AUA 2013 Relevant Abstracts

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AUA 2013 Relevant Abstracts

Post by webslave »

Pretty good crop this year. Things seem to be moving in the right direction. Infection theorists nowhere to be seen, need for muscle and nerve focus becoming more apparent, commonality of CP/CPPS and IC starting to be accepted.
Urine Chemokines Reflect Contribution Of Bladder In The Symptoms Of Chronic Prostatitis
Pradeep Tyagi; Kim Killinger; Gregory McLennan; Jayabalan Nirmal; Naoki Yoshimura; Michael Chancellor; Kenneth Peters

Introduction and Objectives
The present study postulates that the pathophysiology of NIH category III Chronic Prostatitis (CP) or Chronic Pelvic Pain Syndrome (CPPS) may not be as prostate centric as for NIH categories I and II CP/CPPS. A preclinical study from our group recently reported sensitization of bladder afferents following induction of localized inflammation in prostate. Therefore, we hypothesized a contribution of bladder in the cardinal symptoms of NIH category III CP/CPPS patients which was assessed by levels of inflammatory cytokines/chemokines in their urine collected without expressing prostate.

Methods
At baseline, urine was collected from 21 patients fulfilling the NIH definition of CP/CPPS without digital rectal exam or any other physical manipulation of prostate. 14 CP/CPPS patients consented to a prospective open-label, one arm 12 week therapy (NCT00701311) of PDE4 inhibitor and urine was collected at multiple visits and frozen during therapy and at 16 week followup. Urine from age matched 10 male asymptomatic subjects was also collected to serve as controls. Frozen specimens were analyzed after thawing ( 50µL by MILLIPLEX MAP immunoassay.

Results
Urine dipstick done after each urine collection to rule out presence of urinary infection. Compared to controls, the urine levels of CXCL-1, IL-8, CXCL-10 and CCL5 (RANTES) were significantly (5-20 fold) elevated in CP/CPPS (Mann-Whitney U test; p<0.05)(attached fig). Higher levels of CXCL-10 (169.8 ± 46.38 vs. 31.45 ± 16.83pg/mL) and lower levels of sIL-1RA (43.10 ± 9.66 vs. 128.7 ± 49.37pg/mL) in CPPS relative to controls suggest involvement of T-lymphocytes in concert with chronic inflammation. Bivariate and multivariate association of improved symptom scores (Chronic Prostatitis Symptom Index (CPSI), visual analog scale (VAS) following PDE4 treatment demonstrated a strong correlation with reduced urine levels of CXCL-10, CXCL-8, CCL5, CCL2 and PDGF (Pearson r =0.83- 0.97; p<0.05).

Conclusions
These results support the consensus of CP/CPPS as a regional syndrome and akin to results from pre-clinical study, treatment associated reduction in urinary chemokines reveal a molecular contribution from bladder in the genesis of symptoms. Urine chemokines can be useful in monitoring patient response to new therapeutic intervention for CP/CPPS.

Understanding the Mechanistic Role of Pain Appraisals and Behavioural Coping Strategies between Pain and Quality of Life in Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS)
Dean A. Tripp; J. Curtis Nickel; Adrijana Koljuskov; Daniel Shoskes; Michel Pontari; Mark S. Litwin; Mary F. McNaughton-Collins

Introduction and Objectives
Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is characterized by pelvic pain and is largely refractory. Studies have correlated pain, depression, catastrophizing and sedentary behavior on quality of life (QoL) or pain, showing the saliency of psychosocial factors. However, no study has examined a comprehensive list of pain appraisal and behavioural coping strategies as mechanisms in the relationship between pain and QoL. From a self-regulation model, understanding how appraisals and coping interact with outcomes like pain and QoL are important in advancing patient management.

Methods
Men (n=168) previously enrolled in the NIH Chronic Prostatitis Cohort study in North American tertiary care centers (6-U.S., 1-Canada) completed a one-time survey of validated self-report measures (QoL:SF-12; demographics; pain: McGill; behavioural pain coping:CPCI; catastrophizing:PCS; Social Support:MSPSS). Data were examined for normality and missing values. Associations of validated pain appraisals (Catastrophizing) and behavioural coping (Illness-focused coping) with outcomes of pain and QoL were examined. Multivariable mediation models tested mediation roles between pain and QoL.

