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Clinical features, survival times and COX-1 and COX-2
expression in cats with transitional cell carcinoma of the urinary
bladder treated with meloxicam
Citation for published version:
Bommer, NX, Hayes, AM, Scase, TJ & Gunn-Moore, DA 2012, 'Clinical features, survival times and COX-1
and COX-2 expression in cats with transitional cell carcinoma of the urinary bladder treated with
meloxicam', Journal of Feline Medicine and Surgery, vol. 14, no. 8, pp. 527-33.
https://doi.org/10.1177/1098612X12442041
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Journal of Feline
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Clinical features, survival times and COX-1 and COX-2 expression in cats with transitional cell
carcinoma of the urinary bladder treated with meloxicam
Nicholas X Bommer, Alison M Hayes, Timothy J Scase and Danièlle A Gunn-Moore
Journal of Feline Medicine and Surgery 2012 14: 527 originally published online 9 March 2012
DOI: 10.1177/1098612X12442041
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442041
2012
JFM14810.1177/1098612X12442041Bommer et alJournal of Feline Medicine and Surgery
Original Article
Clinical features, survival times and
COX-1 and COX-2 expression in
cats with transitional cell carcinoma
of the urinary bladder treated with
meloxicam
Journal of Feline Medicine and Surgery
14(8) 527–533
© ISFM and AAFP 2012
Reprints and permission:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1098612X12442041
jfms.com
Nicholas X Bommer1, Alison M Hayes2, Timothy J Scase3
and Danièlle A Gunn-Moore1
Abstract
Records of 11 cats with transitional cell carcinoma of the urinary bladder, which had been treated with meloxicam,
were reviewed for signalment, duration of clinical signs prior to diagnosis, results of diagnostic imaging, whether
or not concurrent surgery was performed and survival. Immunohistochemical expression of cyclo-oxygenase-1
(COX-1) and cyclo-oxygenase-2 (COX-2) was assessed in the tumours of seven cats. Tumour location varied
greatly. The cats had a mean age of 13 years. Three cats had a previous diagnosis of feline idiopathic cystitis of
up to 2008 days duration. Ten of the cats showed clinical improvement (reduction of haematuria and/or dysuria),
with a mean survival time (MST) of 311 days (range 10–1064); 1-year survival of 50%. All seven bladders assessed
for COX staining were COX-1 positive and five were COX-2 positive. The MST for the COX-2-positive cats was 123
days, the MST for the COX-2-negative cases was 375 days.
Accepted: 22 February 2012
Introduction
Transitional cell carcinoma (TCC) is the most prevalent
neoplasm of the urinary bladder in dogs and cats.1,2 The
most common tumour location in dogs is at the trigone.3
However, in the largest study of feline bladder TCC
to date, 55% of 20 tumours occurred at sites distant to
the trigone.4
Several risk factors have been identified in dogs,
including female gender, breed (Scottish Terrier, Shetland
Sheepdog, Fox Terrier, Beagle, West Highland White terrier and Airedale Terriers), obesity, exposure to topical
and environmental insecticides, local industrial activity
and possibly cyclophosphamide treatment.5–9 However,
risk factors are largely unknown in cats, although older
cats and male cats appear to be predisposed.4,10,11
In canine studies, treatment may involve surgery
and/or medical management. Treatment by surgery
alone, using partial cystectomy, resulted in median
survival times (MST) of 8612 and 106 days.13 However,
owing to the trigonal location of TCC in dogs and the
difficulty in achieving complete surgical margins,
several studies have focussed on medical management. Chemotherapy regimes used in dogs with TCC
have included an anthracyclin with a platinum drug;
doxorubicin with cyclophosphamide; intravesicular
thiotepa; carboplatin with piroxicam; cisplatin; mitoxantrone with piroxicam, gemcitabine with piroxicam;
and vinblastine; with MST of 358, 259, 57, 161, <180,
350, 230 and 147 days, respectively.12,14–19 Therapy
with the non-steroid anti-inflammatory drug (NSAID)
piroxicam given alone resulted in an MST of 181 days
in 34 dogs, with six complete/partial remissions and
