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Figure legends
Figure 1. Survival outcomes of 162 cases with pre-operative treatment are shown. a: PFS curves of
high and low AGR cases. b: OS curves of high and low AGR cases.
Figure 2. Pre-operative chemotherapy treatment ARDI was compared with AGR by the correlation
coefficient analysis.
Supplementary Figure S1. Survival outcomes of 162 cases with pre-operative treatment are shown.
a: PFS curves of high and low albumin cases. b: OS curves of high and low albumin cases.
Supplementary Figure S2. Survival outcomes of 162 cases with pre-operative treatment are shown.
a: PFS curves of high and low globulin cases. b: OS curves of high and low globulin cases.
Supplementary Figure S3. Survival outcomes of 429 cases without pre-operative treatment are shown.
a: PFS curves of high and low AGR cases. b: OS curves of high and low AGR cases.
15
Table 1. Patients' characteristics
Variable
Age, mean ± SD (years)
Sex
Male
Female
Body mass index, mean ± SD (kg/m2)
Tumor location
Head
Body or tail
Resectability at the diagnosis
Resectable
Borderline resectable
Unresectable
CEA, mean ± SD (ng/mL)
CA19-9, mean ± SD (U/mL)
DUPAN-2, mean ± SD (U/mL)
SPan-1, mean ± SD (U/mL)
NLR
High ( > 2.33)
Low ( < 2.33)
PLR
High ( > 160)
Low ( < 160)
PNI
High ( > 45)
Low ( < 45)
AGR
High ( > 1.33)
Low ( < 1.33)
Preoperative therapy
FFX
GnP
GS
NACRT (S-1)
Others
RDI (%)
High ( > 80)
Low ( < 80)
Operative procedure
Pancreaticoduedenectomy
Distal pancreatectomy
Total pancreatectomy
Tumor size, mean ± SD (mm)
Pathological TNM stage
0
IA
IIA
IIB
III
IV
n=162
66.8 ± 8.9
91 (56.2)
71 (43.8)
20.9 ± 3.5
127 (78.4)
35 (21.6)
63 (39.1)
66 (41.0)
32 (19.9)
5.4 ± 22.2
676 ± 1783
934 ± 2696
84.3 ± 143.7
83 (51.2)
79 (48.8)
80 (49.4)
82 (50.6)
79 (48.8)
83 (51.2)
80 (49.4)
82 (50.6)
21 (13.0)
44 (27.2)
39 (24.1)
42 (25.9)
16 (9.8)
114 (70.4)
48 (29.6)
130 (80.2)
29 (17.9)
3 (1.9)
24.1 ± 8.9
5 (3.1)
8 (5.0)
72 (44.7)
66 (41.0)
6 (3.7)
4 (2.5)
NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio;
PNI, prognostic nutritional index; AGR, albumin–globulin ratio;
FFX, FOLFIRINOX; GnP, gemcitabine and nab-paclitaxel;
GS, gemcitabine and tegafur/gimeracil/oteracil (S-1);
NAT, neoadjuvant therapy; RDI: relative dose intensity
continuous variables: average ± standard deviation
Table 2. Association of AGR and clinicopathological characteristics in 162 patients treated with preoperative therapy and surgical resection
Variables
High AGR (n=80)
Low AGR (n=82)
P value
0.156
Age, years
65.8 ± 9.3
67.8 ± 8.5
Sex
0.754
Male
46 (57.5)
45 (54.9)
Female
34 (42.5)
37 (45.1)
0.468
Body mass index (kg/m )
21.1 ± 4.0
20.6 ± 3.0
Tumor location
0.013*
Head
56 (70.0)
71 (86.6)
Body or tail
24 (30.0)
11 (13.4)
Resectability at the diagnosis
0.053
Resectable
