Int J Colorectal Dis

DOI 10.1007/s00384-014-2098-1

ORIGINAL ARTICLE

General anesthesia combined with epidural anesthesia

ameliorates the effect of fast-track surgery by mitigating
immunosuppression and facilitating intestinal functional
recovery in colon cancer patients
Wan-Kun Chen & Li Ren & Ye Wei & De-Xiang Zhu &
Chang-Hong Miao & Jian-Min Xu

Accepted: 11 December 2014

# Springer-Verlag Berlin Heidelberg 2015

Abstract sevoflurane. In comparison with those in the G group, signif-

Purpose The purpose of this study is to investigate the influ-
ence of anesthetic methods on markers of anti-tumor immu-
nity and intestinal functions in fast-track surgery in colon
cancer (CC) patients during the perioperative period.
Patients and methods A total of 53 patients with American
Society of Anesthesiologists (ASA) I-II status randomly re-
ceived general anesthesia (G group, n=27) or general anes-
thesia combined with epidural anesthesia (E group, n=26) for
surgical tumor resection. The recovery times of intestinal
function were evaluated in both groups postoperatively. The
frequencies of different subsets of CD4+ T cells and myeloid-
derived suppressor cells and C-reactive protein (CRP) were
measured by flow cytometry and enzyme-linked immunosor-
bent assay, respectively, before anesthesia (t0), 1 h after the
beginning of surgery (t1), 1 h after the end of surgery (t2), and
on day 2 (t3) and day 5 (t4) post-surgery.
Results There was no significant difference in demographic
characteristics between the two groups, but the E group of
patients received significantly lower amounts of morphine and
icantly greater numbers of lymphocytes and elevated frequen-
cies of Th1 cells were detected at t3 and t4 post-surgery in the
E group (p<0.01). Significantly lower percentages of Th2
cells and regulatory T cells were detected in the E group at
t2–4 post-surgery. Whereas the levels of plasma CRP in-
creased post-surgery in both groups, the levels of CRP were
significantly lower in the E group than those in the G group at
t3–4 post-surgery (p<0.05). The times to the first flatus and to
tolerate a full diet were significantly shorter in the E group
than those in the G group (p<0.01).
Conclusion General anesthesia combined with epidural anes-
thesia plays an important role in fast-track surgery, mitigating
the surgical stress-related impairment of anti-tumor immune
responses and hastening the recovery of intestinal function.
This combination might also help to improve long-term out-
comes for CC patients.
Keywords Anesthesia . Colon cancer . Fast-track . T helper .
MDSCs . Postoperative ileus

Wan-Kun Chen, Li Ren, Ye Wei, and De-Xiang Zhu contributed to this

work equally and should be considered as first co-authors.
L. Ren : Y. Wei : D.<X. Zhu : J.<M. Xu (*)
Department of General Surgery, Zhongshan Hospital, Fudan
University, Shanghai 200032, China
e-mail: xujmin@aliyun.com Introduction
W.<K. Chen : C.<H. Miao (*)
Colon cancer (CC) is one of the most common cancers world-
Department of Anesthesiology, Fudan University Shanghai Cancer
Center, Shanghai Medical College, Fudan University, wide [1]. Its incidence is increasing around the world, espe-
Shanghai 200032, China cially in Africa and Asia [1, 2]. Currently, surgical removal of
e-mail: miaochh@aliyun.com the tumor is the primary strategy for the treatment of CC.
W.<K. Chen : C.<H. Miao
However, postoperative metastasis and the recurrence of tu-
Department of Oncology, Shanghai Medical College, Fudan mor affect the prognosis of CC. The recurrence and metastasis
University, Shanghai 200032, China of CC depend not only on the histopathologic type and clinical

