Surgical Oncology 37 (2021) 101526

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Surgical Oncology
journal homepage: http://www.elsevier.com/locate/suronc

Cancer related nutritional and inflammatory markers as predictive

parameters of immediate postoperative complications and long-term
survival after hepatectomies
Sohan Lal Solanki a, *, Jasmeen Kaur b, Amit M. Gupta c, Shraddha Patkar c, Riddhi Joshi d,
Reshma P. Ambulkar a, Akshay Patil e, Mahesh Goel c
a
Department of Anesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
b
Department of Anesthesiology and Perioperative Medicine, Augusta University Medical Center, Augusta, GA, USA
c
Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
d
Department of Anaesthesia, Dubbo Base Hospital, Dubbo, NSW, Australia
e
Clinical Research Secretariat, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: The overall survival (OS), disease-free survival (DFS) and complications after liver resections is
Albumins unsatisfactory. Cancer-related malnutrition and inflammation have an effect on survival but not studied/not
Disease-free survival clear on postoperative complications.
Hepatectomy
Methods: We retrospectively analyzed prospectively maintained database of 309 patients. The outcome variables
Inflammation
Postoperative complications
included complications in terms of Clavien-Dindo (CD) Score, OS and DFS; We studied effect of preoperative
albumin globulin ratio (AGR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and
aspartate transaminase to platelet ratio index (APRI) and dynamic change from pre-operative to postoperative
value (Delta-AGR, Delta-NLR, Delta-PLR and Delta-APRI) on complications, OS and DFS.
Results: Total 98 patients (31.71%) had postoperative complications. Fifty patients had CD 1 & 2 and 35
(11.33%) had CD 3 & 4, and 13 (4.12%) had mortality (CD 5). Low AGR, high NLR, high PLR and high Delta-AGR
and high Delta-APRI predicted increased major complications. Preoperative high NLR predicted worse OS and
low AGR predicted worse OS and DFS. Delta-APRI showed trends towards worse OS and DFS.
Conclusion: These serum inflammatory markers can predict immediate postoperative complications. Preoperative
AGR and preoperative NLR can predict survival after liver resections. High Delta-AGR, which is a new entity, is
predicting more postoperative complications and needs further detailed studies.

1. Introduction Albumin/globulin ratio (AGR), has been known as a prognostic indica­

Liver resection (anatomical and non-anatomical) is considered as a
curative treatment for primary hepatocellular cancers (HCC) and liver
metastasis from cancer of other organs (mostly from colorectal cancers).
Cancer-related malnutrition, as well as cancer-related inflammation
(CRI), are common and it has an effect on quality of life, overall survival
(OS), disease-free survival (DFS)/recurrence-free survival (RFS) and
recurrence [1].
Albumin is an important marker that reflects nutritional status of a
person. Many studies have shown it to be an independent predictor of
postoperative complications and overall survival [2,3].
tor in several types of cancers, including HCC, gastric cancer, colorectal
cancer, breast cancer, ovarian cancer and nasopharyngeal carcinoma [4,
5].
It is shown that, in solid organ tumors, inflammation often appears
before the tissue malignant transformation. Cancer metastasis and
tumor recurrence is often aggravated by microenvironment provided by
systemic immune response [1]. Several CRI parameters like neutrophil
to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and
aspartate transaminase (AST) to platelet ratio index (APRI) have been
proposed to improve survival prediction for patients after resection of
HCC. These can be easily calculated using complete blood count and

* Corresponding author. Department of Anesthesiology, Critical Care and Pain, 2nd Floor, Main Building, Tata Memorial Hospital, Parel, Mumbai, 400012, India.
E-mail address: me_sohans@yahoo.co.in (S.L. Solanki).

