showed nuclear positivity in T lymphocytes, while CD68 showed membrane positivity in macrophage cells, PD-1 and PDL1 also showed membrane positivity both in tumor cells and microenvironment immune cells. As shown in Supplementary Table 1 (available in www.besjournal.com), no significant difference was found in 18 factors, including sex, histological classification, sites of involvement, absolute blood lymphocyte count, absolute blood lymphocyte count score, absolute blood neutrophil count score, absolute blood neutrophil count, platelet count, platelet count score, neutrophil-to-lymphocyte ratio (NLR), NLR score, monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), PLR score, lymphoma infiltrating CD4-positive T cells, lymphoma infiltrating Foxp3-positive T cells, lymphoma infiltrating CD68-positive macrophages, lymphoma infiltrating CD163-positive macrophages, or PD-1 score. The other 13 factors, including age, Ann Arbor stage, B symptoms, ECOG performance status, absolute blood monocyte count, CD8+ T cells, LDH, iron, albumin, and β2MG were significantly different among the four groups. The baseline characteristics with stratification using the revised IPI (Supplementary Table 2, available in www.besjournal.com) and NCCN-IPI (Supplementary Table 3, available in www.besjournal.com) showed similar results as those stratified using the IPI (Supplementary Table 1, available in www.besjournal.com). Table 1 summarizes the important factors from the three scoring systems and shows that there were differences in some of the factors, including blood lymphocyte score, blood monocytes, platelet count, NLR, MLR, and PLR among all three scoring systems. Only factors that were significantly different in the two scoring systems were chosen for further analysis to ensure the accuracy of further statistical analysis (Table 2).
Table Supplementary Table 1. Baseline Characteristics of Patients by IPI Stratification
Factors Low IPI Low to intermediate IPI High to intermediate IPI High IPI P value Sex 0.645 Male 19 (15.0%) 26 (20.47%) 19 (14.96%) 14 (11.02%) Female 15 (11.8%) 17 (13.39%) 12 (9.45%) 5 (3.94%) Age 49.18 ± 15.06 57.58 ± 12.97 56.61 ± 12.36 62.37 ± 14.28 0.005 Histological classification 0.571 DLBCL 13 (10.24%) 16 (12.60 %) 9 (7.09%) 4 (3.15%) GCB DLBCL 20 (15.75%) 24 (18.90%) 18 (14.17%) 12 (9.45%) Non-GCB MCL 1 (0.79%) 3 (2.36%) 4 (3.15%) 3 (2.36%) Sites of involvement 0.94 nodal 21 (16.54%) 29 (22.83%) 21 (16.54%) 13 (10.24%) extranodal 13 (10.24%) 14 (11.02%) 10 (7.87%) 6 (4.72%) Ann Arbor stage 0.000 Ⅰ 9 (7.09%) 1 (0.79%) 0 (0.00%) 0 (0.00%) Ⅱ 12 (9.45%) 16 (12.60%) 2 (1.57%) 1 (0.79%) Ⅲ 10 (7.87%) 19 (14.96%) 17 (13.39%) 3 (2.36%) Ⅳ 3 (2.36%) 7 (5.51%) 12 (9.45%) 15 (11.81%) B symptom 0.000 Yes 3 (2.36%) 8 (6.30%) 21 (16.54%) 10 (7.87%) No 31 (24.41%) 35 (27.56%) 10 (7.87%) 9 (7.09%) ECOG performance status 0.000 0 21 (16.54%) 25 (19.69%) 7 (5.51%) 4 (3.15%) 1 8 (6.30%) 4 (3.15%) 1 (0.79%) 2 (1.57%) 2 5 (3.94%) 13 (10.24%) 21 (16.54%) 13 (10.24%) 3 0 (0.00%) 1 (0.79%) 2 (1.57%) 0 (0.00%) Absolute count of lymphocytes in blood 1.47 ± 0.63 1.57 ± 0.70 1.49 ± 0.79 1.33 ± 0.82 0.717 Score of absolute count of lymphocytes in blood 0.27 0 ( < 1.1 × 109/L) 10 (7.87%) 10 (7.87%) 14 (11.02%) 9 (7.09%) 1 (1.1-3.2 × 109/L) 23 (18.11%) 32 (25.20%) 15 (11.81%) 9 (7.09%) 2 (≥ 3.2 × 109/L) 1 (0.79%) 1 (0.79%) 2 (1.57%) 1 (0.79%) Absolute count of monocytes in blood 0.30 ± 0.21 0.43 ± 0.24 0.52 ± 0.28 0.32 ± 0.28 0.003 Score of absolute count of monocytes in blood 0.018 0 ( < 0.1 × 109/L) 8 (6.30%) 6 (4.72%) 3 (2.36%) 5 (3.94%) 1 (0.1-0.6 × 109/L) 24 (18.90%) 27 (21.26%) 16 (12.60%) 13 (10.24%) 2 (≥ 0.6 × 109/L) 2 (1.57%) 10 (7.87%) 12 (9.45%) 1 (0.79%) Absolute count of neutrophils in blood 4.47 ± 1.78 4.28 ± 1.98 4.06 ± 1.95 4.33 ± 3.27 0.899 Score of absolute count of lymphocytes in blood 0.294 0 ( < 1.8 × 109/L) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.79%) 1 (1.8-6.3 × 109/L) 28 (22.05%) 35 (27.56%) 26 (20.47%) 17 (13.39%) 2 (≥ 6.3 × 109/L) 6 (4.72%) 7 (5.51%) 2 (1.57%) 1 (0.79%) Platelet count 202.41 ± 68.82 209.84 ± 115.95 179.13 ± 76.69 177.42 ± 101.30 0.42 Score of platelet count 0.102 0 ( < 125 × 109/L) 1 (0.79%) 8 (6.30%) 7 (5.51%) 6 (4.72%) 1 (125-350 × 109/L) 32 (25.20%) 31 (24.41%) 23 (18.11%) 12 (9.45%) 2 (≥ 350 × 109/L) 1 (0.79%) 4 (3.15%) 1 (0.79%) 1 (0.79%) NLR 3.50 ± 2.22 3.12 ± 1.68 3.38 ± 2.40 4.98 ± 5.01 0.098 Score of NLR 0.197 0 ( < 0.56) 0 (0.00%) 1 (0.79%) 2 (1.57%) 1 (0.79%) 1 (0.56-5.73) 30 (23.62%) 39 (30.71%) 27 (21.26%) 13 (10.24%) 2 (≥ 5.73) 4 (3.15%) 3 (2.36%) 2 (1.57%) 5 (3.94%) MLR 0.23 ± 0.17 0.33 ± 0.26 0.39 ± 0.28 0.35 ± 0.35 0.091 Score of MLR 0.048 0 ( < 0.03) 4 (3.15%) 0 (0.00%) 1 (0.79%) 1 (0.79%) 1 (0.03-0.19) 11 (8.66%) 15 (11.81%) 4 (3.15%) 8 (6.30%) 2 (≥ 0.19) 19 (14.96%) 28 (22.05%) 26 (20.47%) 10 (7.87%) PLR 155.56 ± 79.62 154.89 ± 105.42 149.83 ± 92.57 185.95 ± 140.75 0.645 Score of PLR 0.205 0 ( < 39.06) 0 (0.00%) 0 (0.00%) 2 (1.57%) 2 (1.57%) 1 (39.06-318.18) 33 (25.98%) 40 (31.50%) 27 (21.26%) 15 (11.81%) 2 (≥ 318.18/L) 1 (0.79%) 3 (2.36%) 2 (1.57%) 2 (1.57%) Infiltrating CD4+ T cells 305.74 ± 273.14 245.74 ± 186.81 286.94 ± 215.00 229.26 ± 230.87 0.546 Infiltrating Foxp3+ T cells 150.59 ± 122.05 126.74 ± 110.15 135.87 ± 144.27 147.00 ± 150.44 0.86 Infiltrating CD8+ T cells 304.41 ± 225.75 207.21 ± 144.33 194.52 ± 108.19 273.68 ± 123.21 0.017 Infiltrating CD68+ macrophages 153.24 ± 78.42 122.21 ± 64.64 116.77 ± 52.94 123.32 ± 58.99 0.106 Infiltrating CD163+ macrophages 122.06 ± 72.19 99.19 ± 63.68 113.65 ± 76.73 122.47 ± 77.20 0.481 Score of PD-1 0.359 0 (-) 16 (12.60%) 16 (12.60%) 16 (12.60%) 9 (7.09%) 1 (+) 10 (7.87%) 13 (10.24%) 3 (2.36%) 7 (5.51%) 2 (++) 4 (3.15%) 9 (7.09%) 5 (3.94%) 2 (1.57%) 3 (+++) 4 (3.15%) 5 (3.94%) 7 (5.51%) 1 (0.79%) Score of PD-L1 0.041 0 (-) 2 (1.57%) 11 (8.66%) 3 (2.36%) 2 (1.57%) 1 (+) 12 (9.45%) 10 (7.87%) 15 (11.81%) 5 (3.94%) 2 (++) 13 (10.24%) 19 (14.96%) 6 (4.72%) 7 (5.51%) 3 (+++) 7 (5.51%) 3 (2.36%) 7 (5.51%) 5 (3.94%) Serum LDH 199.76 ± 58.53 290.48 ± 214.14 372.89 ± 251.58 531.86 ± 540.27 0.000 Score of serum LDH 0.001 0 ( < 250 U/L) 30 (23.62%) 29 (22.83%) 13 (10.24%) 8 (6.30%) 1 (250-500 U/L) 4 (3.15%) 6 (4.72%) 11 (8.66%) 5 (3.94%) 2 (≥ 500 U/L) 0 (0.00%) 8 (6.30%) 7 (5.51%) 6 (4.72%) Serum iron 16.56 ± 9.00 12.28 ± 6.47 11.96 ± 6.50 8.91 ± 4.05 0.001 Score of serum iron 0.02 0 ( < 7.8 μmol) 2 (1.57%) 9 (7.09%) 7 (5.51%) 9 (7.09%) 1 (7.8-32.2 μmol) 32 (25.20%) 34 (26.77%) 24 (18.90%) 10 (7.87%) 2 (≥ 32.2 μmol) 1 (0.79%) 0 (0.00%) 0 (0.00%) 0 (0.00%) Serum albumin 43.33 ± 4.80 41.46 ± 5.32 39.99 ± 6.06 36.85 ± 6.80 0.001 Score of serum iron 0.003 0 ( < 40 g/L) 7 (5.51%) 14 (11.02%) 15 (11.81%) 13 (10.24%) 1 (40-55 g/L) 27 (21.26%) 29 (22.83%) 16 (12.60%) 6 (4.72%) 2 (≥ 55 g/L) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) Serum β2MG 1.98 ± 1.70 2.74 ± 1.58 3.30 ± 2.22 5.08 ± 4.63 0.000 Score of serum β2MG 0.000 0 ( < 3 mg/L) 31 (24.41%) 26 (20.47%) 15 (11.81%) 6 (4.72%) 1 (≥ 3 mg/L) 3 (2.36%) 17 (13.39%) 16 (12.60%) 13 (10.24%) Table Supplementary Table 2. Baseline Characteristics of Patients with Stratification of Revised IPI
