Intravesical Instillation Research Articles

The safety, tolerability and efficacy of LP-10 in subjects with refractory moderate to severe hemorrhagic cystitis: Phase 2a multicenter dose escalation clinical trial.

e24064 Background: Hemorrhagic Cystitis (HC), a rare but highly morbid disease for which there are currently no FDA approved treatments, can occur in cancer survivors including patients with prostate cancer, cervical/uterine cancer and colon cancer. Lipella Pharmaceuticals received orphan disease designation for HC, and recently completed a phase 2a clinical trial of LP-10 (intravesical tacrolimus) for the treatment of HC. Methods: The LP-10 Phase 2a clinical trial was a multi-center, dose-escalation study (clinicaltrials.gov: NCT01393223). The study recruited subjects with moderate to severe refractory HC. These subjects were treated with up to two courses of LP-10 intravesical bladder instillations (liposomal formulation of tacrolimus at 2 mg, 4 mg and 8 mg). Results: Fifteen subjects were screened (14 male and 1 female) and 13 enrolled. All enrolled subjects were male with mean age 67 (range 25-89 years old) with a history of prostate cancer (n = 9), bladder cancer (n = 2) and lymphoma (n = 2). Mean duration of HC was 4 years and ranged from 1-14 years. No subject discontinued treatment or were lost to follow-up. All subjects tolerated LP-10 instillations and completed the study without report of product related serious adverse events. 12 AEs were reported in 6 subjects. Pharmacokinetic analysis demonstrated short duration of low systemic uptake of tacrolimus. A dose response was noted with higher efficacy at both the 4mg and 8 mg dose groups. After LP-10 treatment, the number of cystoscopic bleeding sites and bladder ulcerations decreased and patients’ urinary symptoms improved. Conclusions: This first phase 2a study demonstrated safety and a signal of efficacy at intravesical tacrolimus (LP-10) doses of 4 mg and 8 mg for the treatment for HC, a rare and serious disease. Clinical trial information: NCT01393223 . [Table: see text]

Open Label, Pilot Evaluation of the Safety and Efficacy of Intravesical Sustained Release System of Lidocaine and Oxybutynin (TRG-100) for Patients With Interstitial Cystitis/Bladder Pain Syndrome, Overactive Bladder and Patients With Retained Ureteral Stents Following Endourological Interventions

Intravesical instillation of analgesic and anticholinergic drugs have shown efficacy in the treatment of pain and voiding symptoms. Unfortunately, drug loss with urination and dilution in the bladder limit their durability and clinical usefulness. We have recently developed and tested in vitro, a sustained delivery system (TRG-100) of fixed-dose combination of lidocaine and oxybutynin designed to allow for a longer exposure of the urinary bladder to the drugs. To asses the safety and efficacy of TRG-100 in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), overactive bladder (OAB), and endourological intervention stented (EUI) patients in an open-label, prospective study. Thirty-six patients were enrolled: 10 IC/BPS, 10 OAB, and 16 EUI. EUI patients received a once-weekly installation until stent removal, OAB and IC/BPS patient received weekly installations for 4 consecutive weeks. Treatment effect was assessed by visual analog scale (VAS) score for the EUI group, voiding diaries for OAB group and VAS score, voiding diaries and O'Leary Sant Questionnaires for the IC/BPS group. The EUI group showed a mean 4-point improvement in their VAS score. The OAB group showed 33.54% reduction in frequency of urination and IC/PBS group showed a mean of 3.2-point improvement in their VAS score, 25.43% reduction in frequency of urination, and a mean 8.1-point reduction in O'Leary Sant Questionnaires score. All changes were statistically significant. Intravesical instillation of TRG-100 was found to be safe and efficient in reducing pain and irritative bladder symptoms in our study population. TRG-100 efficacy and safety should be further assessed in a large, randomized control trial.

Safety of locally administered large surface area microparticle paclitaxel and docetaxel in combination with standard of care cancer therapies.

