Non-infectious Cystitis Research Articles

Management Strategies for Patients with Non-Infectious Cystitis: A Review of the Literature.

The management of noninfectious cystitis continues to evolve as new treatments continue to be developed and investigated. This review aims to synthesize the most recent data regarding management strategies for noninfectious cystitis focused on non-ulcerative, ulcerative, eosinophilic, and ketamine-induced cystitis. Several novel treatments have shown promise as management options including combination antihistamine therapy, phosphodiesterase 5 inhibitors, alpha lipoic acid supplements, and onabotulinumtoxin A. Recent studies have also found pentosan polysulfate sodium to have adverse ophthalmologic effects. For patients with ulcerative cystitis, recent research has shown that fulguration with or without triamcinolone injections should not be delayed. The treatment of noninfectious cystitis should be patient specific based on factors including etiology and symptom profile. Multimodal regimens are often the most effective. Treatment should be started with conservative options and escalated as necessary to oral treatments, intravesical options, or procedural management.

Destroyed bladders: Characterization of progressive inflammatory cystitis.

We identified a subset of patients with noninfectious cystitis who develop refractory symptoms marked by diffuse inflammatory changes, reduced bladder capacity, and vesicoureteral reflux (VUR), termed here as "progressive inflammatory cystitis" (PIC). Our objective was to describe the phenotype, disease outcomes, and pathologic findings of PIC. A single institution retrospective cohort study of patients with PIC. Patients with a history of pelvic radiation, urologic malignancy, or neurogenic bladder were excluded. We describe cohort characteristics and use bivariate analyses to compare subgroups. Kaplan-Meier methods estimate time to urinary diversion. From 2008 to 2020, 46 patients with PIC were identified. The median age of symptom onset was 63 years old (interquartile range [IQR]: 56, 70) and the most common presenting symptoms were urinary urgency/frequency (54%) and incontinence (48%). Urodynamics showed a median maximum bladder capacity of 80 mL (IQR: 34, 152), commonly with VUR (68%) and hydronephrosis (59%). Ultimately 36 patients (78%) underwent urinary diversion at a median of 4.5 years (IQR: 2, 6.5) after symptom onset. Significant pathologic findings include presence of ulceration (52%), acute and chronic inflammation (68%), including eosinophils (80%), lymphoid follicles (56%), and mast cells in both lamina and muscularis propria (76%). PIC is a newly defined entity characterized by significantly diminished bladder capacity, upper tract changes, and relatively quick progression to urinary diversion. Larger prospective cohort studies are required to further characterize this severe phenotype of chronic noninfectious cystitis, aid earlier diagnosis, and guide management decisions.

A retrospective study of late adverse events in proton beam therapy for prostate cancer.

The efficacy and safety of proton beam therapy (PBT) were retrospectively evaluated in 111 consecutive patients with prostate cancer who underwent definitive PBT between 2008 and 2012. Following exclusion of 18 patients due to treatment suspension, loss to follow-up, and histology, the analysis included 93 patients with a median age of 68 years (range, 49–81 years). A total of 7, 32 and 54 prostate cancer patients were classified as low-, intermediate- and high-risk, respectively, as follows: High-risk, T≥3a or prostate-specific antigen (PSA) ≥20 ng/ml or Gleason Score ≥8; low-risk, T ≤2b and PSA≤10 ng/ml and Gleason Score=6; intermediate-risk, all other combinations. The median initial prostate-specific antigen (PSA) level was 9.75 ng/ml (range, 1.4–100 ng/ml) and the median Gleason score was 7 (range, 6–10). Patients with low-risk disease received 74 GyE (relative biological effectiveness=1.1) in 37 fractions, and those at intermediate or higher risk received 78 GyE in 39 fractions. Complete androgen blockade (CAB) therapy was performed from 6 months prior to PBT for patients with intermediate- or high-risk disease. CAB was continued during PBT and then terminated at the end of PBT for intermediate-risk patients. Patients at high risk continued CAB for 3 years. No combination therapy was used for low-risk patients. All the patients were followed up for >2 years after PBT, and all but one were PSA failure-free. The Common Terminology Criteria for Adverse Events v.4.0 was used to evaluate late adverse events. One patient developed grade 3 non-infectious cystitis and hematuria. Grade 2 urinary frequency was observed in 1 patient, and grade 2 rectal bleeding occurred in 4 patients. Of the 4 patients with grade 2 rectal bleeding, 2 received anticoagulant therapy, but none had diabetes mellitus or another high-risk comorbidity. The median time to occurrence of an adverse event of grade ≥2 was 14 months (range, 3–41 months). Therefore, the present retrospective study revealed that PBT at 78 GyE/39 Fr was well-tolerated and achieved good tumor control in patients with prostate cancer.

