# Pancreatoduodenectomy with or without Pyloric Preservation: A Clinical Outcomes Comparison

Authors: Sean P. Dineen; Christina L. Roland; Roderich E. Schwarz
Journal: HPB Surgery
 (2008)

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## Abstract

Pyloric preservation (PP) can frequently be performed at the time of pancreatoduodenectomy (PD), although some reports have linked it to inferior outcomes such as delayed gastric emptying (DGE). We reviewed records in a single-surgeon practice to assess outcomes after PD with or without PP. There were 133 PDs with 67 PPPDs and 66 PDs. Differences between PPPD and PD groups included cancer frequency, tumor size, OR time, blood loss, and transfusion rate. However, postoperative morbidity rate and grade, NG tube duration, NGT reinsertion rate, DGE, and length of stay were similar. There was no difference among patients with pancreatic cancer. No detrimental outcomes are associated with pyloric preservation during PD. Greater intraoperative ease and superior survival in the PPPD group are due to confounding, tumor-related variables in this nonrandomized comparison. Nevertheless, we intend to continue the use of PP with our technique in patients who meet the stated criteria.


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## Body

## 1. Background

Pancreatic  cancer continues to carry a
dismal prognosis with a 5-year survival of approximately five percent  [1]. For patients that present with resectable disease,
pancreatoduodenectomy (PD) offers the best chance for cure among otherwise poor
treatment options [2]. The standard PD, or Whipple-Kausch operation, involves resection of
the head of the pancreas, duodenum, common bile duct, gallbladder, and distal
stomach including the pylorus. A gastrojejunostomy restores GI continuity to
the stomach. However, there is debate regarding the necessary extent of
resection. In the 1970s, Traverso and Longmire popularized a pylorus-preserving
pancreatoduodenectomy, initially for chronic pancreatitis [3]; interestingly, both initial PDs by Kausch in 1909 and Whipple in 1934
involved preservation of the antrum and pylorus. A pylorus-preserving PD (PPPD)
is similar to the “classic” or standard PD except that the distal stomach and
pylorus are left intact and continuity is restored through a
duodenojejunostomy. The rationale for this modification is that it may allow
for normal long-term gastric function, with a controlled release of gastric
contents and a reduced gastric accumulation of small bowel succus. However,
there are some reports indicating that this technique may generate
postoperative challenges due to delayed gastric emptying (DGE) [4–7]. Additionally, there are concerns about the adequacy of margins for
cancer operations in which the pylorus is preserved [8]. Prospective randomized trials [6, 9–11], three meta-analyses [8, 12, 13], and an extensive literature
review [7] have not led to uniformly
congruent or firm conclusions whether
PPPD has beneficial or adverse effects, although most larger trials and the
more recent pooled analyses have failed to show that an increased frequency of
DGE is clearly associated with PPPD. The reasons for a lack of clear
interpretability of outcome differences between PD and PPPD in some randomized
controlled trials are lack of power and confounding factors affecting the
outcomes of interest. For instance, Lin et al. randomized 36 patients and were
able to compare 19 PDs to 14 PPPDs; the only obvious difference was a delayed
gastric emptying in 1 of 19 PD patients, and 6 of 14 individuals after PPPD [14]. Yeo et al. performed a
large, single institution trial of 146 “standard” locoregional pancreatic head
resections (with an 86% PPPD rate),
compared to 148 radical PDs without PP, but with extended lymphadenectomy and
perivascular mesenteric soft tissue dissection; the groups were well balanced
regarding tumor type, stage, and operative findings, but the resulting
complication rate, delayed gastric emptying, and hospital stay were all
significantly higher in the radical dissection group and therefore not
attributable to any PPPD per se [10]. The purpose of the current study was to analyze our clinical experience
with PPPD compared to standard PD based on indications and clinical outcomes,
as all procedures followed the same regional and retroperitoneal soft tissue
dissection strategy, and the PP with subsequent duodenal anastomosis was the
only different component between the two techniques.