https://doi.org/10.1016/j.suronc.2021.101526
Received 17 September 2020; Received in revised form 27 December 2020; Accepted 25 January 2021
Available online 4 February 2021
0960-7404/© 2021 Elsevier Ltd. All rights reserved.
S.L. Solanki et al.
liver function tests. These serum inflammatory indices are shown to
have a significant effect on OS and DFS/RFS for liver cancers [1].
In the majority of these studies, pre-operative parameters were used
to calculate AGR and one or two of the CRI parameters like NLR, PLR and
APRI were studied concerning mortality, morbidity, OS and DFS or RFS.
Some studies focused on the clinical significance of the dynamic change
of pre-treatment and post-treatment NLR (Delta-NLR)in liver cancers,
biliary-tract cancers, colon cancers and esophageal cancers [6–9]; dy­
namic change of pre-treatment and post-treatment PLR (Delta-PLR) in
biliary tract cancers [7], and dynamic change of pre-treatment and
post-treatment APRI (Delta-APRI) in liver fibrosis [10]. These dynamic
changes in inflammatory markers were shown to reflect the change of
balance between host inflammatory response and immune response
treatment.
Effects of preoperative AGR, and NLR, PLR and APRI and post­
operatively Delta-AGR, Delta-NLR, Delta-PLR and Delta-APRI on post­
operative morbidity were not studied collectively in liver resections.
This study was planned to know the postoperative complications
(morbidity), OS and DFS and effect of preoperative AGR, NLR, PLR and
APRI and dynamic change from pre-operative to postoperative value
(Delta-AGR, Delta-NLR, Delta-PLR and Delta-APRI) on postoperative
morbidity, OS and DFS after liver resections.
2. Methods
After Institutional Ethics Committee (IEC) approval (IEC/0317/
1837/002, dated March 21st, 2017), we retrospectively analyzed pro­
spectively maintained database of 309 patients who had undergone liver
resections from January 2013 to December 2016. All these patients were
followed up to December 2019. A waiver of consent was granted from
IEC for analysis of data and publication. Pre-operative demographic data
like age, gender, body mass index (BMI), American Society of Anes­
thesiology (ASA) physical class, Eastern Cooperative Oncology Group
(ECOG) status, diagnosis, disease status, biochemical investigations
comprising of complete blood count including hemoglobin, platelets,
leucocyte count, neutrophil and lymphocyte count, liver function tests;
including albumin, globulin, bilirubin, and AST were noted. Diagnosis,
pre-operative stenting and chemotherapy, future liver remnant (FLR)
and presence of cirrhosis were also noted. Anesthesia protocol were
similar in all the patients with general anesthesia along with thoracic
epidural analgesia. Maintenance of anesthesia was done with isoflurane
or sevoflurane in oxygen with nitrous oxide or air. In all the cases, an
arterial catheter was placed for invasive blood pressure monitoring and
fluid therapy was guided by pulse pressure variation. Intraoperative
data like blood loss, urine output, duration of surgery and extubation at
end of surgery were noted. All patients underwent all routine investi­
gation like complete blood count, liver function test, coagulation profile
and serum electrolytes; preoperatively and also on postoperative day
one (POD 1), POD 3, POD 5 and POD 7. Antibiotic prophylaxis (piper­
acillin with tazobactum combination) was given 30 min prior to in­
duction of anesthesia and postoperatively for three days for all liver
resections. Duration of antibiotics was tailored according to individu­
alized postoperative recovery status. Abdominal drains were used for all
patients as the protocol and decision regarding removal of drain was
individualized based on content, color and quantity of drainage fluid
and also clinical condition.
AGR, NLR, PLR and APRI were calculated in the preoperative period
and on the first postoperative day (POD). APRI was calculated by APRI
= [AST (U x L− 1)/upper limit of normal (U x L− 1)] × 100/platelets (109
L− 1). Delta-AGR, Delta-NLR, Delta-PLR and Delta-APRI were defined
and calculated as the difference between preoperative and first POD
values respectively (AGR, NLR, PLR and APRI).
The outcome variables included post-operative morbidity in terms of
Clavien-Dindo (CD) Score [11]where CD 1 and 2 considered as minor