Results
Multivariable mediation analyses for the relationship between pain and physical QoL was run with mediators of Illness-Focused Coping (IF-coping), Wellness-Focused Coping (WF-coping), Social Support and Catastrophizing showing that only IF-coping was a significant mediator of this relationship (<.001). Follow-up analyses of subscales for IF-coping (Guarding, Resting, Asking for Assistance, Medication Use) showed Guarding was a unique mediator. Mediation analyses between pain and mental QoL was run with mediators of IF-coping, Social Support and Catastrophizing showing support and catastrophizing were significant mediators (<.001). Subscale follow-ups for support (Family, Friends, Significant Other) and Catastrophizing (Rumination, Magnification, Helplessness) showed Friends and Helplessness were unique mediators.

Conclusions
These results suggest that IF-coping, Helpless Catastrophic pain appraisals and Friends act as mechanisms that drive and buffer the negative association between pain and QoL indices. Due to the nature of these associations, the hypothesis that symptoms may be physically and mentally disabling through behavioural, cognitive and environmental mechanisms is supported.

Etiologic Evaluation of Erectile Dysfunction in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Gregory Lieser; Daniel Shoskes

Introduction and Objectives
A high proportion of men with Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH category III prostatitis, complain of erectile dysfunction (ED). The etiology of ED in these patients is not known. We present a cohort of patients with ED and CP/CPPS evaluated with hormonal, endothelial and vascular hemodynamic tests and correlated these findings with their symptom severity and disease phenotype.

Methods
A cohort of patients with both ED and CP/CPPS who completed full ED evaluation was identified from our Men's Health Registry. None had ED prior to developing CP/CPPS. The CP/CPPS phenotype was determined clinically using the UPOINT system. International Index of Erectile Function (IIEF) and NIH Chronic Prostatitis Symptom Index (CPSI) scores assessed symptom severity. Patients had color penile Doppler with pharmacologic erection, Endopat measurement of peripheral arterial tone (PAT) plus free and total serum testosterone.

Results
A total of 10 patients met all criteria, with a mean age of 32.9 (range 19-43). There was no correlation between severity of ED or CPPS symptoms by IIEF (mean 32 +/- 8.7) and CPSI (mean 20.9 +/-4.2) scores. One patient had a marginally low total testosterone (260 ng/dl, mean of group 478). Three patients had abnormal PAT (suggesting early systemic arterial disease). Four patients had abnormal penile hemodynamics: 3 with decreased arterial flow (peak systolic velocity < 30 cm/s), 1 with veno-occlusive disease (end diastolic velocity > 5 cm/s) and 1 patient with both arterial and venous disease. In this young cohort, age did not correlate with vascular findings. Interestingly, both patients with veno-occlusive disease were positive for the pelvic floor Tenderness domain in their UPOINT phenotype and all 3 patients with decreased arterial penile blood flow were positive for both Tenderness and Psychosocial (depression or catastrophizing) domains (p=0.03 by Fisher Exact test).

Conclusions
Most young men who develop ED as a complication of CP/CPPS have normal hormonal and hemodynamic testing, suggesting a psychogenic cause related to pain and/or stress. There is however a smaller but potentially significant group with abnormal hemodynamics that may point to increased cardiac risk. This association between abnormal hemodynamics and pelvic floor spasm may suggest an etiologic link and could support the benefit of pelvic floor physical therapy for ED in those CP/CPPS patients positive for the domain in their UPOINT phenotype.

Prostate-to-bladder afferent cross-sensitization as a mechanism inducing bladder overactivity in prostatic inflammation
Yasuhito Funahashi; Ryosuke Takahashi; Pradeep Tyagi; Momokazu Gotoh; Naoki Yoshimura

Introduction and Objectives
Patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) often exhibit irritative bladder symptoms despite no evidence of bladder inflammation. We previously reported that afferent cross-sensitization between prostate and bladder is a possible mechanism for this association (2012 AUA). The present study investigated the effects of prostatic inflammation on bladder activity and afferent nerve function using a rat model of nonbacterial prostatitis.