## 2. Patients and Methods

Clinical, operative, and pathologic
information had been prospectively collected. The database contains information
from patients treated by a single surgeon in an academic tertiary care practice
setting. Patients were included over a ten-year period from 1997 to 2007. All
133 individuals presented with either a head of pancreas or other periampullary
malignancy that was biopsy proven, or had suspicious findings for malignancy
within a mass lesion, complex cystic lesion, or ductal stricture affecting the
periampullary tissues. All patients had undergone preoperative clinical and
imaging evaluation; the latter included computed tomography for all, and
magnetic resonance imaging, endoscopic ultrasound, or endoscopic retrograde
cholangiopancreatography as deemed indicated. Based on this preoperative
evaluation, all patients were considered suitable candidates for partial
pancreatoduodenectomy. Preoperative biliary decompression for jaundiced
patients was not routinely requested, but was in place in the majority of
patients prior to any surgical consultation or operative planning.PPPD was performed whenever deemed safe and feasible, based
on the intraoperative
assessment. This included examination of the mobility of the pyloric ring to
exclude inflammatory or neoplastic involvement with the resection specimen. The
presence of suspicious perigastric lymph nodes, prohibitive for a PPPD, was
examined. Normal anatomy of the distal stomach was ascertained, and patients
with known preoperative gastric motility disorders were also excluded from
PPPD. Finally, an assessment of whether the pyloric vagal innervation alongside
the right gastric vasculature could be preserved was made prior to committing
to a PPPD, as sacrificing this structure may contribute to delayed gastric
emptying. The technique we employ for PPPD is modified in a sense that the
right gastric artery is preserved whenever possible, and regarding the
consistent use of our preferred anastomotic technique. Figure1 illustrates the
distal stomach and pylorus of a typical patient and the tissue bridge that
remains after the resection described. Figure 2 shows the duodenojejunostomy,
which in every case was a hand-sewn, dual layer continuous anastomosis in
antecolic position. All gastrojejunostomies in the PD group were equally
furbished in antecolic position. The management practice with nasogastric tubes
(NGTs) changed during the study interval; during the first five years, NGTs
were routinely utilized, and usually removed on postoperative day 1 or 2, based
on the amount of gastric aspirate observed; during the later half, an
orogastric tube was used intraoperatively, and this was routinely removed at
the time of endotracheal extubation. This practice did not differ between PPPD
and PD patients. Similarly, placement of a jejunostomy took place routinely as
described [15]; its postoperative use in
hospital and occasional use after discharge did not differ between the groups.Preservation
of the right gastric vasculature and pyloric vagal innervation.
(a)
Appearance prior to dissection. The arrow
marks the course of right gastric artery, right gastric vein, and pyloric vagal
branches(b)
Findings after duodenal transection. The
arrow marks the preserved neurovascular structuresAntecolic
duodenojejunostomy, hand-sutured dual-layer technique.
(a)
Posterior outer layer completed(b)
Posterior inner layer completed(c)
All sutures completedThe
definition of DGE varies among authors, as reviewed in detail before [16]; in this study, simple NGT reinsertion need did not automatically
qualify for a diagnosis of delayed gastric emptying. We determined a patient to
have DGE if there was nausea and vomiting requiring NGT reinsertion for longer
than 7 days combined with the inability to take oral nutrition or hydration by
postoperative day 10, or if the inability to tolerate oral intake prolonged the
patient’s hospital stay by more than 2 days. Patients requiring NGT placement
during critical care support in the intensive care unit were not included in
this group, unless NGT drainage exceeded 1200 mL per 24 hours for greater than
three days. Patients with DGE were also classified according to the
international study group definition [16]. All patients with postoperative NGT reinsertion did undergo an
additional, separate analysis. Postoperative complications were graded
according to the 5-grade scale proposed by DeOliveira et al. [17]. Pancreatic leak of fistula
formation was graded according to the international study group definition [18]. Postoperative lethal events
included those occurring during the in-hospital stay or within 30 days after
the procedure, whichever came last.Continuous
data between the PD and PPPD groups were compared via student’st-test
or Mann-Whitney analysis, based on the original data distribution. Chi square
contingency testing was employed for categorical data. Survival data were
analyzed with nonparametric Kaplan-Meier statistics; for group differences, a
log-rank test was performed. Length of NGT duration and length of hospital stay
comparison involved a nonparametric product-limit method as utilized earlier [19]. In-hospital deaths were
excluded from this analysis, and group comparisons were performed with a
Peto-Peto-Wilcoxon test. All calculations were performed using StatView
software for Macintosh, version 5.0.1 (SAS Institute Inc.,
Cary, NC). Statistical
significance of group differences was assumed at a P value of
<.05.


