Agenesis of the Dorsal Pancreas with Chronic

Vallath Balakrishnan, Vekateswara A Narayanan, Ismail Siyad, Lakshmi Radhakrishnan,
Prem Nair
Digestive Diseases Institute, Amrita Institute of Medical Sciences. Cochin, India
ABSTRACT
Context Agenesis of the dorsal pancreas is a
rare developmental anomaly. This anomaly
may be complicated by recurrent acute and
chronic pancreatitis.
Case report We report the case of a 28-year-
old female with agenesis of the dorsal
pancreas and chronic calcific pancreatitis. The
diagnosis of agenesis of the dorsal pancreas is
discussed and the genetic changes leading to
it are reviewed. The possibility of the patient
having tropical pancreatitis is mentioned.
Conclusions This is probably the first report
of chronic calcific pancreatitis complicating
agenesis of the dorsal pancreas.
INTRODUCTION
Developmental anomalies of the pancreas are
rarely seen. Pancreas divisum is the most
common anomaly (seen in 5-10% of
Caucasians) the others being an annular
pancreas, a heterotrophic pancreas, ansa
pancreatica, anomalous pancreaticobiliary
union and partial pancreatic agenesis [1, 2].
Agenesis of the dorsal pancreas is a very rare
anomaly: it may be asymptomatic and
incidentally detected on imaging or may be
associated with attacks of pancreatitis.
CASE REPORT
A 28-year-old female presented to our
pancreas clinic complaining of recurrent
upper abdominal pain of 5 months duration
radiating to the back. She had lost 5 kg within
the previous five months and was found to be
a diabetic. Physical examination revealed a
markedly emaciated female with a BMI of
14.2 but systemic examination was normal.
Her serum amylase was normal at the time of
admission.
Hemogram,
erythrocyte
sedimentation rate, hemoglobin, liver function
tests, renal function tests, serum electrolytes,
thyroid function tests, serum calcium,
phosphorous and autoimmune markers were
all normal. There was no history of trauma,
drug intake or alcoholism. The patient’s
postprandial blood sugar was 338 mg/dL and
CA 19-9 was 106 U/mL (reference range: 0-
37 U/mL). The serum C-peptide level was 1.5
ng/mL (reference range: 1-3 ng/mL). The
stool elastase level was 100 µg/g feces
(reference values: greater than 200 µg/g
feces). On abdominal ultrasonography, only
the pancreatic head, not the body or tail, was
visualized. Computerized tomography (CT
scan) of the abdomen revealed a mildly
atrophic pancreatic head with specks of
calcification and mild dilatation of the
pancreatic duct in the head region, but the
dorsal duct system was not seen (Figure 1).
The liver, gallbladder, common bile duct and
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kidneys were normal. With the suspicion of
agenesis of the dorsal pancreas, endoscopic
retrograde pancreatography (ERCP) was
carried out. During ERCP, the minor papilla
was not seen even after careful examination.
The major papilla was normal. Selective
cannulation of the pancreatic duct was carried
out. The cannula could not be advanced
beyond the head region. This was confirmed
using a 0.018 inch hydrophilic guidewire
(Glidewire, Terumo Co., Tokyo, Japan) which
could not be passed across the spine.(Figure
2). A pancreatogram showed a short
branching duct in the head region with
tapering and terminal arborization to the right
of the spine (Figure 3). The diagnosis of
agenesis of the dorsal pancreas with
associated chronic pancreatitis and diabetes
mellitus was made. There was no family
history of pancreatitis. The SPINK1 mutation
was negative on gene sequencing (done at the
Bangalore Genei Division, Sanmar Speciality
Chemicals, Bangalore, India). Contrast
studies did not reveal any intestinal
malrotation. The patient had no other
associated congenital abnormalities.
Figure 1. CT scan of the abdomen showing a slightly
atrophic head of the pancreas with specks of
The patient was started on analgesics,
pancreatic enzyme supplements, a diabetic
diet and human Mixtard
®
insulin (30/70) at a
dose of 20 units in the morning and 12 units
in the evening. Her symptoms have improved;
she feels well and is currently being followed
up in the clinic.
calcification, and non-visualization of the body and the
tail of pancreas.
