Reverse Thermal Gel Research Articles

Extracellular matrix stiffness mediates insulin secretion in pancreatic islets via mechanosensitive Piezo1 channel regulated Ca2+ dynamics

The pancreatic islet is surrounded by ECM that provides both biochemical and mechanical cues to the islet β-cell to regulate cell survival and insulin secretion. Changes in ECM composition and mechanical properties drive β-cell dysfunction in many pancreatic diseases. While several studies have characterized changes in islet insulin secretion with changes in substrate stiffness, little is known about the mechanotransduction signaling driving altered islet function in response to mechanical cues. We hypothesized that increasing matrix stiffness will lead to insulin secretion dysfunction by opening the mechanosensitive ion channel Piezo1 and disrupting intracellular Ca2+ dynamics in mouse and human islets. To test our hypothesis, mouse and human cadaveric islets were encapsulated in a biomimetic reverse thermal gel (RTG) scaffold with tailorable stiffness that allows formation of islet focal adhesions with the scaffold and activation of Piezo1 in 3D. Our results indicate that increased scaffold stiffness causes insulin secretion dysfunction mediated by increases in Ca2+ influx and altered Ca2+ dynamics via opening of the mechanosensitive Piezo1 channel. Additionally, inhibition of Piezo1 rescued glucose-stimulated insulin secretion (GSIS) in islets in stiff scaffolds. Overall, our results emphasize the role mechanical properties of the islet microenvironment plays in regulating function. It also supports further investigation into the modulation of Piezo1 channel activity to restore islet function in diseases like type 2 diabetes (T2D) and pancreatic cancer where fibrosis of the peri-islet ECM leads to increased tissue stiffness and islet dysfunction.

The ablative effect of mitomycin reverse thermal gel: Expanding the role for nephron preservation therapy in low grade upper tract urothelial carcinoma.

Assess the real-world ablative effect of mitomycin reverse thermal gel for low-grade upper tract urothelial carcinoma (UTUC) in patients who undergo biopsy only or partial ablation and evaluate utility of complete ablation prior to UGN-101. We retrospectively reviewed low-grade UTUC patients treated with UGN-101 from 15 high-volume centers. Patients were categorized based on initial endoscopic ablation (biopsy only, partial ablation, or complete ablation) and by size of remaining tumor (complete ablation, <1cm, 1-3cm, or >3cm) prior to UGN-101. The primary outcome was rendered disease free (RDF) rate at first post-UGN-101 ureteroscopy (URS), defined as complete response or partial response with minimal mechanical ablation to endoscopically clear the upper tract of visible disease. One hundred and sixteen patients were included for analysis after excluding those with high-grade disease. At first post-UGN-101 URS, there were no differences in RDF rates between those who at initial URS (pre-UGN-101) had complete ablation (RDF 77.0%), partial ablation (RDF 55.9%) or biopsy only (RDF 66.7%) (P = 0.14). Similarly, a complimentary analysis focusing on tumor size (completely ablated, <1cm, 1-3cm or >3cm) prior to UGN-101 induction did not demonstrate significant differences in RDF rates (P = 0.17). The results of the early real-world experience suggest that UGN-101 may play a role in initial chemo-ablative cytoreduction of larger volume low-grade tumors that may not initially appear to be amenable to renal preservation. Further studies will help to better quantify the chemo-ablative effect and to identify clinical factors for patient selection.

1756-P: Extracellular Matrix Stiffness Mediates Insulin Secretion in Pancreatic Islets via Phosphofructokinase Activity