25 (31.3)
38 (46.9)
Borderline resectable
35 (42.5)
32 (39.5)
Unresectable
21 (26.2)
11 (13.6)
6.6 ± 3.5
412 ± 951
334 ± 564
54.3 ± 61.9
4.3 ± 3.5
933 ± 2303
1519 ± 3665
113.6 ± 188.6
37 (46.3)
43 (53.8)
46 (56.1)
36 (43.9)
39 (48.8)
41 (51.2)
41 (50.0)
41 (50.0)
52 (65.0)
28 (35.0)
27 (32.9)
55 (67.1)
Preoperative therapy
FFX
GnP
GS
NACRT (S-1)
Others
ARDI, mean ± SD (ng/mL)
11 (13.8)
23 (28.8)
14 (17.5)
21 (26.3)
11 (13.6)
89.4 ± 15.8
10 (12.2)
21 (25.6)
25 (30.5)
21 (25.6)
5 (6.1)
85.7 ± 18.9
Operative procedure
Pancreaticoduedenectomy
Distal pancreatectomy
Total pancreatectomy
Postoperative hospital stay period (days)
59 (73.8)
19(23.8)
1 (2.5)
24.2 ± 9.6
71 (86.6)
10 (12.2)
1 (1.2)
25.8 ± 13.6
23.6 ± 9.8
24.6 ± 7.9
58 (72.5)
22 (27.5)
64 (78.1)
18 (21.9)
61 (76.3)
19 (23.7)
75 (91.5)
7 (8.5)
22 (27.5)
58 (72.5)
43 (52.4)
39 (47.6)
19 (23.8)
61 (76.2)
40 (48.8)
42 (51.2)
33 (41.3)
47 (58.7)
31 (37.8)
51 (62.2)
14 (17.5)
66 (82.5)
6 (7.3)
76 (92.7)
13 (16.3)
67 (83.7)
10 (12.2)
72 (87.8)
27 (33.8)
53 (66.2)
40 (48.8)
42 (51.2)
26 (32.5)
54 (67.5)
35 (42.7)
47 (57.3)
22 (27.5)
58 (72.5)
36 (43.9)
46 (56.1)
5 (6.3)
75 (93.2)
9 (11.0)
73 (89.0)
48 (60.0)
32 (40.0)
38 (46.3)
44 (53.7)
69 (86.3)
11 (13.7)
69 (84.2)
13 (15.8)
49 (71.0)
20 (29.0)
52 (75.4)
17 (24.6)
CEA, mean ± SD (ng/mL)
CA19-9, mean ± SD (U/mL)
DUPAN-2, mean ± SD (U/mL)
SPan-1, mean ± SD (U/mL)
NLR
High ( > 2.33)
Low ( < 2.33)
PLR
High ( > 160)
Low ( < 160)
PNI
High ( > 45)
Low ( < 45)
Pathological findings
Tumor size (mm)
Serosal invasion
(+)
(-)
Retroperitoneal invasion
(+)
(-)
Bile duct invasion
(+)
(-)
Duodenum invasion
(+)
(-)
Portal venous system invasion
(+)
(-)
Regional artery invasion
(+)
(-)
Nerve plexus invasion
(+)
(-)
Lymphatic invasion
(+)
(-)
Venous invasion
(+)
(-)
Lymph node metastasis
(+)
(-)
Peritoneal cytology
(+)
(-)
Pathological TNM stage
0 or I or IIA
IIB or III or IV
Adjuvant chemotherapy
(+)
(-)
Adjuvant chemotherapy course completion
(+)
(-)
NLR, neutrophil–lymphocyte ratio; PLR, platelet-lymphocyte ratio;
PNI, prognostic nutritional index; AGR, albumin–globulin ratio;
FFX, FOLFIRINOX; GnP, gemcitabine and nab-paclitaxel;
GS, gemcitabine and tegafur/gimeracil/oteracil (S-1); CEA, carcinoembryonic antigen;
CA19-9, carbohydrate antigen 19-9; ARDI, average relative dose intensity
continuous variables: average ± standard deviation
Statistically significant
0.498
0.063
0.005*
0.011*
0.271
0.877
<0.0001*
0.508
0.180
0.122
0.393
0.482
0.468
0.010*
0.001*
0.001*
0.748
0.058
0.506
0.057
0.198
0.034*
0.403
0.086
0.826
0.701
Table 3. Clinicopathological factors of survival outcomes in 162 patients treated with preoperative therapy and surgical resection
Variables
PFS Univariate analysis
OS Univariate analysis
P value
HR (95% CI)
HR (95% CI)
P value