DISCUSSION
The present case is the first report of chronic
calcific pancreatitis affecting the head of the
pancreas in association with agenesis of the
dorsal pancreas. Pancreatic anomalies may be
due to malfusion (e.g., pancreas divisum) or
malrotation (e.g., annular pancreas, partial
agenesis) [3]. The exact prevalence of
agenesis of the dorsal pancreas is not known;
Figure 3. Short branching duct in the head of the
pancreas with tapering and terminal arborization, to the
right of the spine.
Figure 2. Hydrophilic guidewire arrested in the
pancreatic duct in the head region due to its inability to
pass any further.
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however, only about 20 cases have been
reported in the literature. There are no reports
of autopsy series. Agenesis of the dorsal
pancreas may be asymptomatic, detected only
incidentally on abdominal imaging or may be
associated with recurrent acute pancreatitis or
diabetes mellitus.
Prior to 1979, agenesis of the dorsal pancreas
was diagnosed only after laparotomy. The
first pre-operative diagnosis of this anomaly
was made by Sano et al. using ERCP and a
CT scan. A diagnosis of agenesis of the dorsal
pancreas can pose problems. Abdominal
ultrasound has limitations in diagnosing
pancreatic disorders because of non-
visualization of the body and the tail of the
pancreas due to interference from bowel gas
or even technical failure [1, 4].
Computerized tomography [5] or MRI [6]
helps in diagnosing agenesis of the dorsal
pancreas by demonstrating the absence of the
pancreatic body and tail and the presence of a
normal head region. However, atrophy of the
body and the tail of the pancreas secondary to
acute pancreatitis, with sparing of the
uncinate process may mimic dorsal pancreatic
agenesis and has been labeled pseudo-
agenesis [7]. Such atrophy may be associated
with hypertrophy of the ventral pancreas.
Suda et al. point out the fallacies of
diagnosing dorsal pancreas agenesis by
imaging modalities alone [8]. They reported
two elderly patients, both of whom had an
initial diagnosis of agenesis of the dorsal
pancreas based on imaging; however, it was
subsequently proven by surgery and biopsies
to be atrophy of the body and the tail of the
pancreas secondary to tumor obstruction of
the proximal main pancreatic duct.
Magnetic resonance cholangiopancreato-
graphy (MRCP) [8] or ERCP can confirm the
diagnosis of dorsal pancreas agenesis
suspected on CT or MRI. ERCP can show the
absence of the minor papilla and the complete
absence of the dorsal duct system, and
demonstrate a short ventral duct [9]. ERCP
can also help in ruling out pancreas divisum,
by demonstrating obstruction, tapering, or
stenosis of the pancreatic duct and by
differentiating it from a pancreatic tumor.
Recently, endoscopic ultrasonography has
been shown to be useful in the diagnosis of
agenesis of the dorsal pancreas [10].
The association of agenesis of the dorsal
pancreas with pancreatitis is controversial and
the mechanism for associated pancreatitis is
speculative. Sphincter of Oddi dysfunction or
dyskinesia and compensatory hypertrophy
and hypersecretion of the remaining ventral
pancreas with raised intraductal pressure have
been proposed to explain the pancreatitis [11].
Genetic mutations such as that of SPINK1
may be predisposing factors [12]. Mutations
in the SPINK1 gene have been reported to be
associated with idiopathic and tropical
pancreatitis. However, these genes, because
of their high frequency in the population and
low penetrance, are more likely to be disease
modifiers rather than the cause of the disease.