morbidity and CD 3 and 4 considered as major morbidity and CD 5 as
mortality, 90-day mortality, DFS and OS and effect of AGR, NLR, PLR,
2
Surgical Oncology 37 (2021) 101526
APRI and effect of Delta-AGR, Delta-NLR, Delta-PLR and Delta-APRI on
these variables. DFS was defined as the duration between the date of
surgery to the date of recurrence or death due to any cause or date of last
follow-up. OS was defined as the duration between the date of surgery to
date of death due to any cause or date of last follow up.
Descriptive statistics were summarized using frequencies, percent­
ages, medians, and ranges. Continuous data were presented as mean
(SD) and medians with IQR. Categorical variables were analyzed by
Pearson’s χ2 tests and continuous variables by Student t-tests and Mann
whitey. Receiver-operating characteristic (ROC) curve and Youden
index was used to establish the cut-off values of preoperative and delta
(the difference between preoperative and postoperative day 1values) of
AGR, NLR, PLR and APRI respectively in predicting morbidity. Kaplan-
Meier method was used for the estimation of the probability of DFS and
OS. Univariate analysis was performed by comparing groups with the
log-rank test. Multivariable analysis was performed using Cox-hazard
proportional model. A p-value ≤0.05 in a two-tailed test was consid­
ered statistically significant. Statistical analyses were performed using
SPSS (the statistical package for social sciences) IBM Corp. Released
2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM
Corp.
3. Results
The study included 309 patients from January 2013 to December
2016. There were 192 (62.1%) males and 117 (37.9%) females. The
median (range) and mean with standard deviation of age was 55.00
years (7–84 years) and 52.57 ± 14.00 years respectively. As per ASA
classification, there were 149(48.2%), 138 (44.7%) and 22 (7.1%) pa­
tients in ASA I, II and III respectively. Out of 309 patients, 147 were
metastasis to liver, 142 were diagnosed as primary liver cancers and 20
patients were having benign liver tumors. The median MELD score was 8
(range 6–20) and median FLR was 54% (Range 29–88%) for major
hepatectomies (resection of 3 or more liver segments). Preoperatively,
cirrhosis was present in 67 (21.7%) out of 309 patients.
The mean blood loss was 2081.06 ± 2719.45 ml (range of
50.00–33,000.00 ml). Mean duration of surgery was 296.59 ± 131.53
min. Intraoperative mean urine output was 506 ± 488 ml (50–6500 ml).
The mean albumin, AST, platelets before surgery was 3.99 ± 0.45 g
dl− 1(2.26–5.10 g dl− 1), 50.15 ± 54.29 units x L− 1 (12.00–578.00units x
L− 1) and 286.80 ± 136.12 × 109 per liter (52.00–953.00 × 109 per liter)
respectively.
In the postoperative period, patients were assessed for morbidity
based on CD Score. Total 98 patients (31.71%) had complications
postoperatively. Two hundred and eleven patients (68.29%) had no
morbidity or complications. Fifty patients had CD 1 & 2 complications
and 48 patients had major complications, out of these 48 patients, 35
(11.33%) had CD 3 & 4 complications and 13 patients (4.21%) had
death in hospital and were included in CD 5 complications. Seventeen
patients died within 90 days of surgery. Out of 48 major complications,
biliary complications were seen in 10 patients, intrabdominal collec­
tions in 9 patients, hemorrhage in 4 patients, posthepatectomy liver
failure (grade B) in 4 patients, respiratory complications in 7 patients,
wound infection in one patient, and 13 patients had multiorgan failure
leading to mortality.
Morbidity (major, minor/no morbidity) were similar in patients for
age (more than or less than 55 years), BMI (more than or less than 23 kg
m− 2), gender, ASA grading, ECOG status, preoperative chemotherapy
status and diagnosis in terms of liver metastasis, primary liver cancer or
benign liver tumor. Morbidity (major, minor/no morbidity) were
significantly higher in patients with no biliary stenting in the preoper­
ative period but the number of patients with stenting was only 14
(Table 1).
Mean OS was 30.31 ± 20.03 months (range 0–81.64 months) and
mean DFS was 26.31 ± 20.43 months (range 0–81.64 months). OS and
DFS were similar in patients for age (more than or less than 55 years),
S.L. Solanki et al. Surgical Oncology 37 (2021) 101526