stage of the tumor but also on the immune function of the
patient [3, 4]. Hence, protection of immune function in indi-
vidual patients during the perioperative period might be cru-
cial for improving the outcomes of patients with CC.
Surgical procedures and related inflammation have been
suggested to suppress immune competence [5], cause surgical
stress that can activate the sympathetic nervous system (SNS)
and the hypothalamic-pituitary-adrenal (HPA) axis to induce
the neuroendocrine response [6, 7], and increase the release of
hormones, such as catecholamines (norepinephrine and epi-
nephrine), adrenocorticotropic hormone, and cortisol, which
inhibit pro-inflammatory T cell responses [8]. To reduce sur-
gical stress, fast-track surgery, or an enhanced recovery after
surgery (ERAS) protocol, has been introduced for the man-
agement of CC patients [9] and has been demonstrated to
promote postoperative recovery [10, 11]. Our previous study
has also shown that epidural anesthesia and/or analgesia might
be associated with improved overall survival in patients with
operable cancer, especially in CC [12]. However, little is
known about the influence of anesthetic methods on the
anti-tumor immune response and the role of anesthetic strate-
gies in fast-track surgery.
T cells play an important role in anti-tumor immunity.
Although antigen-specific cytotoxic CD8+ T cells are crucial
for the control of tumor growth, our understanding of the
importance of CD4+ T cells in orchestrating immune re-
sponses has grown dramatically over the past decade [13,
14]. CD4+ T cells exist in diverse subsets, such as T helper
(Th) 1, Th2, and Th17 cells and regulatory T cells (Tregs),
which play opposite roles in modulating immune responses to
tumor cells [15]. In addition, these immunocompetent cells
secrete different types of cytokines and effector molecules,
such as interferon (IFN)-γ, interleukin (IL)-4, IL-17A, and
transforming growth factor (TGF)-β1, which also mediate
anti-tumor immunity [16]. Moreover, myeloid-derived sup-
pressor cells (MDSCs) are heterogeneous cells derived from
immature myeloid cells that are HLA-DR−, CD11b+, CD14−,
CD15+, and/or CD33+. Previous studies have shown that
MDSCs can negatively regulate anti-tumor immunity in pa-
tients with cancers [17, 18]. A higher frequency of peripheral
blood CD14+HLA-DR−/low MDSCs is associated with tumor
immune evasion in patients with cancers [19, 20]. More
importantly, MDSCs can inhibit NK cell, macrophage, and
T cell activity and enhance angiogenesis, thereby promoting
the growth and metastasis of cancer cells [21, 22]. The impact
of different anesthetic strategies on the frequencies of periph-
eral blood CD4+ T cells and MDSCs in patients with CC
during the perioperative period is still unknown.
In addition, postoperative ileus (POI) is a frequent, frus-
trating occurrence for patients undergoing bowel resection.
The etiology of POI is complex, but new insights into the
pathophysiology of POI have also involved the adaptive im-
mune system [23].
Int J Colorectal Dis
By observing the frequencies of peripheral blood CD4+ T
cells and MDSCs and the recovery time of intestinal functions
during the perioperative period, this study aimed to investigate
the influences of general anesthesia with or without epidural
anesthesia on CC patients undergoing fast-track surgery and to
further improve the perioperative management strategy for
cancer patients.
Materials and methods
This prospective randomized trial (NCT01978717) was ap-
proved by the Ethics Committee of Zhongshan Hospital,
Fudan University (Shanghai, People’s Republic of China),
and written informed consent was obtained from each patient.
A total of 53 patients undergoing open CC surgery were
continually recruited at the inpatient service of the Department
of General Surgery, Zhongshan Hospital, Fudan University,
from Oct. 2011 to Apr. 2012. These patients were all subjected
to the fast-track processing of surgery and randomized via a
computer-generated number sequence to receive general an-
esthesia only (G group, n=27) or general anesthesia combined
with epidural anesthesia (E group, n=26). The inclusion
criteria included an age between 18 and 75 years, an American
Society of Anesthesiologists (ASA) grade<III, and a body
mass index (BMI) between 18.5 and 30. The exclusion criteria
included a history of abdominal surgery, endocrine or immune
system dysfunction (such as diabetes, thyroid disease, multi-
ple sclerosis, and rheumatoid arthritis), recent blood transfu-
sions, preoperative treatment with opioids, hormone, non-
steroidal anti-inflammatory, or other immunomodulatory sub-
stances, and contraindication to epidural anesthesia.
According to the FastTrack protocol, no premedications
were administered, and all patients were fasted 6 h to solids
and 2 h to clear liquids. The FastTrack protocol was described
in our previous study [11].
The E group of patients was subjected to epidural puncture
between T10 and T11 in the left lateral position, followed by
insertion of an epidural catheter using the paramedian ap-
proach and loss-of-resistance technique. The patients were
tested with 3 ml of 2 % lidocaine through the epidural catheter
after the results of an aspiration test for blood and cerebrospi-
nal were negative. Each patient was provided with 8 ml of
0.375 % bupivacaine after the induction of general anesthesia.
The patients were also administered 4 ml of bupivacaine every
50 min until the end of surgery.
All patients were subjected to the induction of general
anesthesia by intravenously administered fentanyl (5 μg·
kg−1), propofol (plasma target-controlled infusion using
Marsh pharmacokinetic and Graseby 3500 TCI pump, target
plasma concentration 4 μg·ml−1) and rocuronium (0.8 mg·
kg−1). Subsequent to orotracheal intubation, all patients were