Factors Very Good Good Poor P Value Sex 0.529 Male 16 (12.60%) 29 (22.83%) 33 (25.98%) Female 14 (11.02%) 18 (14.17%) 17 (13.39%) Age 48.73 ± 14.76 57.15 ± 13.412 58.80 ± 13.28 0.006 Histological classification 11 (8.66%) 18 (14.17%) 13 (10.24%) 0.369 DLBCL GCB 18 (14.17%) 26 (20.47%) 30 (23.62%) DLBCL Non-GCB 1 (0.79%) 3 (2.36%) 7 (5.51%) MCL Sites of involvement 0.908 Nodal 20 (15.75%) 30 (23.62%) 34 (26.77%) Extranodal 10 (7.87%) 17 (13.39%) 16 (12.60%) Ann Arbor stage 0.000 Ⅰ 7 (5.51%) 3 (2.36%) 0 (0.00%) Ⅱ 11 (8.66%) 17 (13.39%) 3 (2.36%) Ⅲ 9 (7.09%) 20 (15.75%) 20 (15.75%) Ⅳ 3 (2.36%) 7 (5.51%) 27 (21.26%) B symptom 0.000 Yes 0 (0.00%) 11 (8.66%) 31 (24.41%) No 30 (23.62%) 36 (28.35%) 19 (14.96%) ECOG performance status 0.000 0 21 (16.54%) 25 19.69 (%) 11 (8.66%) 1 8 (6.30%) 4 (3.15%) 3 (2.36%) 2 1 (0.79%) 17 (13.39%) 34 (26.77%) 3 0 (0.00%) 1 (0.79%) 2 (1.57%) Absolute count of lymphocytes in blood 1.44 ± 0.64 1.58 ± 0.69 1.43 ± 0.80 0.565 Score of absolute count of neutrophils in blood 0.074 0 ( < 1.1 × 109/L) 10 (7.87%) 10 (7.87%) 23 (18.11%) 1 (1.1-3.2 × 109/L) 19 (14.96%) 36 (28.35%) 24 (18.90%) 2 (≥ 3.2 × 109/L) 1 (0.79%) 1 (0.79%) 3 (2.36%) Absolute count of monocytes in blood 0.29 ± 0.21 0.42 ± 0.24 0.44 ± 0.29 0.033 Sore of absolute count of monocytes in blood 0.191 0 ( < 0.1 × 109/L) 8 (6.30%) 6 (4.72%) 8 (6.30%) 1 (0.1-0.6 × 109/L) 20 (15.75%) 31 (24.41%) 29 (22.83%) 2 (≥ 0.6 × 109/L) 2 (1.57%) 10 (7.87%) 13 (10.24%) Absolute count of neutrophils in blood 4.47 ± 1.76 4.30 ± 1.98 4.17 ± 2.51 0.832 Score of absolute count of neutrophils in blood 0.137 0 ( < 1.8 × 109/L) 0 (0.00%) 1 (0.79%) 4 (3.15%) 1 (1.8-6.3 × 109/L) 24 (18.90%) 39 (30.71%) 43 (33.86%) 2 (≥ 6.3 × 109/L) 6 (4.72%) 7 (5.51%) 3 (2.36%) Platelet count 204.43 ± 69.12 207.92 ± 112.60 178.48 ± 85.86 0.255 Score of platelet count 0.085 0 ( < 125 × 109/L) 1 (0.79%) 8 (6.30%) 13 (10.24%) 1 (125-350 × 109/L) 28 (22.05%) 35 (27.56%) 35 (27.56%) 2 (≥ 350 × 109/L) 1 (0.79%) 4 (3.15%) 2 (1.57%) NLR 3.63 ± 2.34 3.08 ± 1.62 3.99 ± 3.66 0.265 Score of NLR 0.376 0 ( < 0.56) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.56-5.73) 26 (20.47%) 43 (33.86%) 40 (31.50%) 2 (≥ 5.73) 4 (3.15%) 3 (2.36%) 7 (5.51%) MLR 0.23 ± 0.18 0.32 ± 0.26 0.38 ± 0.31 0.068 Score of MLR 0.062 0 ( < 0.03) 4 (3.15%) 0 (0.00%) 2 (1.57%) 1 (0.03-0.19) 10 (7.87%) 16 (12.60%) 12 (9.45%) 2 (≥ 0.19) 16 (12.60%) 31 (24.41%) 36 (28.35%) PLR 161.63 ± 82.79 151.08 ± 101.63 163.56 ± 113.30 0.82 Score of PLR 0.125 0 ( < 39.06) 0 (0.00%) 0 (0.00%) 4 (3.15%) 1 (39.06-318.18) 29 (22.83%) 44 (34.65%) 42 (33.07%) 2 (≥ 318.18/L) 1 (0.79%) 3 (2.36%) 4 (3.15%) Infiltrating CD4+ T cells 330.83 ± 281.13 234.83 ± 182.68 265.02 ± 220.63 0.187 Infiltrating Foxp3+ T cells 170.27 ± 116.37 116.21 ± 110.89 140.10 ± 145.21 0.192 Infiltrating CD8+ T cells 325.00 ± 231.48 202.34 ± 140.29 224.60 ± 119.37 0.004 Infiltrating CD68+ macrophages 152.33 ± 80.24 125.43 ± 65.40 120.40 ± 54.92 0.095 Infiltrating CD163+ macrophages 116.67 ± 70.68 104.57 ± 66.70 117.00 ± 76.24 0.646 Score of PD-1 0.787 0 (-) 14 (11.02%) 18 (14.17%) 25 (19.69%) 1 (+) 8 (6.30%) 15 (11.81%) 10 (7.87%) 2 (++) 4 (3.15%) 9 (7.09%) 7 (5.51%) 3 (+++) 4 (3.15%) 5 (3.94%) 8 (6.30%) Score of PD-L1 0.041 0 (-) 2 (1.57%) 11 (8.66%) 5 (3.94%) 1 (+) 8 (6.30%) 14 (11.02%) 20 (15.75%) 2 (++) 13 (10.24%) 19 (14.96%) 13 (10.24%) 3 (+++) 7 (5.51%) 3 (2.36%) 12 (9.45%) Serum LDH 199.58 ± 62.01 282.88 ± 206.24 433.30 ± 389.94 0.001 Score of serum LDH 0.001 0 ( < 250 U/L) 26 (20.47%) 33 (25.98%) 21 (16.54%) 1 (250-500 U/L) 4 (3.15%) 6 (4.72%) 16 (12.60%) 2 (≥ 500 U/L) 0 (0.00%) 8 (6.30%) 13 (10.24%) Serum iron 16.09 ± 9.08 12.94 ± 6.92 10.80 ± 5.85 0.007 Score of serum iron 0.036 0 ( < 7.8 μmol) 2 (1.57%) 9 (7.09%) 16 (12.60%) 1 (7.8-32.2 μmol) 27 (21.26%) 38 (29.92%) 34 (26.77%) 2 (≥ 32.2 μmol) 1 (0.79%) 0 (0.00%) 0 (0.00%) Serum albumin 43.43 ± 5.10 41.56 ± 5.10 38.80 ± 6.47 0.002 Score of serum iron 0.004 0 ( < 40 g/L) 7 (5.51%) 14 (11.02%) 28 (22.05%) 1 (40-55 g/L) 23 (18.11%) 33 (25.98%) 22 (17.32%) 2 (≥ 55 g/L) 0 (0.00%) 0 (0.00%) 0 (0.00%) Serum β2MG 1.98 ± 1.73 2.68 ± 1.59 3.98 ± 3.41 0.002 Score of serum β2MG 0.000 0 ( < 3 mg/L) 28 (22.05%) 29 (22.83%) 21 (16.54%) 1 (≥ 3 mg/L) 2 (1.57%) 18 (14.17%) 29 (22.83%) Table Supplementary Table 3. Baseline Characteristics of Patients with Stratification of NCCN-IPI
Factors Low IPI Low to Intermediate IPI High to Intermediate IPI High IPI P Value Sex 0.263 Male 18 (14.17%) 14 (11.02%) 30 (23.62%) 16 (12.60%) Female 7 (5.51%) 15 (11.81%) 20 (15.75%) 7 (5.51%) Age 43.16 ± 12.25 49.14 ± 12.46 62.14 ± 10.60 64.22 ± 11.49 0.000 Histological classification 0.199 DLBCL 11 (8.66%) 13 (10.24%) 14 (11.02%) 4 (3.15%) GCB DLBCL 13 (10.24%) 15 (11.81%) 31 (24.41%) 15 (11.81%) Non-GCB MCL 1 (0.79%) 1 (0.79%) 5 (3.94%) 4 (3.15%) Sites of involvement 0.298 Nodal 17 (13.39%) 15 (11.81%) 35 (27.56%) 17 (13.39%) extranodal 8 (6.30%) 14 (11.02%) 15 (11.81%) 6 (4.72%) Ann Arbor stage 0.003 Ⅰ 5 (3.94%) 4 (3.15%) 1 (0.79%) 0 (0.00%) Ⅱ 7 (5.51%) 9 (7.09%) 12 (9.45%) 3 (2.36%) Ⅲ 10 (7.87%) 19 (14.96%) 24 (18.90%) 6 (4.72%) Ⅳ 3 (2.36%) 7 (5.51%) 13 (10.24%) 14 (11.02%) B symptom 0.009 Yes 2 (1.57%) 9 (7.09%) 19 (14.96%) 12 (9.45%) No 23 (18.11 %) 20 (15.75%) 31 (24.41%) 11 (8.66%) ECOG performance status 0.002 0 18 (14.17%) 16 (12.60%) 18 (14.17%) 5 (3.94%) 1 5 (3.94%) 4 (3.15%) 4 (3.15%) 2 (1.57%) 2 2 (1.57%) 8 (6.30%) 26 (20.47%) 16 (12.60%) 3 0 (0.00%) 1 (0.79%) 2 (1.57%) 0 (0.00%) Absolute count of lymphocytes in blood 1.50 ± 0.70 1.46 ± 0.54 1.56 ± 0.74 1.36 ± 0.90 0.753 Score of absolute count of lymphocytes in blood 0.238 0 ( < 1.1 × 109/L) 7 (5.51%) 8 (6.30%) 16 (12.60%) 12 (9.45%) 1 (1.1-3.2 × 109/L) 17 (13.39%) 21 (16.54%) 32 (25.20%) 9 (7.09%) 2 (≥ 3.2 × 109/L) 1 (0.79%) 0 (0.00%) 2 (1.57%) 2 (1.57%) Absolute count of monocytes in blood 0.34 ± 0.21 0.37 ± 0.27 0.45 ± 0.24 0.40 ± 0.33 0.315 Score of absolute count of monocytes in blood 0.621 0 ( < 0.1 × 109/L) 5 (3.94%) 6 (4.72%) 6 (4.72%) 5 (3.94%) 1 (0.1-0.6 × 109/L) 18 (14.17%) 16 (12.60%) 33 (25.98%) 13 (10.24%) 2 (≥ 0.6 × 109/L) 2 (1.57%) 7 (5.51%) 11 (8.66%) 5 (3.94%) Absolute count of neutrophils in blood 4.84 ± 1.87 4.32 ± 1.94 3.85 ± 1.62 4.60 ± 3.31 0.235 Score of absolute count of neutrophils in blood 0.319 0 ( < 1.8 × 109/L) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.79%) 1 (1.8-6.3 × 109/L) 19 (14.96%) 23 (18.11%) 44 (34.65%) 20 (15.75%) 2 (≥ 6.3 × 109/L) 6 (4.72%) 5 (3.94%) 3 (2.36%) 2 (1.57%) Platelet count 209.16 ± 69.44 221.93 ± 131.66 182.16 ± 68.50 176.35 ± 103.09 0.187 Score of platelet count 0.038 0 ( < 125 × 109/L) 1 (0.79%) 4 (3.15%) 9 (7.09%) 8 (6.30%) 1 (125-350 × 109/L) 23 (18.11%) 21 (16.54%) 40 (31.50%) 14 (11.02%) 2 (≥ 350 × 109/L) 1 (0.79%) 4 (3.15%) 1 (0.79%) 1 (0.79%) NLR 3.81 ± 2.47 3.21 ± 1.49 2.93 ± 1.60 5.14 ± 4.94 0.011 Score of NLR 0.058 0 ( < 0.56) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.79%) 1 (0.56-5.73) 21 (16.54%) 28 (22.05%) 44 (34.65%) 16 (12.60%) 2 (≥ 5.73) 4 (3.15%) 1 (0.79%) 3 (2.36%) 6 (4.72%) MLR 0.26 ± 0.18 0.30 ± 0.29 0.32 ± 0.21 0.42 ± 0.39 0.227 Score of MLR 0.553 0 ( < 0.03) 3 (2.36%) 0 (0.00%) 1 (0.79%) 1 (0.79%) 1 (0.03-0.19) 7 (5.51%) 10 (7.87%) 13 (10.24%) 8 (6.30%) 2 (≥ 0.19) 15 (11.81%) 18 (14.17%) 36 (28.35%) 14 (11.02%) PLR 158.15 ± 78.30 172.90 ± 119.55 135.30 ± 70.33 191.08 ± 144.61 0.136 Score of PLR 0.029 0 ( < 39.06) 0 (0.00%) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (39.06-318.18) 24 (18.90%) 26 (20.47%) 48 (37.8%) 17 (13.39%) 2 (≥ 318.18/L) 1 (0.79%) 3 (2.36%) 1 (0.79%) 3 (2.36%) Infiltrating CD4+ T cells 311.72 ± 309.52 222.55 ± 159.50 285.28 ± 207.97 247.91 ± 225.64 0.462 Infiltrating Foxp3+ T cells 165.92 ± 113.51 121.10 ± 124.04 137.24 ± 131.47 132.74 ± 139.82 0.631 Infiltrating CD8+ T cells 351.60 ± 240.84 175.52 ± 142.07 216.40 ± 119.50 251.74 ± 123.24 0.000 Infiltrating CD68+ macrophages 155.60 ± 86.65 135.52 ± 54.02 117.30 ± 63.03 121.74 ± 55.73 0.104 Infiltrating CD163+ macrophages 120.00 ± 72.86 116.21 ± 79.53 103.36 ± 79.53 118.57 ± 70.69 0.723 Score of PD-1 0.878 0 (-) 12 (9.45%) 12 (9.45%) 21 (16.54%) 12 (9.45%) 1 (+) 8 (6.30%) 6 (4.72%) 12 (9.45%) 7 (5.51%) 2 (++) 3 (2.36%) 6 (4.72%) 9 (7.09%) 2 (1.57%) 3 (+++) 2 (1.57%) 5 (3.94%) 8 (6.30%) 2 (1.57%) Score of PD-L1 0.133 0 (-) 1 (0.79%) 4 (3.15%) 12 (9.45%) 1 (0.79%) 1 (+) 7 (5.51%) 12 (9.45%) 16 (12.60%) 7 (5.51%) 2 (++) 11 (8.66%) 11 (8.66%) 15 (11.81%) 8 (6.30%) 3 (+++) 6 (4.72%) 2 (1.57%) 7 (5.51%) 7 (5.51%) Serum LDH 202.28 ± 62.28 265.63 ± 133.64 294.84 ± 204.54 584.59 ± 519.76 0.000 Score of serum LDH 0.006 0 ( < 250 U/L) 22 (17.32%) 18 (14.17%) 32 (25.20%) 8 (6.30%) 1 (250-500 U/L) 3 (2.36%) 7 (5.51%) 10 (7.87%) 6 (4.72%) 2 (≥ 500 U/L) 0 (0.00 %) 4 (3.15%) 8 (%) 9 (7.09%) Serum iron 14.77 ± 5.40 14.78 ± 10.44 12.45 ± 6.31 9.15 ± 5.09 0.019 Score of serum iron 0.041 0 ( < 7.8 μmol) 2 (1.57%) 6 (4.72%) 7 (5.51%) 10 (7.87%) 1 (7.8-32.2 μmol) 23 (18.11%) 22 (17.32%) 24 (18.90%) 13 (10.24%) 2 (≥ 32.2 μmol) 0 (0.00%) 1 (0.79%) 0 (0.00%) 0 (0.00%) Serum albumin 44.14 ± 4.81 42.00 ± 5.65 40.44 ± 5.40 37.05 ± 6.43 0.000 Score of serum iron 4 (3.15%) 9 (7.09%) 21 (16.54%) 15 (11.81%) 0.004 0 ( < 40 g/L) 21 (16.54%) 20 (15.75%) 29 (22.83%) 8 (6.30%) 1 (40-55 g/L) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 2 (≥ 55 g/L) Serum β2MG 1.68 ± 0.92 2.56 ± 1.77 3.19 ± 2.13 4.71 ± 4.31 0.000 Score of serum β2MG 0.000 0 ( < 3 mg/L) 23 (19.66%) 21 (16.54%) 26 (20.47%) 8 (6.30%) 1 (≥ 3 mg/L) 2 (1.57%) 8 (6.30%) 24 (18.90%) 15 (11.81%) Table 1. Results of ANOVA and Chi-Square Tests in Different Risk Stratification Models
Factors P Value IPI R-IPI NCCN-IPI Age 0.005 0.006 0.000 Sex 0.645 0.529 0.263 Histological classification 0.571 0.369 0.199 Sites of involvement 0.940 0.908 0.298 Ann Arbor stage 0.000 0.000 0.003 B symptom 0.000 0.000 0.009 ECOG performance status 0.000 0.000 0.002 Absolute count of lymphocytes in blood 0.717 0.565 0.753 Score of absolute count of lymphocytes in blood 0.270 0.074 0.238 Absolute count of monocytes in blood 0.003 0.033 0.315 Score of absolute count of monocytes in blood 0.018 0.191 0.621 Absolute count of neutrophils in blood 0.899 0.832 0.235 Score of absolute count of neutrophils in blood 0.294 0.137 0.319 Platelet count 0.420 0.255 0.187 Score of platelet count 0.102 0.085 0.038 NLR 0.098 0.265 0.011 Score of NLR 0.197 0.376 0.058 MLR 0.091 0.068 0.227 Score of MLR 0.048 0.062 0.553 PLR 0.645 0.820 0.136 Score of PLR 0.205 0.125 0.029 Infiltrating CD4+T cells 0.546 0.187 0.462 Infiltrating FOXP3+ T cells 0.860 0.192 0.631 Infiltrating CD8+T cells 0.017 0.004 0.000 Infiltrating CD68+ macrophages 0.106 0.095 0.104 Infiltrating CD163+ macrophages 0.481 0.646 0.723 Score of PD-1 expression 0.359 0.787 0.878 Score of PD-L1 expression 0.041 0.041 0.133 Serum LDH 0.000 0.001 0.000 Score of serum LDH 0.001 0.001 0.006 Serum iron 0.001 0.007 0.019 Score of serum iron 0.020 0.036 0.041 Serum albumin 0.001 0.002 0.000 Score of serum albumin 0.003 0.004 0.004 Serum β2MG 0.000 0.002 0.000 Score of serum β2MG 0.000 0.000 0.000 Note. NLR, neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio, PLR, platelet-to-lymphocyte ratio. Table 2. Likelihood Ratio Tests of Various Factors in Estimating the Risk Stratification by Multinomial Logistic Regression
Factors Likelihood Ratio Tests IPI R-IPI NCCN-IPI Chi-square df P Value Chi-square df P Value Chi-square df P Value Age 28.197 3 0.000 58.676 3 0.000 14.049 2 0.001 Ann Arbor stage 54.930 9 0.000 26.311 9 0.002 30.882 6 0.000 B symptoms 2.782 3 0.427 2.825 3 0.419 5.890 2 0.053 ECOG performance status 14.246 9 0.114 15.068 9 0.089 3.284 6 0.772 Absolute count of monocytes in blood 17.854 3 0.000 6.974 3 0.073 1.619 2 0.445 Infiltrating CD8+ T cells 9.105 3 0.028 8.921 3 0.030 3.336 2 0.189 Score of PD-L1 expression in lymphoma tissue 24.488 9 0.004 15.810 9 0.071 12.041 6 0.061 Score of serum LDH 12.444 6 0.053 10.045 6 0.123 3.975 4 0.409 Score of serum iron 11.475 6 0.075 2.141 6 0.906 4.113 4 0.391 Score of serum albumin 10.868 3 0.012 0.932 3 0.818 1.049 2 0.592 Score of serum β2MG 12.385 3 0.006 3.035 3 0.386 2.367 2 0.306 Figure 1. Immunohistochemistry of CD4, Foxp3, CD8, CD68, PD-1, and PD-L1 in aggressive B cell lymphoma. (A, C, E, G, I, K) Representative case of diffuse large B cell lymphoma (DLBCL) stained with CD4, FOXP3, CD8, CD68, PD-1, and PD-L1 antibodies. (B, D, F, H, J, L) Representative case of mantle cell lymphoma (MCL) stained with CD4, Foxp3, CD8, CD68, PD-1, and PD-L1 antibodies. Original magnification, × 200.