Table 1
Association of clinico-demographic factors and morbidity, overall survival and disease-free survival.
Factors Categories Major Morbidity CD Minor Morbidity CD No p- Overall P- Disease-free p-
3&4 1&2 Morbidity value Survival, % value Survival, % value

Age (Years) <55 24(50) 18(36) 108(51.2) 0.151 76.40 0.16 56 0.36
≥55 24(50) 32(64) 103(48.8) 71.80 53
2
BMI (kg/m ) <23 25(53.2) 27(55.1) 100(47.8) 0.581 71.60 0.65 52 0.339
≥23 22(46.8) 22(44.9) 109(52.2) 76.90 57
Sex MALE 33(68.8) 31(62) 128(60.7) 0.581 75.80 0.63 57 0.616
FEMALE 15(31.3) 19(38) 83(39.3) 70.80 50
ASA I 18(37.5) 29(58) 102(48.3) 0.286 80.90 0.29 57 0.233
II 26(54.2) 19(38) 93(44.1) 69.30 54
III 4(8.3) 2(4) 16(7.6) 59.90
ECOG 0–1 29 (90.6) 29(93.54) 114(98.27) 0.997 72.20 0.85 50 0.865
2–3 3 (9.4) 2(6.46) 2(1.73) 71.40 57
Preoperative NO 24(50) 25(50) 103(49.5) 0.997 77.6 0.14 59 0.134
Chemotherapy YES 24(50) 25(50) 105(50.5) 69.9 50
Preoperative NO 41(85.4) 47(94) 200(98) 0.001 74.10 0.02 56 0.004
Biliary Stent YES 7(14.6) 3(6) 4(2) 61.20 29
Diagnosis Liver 21(43.8) 17(34) 109(51.7) 0.069 72.90 0.03 52 0.001
Metastasis
Primary Liver 26(54.2) 27(54) 89(42.2) 72.20 51
Cancer
Benign Liver 1(2.1) 6(12) 13(6.2) 100.00 100
Tumor

ASA: American Society of Anesthesiology; BMI: Body Mass Index; CD: Clavien-Dindo Score; ECOG: Eastern Cooperative Oncology Group.

BMI (more than or less than 23 kg m− 2), gender, ASA grading, ECOG
status and preoperative chemotherapy status. OS and DFS were also
significantly higher in patients with no biliary stenting in the preoper­
ative period but the number of patients with stenting was only fourteen.
We used the continuous variable (AGR, NLR, PLR and APRI) as the
test variable and the morbidity as the state variable. When we investi­
gated the cut-off value for the AGR, NLR, PLR and APRI based on
morbidity using the receiver operating characteristic (ROC) curve, we
found the appropriate cut-off value for the AGR to be 1.11 (area under
curve [AUC]: 0.60), NLR to be 3.68 AUC: 0.57, PLR to be 235.46
(AUC:0.58), and APRI to be 0.80 (AUC:0.56).
When we investigated the cut-off value for the Delta-AGR, Delta-
NLR, Delta-PLR, Delta-APRI based on morbidity using the ROC curve,
we found the appropriate cut-off value for the Delta-AGR to be 0.08
(AUC: 0.57), Delta-NLR to be 12.25 (AUC: 0.51), Delta-PLR to be 424
(AUC:0.56), and Delta-APRI to be 1.36 (AUC:0.59) (Fig. 1).
Based on the above cut off, patients were divided into high and low
groups and were analyzed as a predictive biomarker of morbidity, OS
and DFS (Table 2 and Table 3).
Low AGR group predicted 23.10%(CI:15.38%–32.36%) major

Fig. 1. Receiver operating Characteristic curves for cut-off values of AGR, NLR, PLR and APRI.

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S.L. Solanki et al. Surgical Oncology 37 (2021) 101526

Table 2
Preoperative values of biomarkers (NLR, PLR, AGR, and APRI) and Difference between preoperative and postoperative day 1 value of biomarkers (Delta NLR, Delta
PLR, Delta AGR and Delta APRI) in predicting postoperative morbidity.
Variable name Group Major Morbidity % and 95% CI Minor Morbidity (%) % and 95% CI No Morbidity (%) % and 95% CI p-value