18 dogs with stable disease.20 Therapy with another
NSAID, deracoxib, given alone resulted in an MST of
323 days in 26 dogs, with four partial remissions and
17 dogs with stable disease.21
1Royal
(Dick) School of Veterinary Studies, Division of Veterinary
Clinical Sciences, The University of Edinburgh, Roslin, UK
2Longacre, Ely, UK
3Bridge Pathology Ltd, Bristol, UK
Corresponding author:
Danièlle Gunn-Moore BSc, BVM&S, PhD, MACVSc, MRCVS,
RCVS Specialist in Feline Medicine, Royal (Dick) School of
Veterinary Studies, Division of Veterinary Clinical Sciences,
The University of Edinburgh, Hospital for Small Animals,
Easter Bush Veterinary Centre, Roslin EH25 9RG, UK
Email: Danielle.Gunn-Moore@ed.ac.uk
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Journal of Feline Medicine and Surgery 14(8)
528
There are few studies on the treatment of TCC of the
urinary bladder in cats, with only 48 confirmed cases
reported in the literature, of which only 31 have accompanying clinical information.4,10,11,22–32 While it is therefore difficult to draw meaningful conclusions as to the
efficacy of different treatment options, the MST in the
largest of these studies (n = 20 cats) was 261 days.4 The
majority of cats that were not treated were euthanased at
the time of diagnosis.4,11,24,31 However, one cat was euthanased after 10 days,32 two cats survived 3 weeks10,27 and
another survived for 276 days4 without specific treatment. Cats treated with surgery alone (n = 5) have survived for between 2 days and 6 months.4,10,11 Eight of the
cats in the study by Wilson et al were treated with surgery alone or with adjunctive therapy; in these cats the
progression-free interval was 89 days.4 Owing to the
demonstrated efficacy of piroxicam in dogs, NSAIDs
have also been investigated for the treatment of TCC in a
small number of cats. Wilson et al demonstrated survival
times of 1, 23 and 208 days with the use of piroxicam
alone in three cats.4
The exact anti-tumour action of piroxicam is
unknown.33 One proposed mechanism is the inhibition
of cyclo-oxygenase 2 (COX-2), as this isoenzyme is overexpressed in various neoplasms, including bladder TCC,
as seen in all 21 dogs in one study.34 However, Beam et al
demonstrated COX-2 expression in only 37% of feline
TCCs,35 suggesting that COX-2 inhibitors may have less
potential as anti-tumour agents in cats compared to
dogs. Meloxicam, rather than piroxicam, was chosen in
the current study for a number of reasons: it is believed
to have more selective inhibition of COX-2 over COX-1
and so may have potentially less gastrointestinal and
renal side effects; it has been shown to inhibit proliferation in cell lines (albeit canine) in a dose-dependent manner similar to piroxicam;33 the authors had experienced
significant side effects when using piroxicam in cats in
their clinic but had, anecdotally, heard of good responses
with meloxicam treatment of feline TCC in other clinics.
Meloxicam is relatively safe for the long-term treatment
of cats,36 even elderly cats with concomitant diseases
(such as osteoarthritis and stable chronic kidney disease);37 it is licensed for long-term use in cats in the UK,
albeit for the treatment of osteoarthritis.
Therefore, the aim of this study was to evaluate
the clinical features and outcome of cats with TCC of
the urinary bladder that were treated with meloxicam.
Additionally, COX expression in TCC samples was evaluated and related to the clinical response to treatment.
Materials and methods
Clinical information
Clinical records were reviewed for all cats that presented
with a urinary bladder mass to the Royal (Dick) School
of Veterinary Studies (RDSVS), University of Edinburgh,
between January 2001 and February 2008. Additional
cases were collected during the same time frame from
UK veterinary practitioners who contacted the RDSVS
for advice. Inclusion criteria included the presence of a
bladder mass identified on radiographic and/or ultrasonographic diagnostic imaging or direct visualisation
at surgery, a diagnosis of TCC based on histopathology
or cytology, a history of medical management with
meloxicam (Metacam; Boehringer Ingelheim) and followup information being obtainable.