Multinomial logistic regression models were developed for the IPI, R-IPI, and NCCN-IPI subgroups to explore the probability of risk estimates for patients with aggressive B cell lymphomas using a combination of the factors selected from the ANOVA and chi-square test results (Tables 3, 4). As shown in Table 3, when the Ann Arbor stage data were considered, the concordance rates of the predicted risk stratification using multinomial logistic regression were 85.1%-100.0%. The concordance rates between the actual and predicted stratification were both 100.0% in the NCCN-IPI group. In comparison, when the Ann Arbor stage data were not considered (Table 4), the concordance rates of the predicted risk stratification decreased slightly to 81.4%-100.0%. To further investigate the difference in the estimated risk stratification using the above clinicopathological factors with or without the Ann Arbor stage data, a paired t-test was performed to compare the results of Tables 3 and 4. As shown in Table 5, no significant difference in the estimated risk stratification was detected using the above clinicopathological factors with or without the Ann Arbor stage data.
Table 3. Concordance Rate of Predicted Risk Stratification Using Multinomial Logistic Regression (Influence of Ann Arbor Stages Considered)
Score Models Stratification Predicted Stratification Concordance Rate Low risk Low-intermediate risk High intermediate risk High risk IPI Low risk 34 (26.77%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 100.0% Low-intermediate risk 0 (0.00%) 41 (32.28%) 3 (2.36%) 0 (0.00%) 93.0% High-intermediate risk 0 (0.00%) 3 (2.36%) 28 (22.05%) 0 (0.00%) 90.3% High risk 0 (0.00%) 0 (0.00%) 0 (0.00%) 19 (14.96%) 100.0% NCCN-IPI Low risk 25 (19.69%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 100.0% Low-intermediate risk 0 (0.00%) 29 (22.83%) 0 (0.00%) 0 (0.00%) 100.0% High-intermediate risk 4 (3.15%) 2 (1.57%) 41 (32.28%) 3 (2.36%) 100.0% High risk 0 (0.00%) 0 (0.00%) 0 (0.00%) 23 (18.11%) 100.0% R-IPI Observed Very good good Poor Concordance rate Very good 30 (23.62%) 0 (0.00%) 0 (0.00%) 100.0% Good 0 (0.00%) 40 (31.50%) 7 (5.51%) 85.1% Poor 0 (0.00%) 6 (4.72%) 44 (34.65%) 88.0% Table 4. Concordance Rate of Predicted Risk Stratification by Multinomial Logistic Regression (influence of Ann Arbor stages not considered)
Score Models Stratification Predicted Stratification Concordance Rate Low risk Low-intermediate risk High intermediate risk High risk IPI Low risk 33 (25.98%) 0 (0.00%) 0 (0.00%) 1 (0.79%) 97.1% Low-intermediate risk 1 (0.79%) 35 (27.56%) 6 (4.72%) 1 (0.79%) 81.4% High-intermediate risk 0 (0.00%) 4 (3.15%) 27 (21.26%) 0 (0.00%) 87.1% High risk 0 (0.00%) 0 (0.00%) 0 (0.00%) 19 (14.96%) 100.0% NCCN-IPI Low risk 25 (19.69%) 0 (0.00%) 2 (1.57%) 0 (0.00%) 100.0% Low-intermediate risk 0 (0.00%) 29 (22.83%) 0 (0.00%) 0 (0.00%) 100.0% High-intermediate risk 0 (0.00%) 0 (0.00%) 50 (39.37%) 0 (0.00%) 100.0% High risk 1 (0.79%) 0 (0.00%) 0 (0.00%) 22 (17.32%) 95.7% R-IPI Observed Very good good Poor Concordance rate Very good 30 (23.62%) 0 (0.00%) 0 (0.00%) 100.0% Good 0 (0.00%) 41 (32.28%) 6 (4.72%) 87.2% Poor 0 (0.00%) 6 (4.72%) 44 (34.65%) 88.0% Table 5. Paired t Test on the Concordance Rates of Three Predicted Stratification Models with and without Ann Arbor Stage Data
Variables Paired Differences t df P Value Mean Std. Deviation Std. Error Mean Pair 1 Estimated IPI risk stratification 4.425 4.996 2.498 1.771 3 0.175 Pair 2 Estimated NCCN-IPI risk stratification 1.075 2.150 1.075 1.000 3 0.391 Pair 3 Estimated R-IPI risk stratification -0.700 1.212 0.700 -1.000 2 0.423
doi: 10.3967/bes2017.065
Role of Immune Microenvironmental Factors for Improving the IPI-related Risk Stratification of Aggressive B Cell Lymphoma
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Abstract:
Objective To investigate the risk stratification of aggressive B cell lymphoma using the immune microenvironment and clinical factors. Methods A total of 127 patients with aggressive B cell lymphoma between 2014 and 2015 were enrolled in this study.CD4, Foxp3, CD8, CD68, CD163, PD-1, and PD-L1 expression levels were evaluated in paraffin-embedded lymphoma tissues to identify their roles in the risk stratification.Eleven factors were identified for further evaluation using analysis of variance, chi-square, and multinomial logistic regression analysis. Results Significant differences in 11 factors (age, Ann Arbor stage, B symptom, ECOG performance status, infiltrating CD8+ T cells, PD-L1 expression, absolute blood monocyte count, serum lactate dehydrogenase, serum iron, serum albumin, and serum β2-microglobulin) were observed among patient groups stratified by at least two risk stratification methods[International Prognostic Index (IPI), revised IPI, and NCCN-IPI models](P < 0.05).Concordance rates were high (81.4%-100.0%) when these factors were used for the risk stratification.No difference in the risk stratification results was observed with or without the Ann Arbor stage data. Conclusion We developed a convenient and inexpensive tool for use in risk stratification of aggressive B cell lymphomas, although further studies on the role of immune microenvironmental factors are needed. -
Key words:
- Aggressive B cell lymphoma /
- Tumor microenvironment /
- Tumor-infiltrating lymphocytes /
- PD-1 /
- PD-L1 /
- IPI /
- Risk stratification
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Figure 1. Immunohistochemistry of CD4, Foxp3, CD8, CD68, PD-1, and PD-L1 in aggressive B cell lymphoma. (A, C, E, G, I, K) Representative case of diffuse large B cell lymphoma (DLBCL) stained with CD4, FOXP3, CD8, CD68, PD-1, and PD-L1 antibodies. (B, D, F, H, J, L) Representative case of mantle cell lymphoma (MCL) stained with CD4, Foxp3, CD8, CD68, PD-1, and PD-L1 antibodies. Original magnification, × 200.