Pancreatic islets are surrounded by extracellular matrix (ECM) which provides mechanical and biochemical cues to the β-cells that regulate survival and insulin secretion. Changes to ECM stiffness have been correlated to dysfunction in insulin secretion that is directly coupled to glucose metabolism; however, the mechanisms of mechanotransduction regulating insulin secretion have not been studied in the islet. We hypothesize that increasing matrix stiffness will increase islet glucose sensitivity by increasing phosphofructokinase (PFK) activity. To determine the effect of changes in ECM stiffness on islet function we encapsulated mouse islets in a reverse thermal gel (RTG) scaffold with increasing stiffness as determined by rheological analysis. Glucose-stimulated insulin secretion, PFK activity, and PFK expression was measured after 24 hours of culture. Proliferation was analyzed by immunohistochemistry of Ki-67. Reactive oxygen species (ROS) were measured via confocal microscopy of islets transfected with an adenoviral ROS sensor. We found that increasing RTG wt% yielded increasing stiffness at 40°C. Insulin secretion increased as the matrix stiffness increased in basal (2mM) and high glucose (20mM) conditions. Insulin secretion at 20mM glucose normalized to 2mM glucose (stimulation index) decreases with matrix stiffness indicating dysfunction to insulin secretion. PFK activity increased in islets encapsulated in stiffer RTGs. No changes in proliferation were observed in any samples compared to controls. Our results support a role for ECM stiffness in regulating insulin secretion via PFK activity. This work provides insight into how changes in ECM stiffness contribute to islet dysfunction, as in pancreatitis and T2D. Our results will inform future development of mechanically tuned microenvironments for differentiation of iPSCs into functional β-cells and provide novel targets to protect against islet dysfunction in T2D. Disclosure C.Garcia: None. K.Holcomb: None. N.L.Farnsworth: None. Funding American Diabetes Association (7-21-JDF-020 to N.L.F.); National Institutes of Health (1F31DK132926-01A1); JDRF (3-APF-2019-749-A-N, 1-FAC-2020-891-A-N)

Editorial Comment.

No AccessJournal of UrologyAdult Urology23 Feb 2023Editorial Comment Antonio Franc and Riccardo Autorino Antonio FrancAntonio Franc Department of Urology, Rush University, Chicago, Illinois More articles by this author and Riccardo AutorinoRiccardo Autorino Department of Urology, Rush University, Chicago, Illinois More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003185.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, Publish Ahead of Print, pp. – REFERENCES 1. . Durability of response to primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel: OLYMPUS trial final report. J Urol.2022; 207(4):779-88. Link, Google Scholar 2. . Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol.2020; 21(6):776-785. Crossref, Medline, Google Scholar 3. . Efficacy and safety of mitomycin gel (UGN-101) as an adjuvant therapy after complete endoscopic management of upper tract urothelial carcinoma. J Urol.2023; 209(5):000-000. Google Scholar Submitted July 22, 2022; accepted January 10, 2023; published 000. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antonio Franc Department of Urology, Rush University, Chicago, Illinois More articles by this author Riccardo Autorino Department of Urology, Rush University, Chicago, Illinois More articles by this author Expand All Submitted July 22, 2022; accepted January 10, 2023; published 000. Advertisement PDF downloadLoading ...

Efficacy and Safety of Mitomycin Gel (UGN-101) as an Adjuvant Therapy After Complete Endoscopic Management of Upper Tract Urothelial Carcinoma.

We describe a novel application of the reverse thermal polymer gel of mitomycin C (UGN-101) as adjuvant therapy after complete endoscopic ablation of upper tract urothelial carcinoma. We retrospectively reviewed patients treated with UGN-101 from 15 high-volume centers. Adjuvant therapy was defined as treatment administered following visually complete endoscopic ablation. Response at primary endoscopic evaluation was defined as no visual tumor or negative biopsy. Ipsilateral disease-free and progression-free survival were estimated by the Kaplan-Meier method. Ureteral stenosis and other adverse events were abstracted from the medical records. Ureteral stenosis was defined as a condition requiring ureteral stent or nephrostomy, or that would typically warrant stent or nephrostomy. Adjuvant UGN-101 after complete endoscopic ablation was used in 52 of 115 (45%) renal units in the oncologic analysis. At first endoscopic evaluation, 36/52 (69%) were without visible disease. At 6.8 months' median follow-up, the ipsilateral disease-free rate was 63%. Recurrence after adjuvant UGN-101 therapy was more likely in multifocal tumors compared to unifocal (HR 3.3, 95% CI 1.07-9.91). Compared with UGN-101 treatment for chemoablation of measurable disease, there were significantly fewer disease detections with adjuvant therapy (P < .001). Ureteral stenosis after UGN-101 was diagnosed in 10 patients (19%) undergoing adjuvant therapy compared to 17 (29%) undergoing chemoablative therapy (P = .28). In patients being considered for UGN-101, maximal endoscopic ablation prior to UGN-101 treatment may result in fewer patients with disease at first endoscopy and possibly fewer adverse events than primary chemoablative therapy. Longer follow-up is needed to determine if UGN-101 after complete endoscopic ablation will lead to durable disease-free interval.