Preoperative NLR Low 12.6 (8.41–17.94) 14.1 (9.64–19.59) 73.3 (66.71–79.21) 0.032
High 21.6 (14.04–30.81) 19.6 (12.41–28.65) 58.8 (48.64–68.48)
Preoperative PLR Low 13 (9.02–17.98) 13.4 (9.38–18.45) 73.5 (67.44–79.02) 0.003
High 23.5(14.09–35.38) 25 (15.29–36.98) 51.5 (39.03–63.78)
Preoperative AGR Low 23.1(15.38–32.36) 22.1 (14.57–31.31) 54.8 (44.74–64.59) 0.002
High 12.1 (7.83–17.61) 12.6 (8.26–18.21) 75.3 (68.5–81.22)
Preoperative APRI Low 13.5 (9.26–18.64) 15.2 (10.8–20.65) 71.3 (64.88–77.14) 0.067
High 22.7 (13.79–33.79) 20 (11.65–30.83) 57.3 (45.38–68.69)
Delta NLR Low 13.6 (9.39–18.89) 15.9 (11.34–21.42) 70.5 (63.95–76.4) 0.316
High 20.5 (12.6–30.39) 15.9 (8.98–25.25) 63.6 (52.69–73.63)
Delta PLR Low 15.2 (11.15–19.94) 16.2 (12.1–21.13) 68.6 (62.77–74.01) 0.400
High 25 (5.49–57.19) 25 (5.49–57.19) 50 (21.09–78.91)
Delta AGR Low 14.6 (10.1–20.23) 14.6 (10.1–20.23) 70.7 (63.99–76.86) 0.001
High 28.3 (16.79–42.35) 28.3 (16.79–42.35) 43.4 (29.84–57.72)
Delta APRI Low 12 (6.36–20.02) 10 (4.9–17.62) 78 (68.61–85.67) 0.013
High 19 (13.33–25.67) 20.2 (14.35–26.96) 60.7 (52.56–67.78)

AGR: Albumin Globulin Ratio; APRI: Aspartate transaminase to Platelet Ratio Index; CI: Confidence Interval.
NLR: Neutrophil Lymphocyte Ratio; PLR: Platelet Lymphocyte Ratio.