Abdominal pain and diabetes mellitus are the
most common symptoms of dorsal pancreatic
agenesis [1]. Most of the adult patients who
are reported to have pancreatitis in association
with agenesis of the dorsal pancreas have
presented with these clinical features. A case
of neonatal diabetes mellitus due to
congenital pancreatic agenesis has been
reported [13]. In addition to agenesis of dorsal
pancreas, this baby had other congenital
defects such as cardiac septal defects,
gallbladder agenesis and duodenal
malrotation. Fukuoka et al. have described a
47-year-old female with obstructive jaundice
associated with dorsal pancreatic agenesis,
confirmed by ERCP [14]. At laparotomy, an
enlarged head of the pancreas with absence of
the body and the tail was noticed. A biopsy of
the pancreas showed scattered islets of
Langerhans in diffuse fibrosis, with
destruction of the glandular parenchyma. In a
case report by Wang et al. [1], laparotomy
showed a normal head of the pancreas with
complete agenesis of the body and tail. A
biopsy from the head revealed normal
pancreatic tissue whereas a biopsy from the
presumed body and tail presented only fatty
tissue. Klein et al. [15] has reported a patient
with agenesis of the dorsal pancreas with
weight loss, diabetes mellitus and exocrine
pancreatic deficiency. In another report, a
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female who developed insulin-dependent
diabetes mellitus at 39 years of age was found
to have dorsal pancreas agenesis [16]. Both
sons of the patient also had this anomaly,
verified by CT, but they had no evidence of
diabetes mellitus. Solid and papillary tumors
of the pancreas complicating agenesis of the
dorsal pancreas have been reported in two
patients [17, 18]. In both patients, a successful
resection of the tumor have been performed.
The pancreas develops from the foregut
endoderm as ventral and dorsal buds at the
fourth week of gestation. These buds fuse and
develop into a complex organ composed of
endocrine, exocrine and ductal components.
This developmental process depends upon an
integrated network of transcription factors.
Much of the recent knowledge on genes and
transcription factors exerting influence on
pancreas development has been gained from
studies in knock-out mice [19]. The initial
event in the development of the pancreas is
the outcropping of two buds (ventral and
dorsal) of cells from a specialized endodermal
epithelium located in the region of the foregut
which will become the duodenum (at
embryonic day (e) e8.5 to e9.5 in the mouse).
By e10.5, the partially differentiated
epithelium of the two buds undergoes
branching into a ductal tree. By e13 and e14,
the dorsal and ventral pancreata rotate and
fuse into a single organ. Between e14.5 and
e15.5, the endocrine pancreas differentiates
from the ductal epithelium; on e15.5, acini are
clearly discernible from the ducts. Endocrine
cells differentiate at about e9.5. They undergo
proliferation and organize into islet-like
clusters by e16. The islets are fully formed
shortly after birth (e18-e19). Contrary to
earlier views, the endocrine cells are now
established to be of endodermal and not
neural crest origin.
Expression of sonic hedgehog (Shh) or Indian
hedgehog (Ihh) can suppress pancreas
development. It has been shown that
exclusion of Shh or Ihh in the developing
pancreas anlagen is essential for pancreas
development [20]. At the level of the
pancreas, Shh and Ihh are expressed in the
endoderm anterior and posterior to the
pancreas in the intestinal part but not in the
anterior and posterior pancreatic epithelium.
It has been suggested that the notochord
which is in contact with the dorsal gut
epithelium may exert a negative repressive
signal on Shh expression at the prospective
site of the dorsal pancreas. However, the
notochord is not in contact with the ventral
gut epithelium; hence, signals other than those
from the notochord are likely to be in the
region of the ventral epithelium.
The homeodomain protein HB9 (Hlxb9) is
required for dorsal, but not ventral, bud
initiation [21]. The pancreas-duodenum-
homeodomain protein (Pdx1) is required for
bud expression but the initiation of bud
formation appears normal in homozygous
mice which are mutant for this gene. The
molecular determinants which define the
position of the buds and the localized
expression of Hlxb9 and Pdx1 in the
endoderm are currently unknown.
Several homeodomain and basic helix-loop-
helix (bHLH) transcription factors, notably
Isl1, Nkx2-2, Pax4, Pax6, and NeuroD/Beta2,
have been shown to exert important functions
in the control of pancreatic endocrine cell
differentiation [22]. Even though these factors
are expressed at the early stages of pancreas
development, even in their absence, the initial
steps of pancreas development proceed
normally. In contrast to the bHLH class, the
pancreas transcription factor1 p48 subunit
(Ptf1a), which is required for the generation
of exocrine, but not endocrine, cells and the
homeodomain protein insulin promoter
factor-1 (IPF1) (human locus) / Pdx1 (mouse
locus) are expressed at an early stage in
pancreas development.