Editorial Comment.

No AccessJournal of UrologyAdult Urology1 Jan 2023Editorial CommentThis article comments on the following:Patient and Provider Perception of Transurethral Resection of Bladder Tumor vs Chemoablation for Nonmuscle-invasive Bladder Cancer Treatmentis a letter which has replyReply by Authors Esther L. Finney, Kristian D. Stensland, and Harras B. Zaid Esther L. FinneyEsther L. Finney Institute of Urology, Lahey Hospital and Medical Center, Burlington, Massachusetts More articles by this author , Kristian D. StenslandKristian D. Stensland Department of Urology, University of Michigan, Ann Arbor, Michigan More articles by this author , and Harras B. ZaidHarras B. Zaid Urology Austin, Austin, Texas More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002941.02AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 209(1), pp. 159–160 Reference 1. Primary chemoablation of low-grade intermediate-risk nonmuscle-invasive bladder cancer using UGN-102, a mitomycin-containing reverse thermal gel (Optima II): a phase 2b, open-label, single-arm trial. J Urol. 2022; 207(1):61-69. Link, Google Scholar © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology6 Sep 2022Patient and Provider Perception of Transurethral Resection of Bladder Tumor vs Chemoablation for Nonmuscle-invasive Bladder Cancer TreatmentJournal of Urology10 Oct 2022Reply by Authors Volume 209Issue 1January 2023Page: 159-160 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Esther L. Finney Institute of Urology, Lahey Hospital and Medical Center, Burlington, Massachusetts More articles by this author Kristian D. Stensland Department of Urology, University of Michigan, Ann Arbor, Michigan More articles by this author Harras B. Zaid Urology Austin, Austin, Texas More articles by this author Expand All Advertisement PDF downloadLoading ...

Injectable carbon nanotube-functionalized hydrogel as a tool for cardiac tissue engineering

Abstract Background/Introduction Heart failure (HF) is an expensive major public health problem in the United States and around the world (1). The current treatments for HF are aimed at reducing symptoms, slowing disease progression, and reducing mortality and not aimed at repairing heart muscle or restoring function. Furthermore, even with these treatments, approximately half of patients with HF will die within 5 years of diagnosis (2). Cardiac transplantation remains the only definitive treatment for those affected with end-stage HF, but availability of donor hearts remains a major limitation (3). Purpose The ability of the adult heart to regenerate cardiomyocytes (CMs) lost after injury is limited, generating interest in developing tissue engineering therapies to avoid progression towards HF. Rigid carbon nanotubes (CNTs) scaffolds have been used to improve CMs viability, proliferation, and maturation (4), but require undesirable invasive surgeries for implantation. To overcome this limitation, we engineered an injectable reverse thermal gel (RTG) functionalized with CNTs (RTG-CNT) that transitions from a liquid-solution to a gel-based matrix shortly after reaching body temperature allowing for a liquid-based delivery rapidly followed by a stable-gel localization (5). Methods and results Here we show experimental evidences the RTG-CNT hydrogel, used as a three-dimensional (3D) niche to culture human induced pluripotent stem cells (hiPSC)-CMs, promotes hiPSC-CMs alignment and elongation with increased Cx43 localization and improved contraction function when compared with traditional two-dimensional (2D) fibronectin controls and plain 3D RTG system without CNTs. Moreover, the short-term (4-week) biocompatibility of the RTG-CNT hydrogel was also assessed in a mouse model (intracardial injection). The results confirmed that the RTG-CNT hydrogel is well tolerated by the cardiac tissue. Conclusion Our results indicated that the injectable RTG-CNT hydrogel has the potential to be used as a minimally invasive tool for cardiac tissue engineering efforts. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): NATIONAL HEART, LUNG, AND BLOOD (NHLBI) INSTITUTE

The role of endoscopic management and adjuvant topical therapy for upper tract urothelial cancer.