In PLR group there is no significant difference between high and low

Table 3
PLR in terms of 3-year OS and DFS [OS, p = 0.107 and DFS, p = 0.1570).
Univariate analysis of preoperative values of biomarkers (NLR, PLR, AGR, and
High APRI group predicted 22.7%(95% CI: 13.79%–33.79%) major
APRI) and Difference between preoperative and postoperative day 1 value of
biomarkers (Delta NLR, Delta PLR, Delta AGR and Delta APRI) predicting OS and morbidity against 13.5%(95% CI: 9.26%–18.64%) in low APRI group
DFS at 3 years. which were not statistically significant (p = 0.067). Low APRI group
showed statistically similar OS (p = 0.174) and 3-year DFS (p = 0.11).
Factor Group OS, 3 years [95% CI] DFS, 3 years [95% CI]
High Delta-AGR and high Delta-APRI group were also predictive of
Preoperative NLR Low 79.55 (72.57–84.94) 57.78 (50.14–64.68) higher major morbidity which was statistically significant (Delta-AGR:
High 63.51 (52.4–72.69) 47.29 (36.85–57.03)
28.3%(95% CI: 16.79%–42.35%) vs 14.6%(95% CI: 10.1%–20.23%), p
P-value 0.003 0.103
Preoperative PLR Low 76.67 (70.16–81.95) 56.55 (49.53–62.97) = 0.001 and Delta-APRI: 19.0%(95% CI: 13.33%–25.67%) vs 12.0%
High 66.05 (51.56–77.13) 48.23 (35.08–60.2) (95% CI: 6.36%–20.02%), p = 0.013 respectively).
P-value 0.107 0.157 High and low Delta-NLR groups and high and low Delta-PLR groups
Preoperative AGR Low 62.8 (51.21–72.36) 42.43 (32.08–52.4)
predicted statistically similar major morbidities (Delta-NLR, p = 0.316
High 78.42 (71.14–84.06) 60.35 (52.45–67.35)
P-value 0.004 0.002 and Delta-PLR, p = 0.4 respectively).
Preoperative APRI Low 75.03 (68.15–80.64) 54.85 (47.66–61.46) High and low Delta-NLR, Delta-PLR and Delta-AGR groups showed
High 67.95 (53.64–78.68) 51.28 (37.57–63.41) statistically similar 3-year OS (Delta-NLR, p = 0.642; Delta-PLR, p =
P-value 0.174 0.11 0.697 and Delta-AGR, p = 0.259 respectively) and 3-year DFS (Delta-
Delta NLR Low 76.52 (69.37–82.21) 58.02 (50.37–64.9)
NLR, p = 0.125; Delta-PLR, p = 0.737 and Delta AGR, p = 0.869
High 72.33 (60.52–81.15) 49.75 (38.34–60.14)
P-value 0.642 0.125 respectively). Low Delta-APRI group showed statistically better 3-year
Delta PLR Low 76.1 (70.04–81.1) 64.81 (30.97–85.18) DFS (63.28% [95% CI: 51.96%–72.63%] vs 49.99%[95% CI: 41.76%–
High 74.07 (39.07–90.86) 55.79 (49.33–61.76) 57.66%], p = 0.033) and clinically better yet statistically similar 3-year
P-value 0.697 0.737
OS (77.06%[95% CI: 65.82%–85.02%] vs 70.73%[95% CI: 62.61%–
Delta AGR Low 73.59 (66.32–79.53) 52.68 (45.15–59.66)
High 66.08 (49.55–78.31) 55.03 (39.33–68.23)
77.41%], p = 0.057).
P-value 0.259 0.869 Figs. 2–5 show the effect of preoperative AGR, NLR, PLR and APRI
Delta APRI Low 77.06 (65.82–85.02) 63.28 (51.96–72.63) and dynamic changes from preoperative to postoperative period (Delta-
High 70.73 (62.61–77.41) 49.99 (41.76–57.66) AGR, Delta-NLR, Delta-PLR and Delta-APRI) on OS and DFS. At risk
P-value 0.057 0.033
patients are shown in the all the plots.
OS: Overall Survival; DFS: Disease-Free Survival; AGR: Albumin Globulin Ratio; On performing multivariable analysis, preoperative AGR showed
APRI: Aspartate transaminase to Platelet Ratio Index; NLR: Neutrophil statistically significant correlation (p = 0.010) and Delta-APRI showed
Lymphocyte Ratio; PLR: Platelet Lymphocyte Ratio. CI: Confidence Interval. trend toward significance (p = 0.064) with disease-free survival
outcome; and for overall survival outcome, preoperative NLR (p =
morbidity against 12.1%(CI: 7.83%–17.61%) in high AGR group which 0.049) and preoperative AGR (p = 0.049) showed statistically signifi­
were statistically significant (p = 0.002) and also decreased 3-year OS cant correlation and Delta-APRI showed trend toward significance (p =
and DFS which were statistically significant (3-year OS: 62.2%(95% 0.077) (Table 4).
CI:51.21%–72.36%) vs 78.4%(95% CI: 71.14%–84.06%); p = 0.004 and Similar analysis of all above mentioned inflammatory markers was
3- year DFS: 42.0% (95% CI: 32.08%–52.4%) vs 60.30%(95% CI: done based on extent of liver resection (major vs minor hepatectomy),
52.45%–67.35%); p = 0.002 respectively). which showed different cut-off values for minor and major hepatec­
High NLR and PLR group were statistically significant in terms of tomies (Supplementary Table 1). On performing survival analysis, none
increased major morbidity respectively (NLR:21.6%(95% CI: 14.04%– of the inflammatory markers showed statistical significance based on
30.81%) vs 12.6%(95% CI: 8.41%–17.94%); p = 0.032, PLR:23.5%(95% extent of resection, probably related to low number of events in each
CI:14.09%–35.38%) vs 13.00%(95% CI: 9.02%–17.98%); p = 0.003). cohort. This further strengthens our analysis of whole cohort, indicating
High NLR group showed worse3-year OS, which was statistically that extent of resection might not be the confounding factor affecting
significant (3-year OS: 63.5%(95% CI: 52.4%–72.69%) vs 79.5%(95% survival outcomes.
CI:72.57%–84.94%), p = 0.003) and worse DFS, which was statistically
insignificant (47.29% vs 57.78%, p = 0.103).

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S.L. Solanki et al. Surgical Oncology 37 (2021) 101526

Fig. 2. Represent overall survival and disease-free survival for preoperative AGR and Delta-AGR 2A and 2B showing overall survival predicted by preoperative AGR
and Delta-AGR respectively and 2C and 2D showing disease-free survival predicted by preoperative AGR and Delta-AGR respectively.