Supplementary Table 1. Baseline Characteristics of Patients by IPI Stratification
Factors Low IPI Low to intermediate IPI High to intermediate IPI High IPI P value Sex 0.645 Male 19 (15.0%) 26 (20.47%) 19 (14.96%) 14 (11.02%) Female 15 (11.8%) 17 (13.39%) 12 (9.45%) 5 (3.94%) Age 49.18 ± 15.06 57.58 ± 12.97 56.61 ± 12.36 62.37 ± 14.28 0.005 Histological classification 0.571 DLBCL 13 (10.24%) 16 (12.60 %) 9 (7.09%) 4 (3.15%) GCB DLBCL 20 (15.75%) 24 (18.90%) 18 (14.17%) 12 (9.45%) Non-GCB MCL 1 (0.79%) 3 (2.36%) 4 (3.15%) 3 (2.36%) Sites of involvement 0.94 nodal 21 (16.54%) 29 (22.83%) 21 (16.54%) 13 (10.24%) extranodal 13 (10.24%) 14 (11.02%) 10 (7.87%) 6 (4.72%) Ann Arbor stage 0.000 Ⅰ 9 (7.09%) 1 (0.79%) 0 (0.00%) 0 (0.00%) Ⅱ 12 (9.45%) 16 (12.60%) 2 (1.57%) 1 (0.79%) Ⅲ 10 (7.87%) 19 (14.96%) 17 (13.39%) 3 (2.36%) Ⅳ 3 (2.36%) 7 (5.51%) 12 (9.45%) 15 (11.81%) B symptom 0.000 Yes 3 (2.36%) 8 (6.30%) 21 (16.54%) 10 (7.87%) No 31 (24.41%) 35 (27.56%) 10 (7.87%) 9 (7.09%) ECOG performance status 0.000 0 21 (16.54%) 25 (19.69%) 7 (5.51%) 4 (3.15%) 1 8 (6.30%) 4 (3.15%) 1 (0.79%) 2 (1.57%) 2 5 (3.94%) 13 (10.24%) 21 (16.54%) 13 (10.24%) 3 0 (0.00%) 1 (0.79%) 2 (1.57%) 0 (0.00%) Absolute count of lymphocytes in blood 1.47 ± 0.63 1.57 ± 0.70 1.49 ± 0.79 1.33 ± 0.82 0.717 Score of absolute count of lymphocytes in blood 0.27 0 ( < 1.1 × 109/L) 10 (7.87%) 10 (7.87%) 14 (11.02%) 9 (7.09%) 1 (1.1-3.2 × 109/L) 23 (18.11%) 32 (25.20%) 15 (11.81%) 9 (7.09%) 2 (≥ 3.2 × 109/L) 1 (0.79%) 1 (0.79%) 2 (1.57%) 1 (0.79%) Absolute count of monocytes in blood 0.30 ± 0.21 0.43 ± 0.24 0.52 ± 0.28 0.32 ± 0.28 0.003 Score of absolute count of monocytes in blood 0.018 0 ( < 0.1 × 109/L) 8 (6.30%) 6 (4.72%) 3 (2.36%) 5 (3.94%) 1 (0.1-0.6 × 109/L) 24 (18.90%) 27 (21.26%) 16 (12.60%) 13 (10.24%) 2 (≥ 0.6 × 109/L) 2 (1.57%) 10 (7.87%) 12 (9.45%) 1 (0.79%) Absolute count of neutrophils in blood 4.47 ± 1.78 4.28 ± 1.98 4.06 ± 1.95 4.33 ± 3.27 0.899 Score of absolute count of lymphocytes in blood 0.294 0 ( < 1.8 × 109/L) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.79%) 1 (1.8-6.3 × 109/L) 28 (22.05%) 35 (27.56%) 26 (20.47%) 17 (13.39%) 2 (≥ 6.3 × 109/L) 6 (4.72%) 7 (5.51%) 2 (1.57%) 1 (0.79%) Platelet count 202.41 ± 68.82 209.84 ± 115.95 179.13 ± 76.69 177.42 ± 101.30 0.42 Score of platelet count 0.102 0 ( < 125 × 109/L) 1 (0.79%) 8 (6.30%) 7 (5.51%) 6 (4.72%) 1 (125-350 × 109/L) 32 (25.20%) 31 (24.41%) 23 (18.11%) 12 (9.45%) 2 (≥ 350 × 109/L) 1 (0.79%) 4 (3.15%) 1 (0.79%) 1 (0.79%) NLR 3.50 ± 2.22 3.12 ± 1.68 3.38 ± 2.40 4.98 ± 5.01 0.098 Score of NLR 0.197 0 ( < 0.56) 0 (0.00%) 1 (0.79%) 2 (1.57%) 1 (0.79%) 1 (0.56-5.73) 30 (23.62%) 39 (30.71%) 27 (21.26%) 13 (10.24%) 2 (≥ 5.73) 4 (3.15%) 3 (2.36%) 2 (1.57%) 5 (3.94%) MLR 0.23 ± 0.17 0.33 ± 0.26 0.39 ± 0.28 0.35 ± 0.35 0.091 Score of MLR 0.048 0 ( < 0.03) 4 (3.15%) 0 (0.00%) 1 (0.79%) 1 (0.79%) 1 (0.03-0.19) 11 (8.66%) 15 (11.81%) 4 (3.15%) 8 (6.30%) 2 (≥ 0.19) 19 (14.96%) 28 (22.05%) 26 (20.47%) 10 (7.87%) PLR 155.56 ± 79.62 154.89 ± 105.42 149.83 ± 92.57 185.95 ± 140.75 0.645 Score of PLR 0.205 0 ( < 39.06) 0 (0.00%) 0 (0.00%) 2 (1.57%) 2 (1.57%) 1 (39.06-318.18) 33 (25.98%) 40 (31.50%) 27 (21.26%) 15 (11.81%) 2 (≥ 318.18/L) 1 (0.79%) 3 (2.36%) 2 (1.57%) 2 (1.57%) Infiltrating CD4+ T cells 305.74 ± 273.14 245.74 ± 186.81 286.94 ± 215.00 229.26 ± 230.87 0.546 Infiltrating Foxp3+ T cells 150.59 ± 122.05 126.74 ± 110.15 135.87 ± 144.27 147.00 ± 150.44 0.86 Infiltrating CD8+ T cells 304.41 ± 225.75 207.21 ± 144.33 194.52 ± 108.19 273.68 ± 123.21 0.017 Infiltrating CD68+ macrophages 153.24 ± 78.42 122.21 ± 64.64 116.77 ± 52.94 123.32 ± 58.99 0.106 Infiltrating CD163+ macrophages 122.06 ± 72.19 99.19 ± 63.68 113.65 ± 76.73 122.47 ± 77.20 0.481 Score of PD-1 0.359 0 (-) 16 (12.60%) 16 (12.60%) 16 (12.60%) 9 (7.09%) 1 (+) 10 (7.87%) 13 (10.24%) 3 (2.36%) 7 (5.51%) 2 (++) 4 (3.15%) 9 (7.09%) 5 (3.94%) 2 (1.57%) 3 (+++) 4 (3.15%) 5 (3.94%) 7 (5.51%) 1 (0.79%) Score of PD-L1 0.041 0 (-) 2 (1.57%) 11 (8.66%) 3 (2.36%) 2 (1.57%) 1 (+) 12 (9.45%) 10 (7.87%) 15 (11.81%) 5 (3.94%) 2 (++) 13 (10.24%) 19 (14.96%) 6 (4.72%) 7 (5.51%) 3 (+++) 7 (5.51%) 3 (2.36%) 7 (5.51%) 5 (3.94%) Serum LDH 199.76 ± 58.53 290.48 ± 214.14 372.89 ± 251.58 531.86 ± 540.27 0.000 Score of serum LDH 0.001 0 ( < 250 U/L) 30 (23.62%) 29 (22.83%) 13 (10.24%) 8 (6.30%) 1 (250-500 U/L) 4 (3.15%) 6 (4.72%) 11 (8.66%) 5 (3.94%) 2 (≥ 500 U/L) 0 (0.00%) 8 (6.30%) 7 (5.51%) 6 (4.72%) Serum iron 16.56 ± 9.00 12.28 ± 6.47 11.96 ± 6.50 8.91 ± 4.05 0.001 Score of serum iron 0.02 0 ( < 7.8 μmol) 2 (1.57%) 9 (7.09%) 7 (5.51%) 9 (7.09%) 1 (7.8-32.2 μmol) 32 (25.20%) 34 (26.77%) 24 (18.90%) 10 (7.87%) 2 (≥ 32.2 μmol) 1 (0.79%) 0 (0.00%) 0 (0.00%) 0 (0.00%) Serum albumin 43.33 ± 4.80 41.46 ± 5.32 39.99 ± 6.06 36.85 ± 6.80 0.001 Score of serum iron 0.003 0 ( < 40 g/L) 7 (5.51%) 14 (11.02%) 15 (11.81%) 13 (10.24%) 1 (40-55 g/L) 27 (21.26%) 29 (22.83%) 16 (12.60%) 6 (4.72%) 2 (≥ 55 g/L) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) Serum β2MG 1.98 ± 1.70 2.74 ± 1.58 3.30 ± 2.22 5.08 ± 4.63 0.000 Score of serum β2MG 0.000 0 ( < 3 mg/L) 31 (24.41%) 26 (20.47%) 15 (11.81%) 6 (4.72%) 1 (≥ 3 mg/L) 3 (2.36%) 17 (13.39%) 16 (12.60%) 13 (10.24%) Supplementary Table 2. Baseline Characteristics of Patients with Stratification of Revised IPI