provided with 1.5–3.5 % sevoflurane for the maintenance of
Int J Colorectal Dis
anesthesia. The levels of anesthesia were monitored using the
bispectral index (BIS), and the patients were provided with
fentanyl and propofol if needed. Esophageal temperature was
monitored and maintained at more than 36 °C throughout the
operation.
At the end of the operation, the patients in the E group
received a patient-controlled epidural analgesia (PECA)
pump (0.125 % bupivacaine and 30 μg·ml−1 morphine,
background infusion 2 ml·h−1, bolus 2 ml, lockout time
15 min) for 24 h. The patients in the G group received a
patient-controlled intravenous analgesia (PICA) pump
(0.5 mg·ml−1 morphine, background infusion 2 ml·h−1,
bolus 2 ml, lockout time 15 min) for 24 h. The patients in
both groups received the patient-controlled analgesia
pump (epidural or intravenous) for 24 h. We removed
the epidural and intravenous anesthesia pump on postop-
erative day (POD) 1, and we used morphine 5 mg intra-
muscular injection for postoperative pain rescue. No pa-
tients received corticosteroids during the perioperative
period.
Except for anesthesia and analgesia methods, both groups
received the same perioperative care protocols described in
our previous study [11].
After surgery, all patients were reviewed four times daily.
Pain intensity was assessed using a 10-cm visual analogue
scale (VAS) on POD 1, POD2, and POD5 at rest and on
coughing. Times to first flatus and to tolerate a full diet, the
complications after surgery, and the length of hospital stay
were recorded.
Peripheral venous blood samples were collected in
sodium heparin anticoagulant tubes before anesthesia
(t0), 1 h after the beginning of surgery (t1), 1 h after the
end of surgery (t2), and on POD 2 (t3) and POD 5 (t4).
Samples were processed according to manufacturer’s in-
structions for flow cytometry analyses on a FACSCalibur
(BD Biosciences, San Diego, CA, USA). Lymphocyte
subpopulations were defined as follows: Th1 =
CD3 + CD8 - IFN-γ + ; Th2 = CD3 + CD8 - IL-4 + ; Th17 =
CD3 + CD8 - IL-17A + ; Treg = CD4 + CD25 + Foxp3 + ; and
MDSCs = CD14 + HLA-DR −/low. (Brefeldin A was from
Sigma-Aldrich, St. Louis, MO, USA, and all other anti-
bodies were from BioLegend, San Diego, CA, USA).
Individual plasma samples were prepared, and the con-
centration of plasma C-reactive protein (CRP) was deter-
mined using specific ELISA kits (Dakewe, Shanghai,
China) according to the manufacturer’s instructions.
The data are expressed as the mean ± standard devi-
ation (SD) or as the median and range. Data were
compared using an independent group t test for para-
metric data and a Mann–Whitney U test for nonpara-
metric data. Categorical data were assessed by Fisher
exact test. p < 0.05 was considered statistically
significant.
Results
All patients completed the study according to the protocol. All
procedures were performed by the same experienced team of
anesthetists and surgeons. The univariate analysis showed that
there was no significant difference in the distributions of
demographic characteristics, including gender, age, and BMI
in both groups (p>0.05, Table 1). In addition, the clinical
stages of the tumors, types of surgery, anesthesia time, and
the amount of blood loss between the two groups of patients
were also similar (p>0.05, Table 1). Furthermore, there was
no significant difference in the values of BIS and intraopera-
tive fluid infusion in both groups. All of the tumors were
confirmed to be adenocarcinomas by postoperative patholog-
ical examination. No patient received blood transfusion during
hospitalization. The G group consumed more morphine and
sevoflurane as compared with that in the E group (p<0.01,
Table 1), suggesting that general anesthesia combined with
epidural anesthesia consumed less dose of anesthetics during
the operation and achieved better analgesic effect on CC
patients undergoing fast-track surgery. After surgery, the
VAS score of patients in the E group were less than that of
patients in the G group (p<0.01, Table 1). After the patient-
controlled analgesia pump was removed in both groups, the
mean VAS scores at rest and on coughing were 2.79 and 4.63,
respectively, in the E group, while the scores in the G group
were 3.86 and 5.53, respectively (p<0.01, Table 1). On
POD5, the VAS scores were not significantly different be-
tween these two groups (p>0.05, Table 1).
To determine the potential mechanisms involved in the
effect of general anesthesia combined with epidural anesthe-
sia, we first investigated the levels of circulating leukocytes in
the G and E groups. As shown in Fig. 1a, b, although no
significant differences of circulating leukocytes and lympho-
cyte were shown at t0 in both groups, dramatically increased
numbers of circulating leukocytes and decreased numbers of
circulating lymphocytes were observed at t3 in both groups,
with the numbers of lymphocytes in the E group increased
23.6 % and 19.1 % as compared with the G group at t3 and t4,
respectively (p<0.01, Figs. 1a and 1b), implying that immune
system might be closely associated with the situation of CC
patients with different anesthesia methods.
Then, we set to study the change of leukocyte subpopula-
tions at various time points in both groups of CC patients
undergoing fast-track surgery. The percentage of Th1 cells
increased with time in both groups, particularly at t3 and t4
(p<0.01, Fig. 1c). As compared with that of the G group, the
percentage of Th1 cells in the E group increased 22.1 and
22.6 % at t3 and t4, respectively (p<0.01, Fig. 1c). Although
the percentages of Th2 cells increased at t3, they both dramat-
ically declined at t4 in both groups (p<0.01, Fig. 1d). Accord-
ingly, the ratios of Th1/Th2 cells in the E group significantly
increased 15.3, 85.3, and 54.1 % as compared with those in
 Int J Colorectal Dis