## 3. Results

### 3.1. Patient Demographics

Between 1997 and 2007, 133 of 184 pancreatic resections
involved a PD (72%); total pancreatectomies were not included in this analysis.
There were 78 women (59%) and 55 men (41%), with a median age of 66 years
(range: 38–87). The
underlying disease mechanisms providing an indication for resection included
110 malignant processes (83%) and 23 benign disorders (17%). PPPDs (n = 67) and
PDs without PP (n = 66) were numerically balanced. Aside from a slight difference
in the frequency of a malignant diagnosis and the primary tumor size, PPPD and
PD groups were comparable regarding demographic and clinicopathologic
parameters (Table 1). Although the distribution of cancer types did not differ
between the two groups in a statistically significant way, the higher percentage
of pancreatic primaries and a greater number of cancers in general in the PD
group reflect greater oncologic challenges here than those in patients
undergoing PPPD.Table 1
Demographic and pathologic data.
DemographicTotal cohortPPPDPDP valuePatients (n)1336766N/AGender (%)Female596652NSMale413448Age, median (range) (years)66 (39–88)66 (45–88)66 (39–86)NSASA group 3 or greater (%)595960NSDiagnostic group (%)Malignant837689.04Benign172411Cancer type (% of patients with cancer)Pancreatic645672NSAmpullary172511Other181917Tumor size, mean (cm)3.13.83.5.01T3+ (%)747375NSN pos. (%)625568NSGrade 3+828478NSTotal LN count, mean (n)14.313.415.3NSR0 rate (%)778371NS


### 3.2. Operative Treatment

The median total operation time for the entire cohort was
6.4 hours, the median estimated blood loss 527 mL, and the overall red blood
cell transfusion rate 23%. Several intraoperative parameters differed between
the PPPD and PD groups. This included total operative time, estimated blood
loss, the amount of intravenous fluid administered, and the blood transfusion
rate (Table2). In all these categories, numbers were more favorable in the
PPPD group. However, there were no differences regarding number of units of
packed red blood cells transfused per patient transfused, or in the
intraoperative urine production.Table 2
Operative
treatment characteristics.
Total cohort (n = 133)PPPD (n = 67)PD (n = 66)P valueOR time (hour)6.45.87<.0001EBL (mL)527413636.006IVF (mL)738167687954.02Transfusion rate (%)231333.007Units PRBC, mean0.560.450.76NSUnits PRBC per transfused patient (n)2.22.22.2NSUrine output per hour operating time, mean (mL)141173118NS


### 3.3. Postoperative In-Hospital Outcome

The postoperative overall complication rate was 39%, with a
14% rate of grade 3 or greater severity that required either interventional
radiologic, operative, or intensive care management. Fifteen patients
experienced a postoperative pancreatic or biliary leak (11%); the leak severity
included grade A (n = 3, 20%), grade B (n = 3, 20%), and grade C (n = 9, 60%). There
were six postoperative lethal events, for an overall mortality rate of 4.5%. As
shown in Table 3, there were no obvious group differences in postoperative
morbidity, leak rate or mortality. The median NGT duration for all patients was
1 day. In 19% of patients, the NGT had to be replaced at least once during the
postoperative course. However, DGE as defined was observed in only two patients
after PPPD, and in three patients past PD. DGE according to the international study
group definition included was observed in eight patients (6%), and included
grades A (n = 5), B (n = 1), and C (n = 2). Two of the individuals with DGE had a
grade B pancreatic leak. In none of these parameters were differences detected
between the PD and PPPD groups (Table 3). One patient with DGE after PPPD had a
biliary leak, the other had no other identifiable accompanying morbidity event.
The median length of stay was 10 days overall. As depicted in Figure 3, the
cumulative length of stay comparison did not reveal significant differences
between the treatment groups, and the subset of patients with a prolonged
hospital stay was similar in the PD and PPPD cohorts.Table 3
Postoperative outcomes.
Total cohort (n = 133)PPPD (n = 67)PD (n = 66)P valueMorbidity (%)393940NSGrade 3+ morbidity (%)141314NSPancreatic leak (%)111211NSLethal events (n)624NSMedian NGT duration (days)112NSNGT reinsertion (%)192117NSDelayed gastric emptying (%)3.83.04.5NSDelayed gastric emptying, international study group definition (%)6.06.06.1NSLength of stay, median (d)101010NSFigure 3
Length
of hospital stay, by resection group.