Factors Very Good Good Poor P Value Sex 0.529 Male 16 (12.60%) 29 (22.83%) 33 (25.98%) Female 14 (11.02%) 18 (14.17%) 17 (13.39%) Age 48.73 ± 14.76 57.15 ± 13.412 58.80 ± 13.28 0.006 Histological classification 11 (8.66%) 18 (14.17%) 13 (10.24%) 0.369 DLBCL GCB 18 (14.17%) 26 (20.47%) 30 (23.62%) DLBCL Non-GCB 1 (0.79%) 3 (2.36%) 7 (5.51%) MCL Sites of involvement 0.908 Nodal 20 (15.75%) 30 (23.62%) 34 (26.77%) Extranodal 10 (7.87%) 17 (13.39%) 16 (12.60%) Ann Arbor stage 0.000 Ⅰ 7 (5.51%) 3 (2.36%) 0 (0.00%) Ⅱ 11 (8.66%) 17 (13.39%) 3 (2.36%) Ⅲ 9 (7.09%) 20 (15.75%) 20 (15.75%) Ⅳ 3 (2.36%) 7 (5.51%) 27 (21.26%) B symptom 0.000 Yes 0 (0.00%) 11 (8.66%) 31 (24.41%) No 30 (23.62%) 36 (28.35%) 19 (14.96%) ECOG performance status 0.000 0 21 (16.54%) 25 19.69 (%) 11 (8.66%) 1 8 (6.30%) 4 (3.15%) 3 (2.36%) 2 1 (0.79%) 17 (13.39%) 34 (26.77%) 3 0 (0.00%) 1 (0.79%) 2 (1.57%) Absolute count of lymphocytes in blood 1.44 ± 0.64 1.58 ± 0.69 1.43 ± 0.80 0.565 Score of absolute count of neutrophils in blood 0.074 0 ( < 1.1 × 109/L) 10 (7.87%) 10 (7.87%) 23 (18.11%) 1 (1.1-3.2 × 109/L) 19 (14.96%) 36 (28.35%) 24 (18.90%) 2 (≥ 3.2 × 109/L) 1 (0.79%) 1 (0.79%) 3 (2.36%) Absolute count of monocytes in blood 0.29 ± 0.21 0.42 ± 0.24 0.44 ± 0.29 0.033 Sore of absolute count of monocytes in blood 0.191 0 ( < 0.1 × 109/L) 8 (6.30%) 6 (4.72%) 8 (6.30%) 1 (0.1-0.6 × 109/L) 20 (15.75%) 31 (24.41%) 29 (22.83%) 2 (≥ 0.6 × 109/L) 2 (1.57%) 10 (7.87%) 13 (10.24%) Absolute count of neutrophils in blood 4.47 ± 1.76 4.30 ± 1.98 4.17 ± 2.51 0.832 Score of absolute count of neutrophils in blood 0.137 0 ( < 1.8 × 109/L) 0 (0.00%) 1 (0.79%) 4 (3.15%) 1 (1.8-6.3 × 109/L) 24 (18.90%) 39 (30.71%) 43 (33.86%) 2 (≥ 6.3 × 109/L) 6 (4.72%) 7 (5.51%) 3 (2.36%) Platelet count 204.43 ± 69.12 207.92 ± 112.60 178.48 ± 85.86 0.255 Score of platelet count 0.085 0 ( < 125 × 109/L) 1 (0.79%) 8 (6.30%) 13 (10.24%) 1 (125-350 × 109/L) 28 (22.05%) 35 (27.56%) 35 (27.56%) 2 (≥ 350 × 109/L) 1 (0.79%) 4 (3.15%) 2 (1.57%) NLR 3.63 ± 2.34 3.08 ± 1.62 3.99 ± 3.66 0.265 Score of NLR 0.376 0 ( < 0.56) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.56-5.73) 26 (20.47%) 43 (33.86%) 40 (31.50%) 2 (≥ 5.73) 4 (3.15%) 3 (2.36%) 7 (5.51%) MLR 0.23 ± 0.18 0.32 ± 0.26 0.38 ± 0.31 0.068 Score of MLR 0.062 0 ( < 0.03) 4 (3.15%) 0 (0.00%) 2 (1.57%) 1 (0.03-0.19) 10 (7.87%) 16 (12.60%) 12 (9.45%) 2 (≥ 0.19) 16 (12.60%) 31 (24.41%) 36 (28.35%) PLR 161.63 ± 82.79 151.08 ± 101.63 163.56 ± 113.30 0.82 Score of PLR 0.125 0 ( < 39.06) 0 (0.00%) 0 (0.00%) 4 (3.15%) 1 (39.06-318.18) 29 (22.83%) 44 (34.65%) 42 (33.07%) 2 (≥ 318.18/L) 1 (0.79%) 3 (2.36%) 4 (3.15%) Infiltrating CD4+ T cells 330.83 ± 281.13 234.83 ± 182.68 265.02 ± 220.63 0.187 Infiltrating Foxp3+ T cells 170.27 ± 116.37 116.21 ± 110.89 140.10 ± 145.21 0.192 Infiltrating CD8+ T cells 325.00 ± 231.48 202.34 ± 140.29 224.60 ± 119.37 0.004 Infiltrating CD68+ macrophages 152.33 ± 80.24 125.43 ± 65.40 120.40 ± 54.92 0.095 Infiltrating CD163+ macrophages 116.67 ± 70.68 104.57 ± 66.70 117.00 ± 76.24 0.646 Score of PD-1 0.787 0 (-) 14 (11.02%) 18 (14.17%) 25 (19.69%) 1 (+) 8 (6.30%) 15 (11.81%) 10 (7.87%) 2 (++) 4 (3.15%) 9 (7.09%) 7 (5.51%) 3 (+++) 4 (3.15%) 5 (3.94%) 8 (6.30%) Score of PD-L1 0.041 0 (-) 2 (1.57%) 11 (8.66%) 5 (3.94%) 1 (+) 8 (6.30%) 14 (11.02%) 20 (15.75%) 2 (++) 13 (10.24%) 19 (14.96%) 13 (10.24%) 3 (+++) 7 (5.51%) 3 (2.36%) 12 (9.45%) Serum LDH 199.58 ± 62.01 282.88 ± 206.24 433.30 ± 389.94 0.001 Score of serum LDH 0.001 0 ( < 250 U/L) 26 (20.47%) 33 (25.98%) 21 (16.54%) 1 (250-500 U/L) 4 (3.15%) 6 (4.72%) 16 (12.60%) 2 (≥ 500 U/L) 0 (0.00%) 8 (6.30%) 13 (10.24%) Serum iron 16.09 ± 9.08 12.94 ± 6.92 10.80 ± 5.85 0.007 Score of serum iron 0.036 0 ( < 7.8 μmol) 2 (1.57%) 9 (7.09%) 16 (12.60%) 1 (7.8-32.2 μmol) 27 (21.26%) 38 (29.92%) 34 (26.77%) 2 (≥ 32.2 μmol) 1 (0.79%) 0 (0.00%) 0 (0.00%) Serum albumin 43.43 ± 5.10 41.56 ± 5.10 38.80 ± 6.47 0.002 Score of serum iron 0.004 0 ( < 40 g/L) 7 (5.51%) 14 (11.02%) 28 (22.05%) 1 (40-55 g/L) 23 (18.11%) 33 (25.98%) 22 (17.32%) 2 (≥ 55 g/L) 0 (0.00%) 0 (0.00%) 0 (0.00%) Serum β2MG 1.98 ± 1.73 2.68 ± 1.59 3.98 ± 3.41 0.002 Score of serum β2MG 0.000 0 ( < 3 mg/L) 28 (22.05%) 29 (22.83%) 21 (16.54%) 1 (≥ 3 mg/L) 2 (1.57%) 18 (14.17%) 29 (22.83%) Supplementary Table 3. Baseline Characteristics of Patients with Stratification of NCCN-IPI