e15187 Background: The safety of local delivery of large surface area microparticle paclitaxel (LSAM-PTX) or docetaxel (LSAM-DTX) to solid tumors has been evaluated in Phase 1/2 trials across 156 subjects with 43% (67/156) on various concurrent standard of care (SOC) therapies. Local administration of LSAM-PTX or LSAM-DTX leads to a reduction in systemic drug exposure and drug-related adverse events (AE) and may reduce toxicities encountered in combination systemic treatment regimens. This report summarizes safety findings in subjects co-administered LSAM-PTX or LSAM-DTX and common SOC therapies for treatment of carcinomas. Methods: During the study follow-up periods, AE and serious AE (SAE) were coded (MedDRA 16.1 -23.1) and assessed (NCI CTCAE 3 - 5). Results: In 7 studies (median age 69 years (range 37-96), 61% male, 88% white) (Table), LSAM-PTX administrations occurred as follows: intraperitoneal (n = 31 subjects), intraprostatic (n = 17), and intratumoral (n = 72). A median of 1 cycle (range 1-6) of LSAM-PTX was administered. LSAM-DTX was injected once into bladder tissue after tumor resection followed by a median of 10 cycles (range 7-10) of intravesical instillation in 36 subjects. 59 subjects (median age 65 (range 48-86), 53% male, 88% white) received local LSAM-PTX and concomitant chemotherapy, immunotherapy, or radiation. Rates of subjects who had Grade 3 SAE possibly related to LSAM-PTX were 29%, 24%, 16%, 6.7% and 5.0% in paclitaxel, carboplatin, 5-FU, nab-paclitaxel, and gemcitabine combinations, respectively. Grade 4 SAE possibly related to LSAM-PTX were found in 1 subject each co-administered pembrolizumab (13%), carboplatin (5.9%), and paclitaxel (7.1%). Subjects treated with 5-FU, gemcitabine, and nab-paclitaxel reported no related Grade 4 SAE. No Grade 5 SAE were deemed possibly related to LSAM-PTX. 8 subjects (median age 78 (range 54-89), 100% male, 88% white) received local LSAM-DTX therapy in combination with SOC therapies. No Grade 3-5 AE were reported with LSAM-DTX in combination with gemcitabine, carboplatin, pembrolizumab, avelumab or radiation. Conclusions: Local treatment of solid tumors with LSAM-PTX or LSAM-DTX has the potential to overcome some limitations of SOC therapies by increasing tumor dwell time and reducing systemic toxicities which are often exacerbated in combinatorial treatment regimens. Clinical trial information: NCT00666991 , NCT03636256 , NCT03077659 , NCT04221828 , NCT03029585 , NCT03077685 , NCT04314895 . [Table: see text]

Significance of the FGFR3 mutation in Chinese patients with bladder cancer.

Bladder cancer (BC) is the 10th most common malignancy worldwide. The high recurrence rates of BC lead to significant treatment challenges. With the development of molecular biology techniques, research has shown that gene abnormalities are closely related to the occurrence and development of BC. This study analyzed the detection results of gene mutations in the tissue samples of BC patients and explored the relationship between fibroblast growth factor receptor 3 (FGFR3) and the prognosis and recurrence of BC. This study examined 82 Chinese patients with BC. Of these patients, 34 underwent radical cystectomy (RC), and 48 underwent transurethral resection with intravesical instillation. In addition, multi-gene panel targeted next-generation sequencing (NGS) of the samples was performed. The mutational spectra revealed that C > T was the most common base substitution. Single nucleotide polymorphism (SNP) and deletion (DEL) were the common variant types in our cohort. The top 10 mutant genes were ROS1 (37%), PIK3CA (35%), FGFR3 (34%), BRAF (34%), ERBB2 (32%), ALK (27%), RET (27%), NTRK1 (24%), MET (23%), and EGFR (18%). FGFR3 mutations were detected more frequently in non-muscle-invasive bladder cancer (stages 0a, I) patients than in muscle-invasive bladder cancer (stage II, III, and IV) patients. The top 3 altered types of FGFR3 were p.Ser249Cys, p.Tyr375Cys, and p.Arg248Cys. This study examined the mutated types and frequency of FGFR3 and the prognosis of Chinese BC patients with FGFR mutations. We hope that our findings will enable clinical individualization strategies for BC patients to be optimized.

Physicochemical stability of ready-to-administer mitomycin C solutions for intravesical instillation

ObjectiveThe aim of the study was to investigate the physicochemical stability of mitomycin-containing medicinal products for bladder instillation, formulated with urea as excipient (mito-medac®, Mitomycin medac). For comparison, the stability...

Bladder instillation patterns in a cohort of women with interstitial cystitis/bladder pain syndrome.

To determine intravesical instillation patterns among women receiving treatment for interstitial cystitis/bladder pain syndrome (IC/BPS). Using the Veterans Affairs Informatics and Computing Infrastructure, active female users of the Veterans Affairs system with an ICD-9 diagnosis of IC/BPS (595.1) were randomly sampled. Patients were considered to have IC/BPS (by chart review) if they had two visits complaining of bladder-centric pain in the absence of positive urine culture ≥6 weeks apart or history of bladder pain with one additional visit for bladder-centric pain. We abstracted the dates of intravesical instillations for each patient. A "course" of instillations was defined as ≥1 instillations made with <21 days between visits. We identified 641 women with confirmed diagnosis of IC/BPS, 78 of whom underwent a total of 344 intravesical instillations. On average each subject had 1.5 +/- 0.8 courses between October 2004-July 2016. Each course was an average of 3.1 +/- 2.6 instillations. 55% of courses consisted of one instillation. Only 22% of courses had 6 or more instillations, the number typically recommended to achieve clinical response. Each instillation within a course was an average of 9.4 +/- 4.0 days apart. Most instillations (77%) were a cocktail of two or more drugs. In our cohort, few women with IC/BPS received a recommended treatment course of six weekly instillations, with most receiving only one per course. Future studies are needed to determine if instillation courses were altered from the guideline due to provider practice patterns, early improvement, or poor tolerance of instillations.