Table 1 The demographic and

clinical characteristics of the G group (n=27) E group (n=26) p value
patients
Age (years) 57.9±6.5 57.3±5.3 0.715
Gender (male/female) 15/12 18/8 0.305
BMI 23.8±3.1 24.1±3.4 0.738
ASA grade, n (%) 0.611
I 9(33) 7(27)
II 18(67) 19(73)
Staging of tumor, AJCC, n (%) 0.654
Phase I 2(8) 4(15)
Phase II 19(70) 17(65)
Phase III 6(22) 5(20)
Surgical approach (right hemicolectomy/left hemicolectomy) 22/5 21/5 0.947
Anesthesia time (min) 140±36 143±43 0.784
Blood loss (≤200 ml/>200 ml) 22/6 23/4 0.525
BIS 0.631
At the beginning of surgery 43(38,55) 39(35,49)
At 1 h after the beginning of 44(40,49) 41(36,54)
surgery
VAS score at POD1
At rest 2.95±0.8 1.38±0.4** <0.01
On coughing 3.86±1.7 2.57±0.9** <0.01
VAS score at POD2
At rest 3.86±0.8 2.79±0.9 <0.01
On coughing 5.53±1.2 4.63±1.0 <0.01
VAS score at POD5
At rest 2.11±0.7 1.87±0.7 0.218
On coughing 3.25±1.0 3.21±0.8 0.873
Consumption of morphine (mg) 29.1±6.7 2.12±0.46** <0.01
Consumption of sevoflurane (ml) 31.6±3.5 23.7±1.9** <0.01
**p<0.01 vs. the G group