Age (> 70 years vs. ＜70 years)
1.23 (0.83-1.84)
0.299
1.56 (0.97-2.51)
0.069
Sex (male vs. female)
0.98 (0.66-1.45)
0.936
1.07 (0.67-1.72)
0.766
Tumor location (head vs. body or tail)
0.94 (0.59-1.50)
0.803
0.97 (0.55-1.69)
0.911
Resectability at the diagnosis (R vs. BR / UR) 1.45 (0.96-2.20)
0.075
1.39 (0.83-2.32)
0.209
CEA (> 5.0 IU/ml vs. < 5.0 IU/ml)
CA19-9 (> 37 IU/ml vs. ＜ 37 IU/ml)
DUPAN-2 (> 150 IU/ml vs. ＜ 150 IU/ml)
Span-1 (> 30 IU/ml vs. ＜ 30 IU/ml)
NLR (> 2.33 vs. ＜ 2.33)
PLR (> 160 vs. < 160)
PNI (> 45 vs. < 45)
AGR (> 1.33 vs. < 1.33)
0.92 (0.56-1.51)
1.15 (0.71-1.85)
1.12 (0.76-1.66)
1.20 (0.79-1.83)
1.06 (0.72-1.57)
1.10 (0.75-1.63)
0.84 (0.57-1.25)
0.63 (0.42-0.93)
0.734
0.581
0.565
0.401
0.776
0.625
0.385
0.020*
0.96 (0.54-1.71)
1.11 (0.62-2.00)
1.28 (0.80-2.05)
1.52 (0.89-2.58)
0.91 (0.57-1.46)
0.92 (0.58-1.48)
1.09 (0.68-1.75)
0.62 (0.38-0.99)
0.897
0.728
0.300
0.121
0.707
0.739
0.716
0.045*
ARDI (＞ 80 vs. < 80)
Tumor size (> 20mm vs. < 20mm)
0.83 (0.54-1.27)
1.29 (0.85-1.96)
0.393
0.240
0.77 (0.50-1.28)
1.28 (0.76-2.16)
0.309
0.349
PFS, progression-free survival; OS, overall survival; NAT, neoadjuvant therapy; RDI, average relative dose intensity
NLR: neutrophil lymphocyte ratio, PLR: platelet-lymphocyte ratio,
PNI: prognostic nutritional index, AGR: Albumin-Globulin ratio,
CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9
continuous variables: average ± standard deviation
Statistically significant
Supplementary Table 1. Association of albumin and clinicopathological characteristics in 162 patients treated with preoperative therapy and surgical resection
Variables
High Albumin (n=78) Low Albumin (n=84) P value
Age, years
65.7 ± 9.1
67.9 ± 8.7
0.117
Sex
0.017*
Male
36 (46.2)
55 (65.5)
Female
42 (53.8)
29 (34.5)
Body mass index (kg/m )
21.7 ± 3.9
20.1 ± 2.8
0.003*
Tumor location
0.022*
Head
55 (70.5)
72 (85.7)
Body or tail
23 (29.5)
12 (14.3)
Resectability at the diagnosis
0.022*
Resectable
22 (28.6)
41 (48.8)
Borderline resectable
35 (45.5)
31 (36.9)
Unresectable
20 (25.9)
12 (14.3)
CEA, mean ± SD (ng/mL)
CA19-9, mean ± SD (U/mL)
DUPAN-2, mean ± SD (U/mL)
SPan-1, mean ± SD (U/mL)
6.9 ± 3.6
572 ± 1139
702 ± 2205
61.4 ± 55.9
4.1 ± 3.4
772 ± 2224
1148 ± 3081
105.5 ± 190.2
0.433
0.476
0.297
0.061
NAT RDI
89.6 ± 15.5
85.6 ± 19.0
0.153
Operative procedure
Pancreaticoduedenectomy
Distal pancreatectomy
Total pancreatectomy
57 (73.1)
19 (24.4)
2 (2.5)
73 (86.9)
10 (11.9)
1 (1.2)
25.0 ± 9.4
23.3 ± 8.3
60 (76.9)
18 (23.1)
62 (73.8)
22 (26.2)
64 (82.1)
14 (17.9)
72 (85.7)
12 (14.3)
21 (26.9)
57 (73.1)
44 (52.4)
40 (47.6)
25 (32.1)
53 (67.9)
34 (40.5)
50 (59.5)
39 (50.0)
39 (50.0)
25 (29.8)
59 (70.2)
13 (16.7)
65 (83.3)
7 (8.3)
77 (91.7)
12 (15.4)
66 (84.6)
11 (13.1)
73 (86.9)
31 (39.7)
47 (60.3)
36 (42.9)
48 (57.1)
29 (37.2)
49 (62.8)