Placement of subcutaneous ureteral bypasses without fluoroscopic guidance in cats with ureteral obstruction: 19 cases (2014-2016).

Objectives The purpose of this study was to describe the perioperative and postoperative complications as well as short-term and long-term outcomes in cats with ureteral obstructions treated by placement of a subcutaneous ureteral bypass (SUB) device without imaging control. The second objective of this study was to compare cats treated by SUB device with cats treated by traditional surgical intervention. Methods Data were obtained retrospectively from the medical records (2014-2016) of cats that underwent SUB placement (SUB cats) and cats that underwent traditional ureteral surgery (C cats). Results Nineteen SUB devices were placed without fluoroscopic, radiographic or ultrasonographic guidance in 13 cats. Fifteen traditional interventions (ureterotomy and neoureterocystostomy) were performed in 11 cats. Successful placement of the SUB device was achieved in all cats with only one major intraoperative complication (kinking of the kidney catheter) and one minor intraoperative complication (misplacement of the kidney catheter). Eleven SUB cats recovered from the surgical procedure; two SUB cats and three C cats died during the anaesthesia recovery period. Postoperative SUB complications included anaemia (n = 2), urinary tract infection (UTI) (n = 4), non-infectious cystitis (n = 5) and SUB device obstruction (n = 1). Postoperative traditional surgery complications included anaemia (n = 7), UTIs (n = 6), non-infectious cystitis (n = 1), re-obstruction (n = 4) and ureteral stricture (n = 1). Median postoperative duration of hospitalisation (3 days) was significantly shorter for SUB cats than for C cats ( P = 0.013). Ten SUB cats (76.9%) and four C cats (40%) were still alive at a median follow-up of 225 days and 260 days, respectively. Owners were completely (90%) or mostly (10%) satisfied with the SUB device placement. Conclusions and relevance SUB device placement appears to be an effective and safe option for treating ureteral obstruction in cats, and this study has shown that fluoroscopic guidance is not essential in all cases.

Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial

Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m(2)) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.

Abstract CT340: Phase 1b/2a study of the nanopharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC): results from the planned interim analysis

Abstract Introduction: The inactivation of VHL occurs in most clear cell RCC (ccRCC) tumors and gives rise to the HIF hypoxia response program and to tumor angiogenesis. While antiangiogenic therapies are active in ccRCC, resistance develops in all pts. We hypothesize that dual inhibition strategies will be useful in overcoming resistance. CRLX101 (Cerulean Pharma, Inc., Cambridge, MA, USA), a novel tumor-targeted nanopharmaceutical platform containing camptothecin as its payload, has been shown in pre-clinical models to target HIF and is synergistic with bevacizumab (bev). We combined CRLX101 with bev in refractory mRCC in order to determine the safety and the recommended phase 2 dose (RP2D) of the combination, and to determine its preliminary therapeutic activity in this setting. Experimental Procedures: Pts with mRCC of all histologic subtypes refractory to conventional antiangiogenic therapies were treated every 2 weeks with bev 10 mg/kg and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a standard 3+3 design with an expansion at the RP2D. Pts were treated until progression, death, or prohibitive toxicity. Adverse events were classified (CTCAE v 4.0), and radiographic results were assessed (RECIST v 1.1). Results Summary: 10 pts were enrolled on study with histologies of the following distribution - 6 clear cell, 2 papillary, 2 chromophobe. Pts had a median of 2 prior therapies. No dose limiting toxicities (DLTs) were observed. CRLX101 at its single-agent RP2D (15 mg/m2) was safely combined with standard bev. Two (2) episodes of grade 3 non-infectious cystitis and 1 episode of grade 3 hypertension were observed. All other toxicities were grade 1 or 2. The median progression free survival (PFS) was 7.6 months. One third of evaluable pts (33%) achieved a confirmed partial response (PR) including 1 patient with papillary mRCC; 4 pts (44%) had stable disease, and 2 had progressive disease as their best overall response. Prior therapies in the 3 PRs included sunitinib (all) and everolimus (all). PFS results from the stage 1 cohort exceeded the pre-specified threshold and have triggered 2nd stage accrual. Conclusions: CRLX101 can be safely combined with standard doses of bev in pts with refractory mRCC at a RP2D of 15 mg/m2 q2w of CRLX101. Preliminary outcomes to date are superior to historical controls in refractory ccRCC and suggest potential for clinical benefit across histologic subtypes of mRCC. Citation Format: Stephen M. Keefe, Meliessa Hennessy, Orvar Gunnarsson, Ronac Mamtani, David Vaughn, Jean Hoffman-Censits, Katherine Nathanson, Priti Lal, Priti Lal, Daniel Pryma, Scott Eliasof, Edward Garmey, Roger B. Cohen, Naomi B. Haas. Phase 1b/2a study of the nanopharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC): results from the planned interim analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT340. doi:10.1158/1538-7445.AM2014-CT340