The homeodomain protein Pdx1 is expressed
in the developing pancreatic anlage and leads
to the derivation of all the pancreatic cell
types; mutations in gene IPF1 (human locus) /
Pdx1 (mouse locus ) prevent the development
of the pancreas [23, 24, 25]. Hlxb9, which
encodes HB9, is a homeobox gene which is
expressed in the early stages of pancreatic
development and later in differentiated B cells
[26, 27]. Isl1 is a LIM homeodomain protein
required for the formation of the dorsal
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mesenchyma
for
proper
exocrine
differentiation and also required in the
pancreatic epithelium for islet survival [28].
The ngn3 gene, which codes for the
neurogenin 3 protein, is the key regulator of
endocrine development [29, 30]. Shh and Ihh
are the signaling molecules for the inhibitory
action on pancreas development [31, 32].
Recently, the transcription factor Ptf1a has
been shown to play an essential role in the
development
ofthe
pancreas
from
undifferentiated ventral foregut endoderm,
necessary for the specification of the ventral
pancreas and robust outgrowth of the dorsal
bud [33]. In its absence, ventral pancreas
progenitors differentiate into dorsal cells by
default.
In their experiments on dorsal agenesis of the
pancreas in mice, Li et al. [34] found that
Hlxb9 is expressed in two distinct
developmental phases, first during the
evagination of the pancreatic buds and later in
differentiating B cells. At approximately e8 (8
somatic stage embryonic day), Hlxb9
expression is first evident in the notochord, in
the entire dorsal gut endoderm and in the
ventral endoderm whereas the Pdx1 is
expressed only in the ventral pancreatic
endoderm so that both genes are concurrently
expressed in the ventral anlage while, in the
dorsal anlage, there will be the initiation of
Hb9 expression. At e10.5, only a low level of
Hlxb9 expression remains in the dorsal
pancreatic bud with no expression in the
ventral bud and the notochord whereas, at this
stage, Pdx1 will be expressed in both
pancreatic buds. At e17.5, Hlxb9 expression
reappears in differentiating B cells (only in
insulin-producing B cells, not in the glucagon
or somatostatin cells). At e10.5, Hlxb9
completes the evagination and therefore
subsequent development of the dorsal
pancreatic bud. But the ventral pancreatic
epithelium generates both exocrine and
endocrine cells in the absence of Hlxb9. As a
result, the dorsal pancreatic bud does not
develop in Hlxb9 mutant mice. In contrast,
the ventral pancreatic epithelium develops
and generates both exocrine and endocrine
cell types, thus revealing an early molecular
distinction between the programs for dorsal
and ventral pancreatic development. They
also suggest that the ventral pancreas of
Hlxb9 mutant embryos exhibits a more subtle
perturbation in B cell differentiation and islet
cell organization, indicating a later role for
Hlxb9 in the development of pancreatic B
cells.
Harrison et al., in another set of experiments
in mice, showed that during mouse
development, the dorsal and ventral
pancreatic buds and mature beta cells in the
islets of Langerhans expressed Hlxb9 [27]. In
mice homologous for a null mutation of
Hlxb9, the dorsal lobe of the pancreas failed
to develop. The remnant Hlxb9-/- pancreas
had small islets of Langerhans with reduced
numbers of insulin-producing beta-cells.
Hlxb9-/- beta cells expressed low levels of the
glucose transporter Glut-2 and homeodomain
factor Nkx6-1. Thus, Hlxb9 was shown to be
a key to normal pancreas development and
function.
In humans, mutations in the TCF2 (HNF1B,
VHNF1) gene are associated with maturity-
onset diabetes of the young Type-5, a form of
dominantly inherited type II diabetes mellitus
characterized by pancreatic beta cell
dysfunction at the age of 25 years or younger,
nondiabetic early-onset renal disease, liver
dysfunction, and abnormal urogenital tract
development. In addition to these phenotypes,
variable levels of pancreatic atrophies have
recently been associated with different TCF2
mutations [35]. Moreover, the authors quote
having identified two fetuses with severe
pancreatic hypoplasia, both carrying
previously undescribed severe mutations in
the TCF2 pancreatic genes. They further
studied this gene in mice from the embryonic
stem cells and found that, in the Tcf2 mutant
embryo, the dorsal pancreatic bud was
reduced and the ventral bud was undetectable.