Guidance of adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial

BackgroundIn intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients.MethodsPatients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy.DiscussionThe aim of this trial is to use drug screens in PDO to precise treatment selection for adjuvant instillation therapies in patients with intermediate-risk NMIBC. The ultimate goal of this trial is to reduce the risk of cancer recurrence. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care.Trial registration NCT05024734.

Short-term Outcomes of Hydrodistention with Intravesical Hyaluronic Acid (Cystistat®) Versus Hydrodistention Alone for Treating Interstitial Cystitis: A Randomized Controlled Trial

Background: Interstitial cystitis (IC) is a chronic, debilitating bladder disease that primarily affects middle-aged women and significantly affects their quality of life. Bladder hydrodistention is the usual therapeutic and diagnostic procedure, but symptoms tend to relapse. Adding hyaluronic acid to hydrodistention has been shown to improve the outcomes. Objectives: To compare the therapeutic effects of bladder hydrodistention alone or with intravesical cystistat (40 mg of sodium hyaluronate in a 50 mL vial) in treating IC/bladder pain syndrome (IC/BPS). Methods: This randomized controlled clinical trial was conducted in Imam Reza Hospital of Mashhad in 2017. Twenty-four female IC/BPS patients were selected using clinical examinations and the O`Leary-Sant IC questionnaire to evaluate treatment effects. Patients with a history of other diseases related to the urogenital system and urination frequency less than eight times a day were excluded. The control group (n = 12) underwent hydrodistention under general anesthesia, and the intervention group (n = 12) received intravesical cystistat in addition to hydrodistention weekly for four weeks, followed by monthly for two months. Results: In the control group, the mean baseline score of the questionnaire was 33.2 ± 1.9 and reached 33.9 ± 2.6 after three months, showing no significant change. In the intervention group, the mean baseline score of the questionnaire was 32.6 ± 3.6 and reached 6.4 ± 12.4 at the end of the third month, which indicates a significantly better improvement (P &lt; 0.001). In this study, the disease symptoms resolved in 83.3% of the intervention group after three months of treatment, while the controls did not improve. Conclusions: Based on our study, intravesical instillation of cystistat is effective in treating patients with IC/BPS and has significantly better effects than hydrodistention alone.

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Melatonin induces cell cycle arrest and suppresses tumor invasion in urinary bladder urothelial carcinoma.

Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder tumor followed by intravesical instillation. High rates of mortality, recurrence, and progression in bladder cancer have stimulated the search for alternative adjuvant therapies. The aim of this study was to investigate the potential of melatonin as adjuvant therapy in bladder cancer. Cell viability and clonogenic ability were assessed by an MTT assay and colony formation. Cell cycle and apoptosis analysis were performed by flow cytometry and Hoechst 33342 staining, while cell metastasis capacity was measured by wound healing and transwell assays. Potential mechanisms were investigated by an oncology array and verified via western blotting. The melatonin treatment significantly reduced T24 and UMUC3 bladder cancer cell proliferation and clonogenic ability. G1 arrest and sub-G1 accumulation in the T24 and UMUC3 cells led to cell proliferation suppression and cell death, and Hoechst 33342 staining further verified the apoptosis induction directly by melatonin. Moreover, melatonin weakened cell motility and invasiveness. Based on the oncology array results, we demonstrated that melatonin exerts its anti-cancer effect by down-regulating the HIF-1α and NF-κB pathways and downstream pathways, including Bcl-2, leading to cell cycle arrest and apoptosis induction in the UBUC cells. Overall, these findings support the potential of melatonin as adjuvant therapy in bladder cancer.

Abstract LB246: Enfortumab vedotin, a nectin-4-directed antibody-drug conjugate, demonstrates compelling antitumor activity in non-muscle invasive bladder cancer models which predicts minimal systemic exposure when administered by intravesical instillation in patients

Abstract Enfortumab vedotin (EV) is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder cancers. Preclinically, EV has demonstrated tumor cell killing by direct cytotoxicity and bystander effect and can induce the hallmarks of immunogenic cell death. EV improves survival in adults with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) and is approved in the US, Europe, Japan, and others. Most newly diagnosed bladder cancer cases are non-muscle invasive (NMIBC). Standard treatment of high-risk NMIBC involves transurethral resection followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although response to BCG is high, recurrence is common, and treatment options for patients with BCG-unresponsive tumors are limited, underscoring the significant unmet need. Previously, we demonstrated compelling preclinical antitumor activity of EV in NMIBC models with a favorable safety profile and minimal systemic exposure. EV-mediated antitumor activity was confirmed in a mouse model of NMIBC by both bioluminescence imaging and IHC for hNectin-4-expressing cancer cells. Following intravesical administration of EV, tumor growth inhibition ranged 46-96% across the dose range tested. Colocalization of EV to Nectin-4-positive tumor tissues was confirmed by IHC in the engrafted tumor cells. Systemic EV exposure in tumor-bearing mice was low, consistent with previous nonclinical studies, supporting that the antitumor activity is driven by local exposure within the bladder. In a repeat-dose GLP toxicology study in rats, no systemic toxicities were observed at intravesical doses up to 6-fold higher than the maximum tolerated IV dose. This lack of systemic toxicities that can occur with IV administration in rats was likely due to minimal systemic exposure of both EV and unconjugated MMAE. Currently, the safety, tolerability, and antitumor activity of intravesical EV are being evaluated in a Phase 1 study in adults with high-risk, BCG-unresponsive NMIBC (EV-104, NCT05014139). The initial dose level for EV-104 was selected to be active and predicted to have minimal systemic absorption based on preclinical and known clinical IV data. Here, we present confirmatory clinical data demonstrating that EV and unconjugated MMAE are undetectable in the bloodstream at the starting dose. These findings confirm the translatability of our nonclinical models and provide evidence that intravesical administration of EV in NMIBC is a promising approach that limits systemic exposure. These data support the potential for a favorable safety and activity profile and warrant continued investigation of intravesical EV in patients with NMIBC. Citation Format: Devra Olson, Yen Lin Chia, Enaharo Iboi, Lauren Farr, Maddy Burcher, Anthony Lee, Kelly Hensley, Sean Allred, Abbie Wong, Masashi Shimazaki, Masamichi Mori, Sharsti Sandall, Christopher Carosino. Enfortumab vedotin, a nectin-4-directed antibody-drug conjugate, demonstrates compelling antitumor activity in non-muscle invasive bladder cancer models which predicts minimal systemic exposure when administered by intravesical instillation in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB246.

Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model.

To test if intravesical instillation of both an anti-programmed cell death protein 1 (PD-1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non-muscle-invasive bladder cancer that is refractory to intravesical bacillus Calmette-Guérin can be treated by systemic anti-PD-1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once-weekly instillations of intravesical anti-PD-1 in a murine model. Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or intravesical reovirus + anti-PD-1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long-term immunity and tumour-immune profile. With a median follow-up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9-32.6; P < 0.001), anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001), and reovirus + anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001). Monotherapy with anti-PD-1 or reovirus demonstrated no significant differences in survival (P = 0.067). Mass cytometry showed that reovirus + anti-PD-1 treatment enriched monocytes and decreased myeloid-derived suppressor cells, generating an immuno-responsive tumour microenvironment. Depletion of CD8+ T cells eliminated the survival advantage provided by the intravesical treatment. Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti-PD-1 antibody, or the combination confers superior survival compared to controls. Tumour-immune microenvironment differences indicated myeloid-derived suppressor cells and CD8+ T cells mediate the treatment response.

Abstract 2381: Gold nanorods functionalized with an alpha5beta1 ligand: a simple and robust nanosystem for early bladder cancer detection

Abstract Early detection and removal of bladder cancer (BC) is crucial to prevent tumor recurrence and progression. Various imaging modalities have been used to diagnose BC, including computed tomography urography, intravenous urography, ultrasound echography, multiparametric magnetic resonance imaging, cystoscopy, and cystoscopy in conjunction with intravesical instillation of hexaminolaevulinic acid, a photodynamic diagnostic agent. However, all these imaging techniques show a very poor detection rate of small (&amp;lt;5mm) and flattened cancer lesions. Because of this limitation, patients with BC frequently relapse after initial diagnosis and need frequent follow-ups and treatments, resulting in a poor quality of life. For the same reason, BC has the highest cost/patient among all cancers. We have recently developed a new methodology to detect bladder cancer lesions based on bladder instillation with GNRs@Chit-Iso4, a nanosystem consisting of gold nanorods (GNRs) decorated with chitosan and functionalized with the head-to-tail cyclized [CphgisoDGRG] peptide (Iso4, a selective ligand of alpha5beta1-integrin expressed by BC cells), followed by low-frequency ultrasound-assisted shaking of nanoparticles necessary to prevent their sedimentation, and photoacoustic imaging of targeted tumor lesions. In murine models, this procedure can detect orthotopic BC lesions &amp;lt;0.5 mm, undetectable by standard imaging modalities (Alchera et al., Photoacoustic, 2022). In the attempt to develop a simpler and more effective imaging modality of BC, we have produced and preclinically evaluated new GNRs decorated with lipoic acid-polyethylene glycol (PEG -5KDa) and functionalized with Iso4. The resulting product, obtained by a simple 2-step procedure and called GNRs@PEG5K-Iso4, efficiently recognized alpha5beta1- and alpha5beta1-expressing cells, was stable in 90% urine, and was resistant to freezing- or salt-induced aggregation.GNRs@PEG5K-Iso4 did not undergo sedimentation after instillation into the bladder, thereby avoiding the need of the complex ultrasound-assisted shaking of nanoparticles and could efficiently detect BC lesions smaller than &amp;lt;0.5 mm in murine models. These results suggest that GNRs@PEG5K-Iso4 represents a simple and robust contrast agent for photoacoustic imaging and early diagnosis of small BC lesions. Citation Format: Massimo Alfano, Elisa Alchera, Angelina Sacchi, Alessandro Gori, Irene Locatelli, Anna Maria Gasparri, Barbara Colombo, Giulia Anderluzzi, Paolo Armanetti, Luca Minichetti, Andrea Salonia, Angelo Corti, Flavio Curnis. Gold nanorods functionalized with an alpha5beta1 ligand: a simple and robust nanosystem for early bladder cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2381.