the G group (p<0.01, respectively, Fig. 1e). However, there
was no significant difference in the frequency of Th17 cells
between the two groups throughout the observation period
(Fig. 1f). These results suggested that general anesthesia com-
bined with epidural anesthesia mediate the shift of CD4+ T
cells to Th1 polarization, which is essential in anti-tumor
immunity.
As shown in Fig. 1g, the frequencies of Tregs decreased at
t2 and t3 in both groups, respectively (p<0.01). At t4, the
frequency of Tregs in the G group recovered (p=0.25) while
that in the E group still decreased (p<0.01). The percentages
of Tregs in the E group at t2, t3, and t4 significantly decreased
10.6, 17.5, and 28.0 % as compared with those in the G group
(p<0.01). In addition, the percentage of MDSCs increased at
t3 in both groups (p<0.01, Fig. 1h). The frequency of MDSCs
in the E group recovered at t4 (p=0.11) while that in the G
group still decreased (p<0.01, Fig. 1h). The percentages of
MDSCs at t3 and t4 in the E group significantly decreased
26.6 and 23.9 % as compared with those in the G group
(p<0.01, respectively, Fig. 1h). These data demonstrated that
general anesthesia combined with epidural anesthesia might
mitigate immunosuppression via dowregulating the fre-
quences of immune regulatory cells.
To compare the effect of different anesthetic methods on
perioperative surgical stress, we investigated the plasma CRP
in all patients. The levels of plasma CRP at t0 showed no
significant differences between the E and G groups (Fig. 1i)
and increased at t3 and t4 in both groups, respectively,
(p<0.01, Fig. 1i). The levels of plasma CRP in the E group
at t3 and t4 decreased 25.6 and 17.3 %, respectively, as
compared with that in the G group (p<0.01, Fig. 1i).
Times to the first flatus and to tolerate a full diet in the E
group were significantly faster than those in the G group,
respectively, (p<0.01, Table 2). In the E group, one patient
suffered wound infection, one had gastric retention, and two
had urinary retention. In the G group, one patient suffered
wound infection, one had anastomotic leakage, and two had
gastric retention. However, there was no significant difference
on postoperative complications between the two groups and
there was no mortality in both groups (Table 3), and there was
Int J Colorectal Dis

Fig. 1 The dynamic changes in the frequencies of leukocyte,
lymphocyte, different subsets of CD4+ T cells and MDSCs and plasma
CRP in CC patients during the perioperative period. The data are
expressed as the mean ± SD for each group of patients at each time
point. t0 before surgery, t1 1 h after the beginning of surgery, t2 1 h after
the end of surgery, t3 on day 2 post-surgery, t4 on day 5 post-surgery.
△
p<0.05, △△p<0.01 vs. the values at t0; *p<0.05, **p<0.01 vs. the G
group. a Leukocytes. b Lymphocytes. c Th1. d Th2. e Th1/Th2. f Th17 g
Treg. h MDSCs. i CRP