Intravesical mitomycin C combined with local microwave hyperthermia in non-muscle-invasive bladder cancer with increased European Organization for Research and Treatment of Cancer (EORTC) score risk of recurrence and progression

To assess the activity of intravesical chemotherapy and local microwave hyperthermia (ICLMH) in increasing the disease-free interval (DFI) in patients with non-muscle-invasive bladder cancer (NMIBC) and treatment toxicity. Forty-two patients with a diagnosis of high-risk NMIBC, according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, were treated with an intensive schedule of ICLMH using 40 mg mitomycin C. The treatment consisted of 4 weekly sessions, followed by 6 sessions delivered every 2 weeks, and by 4 monthly sessions, for a total of 14 sessions over 8 months. The DFIs before and after treatment were compared in each patient. The schedule was completed as planned by 32 patients (76.2 %). The percentage of disease-free patients the year before study was 14.9 % (95 % CI 5.5-28.8) versus 88.8 % (95 % CI 73.7-94.8) after ICLMH (p < 0.0001). Patient EORTC scores, multifocality, and tumour stage were all associated significantly and independently with a higher risk of recurrence after ICLMH treatment with HR of 41.1 (p = 0.01), 17.7 (p = 0.02), and 8.5 (p = 0.02), respectively. After a median follow-up of 38 months, 24 patients (57.1 %) did not show evidence of disease, whereas 13 patients (30.9 %) underwent disease recurrence and 5 patients (11.9 %) showed also stage progression. Toxicity consisted in grades 1 and 2 frequency, non-infectious cystitis, and haematuria. ICLMH significantly increases the DFI of NMIBC patients with high EORTC score for recurrence and progression. Toxicity of the intensive treatment schedule was generally mild.

Interim results of a phase 1b/2a study evaluating the nano pharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC).

412 Background: VHL is inactivated in most clear cell RCC (ccRCC) tumors giving rise to the HIF hypoxia response program and tumor angiogenesis. Antiangiogenic therapies are active in ccRCC, but resistance develops in all pts. Dual inhibition strategies may be needed to overcome resistance. CRLX101, a novel nano pharmaceutical formulation of camptothecin, has been shown in pre-clinical models to target HIF. We combined CRLX101 with bev in the treatment of pts with refractory mRCC in order to determine the safety and the recommended phase 2 dose (RP2D) of the combination, and to determine the therapeutic activity of treatment. Methods: Pts with mRCC refractory to conventional antiangiogenic therapies (all subtypes) were treated every 2 weeks with bev 10 mg/kg and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a standard 3+3 design with an expansion at the RP2D. Pts were treated until progression, death, or prohibitive toxicity. Adverse events were classified using CTCAE v 4.0. Radiographic results were assessed by RECIST v1.1. Results: 10 pts were enrolled on study – 6 clear cell, 2 papillary, 2 chromophobe. Median prior number of therapies was 2. No dose limiting toxicities were observed. CRLX101 at its single-agent RP2D (15 mg/m2) was safely combined with standard bev. 2 episodes of grade 3 non-infectious cystitis and 1 episode of grade 3 hypertension were observed. All other toxicities were grade 1 or 2. The median progression free survival (PFS) was 7.6 months which exceeded our pre-specified threshold of 16 weeks and has triggered 2nd stage accrual. 3 of 9 evaluable pts (33%) achieved a confirmed partial response (PR) including 1 patient with papillary mRCC; 4 pts (44%) displayed stable disease, and 2 had progressive disease as their best overall response. Conclusions: Our results demonstrate that CRLX101 can be safely combined with bev in pts with refractory mRCC. The RP2D is 15 mg/m2 q2w of CRLX101 with standard bev. Preliminary outcomes to date suggest that clinical benefit, manifest as prolonged PFS, is conferred to pts with all histologic subtypes of mRCC. Clinical trial information: NCT01625936.