Long-term prevention of bladder cancer progression by alpha1-oleate alone or in combination with chemotherapy.

Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of nonmuscle invasive bladder cancer. Our study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least 4 weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression. Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and in vitro, alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer.

MP08-11 BODY COMPOSITION CAN PREDICT ONCOLOGICAL OUTCOME IN NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS WHO RECEIVE INTRAVESICAL INSTILLATION WITH BACILLUS CALMETTE-GUERIN AFTER TRANSURETHRAL RESECTION OF BLADDER TUMOR

You have accessJournal of UrologyCME1 Apr 2023MP08-11 BODY COMPOSITION CAN PREDICT ONCOLOGICAL OUTCOME IN NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS WHO RECEIVE INTRAVESICAL INSTILLATION WITH BACILLUS CALMETTE-GUERIN AFTER TRANSURETHRAL RESECTION OF BLADDER TUMOR Fan-Ting Liao, Liang-Kang Huang, Chun-Te Wu, Cheng-Keng Chuang, See-Tong Pang, Kai-Jie Yu, Po-Hung Lin, I-Hung Shao, Hung-Cheng Kan, Yuan-Cheng Chu, Ying-Hsu Chang, and Li-Jen Wang Fan-Ting LiaoFan-Ting Liao More articles by this author , Liang-Kang HuangLiang-Kang Huang More articles by this author , Chun-Te WuChun-Te Wu More articles by this author , Cheng-Keng ChuangCheng-Keng Chuang More articles by this author , See-Tong PangSee-Tong Pang More articles by this author , Kai-Jie YuKai-Jie Yu More articles by this author , Po-Hung LinPo-Hung Lin More articles by this author , I-Hung ShaoI-Hung Shao More articles by this author , Hung-Cheng KanHung-Cheng Kan More articles by this author , Yuan-Cheng ChuYuan-Cheng Chu More articles by this author , Ying-Hsu ChangYing-Hsu Chang More articles by this author , and Li-Jen WangLi-Jen Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Review of previous literature showed still conflicted opinions on influence of obesity in bladder cancer (BC) prognosis, while high body mass index(BMI) being an independent risk factor of BC. This study was aimed to find out the impact of body composition, including sarcopenia and obesity, on the oncological prognosis of non-muscle invasive bladder cancer (NMIBC) patients receiving transurethral resection of bladder tumor (TURBT) with adjuvant intravesical instillation (IVI) with Bacillus Calmette-Guerin (BCG). METHODS: We retrospectively recruited patients with NMIBC who had received TURBT with adjuvant IVI with BCG from March 2005 to April 2021. Body composition parameters were evaluated according to analysis of computed tomography (CT) L3 images with artificial intelligence (AI) models and BMI, and was further categorized into sarcopenia and obesity groups. Oncological outcomes including recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) after treatment of TURBT with adjuvant IVI with BCG were analyzed using uni- and multivariate analysis. Impact of sarcopenia and obesity was analyzed with Kaplan-Meier survival exam. RESULTS: Total of 269 patients were enrolled. All patients were diagnosed with NMIBC and majority were Ta or T1, accounting for 44.6% and 50.9% respectively. Among them, 80 patients were sarcopenic and 53 were obese, accounting for 29.7% and 19.7% respectively. Subcutaneous adipose tissue density on CT was a significant predictor for RFS (p=0.011) and psoas muscle density also had significant impact on OS (p=0.044) in multivariate analysis. Sarcopenic or non-obese patients endured significantly fewer BCG IVI than non-sarcopenic or obese patients. Patients with sarcopenia had poorer RFS (p=0.030) and OS (p=0.033). In contrast, obese patients had better OS (p=0.008). CONCLUSIONS: In our study, we first demonstrated that body composition, sarcopenia, and obesity had significant impact on the RFS, PFS and OS in NMIBC patients. Non-sarcopenic and obese patients can significantly endure more BCG IVI and thus may result in superior oncological outcome. In patients with NMIBC, obese group had better OS while sarcopenic patients had worse OS and RFS. Body composition measurements has potentials in assessments of oncological outcomes of NMIBC patients. Source of Funding: No source of funding © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e98 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fan-Ting Liao More articles by this author Liang-Kang Huang More articles by this author Chun-Te Wu More articles by this author Cheng-Keng Chuang More articles by this author See-Tong Pang More articles by this author Kai-Jie Yu More articles by this author Po-Hung Lin More articles by this author I-Hung Shao More articles by this author Hung-Cheng Kan More articles by this author Yuan-Cheng Chu More articles by this author Ying-Hsu Chang More articles by this author Li-Jen Wang More articles by this author Expand All Advertisement PDF downloadLoading ...