Upper tract urothelial carcinoma (UTUC) has traditionally been managed with radical nephroureterectomy, and while this approach remains the gold standard for high-risk disease, endoscopic, kidney-sparing management has increasingly been adopted for low-risk disease as it preserves kidney function without compromising oncologic outcomes. Ureteroscopy and percutaneous renal access not only provide diagnoses by tumor visualization and biopsy, but also enable treatment with electrocautery or laser ablation. Several modalities exist for laser ablative treatments including thulium:YAG, neodymium:YAG, holmium:YAG, and combinations of the preceding. Furthermore, due to high recurrence rates after endoscopic management, adjuvant intracavitary instillation of various agents such as mitomycin C and bacillus Calmette-Guerin have been used given benefits seen in non-muscle invasive urothelial bladder cancer. Other formulations also being studied include gemcitabine, anthracyclines, and immunotherapies. More recently, Jelmyto, a mitomycin reverse thermal gel, has been developed to allow for adequate drug delivery time and potency since urine flow could otherwise dilute and washout topical therapy. In this article, the authors review techniques, indications, best practices, and areas of current investigation in endoscopic management and adjuvant topical therapy for UTUC.

Minimal Patient-Reported Side Effects for a Chemoablative Gel (UGN-102) Used as Frontline Treatment in Adults with Nonmuscle-Invasive Bladder Cancer

Optima II ("OPTimized Instillation of Mitomycin for Bladder Cancer Treatment," clinicaltrials.gov: NCT03558503) was a phase 2b trial evaluating a nonsurgical alternative as a primary treatment for nonmuscle-invasive bladder cancer (NMIBC). Patients received 6 weekly instillations of UGN-102, a mitomycin-containing reverse thermal gel. This is the first study to report on patient-reported side effects of UGN-102. Sixty-three patients enrolled in Optima II from 20 sites. Of these 63 patients, 44 were in the cohort completing a quarterly patient-reported outcome measure assessing side effects. Changes in side effects were evaluated using the Wilcoxon signed-rank test. Associations of 3-month outcomes with demographic and clinical characteristics were examined with regression, controlling for baseline values. Ten of 44 patients (23%) were interviewed after the trial to understand tolerability for future patients making treatment decisions. Transcripts were double-coded using standard methods. In the patient-reported outcome measure cohort (44), 61% were men, 57% aged 65+ years and 89% were non-Hispanic White. UGN-102 did not cause decrements in patient-reported urinary symptoms, bloating/flatulence or malaise at the primary endpoint of 3 months. Sexual function mildly worsened. Future health worries improved. Demographics were not correlated with changes. Clinically, sexual function was correlated with new NMIBC and bloating/flatulence was associated with transurethral resection of bladder tumor within 12 months. In interviews, patients appreciated a nonsurgical alternative, would recommend the gel to other patients and would choose the gel over surgery. A nonsurgical, chemoablative gel (UGN-102) used as a primary treatment for NMIBC offers a more patient-centered therapeutic approach than standard treatments.

MP54-06 LONGITUDINAL HEALTH-RELATED QUALITY OF LIFE OUTCOMES IN ADULTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER RECEIVING A CHEMOABLATIVE GEL AS A PRIMARY TREATMENT (OPTIMA II: PHASE 2B, SINGLE ARM, OPEN-LABEL TRIAL)