### 3.4. Survival

At  a median follow-up of 15 months (20 for
survivors), the overall actuarial survival is statistically superior in the
PPPD group compared to PD patients by univariate analysis; the median survival
time was 26 months after PPPD, and 16 months after PD (P = .03, Figure 4(a)).
This certainly is confounded by the higher percentage of cancer, a greater
frequency of pancreatic cancer, and a larger tumor size in the PD group.
Consequently, the overall survival for cancer patients only (Figure 4(b)), or
for individuals specifically with pancreatic cancer (Figure 4(c)) was not
statistically different between the two- procedure groups.Overall
actuarial survival, by resection group.
(a)
Overall survival, all patients included(b)
Overall survival, cancer patients only(c)
Overall survival, pancreatic cancer patients
only


## 3.1. Patient Demographics

Between 1997 and 2007, 133 of 184 pancreatic resections
involved a PD (72%); total pancreatectomies were not included in this analysis.
There were 78 women (59%) and 55 men (41%), with a median age of 66 years
(range: 38–87). The
underlying disease mechanisms providing an indication for resection included
110 malignant processes (83%) and 23 benign disorders (17%). PPPDs (n = 67) and
PDs without PP (n = 66) were numerically balanced. Aside from a slight difference
in the frequency of a malignant diagnosis and the primary tumor size, PPPD and
PD groups were comparable regarding demographic and clinicopathologic
parameters (Table 1). Although the distribution of cancer types did not differ
between the two groups in a statistically significant way, the higher percentage
of pancreatic primaries and a greater number of cancers in general in the PD
group reflect greater oncologic challenges here than those in patients
undergoing PPPD.Table 1
Demographic and pathologic data.
DemographicTotal cohortPPPDPDP valuePatients (n)1336766N/AGender (%)Female596652NSMale413448Age, median (range) (years)66 (39–88)66 (45–88)66 (39–86)NSASA group 3 or greater (%)595960NSDiagnostic group (%)Malignant837689.04Benign172411Cancer type (% of patients with cancer)Pancreatic645672NSAmpullary172511Other181917Tumor size, mean (cm)3.13.83.5.01T3+ (%)747375NSN pos. (%)625568NSGrade 3+828478NSTotal LN count, mean (n)14.313.415.3NSR0 rate (%)778371NS


## 3.2. Operative Treatment

The median total operation time for the entire cohort was
6.4 hours, the median estimated blood loss 527 mL, and the overall red blood
cell transfusion rate 23%. Several intraoperative parameters differed between
the PPPD and PD groups. This included total operative time, estimated blood
loss, the amount of intravenous fluid administered, and the blood transfusion
rate (Table2). In all these categories, numbers were more favorable in the
PPPD group. However, there were no differences regarding number of units of
packed red blood cells transfused per patient transfused, or in the
intraoperative urine production.Table 2
Operative
treatment characteristics.
Total cohort (n = 133)PPPD (n = 67)PD (n = 66)P valueOR time (hour)6.45.87<.0001EBL (mL)527413636.006IVF (mL)738167687954.02Transfusion rate (%)231333.007Units PRBC, mean0.560.450.76NSUnits PRBC per transfused patient (n)2.22.22.2NSUrine output per hour operating time, mean (mL)141173118NS


