e358 THE JOURNAL OF UROLOGY姞
4S, Supplement, Monday, May 6, 2013
METHODS: Under isoflurane anesthesia, the distal colon was
ligated at the levels of 40mm and 60mm rostral to the anus, and
polyethylene catheters were inserted in between of two ligations of the
colon and in the bladder from the dome in female Sprague-Dawley rats.
1) We examined changes in colon and bladder activity after the appli-
cation of allyl isothiocyanate (AI, 100mM, 300ul), a TRPA1 activator,
into the colon or bladder in an awake condition. Inhibitory effects of the
pretreatment of HC-030031 (HC, 3mg/kg i.v.), a TRPA1 inhibitor, on
colon-to-bladder cross-sensitization induced by AI instilled in the colon
were also examined. 2) We examined whether colon-to-bladder cross-
sensitization was mediated by the hypogastric (sympathetic) or pelvic
(parasympathetic) nerves using bilateral hypogastric or pelvic nerves
transection near the internal iliac vessels.
RESULTS: 1) Intercontraction intervals during continuous sa-
line infusion (0.04ml/min) into the bladder were significantly decreased
90 min after the intracolonic AI application, which significantly in-
creased the baseline pressure in the colon (colon-to-bladder cross-
sensitization). On the other hand, intracolonic baseline pressure was
significantly decreased 30 min after the intravesical AI application,
which significantly increased the baseline pressure in the bladder. In
addition, colon-to-bladder cross-sensitization was completely inhibited
by the i.v. pretreatment of HC. 2) Colon-to-bladder cross-sensitization
via TRPA1 stimulation in the colon was induced in the animals with the
hypogastric nerves transection, but not in those with the pelvic nerves
transection.
CONCLUSIONS: These findings suggest that colon-to-bladder
cross-sensitization via TRPA1 stimulation in the colon is mediated
through the pelvic nerves innervating the colon. However, the TRPA1
receptor expressed in the bladder does not seem to participate in
bladder-to-colon cross-sensitization.
Source of Funding: Department of Defense grant PR110326
868
PHENOTYPE DIRECTED MANAGEMENT OF INTERSTITIAL
CYSTITIS/BLADDER PAIN SYNDROME
J. Curtis Nickel*, Karen Irvine-Bird, Kingston, Canada;
Daniel Shoskes, Cleveland, OH
INTRODUCTION AND OBJECTIVES: A flexible therapeutic
strategy for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) pa-
tients using an individualized phenotype directed treatment plan based
on clinically based UPOINT categorization has been advocated, in-
stead of the traditional algorithmic approach. We initiated such a
treatment plan in our specialized IC/BPS clinic and have assessed the
benefits in our patients during the first two years since implementation.
METHODS: Consecutive patients diagnosed with IC/BPS re-
ferred to a specialized tertiary IC/BPS clinic with at least one follow-up
post-treatment visit (patients assessed for consultation only were ex-
cluded) were categorized according to their UPOINT status (Urinary,
Psychosocial, Organ Specific, Infection, Neuropathic/non-bladder,
Tenderness of pelvic floor) were treated according to previously pre-
sented and published individualized phenotype based treatment plan.
Patients were assessed at baseline and up to 2 years with validated
symptom scores (interstitial cystitis symptom score or ICSI; pain ur-
gency frequency questionnaire or PUF), as well as pain and voiding
assessments.
RESULTS: Follow-up visit data was available for 93 patients
(mean age 45.2; median age 44 years; mean ICSI 13.2 ⫹/⫺3.6).
Patients reported a median of 4 UPOINT domains (mean 3.7 ⫹/⫺.94)
with the following distribution: U⫽100%; P⫽31.5%; O⫽97.8%;
I⫽45.6%; N⫽40%; T⫽55.4%. The mean decrease in ICSI was 3.3
points while the mean percentage decrease was 21.8%. Major clinical
improvement (⬎50% decrease in ICSI) was observed in 30.4% while
47.8% were significantly improved (⬎30% decrease in ICSI) compared
to initial baseline visit. PUF, pain and urgency scoring changes were
comparable. No correlation between number of domains and ICSI
decrease was observed.
Vol. 189, No.
CONCLUSIONS: Almost 50% of previously treated patients
referred to a tertiary IC/BPS clinic, regardless of complexity of condition
(measured by number of UPOINT domains) experienced clinically
significant improvement using an individualized phenotype directed
therapeutic approach.