The important branching phase for pancreatic
bud formation by the Tcf2 gene takes place
between e10.5 and e12.5.
Martin et al. [36] studied the role of retinoic
acid signaling in the development of the
pancreas in mice. The principle behind the
study was the induction of different stimuli
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from neighboring mesodermal tissues for the
development of the pancreas. Retinaldehyde
dehydrogenase 2 (raldh2 gene), which
encodes the enzyme required to synthesize
retinoic acid, is expressed in the dorsal
pancreatic mesenchyma at the early stage of
pancreatic specification. Raldh2-deficient
mice do not develop a dorsal pancreatic bud.
These mutant embryos lack Pdx1 expression
and early glucagon expressing cells, altered
Isl1 and reduced Hlxb9 expressing cells.
Therefore they realized the importance of this
gene for the normal development of the dorsal
pancreatic endoderm at a stage preceding
Pdx1 function.
During pancreatic ontogeny, N-cadherin is
initially expressed in the pancreatic
mesenchyma and later in the pancreatic
endoderm. The analysis of N-cadherin-
deficient mice revealed that these mice suffer
from selective agenesis of the dorsal pancreas
[37].
Several other transcription factors are
involved in pancreatic development. For
example, members of the Pax gene family,
Pax6 and Pax4 are expressed in the endocrine
cells [20]. The NK2 family member, Nkx2-2,
is supposed to be required for the terminal
differentiation of B cells or alternatively,
Nkx2-2 is critically required for the
expression of the insulin gene but not for the
expression of other B cell-specific genes.
NeuroD/Beta2 is a bHLH transcription factor
which is expressed in all pancreatic endocrine
cells. Mist1 also belongs to the bHLH family
of transcription factors and is expressed in the
exocrine cells from e14.5 on. Still another
transcription factor, HNF6, can be detected in
both pancreatic buds as early as e10.5 but,
later, the expression becomes limited to the
exocrine pancreas.
The pancreas has rapidly become one of the
most studied organs with respect to the
functioning of the transcription factors, and
many pancreatic phenotypes have been
described [20]. However, the present data
only allow more general comments to be
made about the epigenetic control of
pancreatic development. One major reason for
this is that most genetic studies have so far
failed to address whether a given transcription
factor exerts its function in pancreatic
progenitor cells and/or in postmitotic cells.
Even though agenesis of the dorsal pancreas
is a rare congenital anomaly, the genetic
studies of this anomaly can provide further
insights into early molecular events
controlling pancreatic development.
The pathogenetic mechanism for chronic
pancreatitis in our patient is not clear. This
patient did not have any of the known risk
factors for chronic pancreatitis. In most of the
reported cases of agenesis of the dorsal
pancreas, the association was with recurrent
acute pancreatitis. In the case described by
Fukuoka et al. [14], laparotomy and biopsy
showed histological evidence of chronic
pancreatitis. Our patient had mild atrophy of
the head of the pancreas with speckled
calcification on CT indicating chronic calcific
pancreatitis. There was failure to demonstrate
the body and the tail of the pancreas by CT
and this was confirmed by ERCP during
which the guide wire could not be advanced
beyond the head of the pancreas and the
contrast medium could not be pushed beyond
the head where there was arborization. The
patient was malnourished, had severe diabetes
mellitus necessitating insulin injections and
had exocrine pancreatic deficiency. She
showed absence of the body and the tail of the
pancreas. To our knowledge, this is the first
report of chronic calcific pancreatitis
associated with dorsal pancreatic agenesis.
This patient comes from Southern India,
which is geographically associated with a
high prevalence of tropical pancreatitis.