Fig. 3. Represent overall survival and disease-free survival for preoperative NLR and Delta-NLR 3A and 3B showing overall survival predicted by preoperative NLR
and Delta-NLR respectively and 3C and 3D showing disease-free survival predicted by preoperative NLR and Delta-NLR respectively.

4. Discussion postoperative complications (11.33% of the patients had major com­

plications CD 3 & 4) and 4.21% patients died within 30 days after liver
The present retrospective analysis showed that 31.71% patients had resections. In previous studies, overall morbidity or immediate

5
S.L. Solanki et al.
Fig. 4. Represent overall survival and disease-free survival for preoperative PLR and Delta-PLR 4A and 4B showing overall survival predicted by preoperative PLR
and Delta-PLR respectively and 4C and 4D showing disease-free survival predicted by preoperative PLR and Delta-PLR respectively.
postoperative complications after open liver resections are reported in
the range of 20–48% [12–14], with major complications around 14.7%
[15]. In our study mean OS is 30.31 ± 20.03 months and mean DFS is
26.31 ± 20.43 months. The OS and DFS or recurrence-free survival
(RFS) remains unsatisfactory after liver resections [16–18].
Effect of cancer-related malnutrition and CRI on postoperative
complications or morbidity were not studied especially after liver re­
sections. Preoperative low AGR predicted statistically significant more
major postoperative morbidities, OS and DFS. Hypoalbuminemia which
ultimately reflect low AGR has been associated with increased post­
operative complications especially surgical site infection [16].
Delta-AGR which is never studied earlier and a value > 0.08 reflected
higher major postoperative complications but not OS and DFS. A more
detailed study on the role of Delta-AGR on prognostic role can be
undertaken.
Albumin being a negative acute-phase protein, decreases in inflam­
matory conditions in the body [19]. Decrease albumin may be due to
impaired liver synthesis because of underlying liver disease. A decreased
albumin and high globulin (total protein-albumin) level reflects chronic
inflammation and this inflammatory process leads to release of
pro-inflammatory cytokines which further promotes growth and pro­
liferation of tumor cells and decrease OS and DFS [2,3,20,21].Although
mean albumin level was 3.99 ± 0.45 g/dl (2.26–5.10 g/dl) in our pa­
tients, low albumin in association with the micro-vascular invasion of
the tumor and aggressive tumor type may reflect an inflammatory and
hyper metabolic state [5,22].Albumin was also shown to inhibit the
growth of HCC [16,23,24]. Hypoalbuminemia is shown to be associated
with larger maximum tumor diameters, increased portal vein throm­
bosis, higher α-fetoprotein levels and other markers of aggressiveness of
HCC [16,24].
Inflammation, which is a normal part of the wound-healing, may be
prolonged in some cases even in the absence of effective decontamina­
tion, because microbial clearance may be incomplete and wound may
fail to heal. This prolonged inflammation also leads to an increased level
of matrix metalloproteases (MMPs), a family of proteases that can
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Surgical Oncology 37 (2021) 101526
degrade the extracellular matrix. The shift in protease balance because
of the increased protease content, and decreased in naturally occurring
protease inhibitors, growth factors rapidly degrade in wound [25]. In
our patients, apart from 4 patients with postoperative hemorrhage, all
other complications can be related to infection and inflammations. This
theory supports that exaggerated inflammatory response might promote
growth factor degradation affecting healing, leading to increased
chances of small bile ductules leakage and also delayed liver regenera­
tive response. Thus all complications post liver resection can be a part of
delayed healing due to exaggerated inflammatory response.
In our study, high NLR showed higher major postoperative compli­
cations and decreased OS. These results agree with the other studies in
terms of OS in patient’s’ undergone liver resections [1,26]. NLR is
known to increase postoperatively till postoperative day 7 and shown to
reflect major complications postoperatively [27]. Increased NLR post­
operatively should increase Delta NLR, but in our study high Delta NLR
although showing clinically high major complications but were statis­
tically similar. NLR reflects either increased neutrophils or decreased
lymphocytes. It is proved that an increase in neutrophils provides a
favourable microenvironment for tumor growth. Relative reduction of
lymphocytes is mediated by cytotoxic cell death and as a result it de­
creases immune function, inhibits tumor proliferation and increases