Data collected included age at diagnosis, breed, gender, duration of urinary tract-related clinical signs prior
to the diagnosis of TCC and previous diagnoses if
known, clinical signs at presentation, method of diagnosis, location of mass within the urinary bladder and size
of the mass, whether metastases were detected, duration
and dose of meloxicam therapy, history of concurrent
surgical treatment, response to treatment, presence of
concurrent urinary tract infection or evidence of renal
failure, duration of survival and cause of death. The
symptom-free interval (SFI) was defined as the time
from initiation of treatment to the first episode of urinary-tract related signs. This and the MST were calculated using the Kaplan-Meier product limit method.
Information for follow-up was determined by examination of the case records or by email communication with
the referring veterinarians.
COX immunohistochemistry
Archived formalin-fixed, paraffin wax-embedded tissue
blocks, where available, were retrieved from the pathologists who made the original definitive diagnosis. The
original histopathological diagnosis was re-confirmed
by one of the authors (TJS). Any drug treatment (including NSAIDs and glucocorticoids) administered prior to
biopsy was ascertained from medical records.
Positive control samples comprised formalin-fixed,
paraffin wax-embedded normal feline bladder mucosa
and feline fetal kidney stained with antibodies to COX-1
and COX-2, respectively. The choice of control tissues
was based on previous studies.34,38–41 Additionally, bladder tissue from five cats that had been euthanased as a
result of non-urological disease had COX-2 immunohistochemistry performed.
Immunolabelling and scoring were performed using
the technique of Hayes et al41 and briefly comprised
microwaving antigen retrieval at pH 6, followed by automated labelling (Techmate Horizon; LJL Biosystems),
using a standard, two-layer indirect method (EnVision;
DakoCytomation). Chromogen staining was developed
with diaminobenzidine and slides were counterstained
with haematoxylin. Polyclonal rabbit anti-ovine COX-1
antibody (Cayman Chemical) at a 1 in 400 dilution, plus a
negative control comprising normal rabbit immunoglobulin fraction (DakoCytomation), diluted 1 in 8000 was used
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Bommer et al
529
Table 1 Details of the 11 cats included in the study
Surgical
Mean
meloxicam treatment
dose
(mg/kg)
PO q24h
Gender Breed
Patient Age at
diagnosis
(years)
Duration Presenting
signs
of
clinical
signs
related
to the
urinary
tract
(days)
1
10
MN
Siamese
425
2
12
MN
DSH
365
3
14
FN
DSH
154
4
16
FN
DSH
2008
5
15
MN
DSH
14
Haematuria, 0.1
dysuria
NP
6
9
FN
Persian
92
NP
7
18
MN
DSH
0
Haematuria, 0.02
dysuria
None
0.02
8
16
MN
Abyssinian 7
9
10
MN
DSH
7
10
11
15
10
FN
MN
DSH
DSH
7
31
Haematuria, 0.2
dysuria
Haematuria 0.03
Haematuria, 0.05
dysuria
Haematuria, 0.05
dysuria
Haematuria,
dysuria
Acute
urethral
obstruction;
haematuria,
dysuria
Haematuria
Haematuria,
dysuria
Survival
Symptom- COX-2
free interval immunostaining (days)
(days)
NP
116
Positive
120
Partial
cystectomy
Partial
cystectomy
NP
183
Positive
246
243
Negative
375
Haematuria Positive
0;
dysuria 121
Haematuria Positive
28;
dysuria 35
630
Positive
123
35
321
Negative
425
NP
Still alive
at 2065
Still alive
at 321**
493
0
0.05 for 10 Pre-pubic
days
urethrostomy
and partial
cystectomy
NP
76*
0.03
0.02
NP
NP
1064
10
0.01
Partial
cystectomy
NP
NP
Partial
cystectomy
365
7
FN = female neuter; MN = male neuter; DSH = domestic shorthair; NP = not performed
*Censored at 10 days when the treatment was changed to piroxicam
**No recurrence of bladder signs, but died of congestive heart failure at 390 days
for the COX-1 arm. For COX-2 immunolabelling, the primary antibody (Polyclonal Anti-PGHS-2 Human
C-terminus) was diluted 1 in 800. A specific pre-immune
serum (Oxford Biomedical Research), diluted 1 in 800,
was used for negative control purposes. A further negative control was performed for all samples in both the
COX-1 and COX-2 arms, using antibody diluent alone
instead of an immunoreactive fraction. Immunolabelling
was described as focal (a single area), multifocal, patchy
(numerous groups, fairly evenly distributed) or diffuse.