Source of Funding: None
869
TREATMENT RESPONSE TO NEUROMODULATION IN
INTERSTITIAL CYSTITIS/PAINFUL BLADDER SYNDROME
(IC/PBS) PATIENTS ACCOMPANY DECREASE IN URINE
CHEMOKINES
Michael Chancellor*, Royal Oak, MI; Pradeep Tyagi, Pittsburgh, PA;
Jayabalan Nirmal, Don Bui, Kenneth Peters, Royal Oak, MI
INTRODUCTION AND OBJECTIVES: Chemokines are re-
sponsible for paracrine signalling within bladder and for also assisting
in the communication between bladder and neurons innervating blad-
der. Therefore, we hypothesized that chronic neuromodulation from
InterStim implant at the spinal cord level in IC/PBS patients will cause
downstream changes in chemokine signalling, which will be reflected in
the differences of chemokine levels measured at the baseline and at
end of treatment.
METHODS: Patients with confirmed diagnosis and long history
of IC/PBS undergoing Interstim were consented for this study. Mid-
stream urine and symptom scores IC symptom problem index(ICSPI
index) were collected at baseline and at 24 weeks after implant.
Collected urine was analyzed for presence of cytokines and chemo-
kines by Luminex xMAP analysis.
RESULTS: Urine chemokine and symptom score data at base-
line and at 24-week was obtained from 16 and 7 subjects, respectively.
At baseline, urine levels of CXCL-1 positively correlated with pain score
(Pearson r⫽0.63, p⫽0.009), urgency (r⫽0.61, p⫽0.01), ICSPI (r⫽0.43,
p⫽0.09) and number of daily voids(r⫽0.44, p⫽0.08). ICSPI and pain
scores also positively correlated with sIL-1RA (r⫽ 0.50, p⫽ 0.04) and
CCL2 positively correlated with daily voids (r⫽ 0.45, p⫽ 0.07). The
median ICSPI index after interstim implant fell from 28 to 14 at 24
weeks (Student’s t test, p⫽0.008, n⫽7). Levels of sIL-1ra (1098⫾452.4
vs 242.2⫾122pg/ml) and MCP-1 (532.4⫾140.7 vs 161.7⫾64.26 pg/ml)
were also significantly reduced at 24 weeks relative to baseline
(p⫽0.04). Multivariable analysis of data revealed that sIL-1ra and
MCP-1 together explained majority of variance in data. Levels of
CXCL-1, CXCL-10, CCL5 (RANTES), IL-8, VEGF, PDGF were also
reduced at 24 weeks, but differences were not significant due to
variability among patients. Lower chemokine levels correlated nega-
tively with ICSPI index at 24 weeks without any statistical significance.
CONCLUSIONS: IC/PBS patients responding favorably to neu-
romodulation showed a corresponding decrease in urine levels chemo-
kines. These results support our hypothesis for the action of chemo-
kines as downstream effectors of neuromodulation response in
bladder, which when secreted into urine can serve as non-invasive
treatment predictors.
Vol. 189, No. 4S, Supplement, Monday, May 6, 2013
Source of Funding: Society of Urodynamics and Female
Urology (SUFU) Neuromodulation Research Grant
870
WHAT HELPS AND WHY? PREDICTING PATIENT OUTCOMES IN
INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME (IC/BPS)
WITH PAIN APPRAISALS AND BEHAVIOURAL COPING
STRATEGIES
Dean A. Tripp*, J. Curtis Nickel, Jillian Mulroy, Laura Katz, Kingston,
Canada; Michel Pontari, Philadelphia, PA; Robert Moldwin, New
York, NY; Mayer Robert, Rochester, NY; Lesley Carr, Toronto,
Canada; Ragi Doggweiler, Knoxville, TN; Claire Yang, Seattle, WA;
Nagendra Mishra, Ahmedabad, India; Jorgen Nordling, Herlev,
Denmark
INTRODUCTION AND OBJECTIVES: IC/BPS is a chronic pel-
vic pain syndrome. Our previous IC/BPS analysis correlated pain,
quality of life (QoL), and psychosocial adjustments with other associ-
ated conditions[1], and catastrophizing and behavioural coping strate-
gies (sedentary resting in reaction to pain) have been found to predict
pelvic pain outcomes for men and women.[2-5] However, no study has
examined a comprehensive list of pain appraisal and behavioural
coping strategies as mechanisms in the relationship between pain and
QoL in these patients. From a self-regulation perspective, appraisals
and coping responses of patients suffering from IC/BPS are important
in advancing patient management.
METHODS: Female patients with IC/BPS (n⫽190) were re-
cruited from tertiary care urology clinics and completed questionnaires
(demographics, O’Leary Sant, McGill Pain Questionnaire, SF12,
Chronic Pain Coping Inventory, Pain Catastrophizing Scale). The data
was examined for univariate and multivariate normality, and a missing
values analysis was conducted. Associations of validated pain apprais-
als (e.g., catastrophizing) and behavioural coping strategies (e.g.,
illness focused coping) with outcomes of pain and QoL in IC/BPS were
examined. Factor reduction was conducted and resulting variables
were input into multivariable mediation models.