Methods
Male SD rats were injected with formalin into the ventral lobes of the prostate. Voiding behavior and conscious cystometry were evaluated after 1 week. Histological analyses (H&E staining, toluidine blue staining, and NGF immunostaining) and ELISA for inflammation-related proteins were performed for the bladder and prostate. Fluorescent dyes (DiI and Fast Blue [FB]) were injected into the prostate and bladder wall, respectively to identify organ-specific afferent neurons. Dye-labeled neurons in S1 dorsal root ganglia (DRG) were dissected using laser-capture microdissection methods, and mRNA levels of TRP receptors and ATP receptors were measured by real-time RT-PCR. Patch-clamp recordings were also performed in capsaicin-sensitive FB- and double-labeled neurons dissociated from L6-S1 DRG.

Results
Prostatitis rats exhibited bladder overactivity as evidenced by decreased single voided volume (metabolic cage) and intercontraction intervals (cystometry). H&E staining showed inflammation restricted inside the prostate, but not in the bladder. The number of activated mast cells and NGF expression increased in the bladder of prostatitis rats. MPO activity, IL-1α, IL-1β, and IL-6 in the formalin-injected prostate was increased, but not in the bladder. TRPV1, TRPA1 and P2X2 mRNA were increased in DiI, FB and double-labeled neurons compared to non-labeled neurons. Patch-clamp recordings showed hyperexcitability of FB- and double-labeled afferent neurons as evidenced by significant increases in spike firing frequency during membrane depolarization and capsaicin-induced inward currents.

Conclusions
Formalin-induced inflammation localized in the prostate induces bladder overactivity associated with increases of bladder mast cell activation and NGF, and enhances functional properties of not only dichotomized afferents, but also bladder afferent neurons. Prostate-to-bladder afferent cross-sensitization through dichotomized afferents following prostatic inflammation is a potential mechanism inducing bladder overactivity in CP/CPPS

Comparison Of Baseline Urologic Symptoms In Men And Women With Interstitial Cystitis/Bladder Pain Syndrome Or Chronic Prostatitis/Chronic Pelvic Pain Syndrome
J. Quentin Clemens; Daniel J. Clauw; Karl J. Kreder; John N Krieger; John W Kusek; H. Henry Lai; Larissa V. Rodriguez; David Williams; Xiaoling Hou; Alisa Stephens; J. Richard Landis

Introduction and Objectives
The clinical features characteristic of interstitial cystitis/ bladder pain syndrome (IC/BPS) are similar to those of chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS). However, no studies have directly compared the clinical characteristics of these syndromes in men and women.

The National Institutes of Health Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) network was established in part to apply novel phenotyping strategies to these conditions. To address one of the hypotheses of the network, that IC/BPS and CP/CPPS represent the same underlying condition, we compared baseline demographic and urologic symptoms in men and women.

Methods
A total of 186 men and 254 women with IC/BPS or CP/CPPS were recruited from six clinical centers across the United States. All subjects underwent an intensive in-person phenotyping evaluation that included demographic data and symptom characteristics and severity.

Results
After adjustment for age, income and symptom duration, most measures of symptom severity were similar across genders (Table). Mean scores for the IC Symptom Index, IC Problem Index and AUA Symptom score were significantly higher in women than men. The most bothersome single symptom in men was pain in the pubic or bladder area (34%), perineal pain (23%), and urinary frequency (17%), while the most bothersome symptom in women was pain in the pubic or bladder area (59%) and urinary frequency (14%).

Conclusions
Numerous studies have described symptoms of patients with either IC/BPS or CP/CPPS. However, this is the first study to prospectively recruit men and women with both urologic pain syndromes and to compare these syndromes using the same instruments. Our findings confirm the similarities between these syndromes. Additional information about the pathophysiology of these symptoms is needed to determine if these common urologic pain syndromes truly represent the same underlying condition.

Application of State-of-the-Art Methods to Search for Microbial Contributions to the Etiology of Urological Chronic Pelvic Pain Syndrome (UCPPS)
J. Curtis Nickel; Alisa Stephens; Jun Chen; Rachael Melton-Kreft; Tracy Spirk; Josh Earl; Mary O'Toole; J. William Costerton; Adrie vanBokhoven; Chris Mullins; Garth Ehrlich

Introduction and Objectives
The presence of microorganisms or an imbalance of the microbial ecology of the lower urinary tract has been implicated in UCPPS. We used culture-independent molecular methods to identify the microbiota of the lower urinary tract in men and women with UCPPS.