Gene Expression Analysis of Urine Sediment: Evaluation for Potential Noninvasive Markers of Interstitial Cystitis/Bladder Pain Syndrome

We determined whether gene expression profiles in urine sediment could provide noninvasive markers for interstitial cystitis/bladder pain syndrome with and/or without Hunner lesions. Fresh catheterized urine was collected and centrifuged from 5 controls, and 5 Hunner lesion-free and 5 Hunner lesion bearing patients. RNA was extracted from pelleted material and quantified by gene expression microarray using the GeneChip® Human Gene ST Array. Three biologically likely hypotheses were tested, including 1) all 3 groups are distinct from each other, 2) controls are distinct from the 2 types combined of patients with interstitial cystitis/bladder pain syndrome and 3) patients with Hunner lesion-interstitial cystitis/bladder pain syndrome are distinct from controls and patients with nonHunner-lesion interstitial cystitis/bladder pain syndrome combined. For statistical parity an unlikely fourth hypothesis was included, that is patients with nonHunner-lesion interstitial cystitis/bladder pain syndrome are distinct from controls and patients with Hunner lesion-interstitial cystitis/bladder pain syndrome combined. Analysis supported selective up-regulation of genes in the Hunner lesion interstitial cystitis/bladder pain syndrome group (hypothesis 3), which were primarily associated with inflammation. The inflammatory profile was statistically similar to that reported in a prior Hunner lesion interstitial cystitis/bladder pain syndrome bladder biopsy study. Gene expression analysis of urine sediment was feasible in this pilot study. Expression profiles failed to discriminate nonHunner-lesion interstitial cystitis/bladder pain syndrome from controls and they are unlikely to be a noninvasive marker for nonHunner-lesion interstitial cystitis/bladder pain syndrome. In contrast, patients with Hunner lesion had increased proinflammatory gene expression in urine sediment, similar to that in a prior microarray study of bladder biopsies. If these preliminary results are validated in future research, they may lead to a noninvasive biomarker for Hunner lesion-interstitial cystitis/bladder pain syndrome.

Split-Bolus MDCT Urography with Synchronous Nephrographic and Excretory Phase Enhancement

Our purpose was to evaluate the utility of CT urography performed using a split contrast bolus that yields synchronous nephrographic and excretory phase enhancement. Five hundred consecutive patients referred for evaluation of possible urinary tract abnormalities (327 for painless hematuria) underwent CT urography with unenhanced scanning of the abdomen and pelvis and scanning during concurrent nephrographic and excretory phase enhancement produced by administration of a split contrast bolus. The enhanced abdomen scan was obtained with abdominal compression; the enhanced pelvis scan was obtained after release of compression. Findings from axial sections and coronal maximum intensity projections were correlated with clinical follow-up and, as available, with laboratory and other imaging studies including cystoscopy, ureteroscopy, urine cytology, surgery, and pathology. Follow-up management for each patient was determined by the clinical judgment of the referring physician. CT urography identified 100% of pathologically confirmed renal cell carcinomas (n = 10) and uroepithelial malignancies involving the renal collecting system or ureter (n = 8). An additional nine renal masses were identified for which no pathologic proof has yet been obtained, including eight subcentimeter solid renal masses and one multiloculated lesion. Fourteen of 19 confirmed cases of uroepithelial neoplasm involving the bladder were identified. CT urography yielded one false-positive for bladder tumor, two false-positives for ureteral tumor, and one patient with a bladder mass who refused further evaluation. CT urography yielded sensitivity and specificity of 100% and 99% and 74% and 99% and positive predictive value and negative predictive value of 80% and 100% and 93% and 99% for the renal collecting system and ureter and bladder, respectively. CT urography was ineffective in identifying 11 cases of noninfectious cystitis. CT urography also depicted numerous other congenital and acquired abnormalities of the urinary tract. Split-bolus MDCT urography detected all proven cases of tumors of the upper urinary tract, yielding high sensitivity and specificity. The split-bolus technique has the potential to reduce both radiation dose and the number of images generated by MDCT urography.