32 (38.1)
52 (61.9)
23 (29.5)
55 (70.5)
35 (41.7)
49 (58.3)
7 (8.9)
71 (91.1)
7 (8.3)
77 (91.7)
46 (58.9)
32 (41.1)
40 (47.6)
44 (52.4)
Pathological findings
Tumor size (mm)
Serosa invasion
(+)
(-)
Retroperitoneum invasion
(+)
(-)
Bile duct invasion
(+)
(-)
Duodenum invasion
(+)
(-)
Portal venous system invasion
(+)
(-)
Regional artery invasion
(+)
(-)
Nerve plexus invasion
(+)
(-)
Lymphatic invasion
(+)
(-)
Venous invasion
(+)
(-)
Lymph node metastasis
(+)
(-)
Peritoneal cytology
(+)
(-)
Pathological TNM stage
0 or I or IIA
IIB or III or IV
0.085
0.219
0.717
0.669
0.001*
0.327
0.011*
0.151
0.822
0.75
0.139
0.159
NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio;
PNI, prognostic nutritional index; AGR, albumin–globulin ratio;
PD, pancreaticoduodenectomy; DP, distal pancreatectomy; TP, total pancreatectomy;
CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9;
NAT, neoadjuvant therapy; RDI, relative dose intensity
continuous variables: average ± standard deviation
Statistically significant
Supplementary Table 2. Association of globulin and clinicopathological characteristics in 162 patients treated with preoperative therapy and surgical resection
Variables
High globulin (n=69) Low globulin (n=93) P value
Age, years
68.3 ± 8.4
65.7 ± 9.2
0.074
Sex
0.873
Male
38 (55.1)
53 (57.0)
Female
31 (44.9)
40 (43.0)
Body mass index (kg/m )
21.2 ± 4.1
20.6 ± 2.9
0.255
Tumor location
0.335
Head
57 (82.6)
70 (75.3)
Body or tail
12 (17.4)
23 (24.7)
Resectability at the diagnosis
0.446
Resectable
30 (44.1)
33 (35.5)
Borderline resectable
27 (39.7)
39 (41.9)
Unresectable
11 (16.2)
21 (22.6)
CEA, mean ± SD (ng/mL)
CA19-9, mean ± SD (U/mL)
DUPAN-2, mean ± SD (U/mL)
SPan-1, mean ± SD (U/mL)
3.9 ± 3.1
799 ± 1563
1435 ± 3531
129.4 ± 202.7
6.6 ± 3.0
585 ± 1934
564 ± 1787
51.7 ± 60.4
0.437
0.451
0.043*
0.001*
NAT RDI
86.6 ± 18.3
88.2 ± 16.9
0.581
Operative procedure
Pancreaticoduedenectomy
Distal pancreatectomy
Total pancreatectomy
Pathological findings
Tumor size (mm)
Serosa invasion
(+)
(-)
Retroperitoneum invasion
(+)
(-)
Bile duct invasion
(+)
(-)
Duodenum invasion
(+)
(-)
Portal venous system invasion
(+)
(-)
Regional artery invasion
(+)
(-)
Nerve plexus invasion
(+)
(-)
Lymphatic invasion
(+)
(-)
Venous invasion
(+)
(-)
Lymph node metastasis
(+)
(-)
Peritoneal cytology
(+)
(-)
Pathological TNM stage
0 or I or IIA
IIB or III or IV
57 (82.6)
11(15.9)
1 (1.5)
73 (78.5)
18 (19.4)
2 (2.1)
25.9 ± 8.4
22.8 ± 9.0
51 (73.9)
18 (26.1)
71 (76.3)
22 (23.7)
62 (89.9)
7 (10.1)
74 (79.6)
19 (20.4)
33 (47.8)
36 (52.2)
32 (34.4)
61 (65.6)
32 (46.4)
37 (53.6)
27 (29.0)
66 (71.0)
29 (42.0)
40 (58.0)
35 (37.6)
58 (62.4)
8 (11.6)
61 (88.4)
12 (12.9)
81 (87.1)
11 (15.9)
58 (84.1)
12 (12.9)
81 (87.1)
29 (42.0)
40 (58.0)
38 (40.9)
55 (59.1)
26 (37.7)
43 (62.3)
35 (37.6)