You have accessJournal of UrologyCME1 May 2022MP54-06 LONGITUDINAL HEALTH-RELATED QUALITY OF LIFE OUTCOMES IN ADULTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER RECEIVING A CHEMOABLATIVE GEL AS A PRIMARY TREATMENT (OPTIMA II: PHASE 2B, SINGLE ARM, OPEN-LABEL TRIAL) Angela Smith, Ramsankar Basak, Dana Mueller, Robert Lipman, Randall Teal, Alison Hilton, Kara Giannone, Myra Waheed, and Angela Stover Angela SmithAngela Smith More articles by this author , Ramsankar BasakRamsankar Basak More articles by this author , Dana MuellerDana Mueller More articles by this author , Robert LipmanRobert Lipman More articles by this author , Randall TealRandall Teal More articles by this author , Alison HiltonAlison Hilton More articles by this author , Kara GiannoneKara Giannone More articles by this author , Myra WaheedMyra Waheed More articles by this author , and Angela StoverAngela Stover More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Low-grade non-muscle-invasive bladder cancer (LG NMIBC) is treated with transurethral resection of the bladder tumor (TURBT), which can worsen health-related quality of life (HRQOL). The trial “OPTimized Instillation of Mitomycin for Bladder Cancer Treatment” (Optima II, clinicaltrials.gov: NCT03558503) is a Phase 2b, open label, multicenter trial evaluating a nonsurgical alternative as a primary treatment. Patients receive six weekly instillations of UGN-102, a mitomycin-containing reverse thermal gel. We report on HRQOL changes at the primary endpoint of 3 months. METHODS: Of 63 patients enrolled in the Optima II trial, 44 were in the HRQOL cohort and completed quarterly questionnaires (61% men, 57% age 65+, and 89% non-Hispanic White). Longitudinal changes were evaluated using the Sign test and correlations with demographic and clinical characteristics with regression. Ten patients (23%) were interviewed and transcripts were double-coded using standard methods. RESULTS: The chemoablative reverse thermal gel did not cause decrements in patient-reported urinary symptoms, bloating/flatulence, or malaise (Figure). Sexual function mildly worsened. Demographic and clinical characteristics were not correlated with HRQOL changes. By 3 months, 31/44 (70%) LG NMIBC patients achieved a complete response (negative endoscopic examination, cytology, and for-cause biopsy). In interviews, patients appreciated a nonsurgical alternative, would recommend the gel to other patients, and would choose the gel over TURBT. CONCLUSIONS: Adults with LG NMIBC receiving a nonsurgical, chemoablative gel as a primary treatment maintained their HRQOL through 3 months, and interviewed patients would recommend the gel to other patients. A Phase 3 trial is warranted. Source of Funding: Bladder Cancer Advocacy Network Patient Survey Network Award, supported by Urogen Pharma © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e928 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Angela Smith More articles by this author Ramsankar Basak More articles by this author Dana Mueller More articles by this author Robert Lipman More articles by this author Randall Teal More articles by this author Alison Hilton More articles by this author Kara Giannone More articles by this author Myra Waheed More articles by this author Angela Stover More articles by this author Expand All Advertisement PDF DownloadLoading ...

Editorial Comment.

No AccessJournal of UrologyNew Technology and Techniques1 Jun 2022Editorial CommentThis article comments on the following:Antegrade Instillation of UGN-101 (Mitomycin for Pyelocalyceal Solution) for Low-Grade Upper Tract Urothelial Carcinoma: Initial Clinical Experienceis a letter which has replyReply by Authors Craig V. Labbate, Mehrad Adibi, and Surena F. Matin Craig V. LabbateCraig V. Labbate Department of Urology, MD Anderson Cancer Center, Houston, Texas More articles by this author , Mehrad AdibiMehrad Adibi Department of Urology, MD Anderson Cancer Center, Houston, Texas More articles by this author , and Surena F. MatinSurena F. Matin Department of Urology, MD Anderson Cancer Center, Houston, Texas More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002454.02AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 207(6), pp. 1309–1310 Reference 1. : Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol 2020; 21: 776. Google Scholar © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyFeb 7, 2022, 12:00:00 AMAntegrade Instillation of UGN-101 (Mitomycin for Pyelocalyceal Solution) for Low-Grade Upper Tract Urothelial Carcinoma: Initial Clinical ExperienceJournal of UrologyMar 3, 2022, 12:00:00 AMReply by Authors Volume 207Issue 6June 2022Page: 1309-1310 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Craig V. Labbate Department of Urology, MD Anderson Cancer Center, Houston, Texas More articles by this author Mehrad Adibi Department of Urology, MD Anderson Cancer Center, Houston, Texas More articles by this author Surena F. Matin Department of Urology, MD Anderson Cancer Center, Houston, Texas More articles by this author Expand All Advertisement PDF DownloadLoading ...