A semi-quantitative estimation of the number of immunolabelled neoplastic cells was made and recorded as <1%,
2–10%, 11–50%, 51–75% and 75–100%. Intensity of labelling was categorised as weak (+), moderate (++) or marked
(+++); relative to the positive control tissue which was categorised as moderate (++). The intensity of labelling in the
nucleus and cytoplasm was recorded separately.
Results
The medical records of 17 cats were examined. Three
were excluded owing to lack of definitive diagnosis of
TCC, one had insufficient clinical history and two cases
were not included because they were not treated with
meloxicam. Details of the 11 cats included in the study
are given on Table 1 (eight domestic shorthair cats, one
Siamese, one Chinchilla Persian and one Abyssinian cat).
All cats were neutered; there were seven (64%) male and
four (36%) female cats. The median age at diagnosis was
14 years (range 9–18 years; mean 13.1 years).
The clinical signs exhibited prior to diagnosis included
haematuria (10/11; 91%), stranguria/dysuria (8/11;
73%) and acute urethral obstruction (1/11; 9%). One cat
had no urinary tract-associated clinical signs; the bladder mass was detected during abdominal ultrasonography performed to investigate vomiting. The median
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Journal of Feline Medicine and Surgery 14(8)
530
duration of urinary-related clinical signs prior to diagnosis was 61.5 days (range 1–2008; mean 310 days).
Three cats had a previous diagnosis of feline idiopathic
cystitis (FIC), based on urinalysis and diagnostic imaging, with intermittent clinical signs from 365, 425 and
2008 days prior to the diagnosis of TCC.
Abdominal contrast radiography and/or ultrasonography were performed in 10 of the cats to determine
bladder mass size, and extent and location of the
mass(es). The remaining cat had TCC characterised
by direct visualisation at exploratory celiotomy.
Radiography was performed in eight (73%) cats and
ultrasonography in seven (64%) cats. Five (46%) cats had
both imaging modalities performed. Tumour location
varied widely between cats, being craniodorsal 4/11
(36%), cranioventral 4/11 (36%), affecting multiple sites
1/11 (9%), causing diffuse thickening of the entire wall
1/11 (9%) and affecting only the trigone area 1/11 (9%).
The trigone was only affected in three (27%) cats.
The diagnosis of TCC was confirmed by histopathology in nine (82%) cats and by cytology of suction
catheter biopsies in two (18%) cats. Two cats had neoplastic transitional cells recorded on urine sediment
examination. One cat had a prior fine needle aspiration
biopsy, which was consistent with the histopathological
diagnosis.
Staging for the presence of metastases was performed
at the time of diagnosis in six cats. Three cats had both
thoracic radiography and abdominal ultrasonography,
two cats had only abdominal ultrasonography and one
cat had only thoracic radiography. No metastases were
detected in any cats at the time of diagnosis.
All cats were treated by oral administration of meloxicam. A mean initial dose of 0.09 mg/kg (range 0.01–0.3)
was given q24h for the first 3–7 days and a mean maintenance dose of 0.04 mg/kg (range 0.01–0.1) was given
thereafter. For 10 (91%) cats, meloxicam was the primary
medical therapy used for treatment of TCC. The cat
with acute urethral obstruction was given meloxicam
0.05 mg/kg q24h for the first 10 days of treatment then
changed to piroxicam (Feldene, Pfizer) 0.3 mg/kg orally
q48h for the following 66 days until euthanasia. This
was instituted because of the severity of disease and the
previously demonstrated efficacy of piroxicam for the
treatment of TCC in dogs.20 That cat also had a cytostomy tube placed followed by pre-pubic urethrostomy
to relieve urinary obstruction. Partial cystectomy was
performed in four cats; surgical margins were reported
as complete for one cat and incomplete in the other
three cats.
Ten of the 11 cats showed clinical improvement. Only
the cat with acute urethral obstruction continued to
show haematuria and dysuria, although its demeanour
did improve. The median SFI was 243 days (range 0–630)
for haematuria and 334 days (range 0–630) for dysuria.