Methods
Uniformly collected urine specimens were obtained in UCPPS and age matched healthy controls (including positive controls with CFS, FM, IBS). Specimens were tested by Ibis T-5000 Universal Biosensor using BAC plate assay. Mass spectometric technology measures unique molecular weights of multiple DNA amplicons generated by PCR to detect the presence and identify the species of all bacteria. Differences in species composition for cases versus controls were assessed using 'distance measure' methods from microbial ecology. PERMANOVA and Cochran-Mantel-Haenszel methods were used to test differences by cohort type in the presence and/or richness of species. Testing, adjusted for sex, was completed for differences in overall composition at the species, genus, and gram-stain level.

Results
Baseline urine specimens were obtained from 257 cases (161 female; 96 male) and 261 controls (164 female; 97 male). A total of 136 species (57 genera) were detected in VB1; VB2 contained 109 species (52 genera). Mean VB2 species count per person was 2.50 and 2.29 among female UCPPS patients and controls respectively; 1.33 and 1.08 for males respectively. Trends were similar for VB1. Overall species composition was not significantly associated with cohort type at any level (p=0.198, 0.612 species level, p=0.313, 0.085 genus level, p=0.279, 0.086 Gram-stain level in VB1 and VB2, respectively). At the species level in VB1, Lactobacillus gasseri and Streptococcus pneumoniae were more prevalent among cases than controls, while Staphylococcus capitis/caprae was underrepresented among cases (OR=3.74, p=0.007 L. gasseri, OR=0.263, p=0.011 S. capitis/caprae, OR=3.45,p=0.007 S. Pneumoniae). VB1 samples among cases were also more likely to have gram-negative organisms than controls (OR=1.88, p=0.008), For VB2 the only statistical difference observed was at the genus level for Corynebacterium (lower prevalence among UCPPS patients compared to controls OR=0.34, p=0.011).

Conclusions
Despite observing some provocative trends, we did not find significant differences in the microbiome detected in lower urinary tract urine specimens from men and women with UCPPS compared to controls using state-of-the-art detection methods.

Impact Of Symptom Duration On Baseline Characteristics Of The Multidisciplinary Approach To Pelvic Pain (Mapp) Study Cohort
Larissa Rodriguez; Alisa Stephens; JQuentin Clemens; Claire Yang; Henry Lai; Deborah Buchwald; Cate Bradley; John Krieger

Introduction and Objectives
Symptom severity in patients with urologic chronic pelvic pain syndromes (UCPPS), has been associated with symptom duration. Compared with the general population, UCPPS patients have higher rates of other somatic syndromes, such as fibromyalgia (FM), irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS), and mental health comorbidities. We hypothesized that UCPPS patients with longer duration of symptoms would also be more likely to report these comorbid conditions. We evaluated cross-sectional associations between symptom duration and 1) symptom severity, and 2) presence of other somatic syndromes and mental health symptoms.

Methods
Baseline data were analyzed from the MAPP Epidemiology and Phenotyping Study, a NIH-sponsored multi-center observational study of patients with UCPPS. Patients were stratified by symptom duration as a discrete (< or >= 2 years) or continuous variable. Symptom severity was assessed by the Genitourinary Pain Index (GUPI), the IC Symptom and Problem Index, and Likert scales for pelvic pain, urgency and frequency. Depression and anxiety were evaluated with the Hospital Anxiety and Depression Scale (HADS) and stress with the Perceived Stress Scale (PSS).

Results
442 participants were included. Males (not females) with symptoms >= 2 years had more severe symptoms than those with < 2 years (p<0.05). When evaluating symptom duration as a continuous variable, adjusting for age and gender, there was an increase in GUPI total and GUPI pain subscale scores for each additional year of symptoms (p<0.01). Females were 62% more likely than males to have other somatic syndromes (p<0.03). On multivariable analysis, there was a significant increase in the likelihood of patients experiencing CFS (1.043/yr) and FM (1.041/yr), but not IBS for each additional year of UCPPS symptoms (p<0.015).