This Month in Adult Urology

This Month in Adult Urology

Editorial Comment.

No AccessJournal of UrologyAdult Urology1 Apr 2022Editorial CommentThis article comments on the following:Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Reportis a letter which has replyReply by Authors Rodrigo Rodrigues Pessoa Rodrigo Rodrigues PessoaRodrigo Rodrigues Pessoa Division of Urology, University of Colorado, Aurora, Colorado More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002350.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 207(4), p. 788

This Month in Adult Urology

This Month in Adult Urology

Preliminary Results of a Reverse Thermal Gel Patch for Fetal Ovine Myelomeningocele Repair

BackgroundPrenatal surgical closure of Myelomeningocele (MMC) is considered part of the current age armamentarium. Clinical data has demonstrated the need for innovative patches to maximize the benefits and decrease the risks of this approach. Our team has developed a minimally invasive reverse thermal gel (RTG) patch with cellular scaffolding properties. Here, we demonstrate the initial gross and microscopic histological effects of this RTG patch in the fetal ovine model of MMC. Materials and MethodsA fetal ovine MMC defect was created at 68-75 days gestation, RTG patch application or untreated at 100-103 days, and harvest at 135-140 days. The RTG was applied to the defect and secured in place with an overlay sealant. Defect areas underwent gross and microscopic analysis for inflammation and skin development. Brains were analyzed for hindbrain herniation and hydrocephalus. ResultsThe untreated fetus (n = 1) demonstrated an open defect lacking tissue coverage, evidence of spinal cord injury, increased caspase-3, Iba1 and GFAP in spinal cord tissues, and hindbrain herniation and ventricular dilation. RTG treated fetuses (n = 3) demonstrated defect healing with well-organized dermal and epidermal layers throughout the entire healed tissue area overlaying the defect with minimal inflammation, reduced caspase-3, Iba1 and GFAP in spinal cord tissues, and no hindbrain herniation or ventricular dilation. ConclusionAn RTG patch applied to MMC defects in fetal sheep promoted skin coverage over the defect, was associated with minimal inflammation of the spinal cord tissues and prevented brain abnormalities. The present findings provide exciting results for future comprehensive radiological, functional, and mechanistic evaluation of the RTG.

Health-related quality of life outcomes in adults with nonmuscle-invasive bladder cancer receiving a mitomycin-containing reverse thermal gel as a primary treatment (Optima II: Phase 2b, single-arm, open-label trial).

270 Background: The standard of care for low-grade non‐muscle‐invasive bladder cancer (LG NMIBC) is transurethral resection of the bladder tumor, which can worsen health‐related quality of life (HRQOL). The “OPTimized Instillation of Mitomycin for Bladder Cancer Treatment” (Optima II, clinicaltrials.gov: NCT03558503) is a Phase 2b, open label, single arm, multicenter trial evaluating a nonsurgical alternative as a primary treatment. Patients receive six weekly instillations of UGN-102, a mitomycin-containing reverse thermal gel with a sustained release time of up to 8 hours. We report on HRQOL changes between baseline and the primary endpoint of 3 months. Methods: A total of 63 patients enrolled in the Optima II trial at 20 sites in the U.S. and 2 sites in Israel between October 2018 and October 2020. Of the 63 patients enrolled, 44 were in the HRQOL cohort and completed a quarterly questionnaire. The QLQ-NMIBC24 has six subscales (urinary symptoms, malaise, future health worries, bloating and flatulence, sexual functioning, and male sexual problems) and five single items (intravesical treatment issues, sexual intimacy, worry about contaminating partner, sexual enjoyment, and female sexual problems) assessed with 24 items. Items were rescaled to 0-100 and reverse-coded so that higher scores indicate worse symptom burden. Longitudinal score changes were evaluated using the Sign test. We examined demographic and clinical characteristics associated with HRQOL change scores with regression modeling. A p-value of ≤0.01 was used. Results: The HRQOL cohort was 61% men, 57% age 65+, and 89% non-Hispanic White. Clinically, most LG NMIBC patients had multiple tumors (88%) with prior NMIBC episodes (77%), and two or more prior transurethral resection of bladder procedures (TURBT) (85%). Approximately half (55%) had their most recent TURBT surgery within 12 months of trial enrollment. No patients had missing HRQOL data at baseline or the primary end point of 3 months. The chemoablative reverse thermal gel used as a primary treatment did not cause decrements in patient-reported urinary symptoms, bloating/ flatulence, malaise, fever, general health, or future health worries. Sexual function mildly worsened between baseline and 3 months, and abated by 6 months. Demographic and clinical characteristics were not correlated with HRQOL change scores. By 3 months, 31/44 (70%) LG NMIBC patients achieved a complete response (negative endoscopic examination, cytology, and for-cause biopsy) and 0 experienced a recurrence. By 12 months, 8/44 (18%) patients had a recurrence. Conclusions: Adults with LG NMIBC in a Phase 2b trial who received a mitomycin-containing reverse thermal gel with sustained release maintained their HRQOL through 3 months. A Phase 3 trial is warranted. Clinical trial information: NCT03558503.