malignant potential of growth. Both these process leads to tumor
recurrence and decrease OS and DFS/RFS [28].
In this study, a high level of PLR is associated with higher post­
operative complications but statistically similar OS and DFS. OS and DFS
was in contrast to few previous studies which showed worse OS and DFS
with high PLR in HCC patients [1,5,29,30]. High and low Delta PLR are
showing similar postoperative complications and OS and DFS in our
study. These were in contrast to the previous study which showed an
increased change in PLR showed worse OS and DFS [7], but in agree­
ment with the study by Lin et al. for intrahepatic cholangiocarcinoma
[26]. Platelet count is also a marker of tumor-related systemic inflam­
mation. High platelet counts cause tumor progression by platelet
adhesion and aggregation which leads to the formation and release of
S.L. Solanki et al.
Fig. 5. Represent overall survival and disease-free survival for preoperative APRI and Delta-APRI 5A and 5B showing overall survival predicted by preoperative APRI
and Delta-APRI respectively and 5C and 5D showing disease-free survival predicted by preoperative APRI and Delta-APRI respectively.
platelet granules that contain active proteases, growth factors, matrix
proteins, basic fibroblast growth factor, angiopoietin-1, epidermal
growth factor, chemokines, interleukin-1β and IL-8 cytokines [5].
Zhang et al. [5] mentioned that several studies [31,32] have shown
conflicting results for the prognostic utility of PLR. They explained that
HCC patients from Asia have chronic hepatitis B which leads to cirrhosis
of liver and thrombocytopenia and therefore, inflammation-mediated
increase in platelets is very small or insignificant [33]. In contrast,
Western patients have steatosis of the liver and metabolic syndrome,
which can cause CRI [34,35]. This also explained the insignificant role
of PLR for predicting OS and DFS in our study.
In our study, high APRI predicted clinically more but statistically
similar major postoperative complications but showing a trend toward
predictive marker for high morbidity (p = 0.067). Our study can be
considered following previous studies showing high APRI resulted in
increased major complications after liver resections [17,36,37]. High
and low APRI group predicted similar OS and DFS. APRI is considered a
surrogate indicator of liver biopsy for assessing the stage of fibrosis [17,
38]. Liver fibrosis can rapidly progress into tumor thrombus into the
portal vein and predicts poor prognosis and worse OS and DFS after liver
resections [17,39].
High Delta-APRI is associated with increased major postoperative
complications, and showed trends towards worse OS and DFS. This re­
flects increased fibrosis from preoperative period to postoperative
period and that may be a continuous process [10].
Studies have been carried out to see the positive immunological
impact of aggressive nutritional intervention especially immuno-
nutrition in the perioperative period in patients with altered inflam­
matory markers to reduce the incidence of postoperative complications
7
Surgical Oncology 37 (2021) 101526
and also increase survival outcomes. Thus special care is very important
to reduce the chances of postoperative complications in this selective
subset of the patients with altered inflammatory markers [40,41]. So, we
suggest that Inflammatory markers should be included in the routine
assessment and the oncologists, dieticians along with other health care
professionals should work together to improve the nutritional status of
such patients especially in the hepato-pancreatico-biliary diseases.
Our study has certain limitations. This is a retrospective analysis
from a single center. Around 6.5% patient were diagnosed as a benign
liver tumor which could have affected the overall complications, OS and
DFS. Few parameters were not recorded prospectively for all the patients
and therefore different inflammatory markers have different
denominators.
In conclusion low AGR, high NLR, high PLR and increased dynamic
change in AGR and APRI (high Delta-AGR and high Delta-APRI) pre­
dicted increased major postoperative morbidity or complications. Pre­
operative high NLR predicted worse OS and low AGR predicted worse
OS and DFS. Increased dynamic change in APRI (Delta-APRI) showed
trends towards worse OS and DFS. In our patient population, PLR
doesn’t have any predictive value for OS and DFS. High Delta-AGR,
which is a new entity, is predicting more major postoperative compli­
cations and needs further detailed studies.
Funding
This study didn’t require any funding.
S.L. Solanki et al. Surgical Oncology 37 (2021) 101526

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