Conclusions
Females with UCPPS symptoms <2 years experienced more severe urinary symptoms, higher levels of stress, anxiety and depression than males with symptoms <2 years. Symptom duration was associated with increased severity of urinary symptoms and risk for concomitant somatic disorders. These findings point to gender-specific differences in the likelihood of comorbid conditions and symptom severity in UCPPS patients with longer symptom duration.

The Efficacy of Mirodenafil for Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Middle Aged Patients
Hyun Jun Park; Nam Cheol Park; Tae Nam Kim; Jong Kil Nam

Introduction and Objectives
It has been speculated that PDE5 inhibitors may have an effect on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Mirodenafil is a newly developed, novel pyrrolopyrimidinone compound, which is a potent, reversible, and selective oral PDE5 inhibitor. The aim of this study was to investigate the efficacy of mirodenafil in middle aged patients with CP/CPPS.

Methods
Eighty-eight men with CP/CPPS were randomized, in a single-blind fashion, to receive either levofloxacin (500mg/d)(group 1; 40 patients) or levofloxacin (500mg/d) and mirodenafil (50mg/d)(group 2; 48 patients) for 6 weeks. The International Prostate Symptom Score (IPSS), NIH chronic prostatitis symptom index (NIH-CPSI) and erectile function (EF) domain scores of the International Index of Erectile Dysfunction (IIEF) questionnaire were used to grade the symptoms at the baseline and 6 weeks into the study.

Results
The mean ages of the two groups were 44.2±6.9 and 45.3±7.0 years, respectively. There was no significant difference between group 1 and 2 with regard to age, duration and scores of IPSS, NIH-CPSI and IIEF-EF domain at the baseline. Mirodenafil significantly improved the mean change from baseline in the IPSS at 6 weeks (group 1; -1.1 vs. group 2; -4.3, p<0.05). Significant improvements were also seen in the IPSS voiding subscore (group 1; -0.7 vs. group 2; -3.0, p<0.05). Larger changes from the baseline in the NIH-CPSI at 4 weeks were observed in group 2 (group 1; -3.2 vs. group 2; -7.2, p<0.05). Significant improvements were also seen in the NIH-CPSI voiding domains (group 1; -0.5 vs. group 2; -1.7, p<0.05) and the QoL domains (group 1;-1.0 vs. group 2;-1.8, p<0.05). Group 2 showed a greater increase in the IIEF-EF score and this difference was significant (group 1; +0.2 vs. group 2; +7.8, p<0.05). Commonly reported (1 case or greater) treatment adverse events in group 2 were frequent erections, dyspepsia, and headache (for each, 2 cases or less); however, no patient discontinued treatment due to adverse events.

Conclusions
Mirodenafil 50mg once daily was well tolerated and showed significant symptomatic improvements in middle aged patients with CP/CPPS.
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Wolfcub
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Re: AUA 2013 Relevant Abstracts

Post by Wolfcub »

Thanks for the gathering. I strongly believe my condition has something to do with immune dysfunction affecting nerves. More clinical biomolecular researches are needed.

(Not only has the infection hypothesis been abandoned but also the prostatic calcifications' one)
Age: 30 | Onset Age: 19| Symptoms: Urinary frequency, Urinary urgency, constant 24/7 sensation in the penis (in the tip mainly - burning/pressure/discomfort/"wetness"), Nocturia, discomfort and pressure in the pelvic region radiating to the abdomen and becoming severe as time passes since last urination (resolved in 2014 by myofascial release), Stream velocity is somewhat slow and prolonged with an average velocity of ~13cc/min (and max 18cc/min) found in flowmetry test when bladder is filled with 500cc at age 25 (I always feel like I need to press my abdomen to urinate, improved later on when using alpha blockers)| Helped By: especially MYOFASCIAL RELEASE (especially in the areas of hips and abdomen) - generally resolved my abdominal aches, but penile symptoms remained the same| Worsened By: Coffee and possibly some other food as well| Other comments: Quercetin and acupuncture helped me no more than a placebo effect. Age 25-26: Diagnosed with indirect inguinal hernia and medium hydrocele at the same side. After operation many of the acute symptoms disappeared, but the chronic urinary and pelvic symptoms remained much the same.
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