RESULTS: Patients ranged in age from 21-89 years (M⫽49.8,
SD⫽14.83), were predominantly White (93.7%), with the majority
(73%) in a relationship (married or living with partner). Factor analytic
analyses revealed a 4-factor solution for these variables (catastroph-
izing, illness-focused behavioural coping, cognitive coping, and depres-
sion), which were used for subsequent mediation analyses. Multivari-
able mediation analyses for mental QoL showed catastrophizing
(P⬍.0001) was a full and unique mediator of the effect of pain on
mental QoL. For physical QoL, illness-focused behavioural coping (i.e.,
rest/avoidance, seeking assistance)(P⬍.0001) was a partial and
unique mediator between patient pain and physical QoL.
CONCLUSIONS: These results suggest that catastrophic ap-
praisals and illness-focused behavioural coping act as mechanisms
driving the negative association between pain and QoL indices. In fact,
THE JOURNAL OF UROLOGY姞 e359
the catastrophizing mediation effect supports the hypothesis that symp-
toms may become mentally disabling through the cognitive mecha-
nisms. These results further support an expanding science emphasiz-
ing the importance of biopsychosocial pain/QoL models in Urology.
Source of Funding: None
871
EFFECT OF HERPES SIMPLEX VIRUS (HSV)
VECTOR-MEDIATED INTERLEUKIN 4 GENE THERAPY ON
ENHANCED BLADDER PAIN BEHAVIOR IN RATS WITH
CYCLOPHOSPHAMIDE (CYP)-INDUCED CYSTITIS
Tomohiko Oguchi*, Nagano, Japan; Hitoshi Yokoyama,
Yasuhito Funahashi, Pittsburgh, PA; Osamu Nishizawa, Matsumoto,
Japan; Satoru Yoshikawa, William F Goins, James R Goss,
Joseph C Glorioso, Naoki Yoshimura, Pittsburgh, PA
INTRODUCTION AND OBJECTIVES: Bladder pain syndrome/
interstitial cystitis (BPS/IC) is a serious disease whose main symptoms
are bladder pain and frequent urination. We examined whether sub-
acute chemical cystitis increases pain behavior induced by nociceptive
bladder stimuli and whether gene therapy using replication-deficient
HSV vectors expressing an anti-inflammatory cytokine IL-4 (S4IL4) in
the bladder can suppress bladder overactivity and bladder pain behav-
ior enhanced by chemical cystitis.
METHODS: (1) Saline or CYP (200mg/kg, i.p.) was injected to
female SD rats (n⫽5 each). Two days later, in a conscious condition,
0.3␮M RTx (0.3ml, 1 min) was injected to the bladder through a urethral
catheter to evaluate nociceptive behaviors such as licking (lower ab-
dominal licking) and freezing (motionless head-turning), which were
counted and recorded every 5 seconds for 15 minutes. Urine volume
and frequency were recorded simultaneously. (2) The S4IL4 (3.9⫻109
pfu/ml) or LacZ-expressing control vector, (SHZ, 5⫻108 pfu/ml) in 20␮l
of viral suspension was injected to the bladder wall (n⫽6 each). Twelve
days later, CYP (200mg/kg, i.p.) was injected to HSV-treated rats to
induce chemical cystitis, Two days later, in a conscious condition,
0.3␮M RTx (0.3ml, 1 min) was instilled to the bladder to induce
nociceptive behavior. Urine volume and frequency were recorded si-
multaneously.
RESULTS: (1) After RTx stimulation, freezing, indicative of
bladder-related pain behavior, was significantly increased in CYP cys-
titis rats compared to control (13⫾5 vs. 72⫾17 times, p⬍0.001).
Average voided volume per micturition after RTx was also significantly
decreased in CYP cystitis rats compared to control (0.61⫾0.08 vs.
0.2⫾0.03 ml, p⬍0.01). (2) RTx-induced freezing behavior was signifi-
cantly less in S4IL4-treated CYP rats by 72% than in SHZ-treated CYP
rats (24⫾3 vs. 87⫾10 times, p⬍0.01). Average voided volume after
RTx was significantly greater in S4IL4-treated CYP rats than in SHZ-
treated CYP rats (0.55⫾0.14 vs. 0.28⫾0.08 ml, p⬍0.05).
CONCLUSIONS: In subacute chemical cystitis, low concentra-
tion RTx, which usually does not elicit pain behavior in normal rats,
induced bladder pain behavior and reduced bladder capacity, indicating
bladder hypersensitivity after cystitis. HSV vector-mediated IL-4 gene
therapy reduced bladder overactivity and pain behavior in this cystitis
model, suggesting that anti-inflammatory IL-4 gene therapy could be a
new strategy for treating bladder pain and/or urinary frequency in
patients with BPS/IC.
Source of Funding: NIH DK57267, DK88836 and P01
DK44935