Factors Low IPI Low to Intermediate IPI High to Intermediate IPI High IPI P Value Sex 0.263 Male 18 (14.17%) 14 (11.02%) 30 (23.62%) 16 (12.60%) Female 7 (5.51%) 15 (11.81%) 20 (15.75%) 7 (5.51%) Age 43.16 ± 12.25 49.14 ± 12.46 62.14 ± 10.60 64.22 ± 11.49 0.000 Histological classification 0.199 DLBCL 11 (8.66%) 13 (10.24%) 14 (11.02%) 4 (3.15%) GCB DLBCL 13 (10.24%) 15 (11.81%) 31 (24.41%) 15 (11.81%) Non-GCB MCL 1 (0.79%) 1 (0.79%) 5 (3.94%) 4 (3.15%) Sites of involvement 0.298 Nodal 17 (13.39%) 15 (11.81%) 35 (27.56%) 17 (13.39%) extranodal 8 (6.30%) 14 (11.02%) 15 (11.81%) 6 (4.72%) Ann Arbor stage 0.003 Ⅰ 5 (3.94%) 4 (3.15%) 1 (0.79%) 0 (0.00%) Ⅱ 7 (5.51%) 9 (7.09%) 12 (9.45%) 3 (2.36%) Ⅲ 10 (7.87%) 19 (14.96%) 24 (18.90%) 6 (4.72%) Ⅳ 3 (2.36%) 7 (5.51%) 13 (10.24%) 14 (11.02%) B symptom 0.009 Yes 2 (1.57%) 9 (7.09%) 19 (14.96%) 12 (9.45%) No 23 (18.11 %) 20 (15.75%) 31 (24.41%) 11 (8.66%) ECOG performance status 0.002 0 18 (14.17%) 16 (12.60%) 18 (14.17%) 5 (3.94%) 1 5 (3.94%) 4 (3.15%) 4 (3.15%) 2 (1.57%) 2 2 (1.57%) 8 (6.30%) 26 (20.47%) 16 (12.60%) 3 0 (0.00%) 1 (0.79%) 2 (1.57%) 0 (0.00%) Absolute count of lymphocytes in blood 1.50 ± 0.70 1.46 ± 0.54 1.56 ± 0.74 1.36 ± 0.90 0.753 Score of absolute count of lymphocytes in blood 0.238 0 ( < 1.1 × 109/L) 7 (5.51%) 8 (6.30%) 16 (12.60%) 12 (9.45%) 1 (1.1-3.2 × 109/L) 17 (13.39%) 21 (16.54%) 32 (25.20%) 9 (7.09%) 2 (≥ 3.2 × 109/L) 1 (0.79%) 0 (0.00%) 2 (1.57%) 2 (1.57%) Absolute count of monocytes in blood 0.34 ± 0.21 0.37 ± 0.27 0.45 ± 0.24 0.40 ± 0.33 0.315 Score of absolute count of monocytes in blood 0.621 0 ( < 0.1 × 109/L) 5 (3.94%) 6 (4.72%) 6 (4.72%) 5 (3.94%) 1 (0.1-0.6 × 109/L) 18 (14.17%) 16 (12.60%) 33 (25.98%) 13 (10.24%) 2 (≥ 0.6 × 109/L) 2 (1.57%) 7 (5.51%) 11 (8.66%) 5 (3.94%) Absolute count of neutrophils in blood 4.84 ± 1.87 4.32 ± 1.94 3.85 ± 1.62 4.60 ± 3.31 0.235 Score of absolute count of neutrophils in blood 0.319 0 ( < 1.8 × 109/L) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.79%) 1 (1.8-6.3 × 109/L) 19 (14.96%) 23 (18.11%) 44 (34.65%) 20 (15.75%) 2 (≥ 6.3 × 109/L) 6 (4.72%) 5 (3.94%) 3 (2.36%) 2 (1.57%) Platelet count 209.16 ± 69.44 221.93 ± 131.66 182.16 ± 68.50 176.35 ± 103.09 0.187 Score of platelet count 0.038 0 ( < 125 × 109/L) 1 (0.79%) 4 (3.15%) 9 (7.09%) 8 (6.30%) 1 (125-350 × 109/L) 23 (18.11%) 21 (16.54%) 40 (31.50%) 14 (11.02%) 2 (≥ 350 × 109/L) 1 (0.79%) 4 (3.15%) 1 (0.79%) 1 (0.79%) NLR 3.81 ± 2.47 3.21 ± 1.49 2.93 ± 1.60 5.14 ± 4.94 0.011 Score of NLR 0.058 0 ( < 0.56) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (0.79%) 1 (0.56-5.73) 21 (16.54%) 28 (22.05%) 44 (34.65%) 16 (12.60%) 2 (≥ 5.73) 4 (3.15%) 1 (0.79%) 3 (2.36%) 6 (4.72%) MLR 0.26 ± 0.18 0.30 ± 0.29 0.32 ± 0.21 0.42 ± 0.39 0.227 Score of MLR 0.553 0 ( < 0.03) 3 (2.36%) 0 (0.00%) 1 (0.79%) 1 (0.79%) 1 (0.03-0.19) 7 (5.51%) 10 (7.87%) 13 (10.24%) 8 (6.30%) 2 (≥ 0.19) 15 (11.81%) 18 (14.17%) 36 (28.35%) 14 (11.02%) PLR 158.15 ± 78.30 172.90 ± 119.55 135.30 ± 70.33 191.08 ± 144.61 0.136 Score of PLR 0.029 0 ( < 39.06) 0 (0.00%) 0 (0.00%) 1 (0.79%) 3 (2.36%) 1 (39.06-318.18) 24 (18.90%) 26 (20.47%) 48 (37.8%) 17 (13.39%) 2 (≥ 318.18/L) 1 (0.79%) 3 (2.36%) 1 (0.79%) 3 (2.36%) Infiltrating CD4+ T cells 311.72 ± 309.52 222.55 ± 159.50 285.28 ± 207.97 247.91 ± 225.64 0.462 Infiltrating Foxp3+ T cells 165.92 ± 113.51 121.10 ± 124.04 137.24 ± 131.47 132.74 ± 139.82 0.631 Infiltrating CD8+ T cells 351.60 ± 240.84 175.52 ± 142.07 216.40 ± 119.50 251.74 ± 123.24 0.000 Infiltrating CD68+ macrophages 155.60 ± 86.65 135.52 ± 54.02 117.30 ± 63.03 121.74 ± 55.73 0.104 Infiltrating CD163+ macrophages 120.00 ± 72.86 116.21 ± 79.53 103.36 ± 79.53 118.57 ± 70.69 0.723 Score of PD-1 0.878 0 (-) 12 (9.45%) 12 (9.45%) 21 (16.54%) 12 (9.45%) 1 (+) 8 (6.30%) 6 (4.72%) 12 (9.45%) 7 (5.51%) 2 (++) 3 (2.36%) 6 (4.72%) 9 (7.09%) 2 (1.57%) 3 (+++) 2 (1.57%) 5 (3.94%) 8 (6.30%) 2 (1.57%) Score of PD-L1 0.133 0 (-) 1 (0.79%) 4 (3.15%) 12 (9.45%) 1 (0.79%) 1 (+) 7 (5.51%) 12 (9.45%) 16 (12.60%) 7 (5.51%) 2 (++) 11 (8.66%) 11 (8.66%) 15 (11.81%) 8 (6.30%) 3 (+++) 6 (4.72%) 2 (1.57%) 7 (5.51%) 7 (5.51%) Serum LDH 202.28 ± 62.28 265.63 ± 133.64 294.84 ± 204.54 584.59 ± 519.76 0.000 Score of serum LDH 0.006 0 ( < 250 U/L) 22 (17.32%) 18 (14.17%) 32 (25.20%) 8 (6.30%) 1 (250-500 U/L) 3 (2.36%) 7 (5.51%) 10 (7.87%) 6 (4.72%) 2 (≥ 500 U/L) 0 (0.00 %) 4 (3.15%) 8 (%) 9 (7.09%) Serum iron 14.77 ± 5.40 14.78 ± 10.44 12.45 ± 6.31 9.15 ± 5.09 0.019 Score of serum iron 0.041 0 ( < 7.8 μmol) 2 (1.57%) 6 (4.72%) 7 (5.51%) 10 (7.87%) 1 (7.8-32.2 μmol) 23 (18.11%) 22 (17.32%) 24 (18.90%) 13 (10.24%) 2 (≥ 32.2 μmol) 0 (0.00%) 1 (0.79%) 0 (0.00%) 0 (0.00%) Serum albumin 44.14 ± 4.81 42.00 ± 5.65 40.44 ± 5.40 37.05 ± 6.43 0.000 Score of serum iron 4 (3.15%) 9 (7.09%) 21 (16.54%) 15 (11.81%) 0.004 0 ( < 40 g/L) 21 (16.54%) 20 (15.75%) 29 (22.83%) 8 (6.30%) 1 (40-55 g/L) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 2 (≥ 55 g/L) Serum β2MG 1.68 ± 0.92 2.56 ± 1.77 3.19 ± 2.13 4.71 ± 4.31 0.000 Score of serum β2MG 0.000 0 ( < 3 mg/L) 23 (19.66%) 21 (16.54%) 26 (20.47%) 8 (6.30%) 1 (≥ 3 mg/L) 2 (1.57%) 8 (6.30%) 24 (18.90%) 15 (11.81%) Table 1. Results of ANOVA and Chi-Square Tests in Different Risk Stratification Models