MP48-18 FEMALE PATIENTS WITH LOW-GRADE UPPER TRACT UROTHELIAL CARCINOMA: PRIMARY CHEMOABLATION AND DURABILITY OF RESPONSE IN A SUBGROUP ANALYSIS FROM THE OLYMPUS TRIAL

MP48-18 FEMALE PATIENTS WITH LOW-GRADE UPPER TRACT UROTHELIAL CARCINOMA: PRIMARY CHEMOABLATION AND DURABILITY OF RESPONSE IN A SUBGROUP ANALYSIS FROM THE OLYMPUS TRIAL

PD43-02 PRIMARY CHEMOABLATION OF LOW-GRADE INTERMEDIATE-RISK NON-MUSCLE-INVASIVE BLADDER CANCER USING UGN-102, A MITOMYCIN-CONTAINING REVERSE THERMAL GEL (OPTIMA II): A PHASE 2b, OPEN-LABEL, SINGLE-ARM TRIAL

PD43-02 PRIMARY CHEMOABLATION OF LOW-GRADE INTERMEDIATE-RISK NON-MUSCLE-INVASIVE BLADDER CANCER USING UGN-102, A MITOMYCIN-CONTAINING REVERSE THERMAL GEL (OPTIMA II): A PHASE 2b, OPEN-LABEL, SINGLE-ARM TRIAL