## 3.3. Postoperative In-Hospital Outcome

The postoperative overall complication rate was 39%, with a
14% rate of grade 3 or greater severity that required either interventional
radiologic, operative, or intensive care management. Fifteen patients
experienced a postoperative pancreatic or biliary leak (11%); the leak severity
included grade A (n = 3, 20%), grade B (n = 3, 20%), and grade C (n = 9, 60%). There
were six postoperative lethal events, for an overall mortality rate of 4.5%. As
shown in Table 3, there were no obvious group differences in postoperative
morbidity, leak rate or mortality. The median NGT duration for all patients was
1 day. In 19% of patients, the NGT had to be replaced at least once during the
postoperative course. However, DGE as defined was observed in only two patients
after PPPD, and in three patients past PD. DGE according to the international study
group definition included was observed in eight patients (6%), and included
grades A (n = 5), B (n = 1), and C (n = 2). Two of the individuals with DGE had a
grade B pancreatic leak. In none of these parameters were differences detected
between the PD and PPPD groups (Table 3). One patient with DGE after PPPD had a
biliary leak, the other had no other identifiable accompanying morbidity event.
The median length of stay was 10 days overall. As depicted in Figure 3, the
cumulative length of stay comparison did not reveal significant differences
between the treatment groups, and the subset of patients with a prolonged
hospital stay was similar in the PD and PPPD cohorts.Table 3
Postoperative outcomes.
Total cohort (n = 133)PPPD (n = 67)PD (n = 66)P valueMorbidity (%)393940NSGrade 3+ morbidity (%)141314NSPancreatic leak (%)111211NSLethal events (n)624NSMedian NGT duration (days)112NSNGT reinsertion (%)192117NSDelayed gastric emptying (%)3.83.04.5NSDelayed gastric emptying, international study group definition (%)6.06.06.1NSLength of stay, median (d)101010NSFigure 3
Length
of hospital stay, by resection group.


## 3.4. Survival

At  a median follow-up of 15 months (20 for
survivors), the overall actuarial survival is statistically superior in the
PPPD group compared to PD patients by univariate analysis; the median survival
time was 26 months after PPPD, and 16 months after PD (P = .03, Figure 4(a)).
This certainly is confounded by the higher percentage of cancer, a greater
frequency of pancreatic cancer, and a larger tumor size in the PD group.
Consequently, the overall survival for cancer patients only (Figure 4(b)), or
for individuals specifically with pancreatic cancer (Figure 4(c)) was not
statistically different between the two- procedure groups.Overall
actuarial survival, by resection group.
(a)
Overall survival, all patients included(b)
Overall survival, cancer patients only(c)
Overall survival, pancreatic cancer patients
only