no statistical difference regarding the duration of hospital Previous studies demonstrated that the fast-track surgery
between the two groups (5.41±1.6 days vs. 5.83±1.5 days, protocol attenuated the surgical stress response and accelerat-
p=0.165, Table 3). ed postoperative recovery without compromising patient safe-
ty, and epidural anesthesia and/or analgesia might be associ-
ated with improved overall survival in patients with operable
Discussion cancer (especially CC) undergoing surgery [11, 12]. Com-
bined epidural anesthesia and analgesia to general anesthesia
By investigating the influence of anesthetic methods on intes- may be beneficial as compared with general anesthesia alone
tinal functions and markers of anti-tumor immunity in fast- because epidural anesthesia may prevent the neuroendocrine
track surgery in CC patients during the perioperative period,
our study found that general anesthesia combined with epidu- Table 3 Postoperative complications
ral anesthesia plays an important role in fast-track surgery G group (n=27) E group (n=26) p value
through mitigating the surgical stress-related impairment of
anti-tumor immune responses and hastening the recovery of Wound infection (%) 1 (3.70) 1 (3.84) 0.978
intestinal function. Anastomotic leakage (%) 1 (3.70) 0 (0) 0.322
Gastric retention (%) 2 (7.41) 1 (3.84) 0.575
Table 2 Time of recovery of bowel function Urinary retention (%) 0 (0) 2 (7.69) 0.142
G group (n=27) E group (n=26) p value Urinary tract infection (%) 0 (0) 0 (0)
Mortality (%) 0 (0) 0 (0)
First flatus (hour) 34.5±7.3 28.5±5.6** <0.01 Total (%) 4 (14.8) 4 (15.4) 0.954
Tolerate a full diet (hour) 38.1±8.7 33.9±7.5** <0.01 Duration of hospital stay 5.83±1.5 5.41±1.6 0.165
(day)
**p<0.01 vs. the G group