Figure 1 Kaplan-Meier survival curve for the nine cats that
died during this study. Mean survival time was 264 days.
The short vertical lines represent censored cases: cats 6 and
7 as they were still alive at the time of writing, and cat 9 that
was censored at 10 days as treatment was changed from
meloxicam to piroxicam at that point
Possible gastrointestinal side effects were seen as diarrhoea in the cat treated with piroxicam (which resolved
in 24 h after missing one treatment dose) and an episode
of melaena in a meloxicam-treated cat. One cat developed renal failure after 1 week of treatment with
meloxicam and another cat developed renal failure after
6 months of treatment. The first cat had a trigonal tumour
and hydronephrosis, so the azotaemia was likely to have
been obstructive in origin. Two cats had chronic renal
disease at the time of diagnosis, which did not deteriorate appreciably on therapy.
The MST for all 11 cats was 311 days (range 10–1064)
and a 1-year survival of 50% (Figure 1). The MST for
those cats treated by partial cystectomy and meloxicam
375 days was not statistically different from those
treated with meloxicam alone (123 days; P = 0.87).
Death in eight out of the nine cats that died or were
euthanased was related to the TCC; the remaining
patient was euthanased owing to worsening arthritic
pain and reduced mobility (cat 7). For those cats where
death was a result of complications of TCC, five were
euthanased because of recurrence of lower urinary
tract-related clinical signs; two were euthanased owing
to surgical complications [one because of pre-pubic urethrostomy stoma necrosis (cat 9) and the other as a result
of uroperitoneum following partial cystectomy (cat 11)];
one died spontaneously following dyspnoea caused by
pulmonary metastases and neoplastic pleural effusion
(cat 10).
Post-mortem examination was performed in four
(44%) of the cats that were euthanased or died. Three
cats had TCC metastases at the time of death: in the
lungs, kidney and local lymph nodes in one cat, in the
lungs and pleura of another and in the peritoneum of
the third cat.
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Bommer et al
531
Table 2 COX-1 and COX-2 staining of seven of the cases
Immunolabelling characteristics
COX-1
COX-2
Total negative
Total positive
Percentage positive cells
<1%
2–10%
11–50%
51–75%
>75%
Labelling intensity
Nuclear
+
++
+++
Cytoplasmic
+
++
+++
Distribution
Focal
Multifocal
Patchy
Diffuse
0
7
2
5
0
0
1
2
4
5
0
0
0
0
0
2
0
0
0
0
0
6
0
0
5*
0
0
0
1
6
0
2
0
3
*Three cases ++, two cases + to ++
COX immunohistochemistry was performed on TCC
tissue samples from seven (64%) cats (Table 2). The TCC
of all seven cats were COX-1 positive. Five of the TCCs
(71%) were COX-2 positive and two (29%) were COX-2
negative. All of the normal bladder tissue samples from
the five control cats were COX-2 negative. Treatments
administered within 1 month of biopsy sampling for
histopathology included meloxicam (n = 2), meloxicam
and marbofloxacin (Marbocyl; Vétoquinol) (n = 1)
and no medication (n = 2) for the COX-2-positive cats.
One of the COX-2-negative cats received meloxicam
and amlodipine (Istin; Pfizer) and the other received
pentosan polysulphate sodium (Cartrophen Vet;
Arthropharm) and fluoxetine hydrochloride (Prozac;
Eli Lilly). The MST for cats with COX-2-positive
TCC was 123 days and 375 days for cats with COX-2negative TCC.
Discussion
This study is the first to demonstrate the clinical features
and response to meloxicam therapy (plus or minus surgery) of a group of feline patients with bladder TCC. As
this is a relatively rare neoplasm with a paucity of information in the veterinary literature, this study serves
to augment the body of knowledge on feline TCC in general. Our findings agree with other studies in a number
of areas. Our study confirms that feline TCC is a disease
of geriatric cats, with no breed predisposition and a male
bias.4 Also, unlike dogs and humans, our findings
suggest that the majority of feline cases do not involve
the bladder trigone.4,10 Haematuria is the most common
clinical sign, with urination abnormalities, such as dysuria, stranguria and pollakiuria, also being prevalent,4,10
as our results demonstrate.