MP48-06 PATIENT-REPORTED TREATMENT BURDEN OF INTRAVESICAL THERAPY FOR BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP48-06 PATIENT-REPORTED TREATMENT BURDEN OF INTRAVESICAL THERAPY FOR BLADDER CANCER Amanda Myers, Benjamin Ristau, Matthew Mossanen, Deborah Kaye, Mark Tyson, Stephanie Chisolm, Frank Sloan, Colleen Ball, Angela Smith, and Timothy Lyon Amanda MyersAmanda Myers More articles by this author , Benjamin RistauBenjamin Ristau More articles by this author , Matthew MossanenMatthew Mossanen More articles by this author , Deborah KayeDeborah Kaye More articles by this author , Mark TysonMark Tyson More articles by this author , Stephanie ChisolmStephanie Chisolm More articles by this author , Frank SloanFrank Sloan More articles by this author , Colleen BallColleen Ball More articles by this author , Angela SmithAngela Smith More articles by this author , and Timothy LyonTimothy Lyon More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003294.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical therapy is the mainstay of treatment for non-muscle invasive bladder cancer (NMIBC). However, patients with NMIBC can face time, travel, and financial barriers to access intravesical therapy which may impact patient adherence to treatment. Therefore, we sought to quantify patient-reported treatment burden while receiving intravesical therapy for bladder cancer. METHODS: We conducted a cross-sectional survey of bladder cancer patients in the Bladder Cancer Advocacy Network (BCAN) Patient Survey Network to investigate patient-reported burden of intravesical therapy. Multiple choice survey questions were developed by investigators, then iteratively revised and improved by review from clinician and patient advocate stakeholders during the 2021 BCAN annual meeting. Eligible participants received at least one dose of intravesical therapy, including BCG and/or chemotherapy, delivered in an ambulatory setting. Survey was administered in November 2021 and was available for 1 month to respondents. RESULTS: A total of 233 patients responded to the survey (18% response rate), with a median age of 70 years (range 33-88). Respondents were 36% female and 97% white. A travel time >30 minutes to an intravesical treatment facility was reported by 55% (126/231) of patients, and 33% (77/231) reported personal out-of-pocket costs greater than $25 associated with each trip. Fifty-six percent (129/232) brought caregivers to their appointments. More than half of patients (56%, 129/232) reported spending more than 2 hours on each intravesical instillation, with 18% (42/232) spending more than 4 hours. Missing work for intravesical installations was reported by 36% (82/230) of patients, and of those who did, the majority (70%, 57/81) missed at least half a day of work (4 or more hours). Sixty-one respondents (26%) felt the process of receiving bladder instillations adversely affected their ability to perform regular daily activities. BCG shortages increased travel or wait time for intravesical therapy for 9% (20/229) of respondents. CONCLUSIONS: Bladder cancer patients reported considerable travel distances, time requirements, out-of-pocket costs, and need for caregiver support in the process of receiving intravesical therapy. Innovative intravesical care delivery processes are needed to reduce the burden of care for our bladder cancer patients. Source of Funding: n/a © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e657 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Amanda Myers More articles by this author Benjamin Ristau More articles by this author Matthew Mossanen More articles by this author Deborah Kaye More articles by this author Mark Tyson More articles by this author Stephanie Chisolm More articles by this author Frank Sloan More articles by this author Colleen Ball More articles by this author Angela Smith More articles by this author Timothy Lyon More articles by this author Expand All Advertisement PDF downloadLoading ...