## 4. Discussion

In this series of 133 patients undergoing
pancreatoduodenectomy within a single-surgeon practice, PPPD has been performed
with constant criteria of intraoperative assessment, preservation of pyloric
vagal innervation, and a duodenal lumen-protective anastomotic technique with
dual-layer absorbable suture material. In addition, all duodenojejunostomies
and gastrojejunostomies were placed as antecolic anastomoses. Our analysis of
these prospectively collected data shows no obvious detriments to the use of
PPPD, but also fails to show clear benefits. A PP procedure had been performed
in half of the patients; it was associated with less complex operations based
on reduced operative time, less intraoperative blood loss and fewer
transfusions. However, there were no outcome differences between PD and PPPD
groups regarding length of stay or cancer-specific survival. These apparent
differences between the two procedures need to be interpreted thoughtfully,
because some adverse clinicopathologic features appear to predispose a patient
to the PD group. Importantly, there was no evidence to suggest that PPPDs are
associated with a higher rate of postoperative delayed gastric emptying, or a
greater NGT reinsertion need. Overall, the rate of DGE appears low in this
series in both groups, and with the stated criteria for performing a PPPD, the
outcomes relating to DGE shown here would certainly support its use.The results of our study are consistent with
larger randomized controlled trials and meta-analyses comparing intraoperative
and postoperative outcomes between PPPD and PD. Our observed PPPD-associated
reduction in average total operative time by 1.2 hours, in mean estimated blood
loss by 223 mL, in transfusion rate by 20%, and in average PRBC number
transfused by 0.31 generally correspond to numbers in part reported by others [8, 12, 13]. While it has to be
remembered that these meta-analyses are largely based on the same trials, some
of these randomized trials support similar intraoperative benefits of PPPD [9, 14] while others do not [11]. While the reduced operative
time is intuitive, it is not sensible to assume that the mere addition of a
distal gastrectomy should lead to significantly larger blood loss, transfusion
rate, and possibly margin positivity. In our nonrandomized series, these
findings are best explained with the higher percentage of pancreatic cancer
cases in the PD group, where more challenging dissections tend to be
encountered at the mesenteric vasculature. In our experience, this is the
technical component that governs blood loss as well as margin status. When
subgroups are well balanced regarding pancreatic versus other periampullary
cancers, no differences in blood loss, and a comparable low R1 rate have been
reported [10].DGE is a concern that has been raised
repeatedly in conjunction with the pylorus preserving procedure [4, 14, 20]. The cause of DGE is uncertain, and may involve factors that are either
specific to the PP technique, or common to both PPPD and PD such as the loss of
pancreatic polypeptide production associated with pancreatic head resection [7]. Experimental evidence suggests that preservation of the right gastric
artery and the neurovascular bundle supplying the pylorus are critical to avoid
DGE [21]. Our preferred technique of PPPD makes a strong attempt to preserve the
right gastric artery and the tissue containing the pyloric branch of the vagus
nerve, and we feel this may indeed contribute to the low rate of DGE in our
study. Other factors specific to a PP approach may relate to technical aspects
of the duodenal anastomosis, as this may easily be rendered too narrow through
conventional stapling techniques. Interestingly, both patients in our series
with DGE after PPPD had widely patent anastomoses, too, as documented via
unimpaired radiographic emptying of intragastric contrast. This would rather
suggest a functional disturbance of gastric motility than an anatomic obstacle,
if DGE is still encountered after using the technique described. An antecolic
duodenal reconstruction may be an important determinant to reduce the risk for
DGE. As reported by Hartel et al., in a series of 100 patients undergoing PPPD,
DGE occurred with significantly greater frequency after retrocolic anastomoses
than antecolic reconstructions [22]. This   notion is supported by
a recent randomized prospective trial with 40 patients, although the resulting
NGT duration of 4 versus 19 days, and the hospital stay of 28 versus 48 days
are not applicable to a Western patient series [23]. A prospective evaluation of
50 patients with antecolic PPPD had demonstrated a DGE rate of 12%, higher than
in our experience, but based on a different definition [24]. Importantly, DGE under these
conditions was linked to the presence of other postoperative complications,
including pancreatic leaks. Thus, the position of the duodenal anastomosis in
relation to the transverse colon apparently is more important in determining
DGE than how the pancreatic reconstruction is being performed [25]. Finally, DGE may be induced
by a disturbance in intestinal splanchnic innervation after more radical
resections, as suggested by a higher DGE rate after PD with extended
retroperitoneal dissection compared to the lesser dissection group with a high
PPPD number [10]. We do not perform a
circumferential dissection of the superior mesenteric artery to avoid such
morbidity.Operative radicality in oncologic terms does
not seem to be negatively affected by performing PPPDs. While a minimum number
of 10 to 15 lymph nodes has been suggested to optimize staging accuracy and
associated survival for both pancreatic and other periampullary cancers [26, 27], more radical resections have failed to improve survival of pancreatic
cancer [10, 28, 29]. As our findings regarding
lymph node counts suggest, this “radicality” is not affected by the PPPD
modification. Positive margin resection is a powerful predictor for increased
survival hazards, which also does not seem to be influenced by the performance
of a PP [30]. In our series, the R0
resection rate was higher after PPPD, reflecting the fact that more aggressive
malignancies with greater risks for radial margin involvement tend to require
resection of antrum and pylorus based on intraoperative assessment. In this
context, it should also be noted that volume-outcome relationships regarding
both early postoperative mortality and long-term survival have been well
demonstrated for pancreatic cancer, and that “standard” results as pertaining
to PP procedures have to be carefully judged under these aspects as well [31, 32]. Virtually, all reports on
PPPD and PD comparisons reflect high-volume institutions and cannot easily be
translated into low-volume settings. Comparable morbidity and survival between
PPPD and PD as seen in our results and those of others [11, 33] suggest that the standard PD
is certainly an acceptable procedure for the treatment of periampullary
malignancies. Subtle implications such as the possible need for continued
medication to control gastric acid after PP (which we do not use) would easily
sway our perceived balance in favor of a PD with antrectomy.In conclusion, we report that PPPD is as
effective as PD in resections for pancreatic or other periampullary cancers,
provided the pylorus itself and the surrounding soft tissues are free from
disease. Intraoperative advantages to PPPD are confounded in this series, but
still of potential relevance. An oncologically appropriate procedure with
acceptable early and late postoperative outcomes can be achieved with our PPPD
approach. Although it remains uncertain whether pyloric vagal preservation,
duodenal anastomotic technique, or antecolic reconstruction contribute decisively
to the low rate of postoperative DGE and other morbidity events,
we plan to continue their use within the  described technique whenever judicious
pre- and intra-operative assessment based on individual patient and disease
factors supports a PPPD indication.



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