INTRAVESICAL ELECTROMOTIVE DRUG ADMINISTRATION TECHNIQUE: PRELIMINARY RESULTS AND SIDE EFFECTS

Purpose We performed intravesical electromotive drug administration (EMDA) for various bladder disorders during a 3-year period and assessed the technique, possible applications, complications and outcomes of this procedure. Materials and Methods Intravesical EMDA was performed with local anesthetics for transurethral surgery and in combination with dexamethasone for the treatment of noninfectious chronic cystitis (interstitial/radiation cystitis), with mitomycin C for recurrence prophylaxis of high risk superficial bladder cancer and with oxybutynin/bethanechol for the hyperreflexive/acontractile detrusor. A standardized power source and electrode catheter were used for 215 treatments in 84 patients. Results Transurethral bladder tumor resections were pain-free in 10 of 12 patients. Of the 25 patients with chronic noninfectious cystitis 15 were free of symptoms for a mean of 6.6 months, and there was a 73% increase in mean bladder capacity from 244 before to 421 cc after EMDA. Of the 16 patients with superficial bladder cancer 9 were free of recurrence for a mean of 14.1 months. In 10 of 14 patients with acontractile detrusors urodynamic examination showed detrusor contraction during EMDA of bethanechol. There were no contractions without electric current. EMDA of oxybutynin reduced detrusor hyperreflexia. A bladder ulcer was the single severe local complication and 4.6% of patients, mainly those with chronic cystitis, reported significant post-EMDA bladder/urethral pain. Minor side effects accounted for 23% of all treatments. No systemic side effects occurred. Conclusions Intravesical EMDA is effective and innocuous. The therapeutic concept combines the advantages of increased drug administration without systemic side effects.

Disruption of guinea pig urinary bladder permeability barrier in noninfectious cystitis.

Although most cell membranes permit rapid flux of water, small nonelectrolytes, and ammonia, the apical membranes of bladder epithelial umbrella cells, which form the bladder permeability barrier, exhibit strikingly low permeabilities to these substances. In cystitis, disruption of the bladder permeability barrier may irritate the bladder wall layers underlying the epithelium, causing or exacerbating inflammation, and increasing urinary frequency, urgency, and bladder pain. To determine the effects of inflammation on the integrity of the permeability barrier, guinea pigs were sensitized with ovalbumin, and the bladders were exposed subsequently to antigen by instillation on the urinary side. Inflammation of the bladder wall markedly reduced transepithelial resistance of dissected epithelium mounted in Ussing chambers and increased water and urea permeabilities modestly at 2 h and more strikingly at 24 h after induction of the inflammation. Transmission and scanning electron microscopy of bladders at 30 min and 24 h after antigen exposure revealed disruption of tight junctions, denuding of patches of epithelium, and occasional loss of apical membrane architecture. These permeability and structural effects did not occur in nonsensitized animals in which the bladders were exposed to antigen and in sensitized animals exposed to saline vehicle rather than antigen. These results demonstrate that inflammation of the underlying muscle and lamina propria can disrupt the bladder permeability barrier by damaging tight junctions and apical membranes and causing sloughing of epithelial cells. Leakage of urinary constituents through the damaged epithelium may then exacerbate the inflammation in the underlying muscle layers.

Elevated nitric oxide in the urinary bladder in infectious and noninfectious cystitis

A role for nitric oxide (NO) has been suggested in inflammation and host defense. At higher concentrations, this gas shows cytotoxic effects that may be directed against microorganisms, tumor cells as well as host cells. The aim of the present study was to study the relationship between bladder mucosal inflammation and local production of NO. We measured NO directly in the urinary bladder in patients with infectious cystitis, interstitial cystitis, irradiation cystitis, and cystitis induced by antitumor treatment with bacillus Calmette-Guérin. NO-free air was introduced into the bladder during cystoscopy. The air was aspirated after 5 minutes of incubation and injected into a chemiluminescence NO analyzer. NO levels were 30 to 50 times higher in all varieties of cystitis as compared to controls. NO may contribute to host-defense mechanisms in the bladder during bacterial infection and antitumor treatment. Direct measurement of gaseous NO in the urinary bladder seems to be an attractive diagnostic method for detection of mucosal inflammation.