stress response to surgery by blocking afferent neural trans-
mission, inhibit the HPA excitation caused by noxious stimuli
to reduce cortisol secretion, and provide better postoperative
pain relief [24]. CRP is a non-specific acute-phase protein
synthesized by the liver. Its abnormal increase is associated
with trauma and stress. The postoperative CRP level may
reflect the degree of surgical stress [25]. In our study, the
plasma levels of CRP increased postoperatively in both
groups, and the levels of CRP in the E group are lower than
that in the G group at t3 and t4, which demonstrated that
general anesthesia combined with epidural anesthesia could
alleviate systemic surgical stress response as compared with
general anesthesia alone.
During the perioperative period, the numbers of peripheral
blood leukocytes significantly increased, and the numbers of
lymphocytes decreased at t3 post-surgery in both groups,
demonstrating that surgical trauma and surgical stress trig-
gered systemic inflammation and suppressed immune defense
mechanisms in the postoperative period. Although there was
no significant difference in the numbers of leukocytes be-
tween the two groups, the numbers of lymphocytes in the E
group were significantly greater than that in the G group at t3
which indicated a faster recovery of the immune response in
the E group.
Th1 cells can activate macrophages and NK cells and
enhance the cytotoxicity of CD8+ T cells against tumor cells;
Th2 cells can induce tumor-associated macrophage and den-
dritic cell maturation, which inhibits anti-tumor immune re-
sponse and promotes the growth and metastasis of cancer cells
[14]. Preserving Th1/Th2 balance could attenuate liver metas-
tasis of EL4 cells [26]. In comparison with the G group,
significantly increased percentages of Th1 cells and reduced
frequencies of Th2 cells were detected in the E group. As a
result, the Th1/Th2 balance in E group shifted towards Th1,
which indicated that the Th1/Th2 balance in the E group was
better protected. Precious studies demonstrated that increased
percentages of circulating Th17 cells, Treg, and MDSCs were
correlated with cancer stage and metastasis of CC patients
[27–29]. Our study showed decreased percentages of circulat-
ing Treg and MDSCs in patients of the E group at t3 and t4.
Therefore, general anesthesia combined with epidural anes-
thesia could protect postoperative anti-tumor immune re-
sponse of CC patients.
Anesthetic drugs, especially opioids, have immunosup-
pressive effects [30]. In our study, both groups achieved
similar intraoperative depth of anesthesia, while the patients
in the E group received significantly lower amounts of mor-
phine and sevoflurane. This phenomenon may help to explain
why general anesthesia combined with epidural anesthesia
could protect the anti-tumor response of CC patients.
Inflammation of the intestinal muscularis externa is
the main mechanism underlying POI. The mechanisms
underlying the generalized inhibition of intestinal
Int J Colorectal Dis
motility are primarily associated with the surgical stress
response, panintestinal dissemination of inflammation
mediated by CD4+ T cells, and endogenous opioids
secreted within the gastrointestinal (GI) tract in response
to surgical trauma [31, 32]. Moreover, opioids mediate
analgesia by binding to μ-opioid receptors in the central
nervous system; however, opioids also bind to peripher-
al μ-opioid receptors in the GI tract, resulting in a
disruption of intestinal function, thereby exacerbating
POI [33]. The fast-track surgery protocol has been as-
sociated with accelerated recovery of intestinal function
[11]; our study demonstrated that with lower amounts of
opioid application, general anesthesia combined with
epidural anesthesia could further facilitate postoperative
intestinal functional recovery in CC patients following a
fast-track surgery protocol.
We recognized that our study also had some potential
limitations: the number of patients recruited in our study was
small, which limited our conclusions; to reduce the interfer-
ence from other perioperative factors, the operation types
included only open surgeries for CC; and in order to reduce
the interference factors, the postoperative analgesia method of
the G group was slightly different from current fast-track
surgery protocols. Thus, further studies in a larger population
are warranted.
In conclusion, our data indicated that general and epidural
anesthesia consumed lower amounts of morphine and
sevoflurane to achieve similar intraoperative depth of anes-
thesia and better postoperative analgesic effects. Furthermore,
epidural anesthesia may mitigate surgical stress- and anesthet-
ic drug-related immunosuppression in patients and facilitated
postoperative intestinal functional recovery. Therefore, our
findings demonstrate the crucial role of anesthetic strategy in
fast-track surgery protocols. Further large-scale prospective
trials with CC recurrence and metastasis as the endpoints are
warranted to determine the significance of our observations.
Funding This research is sponsored by Program of Shanghai Subject
Chief Scientist (2012-2014, 12XD1401900). The funders had no role in
the study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Conflict of interest The authors have declared that no competing
interests exist.
References
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011)
Global cancer statistics. CA Cancer J Clin 61:69–90
2. Center MM, Jemal A, Smith RA, Ward E (2009) Worldwide varia-