Tropical pancreatitis is a type of chronic
pancreatitis, generally calcific, which is
commonly seen in young non-alcoholic
subjects in tropical countries [38]. The
patients are often malnourished, with severe
diabetes mellitus and a rapidly progressive
course. The disease is sometimes seen in
close relatives such as siblings or parents. It is
especially common in Southern India where
this patient comes from. These patients have a
high incidence of malignancy complicating
the pancreatitis. Whether the present patient
had tropical pancreatitis is a matter of
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speculation as there are no definite diagnostic
markers for tropical pancreatitis. However,
we could not elicit a history of malnutrition
before the onset of her illness, nor of
substantial cassava intake, both of which are
common associations with tropical
pancreatitis. None of the patient’s immediate
relatives had chronic pancreatitis or diabetes
mellitus. Genetic mutations have been
reported to be associated with chronic
pancreatitis [39, 40]. Mutations involving the
SPINK1 gene have been reported in
association with idiopathic pancreatitis in the
West, in up to 45% of tropical pancreatitis
patients [12] and in 4% of normal controls in
India; however, the SPINK1 mutation was
absent in our patient. The explanation for the
association between pancreatitis and agenesis
of the dorsal pancreas is far from clear.
In recent animal experiments, hedgehog
signaling has recently been shown not to be
restricted to developmental events in the
pancreas, but to retain some of its activity
during adult life [41]. Recent work has
suggested the role of deregulated hedgehog
signaling in pancreatic development and
pancreatic diseases, including diabetes
mellitus, chronic pancreatitis and pancreatic
cancer [42]. Whether deregulations in
hedgehog signaling have had any role in
initiating pancreatitis in our patient is a moot
question. While the exact risk factors for
chronic pancreatitis in our patient are not
apparent, it is possible that as yet unknown
genetic factors or environmental toxins might
have had a contributory role in the initiation
or perpetuation of pancreatitis in this patient.
CONCLUSION
We report a case of chronic calcific
pancreatitis in association with agenesis of the
dorsal pancreas, which is a very rare anomaly
of pancreatic development. To the best of our
knowledge, this is the first time such an
association is being reported. The cause of the
pancreatitis in the present case is not known
even though the possibility of associated
tropical pancreatitis cannot be discounted. We
have reviewed the literature on agenesis of the
dorsal pancreas and its genetic basis.
Received September 19
th
, 2006 - Accepted
October 1
st
, 2006
Keywords Islets of Langerhans; Mutation;
Pancreatic Ducts; Pancreas; Pancreas,
Exocrine; Pancreatitis; Pancreatitis, Acute
Necrotizing;
Pancreatitis,
Chronic;
Transcription Factors
Abbreviations bHLH: basic helix-loop-helix;
e: embryonic day; HLXB9: homeobox HB9
[Homo sapiens]; Hlxb9: homeobox gene HB9
[Mus musculus]; HNF6: hepatocyte nuclear
factor 6; Ihh: Indian hedgehog [Mus
musculus]; IPF1: insulin promoter factor 1,
homeodomain transcription factor [Homo
sapiens]; Ipf1: insulin promoter factor 1,
homeodomain transcription factor [Mus
musculus]; Isl1: ISL1 transcription factor,
LIM/homeodomain [Mus musculus]; Nkx2-2:
NK2 transcription factor related, locus 2
(Drosophila) [Mus musculus]; Nkx6-1: NK6
transcription factor related, locus 1
(Drosophila) [Mus musculus]; Pax2: paired
box gene 2 [Mus musculus]; Pax4: paired box
gene 4 [Mus musculus]; Pax6: paired box
gene 6 [Mus musculus]; Pdx1: pancreatic and
duodenal homeobox gene 1 [Rattus
norvegicus]; PTF1A: pancreas specific
transcription factor, 1a [Homo sapiens];
Ptf1a: pancreas specific transcription factor,
1a [Mus musculus]; raldh2: retinaldehyde
dehydrogenase 2 [Takifugu rubripes]; SHH:
sonic hedgehog homolog (Drosophila) [Homo
sapiens] Shh: sonic hedgehog [Mus
musculus]; TCF2: transcription factor 2,
hepatic; LF-B3; variant hepatic nuclear factor
[Homo sapiens]; Tcf2: transcription factor 2
[Mus musculus]
Correspondence
Vallath Balakrishnan
Digestive Diseases Institute
Amrita Institute of Medical Sciences
Amrita Lane
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Elamakkara P.O.
Cochin, 682 026
Kerala state
India
Phone: +91-484.400.2015/1234
Fax: +91-484.400.2020
E-mail: vbalakrishnan@aims.amrita.edu
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