MP52-03 IMPACT OF GENTAMICIN INTRAVESICAL INSTILLATION ON SYMPTOMATIC UTI FREQUENCY AND BACTERIAL RESISTANCE IN ADULT NEUROGENIC BLADDER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023MP52-03 IMPACT OF GENTAMICIN INTRAVESICAL INSTILLATION ON SYMPTOMATIC UTI FREQUENCY AND BACTERIAL RESISTANCE IN ADULT NEUROGENIC BLADDER PATIENTS Elizabeth J. Adams, Alexander V. Stanisic, Theresa Meyer, Angie Jang, Rachel Berkowitz, Ilina Rosoklija, Elizabeth Yerkes, David Chu, Janna L. Williams, Diana K. Bowen, and Stephanie J. Kielb Elizabeth J. AdamsElizabeth J. Adams More articles by this author , Alexander V. StanisicAlexander V. Stanisic More articles by this author , Theresa MeyerTheresa Meyer More articles by this author , Angie JangAngie Jang More articles by this author , Rachel BerkowitzRachel Berkowitz More articles by this author , Ilina RosoklijaIlina Rosoklija More articles by this author , Elizabeth YerkesElizabeth Yerkes More articles by this author , David ChuDavid Chu More articles by this author , Janna L. WilliamsJanna L. Williams More articles by this author , Diana K. BowenDiana K. Bowen More articles by this author , and Stephanie J. KielbStephanie J. Kielb More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003300.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with neurogenic lower urinary tract dysfunction (NLUTD) may experience recurrent urinary tract infections (UTIs) refractory to traditional preventative measures given their bladder management needs. In smaller scale pediatric studies, intravesical gentamicin instillation has been described as a prophylactic measure to prevent UTIs in patients with NLUTD who catheterize. We describe a robust cohort of adult patients with NLUTD utilizing intravesical gentamicin. The objectives of the study were to 1) Evaluate whether there was a reduction in UTI frequency after initiating gentamicin prophylaxis; 2) Determine if UTI-related hospitalizations decreased with gentamicin use; 3) Assess for increased gentamicin resistance with use of bladder instillations. METHODS: A retrospective cohort study of adult NLUTD patients who have used prophylactic gentamicin instillations at an academic institution between 2007 and 2022 was conducted. All patients intermittently self-catheterized or had an indwelling catheter. Exclusion criteria included absence of at least one symptomatic UTI documented in the medical record prior to gentamicin initiation. The number of UTIs and UTI-related hospitalizations for each patient were abstracted. Urine culture data was reviewed for gentamicin resistance. UTIs were defined as presence of urologic symptoms associated with positive culture. Statistical significance was assessed using Wilcoxon signed-rank test. RESULTS: Forty-three patients with NLUTD were reviewed. Median length of time using gentamicin instillations was 22.9 months (IQR 26.2), with 38 patients continuing to use the instillations at the time of analysis. Overall, there was a significant reduction in the average number of UTIs per year from after initiation of gentamicin from 3.7 [SD=2.7] before gentamicin to 1.6 [SD=2.2] while using gentamicin (p<0.001). The average number of UTI-related inpatient admissions did not significantly change with gentamicin instillation prophylaxis (0.9/year prior to gentamicin initiation, 0.5/year on gentamicin; p=0.06). The proportion of cultured bacteria resistant to gentamicin did not significantly increase after initiation of the instillations (p=0.3). CONCLUSIONS: Gentamicin instillations significantly reduced the number of UTIs experienced by adult NLUTD patients who catheterize and did not increase bacterial resistance to gentamicin. Prospective studies in patients with NLUTD are needed to further define the ideal administrative protocol and patient characteristics for optimal therapeutic success. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e703 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elizabeth J. Adams More articles by this author Alexander V. Stanisic More articles by this author Theresa Meyer More articles by this author Angie Jang More articles by this author Rachel Berkowitz More articles by this author Ilina Rosoklija More articles by this author Elizabeth Yerkes More articles by this author David Chu More articles by this author Janna L. Williams More articles by this author Diana K. Bowen More articles by this author Stephanie J. Kielb More articles by this author Expand All Advertisement PDF downloadLoading ...

MP60-01 MACROPHAGE MIGRATION INHIBITORY FACTOR AND TLR4 SIGNALING ARE INVOLVED IN PAR4-INDUCED PERSISTENT BLADDER PAIN

You have accessJournal of UrologyCME1 Apr 2023MP60-01 MACROPHAGE MIGRATION INHIBITORY FACTOR AND TLR4 SIGNALING ARE INVOLVED IN PAR4-INDUCED PERSISTENT BLADDER PAIN Shaojing Ye, Fei Ma, Dlovan F. D. Mahmood, and Pedro Vera Shaojing YeShaojing Ye More articles by this author , Fei MaFei Ma More articles by this author , Dlovan F. D. MahmoodDlovan F. D. Mahmood More articles by this author , and Pedro VeraPedro Vera More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Interstitial cystitis/Bladder pain syndrome is a painful condition with unknown etiology. Repeated intravesical PAR4 induced persistent bladder hyperalgesia (BHA) in mice that lasts several days after the last stimulus with little or no evidence of bladder inflammation. Our studies showed that spinal macrophage migration inhibitory factor (MIF) and High Mobility Group Box 1 (HMGB1) are critical causative factors. We aimed to dissect this persistent pain pathway and explore effective targets for treating persistent bladder pain. METHODS: Persistent BHA was induced in female mice (WT, TLR4 null, Trif null) by three intravesical instillations (days 0, 2 and 4) with PAR4 agonist (100 uM; 1hr, scrambled peptide as control) under anesthesia. Lower abdominal hypersensitivity was measured by von Frey filaments on days 0-4 and 7-9. Intraperitoneal treatment was performed on days 2-8 and included: ISO-1 (MIF antagonist); 10% DMSO; ethyl pyruvate (EP; inhibits HMGB1 release); and PBS. Awake micturition parameters (voided volume; frequency) were assessed on day 9. Bladder histology assessed inflammation/edema. R was used for all analyses. RESULTS: Inhibition of MIF activity with ISO-1 robustly reversed the PAR4-induced persistent BHA in WT mice (Figure 1A) while treatment with EP partially reduced BHA (Figure 1B). TLR4 deficiency substantially damped persistent pain (Figure 2A) while lack of Trif did not affect PAR4-induced persistent BHA (Figure 2B). No significant effects were noted on micturition volume, frequency, inflammation, or edema. CONCLUSIONS: MIF, HMGB1, and TLR4 signaling activation are required for PAR4-induced persistent BHA. However, Trif may not be critical for persistent bladder pain. Further dissecting TLR4 downstream signaling pathway is necessary to identify important mediators and whether they act centrally or peripherally. This may lead to the discovery of novel potential therapeutic targets to treat persistent bladder pain. Source of Funding: DK121695 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e842 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shaojing Ye More articles by this author Fei Ma More articles by this author Dlovan F. D. Mahmood More articles by this author Pedro Vera More articles by this author Expand All Advertisement PDF downloadLoading ...