In previous studies, the median duration of clinical
signs prior to diagnosis was 28 days,11,25,29–32 compared
with 2 months in our case series. Three cats in the current
study had a prior diagnosis of FIC, with clinical signs
having been present over a prolonged period. While it is
important not to over-interpret these findings when the
numbers are so small, it could potentially be speculated
that these were cases of TCC with a very long time course
that had been originally misdiagnosed. However, it would
seem unlikely that a cat with TCC would survive between
1 and 5.5 years. Alternatively, it could be postulated that
the chronic inflammation from FIC predisposed the cats
to the development of TCC. There is a well-documented
link between chronic inflammation and the development
of some cancers in both animals and humans.42
In the current study, cats with TCC that were treated
with meloxicam therapy (with or without surgical extirpation) had a MST of 8 months (311 days). This compares
to canine patients treated with piroxicam having a MST
of 181 days,20 or those treated with deracoxib having a
MST of 323 days.21 Survival times of our cats treated
with meloxicam were similar to those achieved by
Wilson et al (MST 261 days);4 however, their 20 cats were
treated with chemotherapy, piroxicam, surgery or a combination of these modalities, so it is difficult to compare
treatment options as there was an insufficient number
receiving each treatment to allow for direct comparison.
Our data suggest that meloxicam may have a role to
play in the palliative management of TCC in the urinary
bladder of the cat. Further studies will be required to
improve our knowledge of this drug’s efficacy in feline
TCC and to determine whether a combination of NSAIDs
and cytotoxic agents could confer a survival advantage,
as seen in dogs given piroxicam and mitoxantrone
(reported median survival of 291 days).17
Meloxicam inhibits COX enzymes, preferentially
inhibiting COX-2 over COX-1. As COX-2 is overexpressed in many neoplasms, including canine TCC,34
we were interested in investigating whether COX-2 was
over-expressed in the TCCs in our cases and whether
COX-2 expression was associated with a positive
response to therapy with meloxicam. In order to document over-expression, we first had to determine the level
of COX-2 expression in normal feline bladder. None of
the five normal bladder samples showed any COX-2
expression. However, COX-2 was over-expressed in the
majority of our TCC cases (2/7; 71%), which was notably
higher than previously documented (37%).35 The level of
expression was low (<1%), similar to that for feline oral
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Journal of Feline Medicine and Surgery 14(8)
532
squamous cell carcinoma using the same methodology.41
In the month prior to the biopsies being collected, three
of the cats found to be COX-2-positive and one of the
cats found to be COX-2-negative had received meloxicam. These numbers are too small to be able to say
whether or not meloxicam affected COX-2 staining.
The survival time for the meloxicam-treated cats was
longer in COX-2-negative cats compared with COX-2positive cats. Confirmation of this unexpected finding
would require a larger study. If, however, this finding is
supported by future studies, it might indicate that the
potentially beneficial effects of this NSAID may not be
mediated by COX-2-regulated mechanisms. Indeed,
other anti-neoplastic mechanisms of NSAIDs have been
proposed, including the induction of apoptosis, interference with cell-cycle progression, stimulation of immune
surveillance and reduction of carcinogen activation or
anti-angiogenic effects.42,43
In conclusion, we present the details of 11 cats with
TCC affecting the urinary bladder, their clinical presentation and diagnostic findings, and their clinical outcome following treatment with meloxicam (plus or
minus bladder surgery). The cats had a MST of 311 days
which suggests that meloxicam may have a role to play
in the palliative management of TCC in the urinary bladder of the cat
Acknowledgements The authors would like to thank
Ron Lowe, Andrea Harvey, Bridget O’Farrell, Geraldine Hale
(NationWide Laboratories), Caroline Allen, Claire Devitt,
Jeremy Hopkins, Elliot Beattie, Robina Logan and Andy Armitage who provided case material for this report. Thanks also to
Richard Mellanby and Jodi Miller for their technical support.
Funding We would like to thank both The University of
Edinburgh Development Trust and The Animal Health Trust
for funding the immunohistochemistry.
Conflict of interest The authors do not have any potential
conflicts of interest to declare.
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