tions in colorectal cancer. CA Cancer J Clin 59:366–78
Int J Colorectal Dis
3. Migliore L, Migheli F, Spisni R, Coppede F (2011) Genetics, cyto-
genetics, and epigenetics of colorectal cancer. J Biomed Biotechnol
2011:792362
4. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflamma-
tion, and cancer. Cell 140:883–99
5. Neeman E, Ben-Eliyahu S (2013) Surgery and stress promote cancer
metastasis: new outlooks on perioperative mediating mechanisms
and immune involvement. Brain Behav Immunol 30(Suppl):S32–40
6. Taub DD (2008) Neuroendocrine interactions in the immune system.
Cell Immunol 252:1–6
7. Bellinger DL, Millar BA, Perez S, Carter J, Wood C, ThyagaRajan S,
Molinaro C, Lubahn C, Lorton D (2008) Sympathetic modulation of
immunity: relevance to disease. Cell Immunol 252:27–56
8. Bartal I, Melamed R, Greenfeld K, Atzil S, Glasner A, Domankevich
V, Naor R, Beilin B, Yardeni IZ, Ben-Eliyahu S (2010) Immune
perturbations in patients along the perioperative period: alterations
in cell surface markers and leukocyte subtypes before and after
surgery. Brain Behav Immun 24:376–86
9. Kehlet H (2008) Fast-track colorectal surgery. Lancet 371:791–3
10. Kehlet H, Wilmore DW (2008) Evidence-based surgical care and the
evolution of fast-track surgery. Ann Surg 248:189–98
11. Ren L, Zhu D, Wei Y, Pan X, Liang L, Xu J, Zhong Y, Xue Z, Jin L,
Zhan S, Niu W, Qin X, Wu Z, Wu Z (2012) Enhanced Recovery After
Surgery (ERAS) program attenuates stress and accelerates recovery
in patients after radical resection for colorectal cancer: a prospective
randomized controlled trial. World J Surg 36:407–14
12. Chen WK, Miao CH (2013) The effect of anesthetic technique on
survival in human cancers: a meta-analysis of retrospective and
prospective studies. PLoS One 8:e56540
13. Perez-Diez A, Joncker NT, Choi K, Chan WF, Anderson CC, Lantz
O, Matzinger P (2007) CD4 cells can be more efficient at tumor
rejection than CD8 cells. Blood 109:5346–54
14. Kennedy R, Celis E (2008) Multiple roles for CD4+ T cells in anti-
tumor immune responses. Immunol Rev 222:129–44
15. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T
cell populations (*). Annu Rev Immunol 28:445–89
16. Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regu-
lated by networks of cytokines and transcription factors. Immunol
Rev 238:247–62
17. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells
as regulators of the immune system. Nat Rev Immunol 9:162–74
18. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more
mechanisms for inhibiting antitumor immunity. Cancer Immunol
Immunother 59:1593–600
19. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E,
Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived
suppressor cells correlate with clinical cancer stage, metastatic tumor
burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer
Immunol Immunother 58:49–59
20. Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ (2013)
Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor
cells correlate with extrathoracic metastasis and poor response to
chemotherapy in non-small cell lung cancer patients. Cancer
Immunol Immunother 62:1439–51
21. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor
cells: linking inflammation and cancer. J Immunol 182:4499–506
22. Hoechst B, Gamrekelashvili J, Manns MP, Greten TF, Korangy F
(2011) Plasticity of human Th17 cells and iTregs is orchestrated by
different subsets of myeloid cells. Blood 117:6532–41
23. van Bree SH, Nemethova A, Cailotto C, Gomez-Pinilla PJ, Matteoli
G, Boeckxstaens GE (2012) New therapeutic strategies for postoper-
ative ileus. Nat Rev Gastroenterol Hepatol 9:675–83
24. Snyder GL, Greenberg S (2010) Effect of anaesthetic technique and
other perioperative factors on cancer recurrence. Br J Anaesth 105:
106–15
25. Reissfelder C, Rahbari NN, Koch M, Kofler B, Sutedja N, Elbers H,
Buchler MW, Weitz J (2011) Postoperative course and clinical sig-
nificance of biochemical blood tests following hepatic resection. Br J
Surg 98:836–44
26. Wada H, Seki S, Takahashi T, Kawarabayashi N, Higuchi H, Habu Y,
Sugahara S, Kazama T (2007) Combined spinal and general anes-
thesia attenuates liver metastasis by preserving TH1/TH2 cytokine
balance. Anesthesiology 106:499–506
27. Wang J, Xu K, Wu J, Luo C, Li Y, Wu X, Gao H, Feng G, Yuan BZ
(2012) The changes of Th17 cells and the related cytokines in the
progression of human colorectal cancers. BMC Cancer 12:418
28. Sellitto A, Galizia G, De Fanis U, Lieto E, Zamboli A, Orditura M,
De Vita F, Giunta R, Lucivero G, Romano C (2011) Behavior of
circulating CD4+CD25+Foxp3+ regulatory T cells in colon cancer
patients undergoing surgery. J Clin Immunol 31:1095–104
29. Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, Zhu J, Wei H, Zhao
K (2013) Circulating and tumor-infiltrating myeloid-derived suppres-
sor cells in patients with colorectal carcinoma. PLoS One 8:e57114
30. Afsharimani B, Cabot P, Parat MO (2011) Morphine and tumor
growth and metastasis. Cancer Metastasis Rev 30:225–38
31. The FO, Bennink RJ, Ankum WM, Buist MR, Busch OR,
Gouma DJ, van der Heide S, van den Wijngaard RM, de
Jonge WJ, Boeckxstaens GE (2008) Intestinal handling-
induced mast cell activation and inflammation in human post-
operative ileus. Gut 57:33–40
32. Boeckxstaens GE, de Jonge WJ (2009) Neuroimmune mechanisms
in postoperative ileus. Gut 58:1300–11
33. Kurz A, Sessler DI (2003) Opioid-induced bowel dysfunction: path-
ophysiology and potential new therapies. Drugs 63:649–71