Peritoneal and pulmonary tuberculosis following intravesical administration of Bacillus Calmette-Guérin for bladder cancer.

We report a rare case of peritoneal and pulmonary tuberculosis after intravesical instillation of Bacillus Calmette-Guérin (BCG). A 76-year-old man diagnosed as high-grade urothelial carcinoma (UC) with carcinoma in situ (CIS) was treated with intravesical BCG instillation and transurethral resection of bladder tumor (TUR-BT). Three months later, TUR-BT for recurrent tumors and multiple site biopsy of bladder mucosa were performed. During TUR-BT, near perforation in the posterior wall was observed, and was disappeared after observation with urethral catheterization for 1 week. Two weeks later, he was admitted with a complaint of abdominal distention, and a computed tomography (CT) showed ascites. One week later, CT showed pleural effusion and worsening of ascites. Drainage of pleural effusion and ascites puncture was performed, and elevated adenosine deaminase (ADA) and lymphocytes count were subsequently found. In laparoscopic examination, numerous white nodules were observed in the peritoneum and omentum, and Langhans giant cells were pathologically identified in biopsy specimens. Mycobacterium culture confirmed Mycobacterium tuberculosis complex. The patient was then diagnosed with pulmonary and peritoneal tuberculosis. Anti-tuberculous agents consisting of isoniazid (INH), rifampicin (RFP), and ethambutol (EB) were administered. Six months later, a CT scan showed no evidence of pleural effusion or ascites. There has been no recurrence of either urothelial cancer or tuberculosis during follow-up for 2 years.

MP52-04 PATIENT'S EXPERIENCE AND SATISFACTION WITH INTRAVESICAL GENTAMICIN IRRIGATIONS

You have accessJournal of UrologyCME1 Apr 2023MP52-04 PATIENT'S EXPERIENCE AND SATISFACTION WITH INTRAVESICAL GENTAMICIN IRRIGATIONS Patricia Maymi-Castrodad, Connie Pines, Martin Forchhmeimer, Denise Tate, and Anne Cameron Patricia Maymi-CastrodadPatricia Maymi-Castrodad More articles by this author , Connie PinesConnie Pines More articles by this author , Martin ForchhmeimerMartin Forchhmeimer More articles by this author , Denise TateDenise Tate More articles by this author , and Anne CameronAnne Cameron More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003300.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Gentamicin bladder instillations have been shown to decrease urinary tract infections (UTI) in patients with neurogenic lower urinary tract dysfunction (NLUTD) on intermittent self-catheterization (ISC). Even with proven clinical efficacy of gentamicin irrigation, patient’s experience has not been studied. We aim to assess patient’s experience and satisfaction with intravesical gentamicin irrigations in patient with NGLUTD with refractory recurrent urinary tract infections. METHODS: An interview study of patients who tried gentamicin bladder instillations either presently or in the past. Eligibility was patients with NGLUTD performing CIC and recurrent UTIs (3 culture proven UTI in a year requiring antibiotics). We conducted interviews focusing on patient’s UTI history, bladder health, use of gentamycin, and validated questionnaire Neurogenic Bladder Symptom Scale (NBSS), Spinal Cord Injury Quality of Life (SCI-QOL) Bladder complications, management difficulties, and Patient- Reported Outcome Measurement (PROMIS) Global Health Scale. RESULTS: 36 patients met the inclusion criteria; 56.4% were male and 92.3% White, median age of 61 years (range 33-77). Etiology of NGLUTD were Spinal Cord Injury (71.8%), Spina Bifida (5.1%), Multiple Sclerosis (10.3%), and Transverse Myelitis (2.6%). Only 5.6% had undergone bladder surgery. 77.8% reported still doing gentamicin flushes, with 78.6% very satisfied with the experience. The median number of documented UTI prior to starting irrigations was 3 (range 2-6.5) and the number of documented UTI during the 12 months after was 0 (range 0-1). Reasons for stopping irrigations included difficulty conducting the flushes (12.5%), insurance or other financial reasons (25.0%) or recurrent UTIs (62.5%). The NBSS showed 63.9% of participants when experiencing UTIs can be treated at home with antibiotics and 22.2% required hospital admission. The SCI-QOL showed 83.3% of patient are not limited in their daily activities as a result of their UTIs. The PROMIS showed 44.4 % would rate their QOL as good, 25.0% as very good, and 11.1% as Excellent. CONCLUSIONS: Gentamycin instillations reduce the incidence of UTI in NGLUTD patients performing CIC. Participants reported satisfaction and good QoL when not having UTIs with the use of intravesical gentamicin instillations. Education on technique for the installations and insurance or financial coverage in this population may improve patient’s compliance to maintain reduce risk of UTI. Source of Funding: National Institute of Independent Living and Disability Research © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e703 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Patricia Maymi-Castrodad More articles by this author Connie Pines More articles by this author Martin Forchhmeimer More articles by this author Denise Tate More articles by this author Anne Cameron More articles by this author Expand All Advertisement PDF downloadLoading ...