58 (62.4)
27 (39.1)
42 (60.9)
31 (33.3)
62 (66.7)
8 (11.6)
61 (88.4)
6 (6.5)
87 (93.5)
35 (50.7)
34 (49.3)
51 (54.8)
42 (45.2)
0.798
0.031*
0.854
0.087
0.105
0.032*
NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio;
PNI, prognostic nutritional index; AGR, albumin–globulin ratio;
PD, pancreaticoduodenectomy; DP, distal pancreatectomy; TP, total pancreatectomy;
CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9;
NAT, neoadjuvant therapy; RDI, relative dose intensity
continuous variables: average ± standard deviation
Statistically significant
0.627
0.652
0.508
0.271
0.635
Supplementary Table 3. Association of AGR and clinicopathological characteristics in 127 patients treated with preoperative therapy and pancreatic head resection
P value
Variables
High AGR (n=56)
Low AGR (n=71)
0.744
Age, years
66.9 ± 9.5
67.5 ± 8.8
Sex
0.722
Male
32 (57.1)
38 (53.5)
Female
24 (42.9)
33 (46.5)
Body mass index (kg/m )
0.692
21.1 ± 4.1
20.7 ± 3.1
Resectability at the diagnosis
0.020*
Resectable
14 (25.0)
32 (45.7)
Borderline resectable
27 (48.2)
30 (42.9)
Unresectable
15 (26.8)
8 (11.4)
0.420
0.080
0.005*
0.043*
0.155
8.2 ± 5.0
381 ± 620
285 ± 380
58.4 ± 68.7
4.1 ± 3.4
914 ± 2437
1628 ± 3898
111.8 ± 196.0
24 (42.9)
32 (57.1)
40 (56.3)
31 (43.7)
26 (46.4)
30 (53.6)
39 (54.9)
32 (45.1)
36 (64.3)
20 (35.7)
20 (28.2)
51 (71.8)
Preoperative therapy
FFX
GnP
GS
NACRT (S-1)
Others
ARDI, mean ± SD (ng/mL)
7 (12.5)
13 (23.2)
10 (17.9)
17 (30.4)
9 (16.0)
89.8 ± 16.9
8 (11.2)
17 (23.9)
21 (29.6)
19 (26.8)
6 (8.5)
85.5 ± 18.7
Postoperative hospital stay period (days)
24.7 ± 7.7
25.8 ± 14.3
0.577
23.7 ± 9.7
25.0 ± 7.7
37 (66.1)
19 (33.9)
55 (77.5)
16 (22.5)
0.432
0.167
40 (71.4)
16 (28.6)
66 (93.0)
5 (7.0)
21 (37.5)
35 (62.5)
43 (60.6
28 (39.4)
18 (32.1)
38 (67.9)
39 (54.9)
32 (45.1)
22 (39.3)
34 (60.7)
24 (33.8)
47 (66.2)
1 (1.8)
55 (98.2)
3 (4.2)
68 (95.8)
9 (16.1)
47 (83.9)
10 (14.1)
61 (85.9)
18 (32.1)
38 (67.9)
35 (49.3)
36 (50.7)
16 (35.6)
40 (48.8)
29 (64.4)
42 (51.2)
15 (26.8)
41 (73.2)
32 (45.1)
39 (54.9)
4 (7.1)
52 (92.9)
7 (9.9)
64 (90.1)
37 (66.1)
19 (33.9)
33 (46.5)
38 (53.5)
CEA, mean ± SD (ng/mL)
CA19-9, mean ± SD (U/mL)
DUPAN-2, mean ± SD (U/mL)
SPan-1, mean ± SD (U/mL)
NLR
High ( > 2.33)
Low ( < 2.33)
PLR
High ( > 160)
Low ( < 160)
PNI
High ( > 45)
Low ( < 45)
Pathological findings
Tumor size (mm)
Serosal invasion
(+)
(-)
Retroperitoneal invasion
(+)
(-)
Bile duct invasion
(+)
(-)
Duodenum invasion
(+)
(-)
Portal venous system invasion
(+)
(-)
Regional artery invasion
(+)
(-)
Nerve plexus invasion
(+)
(-)
Lymphatic invasion
(+)
(-)
Venous invasion
(+)
(-)
Lymph node metastasis
(+)
(-)
Peritoneal cytology
(+)
(-)
Pathological TNM stage
0 or I or IIA
IIB or III or IV
Adjuvant chemotherapy
(+)
(-)
Adjuvant chemotherapy course completion
(+)
(-)