Factors P Value IPI R-IPI NCCN-IPI Age 0.005 0.006 0.000 Sex 0.645 0.529 0.263 Histological classification 0.571 0.369 0.199 Sites of involvement 0.940 0.908 0.298 Ann Arbor stage 0.000 0.000 0.003 B symptom 0.000 0.000 0.009 ECOG performance status 0.000 0.000 0.002 Absolute count of lymphocytes in blood 0.717 0.565 0.753 Score of absolute count of lymphocytes in blood 0.270 0.074 0.238 Absolute count of monocytes in blood 0.003 0.033 0.315 Score of absolute count of monocytes in blood 0.018 0.191 0.621 Absolute count of neutrophils in blood 0.899 0.832 0.235 Score of absolute count of neutrophils in blood 0.294 0.137 0.319 Platelet count 0.420 0.255 0.187 Score of platelet count 0.102 0.085 0.038 NLR 0.098 0.265 0.011 Score of NLR 0.197 0.376 0.058 MLR 0.091 0.068 0.227 Score of MLR 0.048 0.062 0.553 PLR 0.645 0.820 0.136 Score of PLR 0.205 0.125 0.029 Infiltrating CD4+T cells 0.546 0.187 0.462 Infiltrating FOXP3+ T cells 0.860 0.192 0.631 Infiltrating CD8+T cells 0.017 0.004 0.000 Infiltrating CD68+ macrophages 0.106 0.095 0.104 Infiltrating CD163+ macrophages 0.481 0.646 0.723 Score of PD-1 expression 0.359 0.787 0.878 Score of PD-L1 expression 0.041 0.041 0.133 Serum LDH 0.000 0.001 0.000 Score of serum LDH 0.001 0.001 0.006 Serum iron 0.001 0.007 0.019 Score of serum iron 0.020 0.036 0.041 Serum albumin 0.001 0.002 0.000 Score of serum albumin 0.003 0.004 0.004 Serum β2MG 0.000 0.002 0.000 Score of serum β2MG 0.000 0.000 0.000 Note. NLR, neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio, PLR, platelet-to-lymphocyte ratio. Table 2. Likelihood Ratio Tests of Various Factors in Estimating the Risk Stratification by Multinomial Logistic Regression
Factors Likelihood Ratio Tests IPI R-IPI NCCN-IPI Chi-square df P Value Chi-square df P Value Chi-square df P Value Age 28.197 3 0.000 58.676 3 0.000 14.049 2 0.001 Ann Arbor stage 54.930 9 0.000 26.311 9 0.002 30.882 6 0.000 B symptoms 2.782 3 0.427 2.825 3 0.419 5.890 2 0.053 ECOG performance status 14.246 9 0.114 15.068 9 0.089 3.284 6 0.772 Absolute count of monocytes in blood 17.854 3 0.000 6.974 3 0.073 1.619 2 0.445 Infiltrating CD8+ T cells 9.105 3 0.028 8.921 3 0.030 3.336 2 0.189 Score of PD-L1 expression in lymphoma tissue 24.488 9 0.004 15.810 9 0.071 12.041 6 0.061 Score of serum LDH 12.444 6 0.053 10.045 6 0.123 3.975 4 0.409 Score of serum iron 11.475 6 0.075 2.141 6 0.906 4.113 4 0.391 Score of serum albumin 10.868 3 0.012 0.932 3 0.818 1.049 2 0.592 Score of serum β2MG 12.385 3 0.006 3.035 3 0.386 2.367 2 0.306 Table 3. Concordance Rate of Predicted Risk Stratification Using Multinomial Logistic Regression (Influence of Ann Arbor Stages Considered)
Score Models Stratification Predicted Stratification Concordance Rate Low risk Low-intermediate risk High intermediate risk High risk IPI Low risk 34 (26.77%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 100.0% Low-intermediate risk 0 (0.00%) 41 (32.28%) 3 (2.36%) 0 (0.00%) 93.0% High-intermediate risk 0 (0.00%) 3 (2.36%) 28 (22.05%) 0 (0.00%) 90.3% High risk 0 (0.00%) 0 (0.00%) 0 (0.00%) 19 (14.96%) 100.0% NCCN-IPI Low risk 25 (19.69%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 100.0% Low-intermediate risk 0 (0.00%) 29 (22.83%) 0 (0.00%) 0 (0.00%) 100.0% High-intermediate risk 4 (3.15%) 2 (1.57%) 41 (32.28%) 3 (2.36%) 100.0% High risk 0 (0.00%) 0 (0.00%) 0 (0.00%) 23 (18.11%) 100.0% R-IPI Observed Very good good Poor Concordance rate Very good 30 (23.62%) 0 (0.00%) 0 (0.00%) 100.0% Good 0 (0.00%) 40 (31.50%) 7 (5.51%) 85.1% Poor 0 (0.00%) 6 (4.72%) 44 (34.65%) 88.0% Table 4. Concordance Rate of Predicted Risk Stratification by Multinomial Logistic Regression (influence of Ann Arbor stages not considered)
Score Models Stratification Predicted Stratification Concordance Rate Low risk Low-intermediate risk High intermediate risk High risk IPI Low risk 33 (25.98%) 0 (0.00%) 0 (0.00%) 1 (0.79%) 97.1% Low-intermediate risk 1 (0.79%) 35 (27.56%) 6 (4.72%) 1 (0.79%) 81.4% High-intermediate risk 0 (0.00%) 4 (3.15%) 27 (21.26%) 0 (0.00%) 87.1% High risk 0 (0.00%) 0 (0.00%) 0 (0.00%) 19 (14.96%) 100.0% NCCN-IPI Low risk 25 (19.69%) 0 (0.00%) 2 (1.57%) 0 (0.00%) 100.0% Low-intermediate risk 0 (0.00%) 29 (22.83%) 0 (0.00%) 0 (0.00%) 100.0% High-intermediate risk 0 (0.00%) 0 (0.00%) 50 (39.37%) 0 (0.00%) 100.0% High risk 1 (0.79%) 0 (0.00%) 0 (0.00%) 22 (17.32%) 95.7% R-IPI Observed Very good good Poor Concordance rate Very good 30 (23.62%) 0 (0.00%) 0 (0.00%) 100.0% Good 0 (0.00%) 41 (32.28%) 6 (4.72%) 87.2% Poor 0 (0.00%) 6 (4.72%) 44 (34.65%) 88.0% Table 5. Paired t Test on the Concordance Rates of Three Predicted Stratification Models with and without Ann Arbor Stage Data
Variables Paired Differences t df P Value Mean Std. Deviation Std. Error Mean Pair 1 Estimated IPI risk stratification 4.425 4.996 2.498 1.771 3 0.175 Pair 2 Estimated NCCN-IPI risk stratification 1.075 2.150 1.075 1.000 3 0.391 Pair 3 Estimated R-IPI risk stratification -0.700 1.212 0.700 -1.000 2 0.423 -
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