47 (83.9)
9 (16.1)
61 (85.9)
10 (14.1)
35 (74.5)
12 (25.5)
44 (72.1)
17 (27.9)
NLR, neutrophil–lymphocyte ratio; PLR, platelet-lymphocyte ratio;
PNI, prognostic nutritional index; AGR, albumin–globulin ratio;
FFX, FOLFIRINOX; GnP, gemcitabine and nab-paclitaxel;
GS, gemcitabine and tegafur/gimeracil/oteracil (S-1); CEA, carcinoembryonic antigen;
CA19-9, carbohydrate antigen 19-9; ARDI, average relative dose intensity
continuous variables: average ± standard deviation
Statistically significant
0.375
<0.0001*
0.553
0.182
0.002*
0.013*
0.012*
0.579
0.630
0.806
0.070
0.192
0.042*
0.754
0.032*
0.806
0.830
Median OS time
Median PFS time
AGR High group 22.3
AGR Low group 17.1
AGR High group 48.7
AGR Low group 32.9
PFS survival rate
OS survival rate
－High group
－Low group
－High group
－Low group
P=0.043*
P=0.019*
Months after therapy induction
Months after therapy induction
Number at risk
AGR High group
80 58 28 18
AGR Low group
82 53 16 11
12
12
11
10
Recurrence-free survival
Figure 1
Number at risk
AGR High group
80 69 48 29
AGR Low group
82 68 33 17
21
16
12
13
10
Overall survival
S-1 based regimens (n=81)
All cases (n=162)
R2<0.5, P=0.131
Other regimens (n=81)
Figure 2
R2<0.5, P=0.011*
R2<0.5, P=0.532
Median OS time
Median PFS time
Albumin High group
Albumin Low group
Albumin High group
Albumin Low group
18.8
18.4
PFS survival rate
37.0
57.9
OS survival rate
－High group
－Low group
－High group
－Low group
P=0.572
P=0.695
Months after therapy induction
Months after therapy induction
Number at risk
Albumin High group
78 55 25 17
Albumin Low group
84 56 19 12
13
13
10
Recurrence-free survival
Supplementary Figure S1
Number at risk
Albumin High group
78 65 47 28
Albumin Low group
84 72 34 18
20
15
11
14
12
Overall survival
Median PFS time
Median OS time
Globulin High group 17.3
Globulin Low group 21.8
Globulin High group 29.7
Globullin Low group 57.9
PFS survival rate
OS survival rate
－High group
－Low group
－High group
－Low group
P=0.005*
P=0.111
Months after therapy induction
Number at risk
Globulin High group
69 44 15 10
Globulin Low group
93 66 29 19
Months after therapy induction
13
11
10
Recurrence-free survival
Supplementary Figure S2
Number at risk
Globulin High group
69 56 29 16
Globulin Low group
93 81 52 30
13
11
21
15
12
Overall survival
Median PFS time
Median OS time
AGR High group 38.6
AGR Low group 33.0
AGR High group 46.2
AGR Low group 57.2
PFS survival rate
OS survival rate
－High group
－Low group
－High group
－Low group
P=0.637
P=0.322
Months after surgery
Months after surgery
Number at risk
AGR High group
267 84
AGR Low group
162 31
36
14
15
Recurrence-free survival
Supplementary Figure S3
Number at risk
AGR High group
267 133 45
AGR Low group
162 66 21
19
12
Overall survival
...
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