LBA02-10 LONG-TERM RECURRENCE FREE SURVIVAL FOLLOWING UGN-101 TREATMENT FOR LOW-GRADE UPPER TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyLate-breaking Abstract II - Malignant1 Sep 2021LBA02-10 LONG-TERM RECURRENCE FREE SURVIVAL FOLLOWING UGN-101 TREATMENT FOR LOW-GRADE UPPER TRACT UROTHELIAL CARCINOMA Nir Kleinmann, Phillip Pierorazio, Jay Raman, Scott Hubosky, Ahmad Shabsigh, Brian Hu, Hristos Kaimakliotis, Marcelino Rivera, Douglas Scherr, Alon Weizer, Raymond Pak, Mark Schoenberg, Elyse Seltzer, and Karim Chamie Nir KleinmannNir Kleinmann More articles by this author , Phillip PierorazioPhillip Pierorazio More articles by this author , Jay RamanJay Raman More articles by this author , Scott HuboskyScott Hubosky More articles by this author , Ahmad ShabsighAhmad Shabsigh More articles by this author , Brian HuBrian Hu More articles by this author , Hristos KaimakliotisHristos Kaimakliotis More articles by this author , Marcelino RiveraMarcelino Rivera More articles by this author , Douglas ScherrDouglas Scherr More articles by this author , Alon WeizerAlon Weizer More articles by this author , Raymond PakRaymond Pak More articles by this author , Mark SchoenbergMark Schoenberg More articles by this author , Elyse SeltzerElyse Seltzer More articles by this author , and Karim ChamieKarim Chamie More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002149.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Standard treatment for low-grade upper tract urothelial carcinoma (LG UTUC) involving the renal pelvis and calyces is radical nephroureterectomy (RNU), or nephron-sparing endoscopic surgery in patients with small, unifocal tumors. The OLYMPUS trial (NCT02793128) previously reported an estimated durability of response of 84% at 12 months in patients achieving complete response (CR) after induction treatment with UGN-101 (JELMYTO), a mitomycin-containing reverse thermal gel. Here, we provide further long-term durability data obtained via post-approval follow-up of participants in the OLYMPUS trial. METHODS: In OLYMPUS, 71 patients were enrolled and treated with ≥1 instillation of UGN-101. Of these, 42 (59%) achieved CR at the primary disease evaluation that occurred 4-6 weeks following completion of induction therapy. At 12 months follow up 23 patients had durable CR and the median duration of response was not estimable. Updates on disease status for the 23 patients with durable CR were collected biannually (data cut off 04 Mar 2021) following study completion and are presented below. RESULTS: Duration of response (DOR) data were available for 15 of the 23 patients who had durable CR. Of the remaining 8 patients, 5 participated at sites that had not yet initiated the follow-up protocol, 2 had no new data available since the last assessment in OLYMPUS, and 1 was lost to follow-up. The median (range) DOR among the 15 available patients was 28.1 months (14.6 to 37.1 months). DOR was calculated as the time from the first documented CR until disease recurrence or death or last adequate disease assessment (for patients with ongoing CR). As of the data cutoff date, 12 (80.0%) patients had an ongoing CR, 2 (13.3%) patients had recurrence of LG UTUC in the ipsilateral side as treated, and 1 (6.7%) patient underwent RNU. Both patients with disease recurrence underwent endoscopic ablation. Notably, RNU was performed due to left ureteral stricture and there was no evidence of UTUC at the time of surgery. No patients had progression to high-grade UTUC or developed metastasis. Disease-specific survival was 100% at last follow-up. CONCLUSIONS: Long-term follow up suggests treatment with UGN-101 for LG UTUC can result in a lengthy period of durable response and may exceed that achieved by surgical nephron-sparing approaches such as laser ablation (42% recurrence after a median follow up of 32 months). Limitations of this study include small sample size and follow-up patient data. Source of Funding: This trial was supported with funding from UroGen Pharma © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1179-e1179 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nir Kleinmann More articles by this author Phillip Pierorazio More articles by this author Jay Raman More articles by this author Scott Hubosky More articles by this author Ahmad Shabsigh More articles by this author Brian Hu More articles by this author Hristos Kaimakliotis More articles by this author Marcelino Rivera More articles by this author Douglas Scherr More articles by this author Alon Weizer More articles by this author Raymond Pak More articles by this author Mark Schoenberg More articles by this author Elyse Seltzer More articles by this author Karim Chamie More articles by this author Expand All Advertisement Loading ...

Pharmacokinetics of UGN-101, a mitomycin-containing reverse thermal gel instilled via retrograde catheter for the treatment of low-grade upper tract urothelial carcinoma

PurposeTo evaluate the pharmacokinetic properties of UGN-101, a mitomycin-containing reverse thermal gel used as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC), in a subset of patients participating in a phase 3 clinical trial.MethodsPharmacokinetic parameters (Cmax, Tmax, AUC(0–6), λz, t½, and AUCinf) were evaluated in six participants (male or female, ≥ 18 years) with biopsy-proven, low-grade UTUC who received the first of 6 once-weekly instillations of UGN-101 to the renal pelvis and calyces via retrograde ureteral catheter. Plasma samples were collected prior to instillation and 30 min, 1, 2, 3, 4, 5, and 6 h post-instillation. Safety was assessed by laboratory evaluations, physical exam, and adverse event monitoring.ResultsThe mean age of the six participants was 69 years; most were male (5/6) and Caucasian (5/6). Mean (SD) Cmax was 6.24 (4.11) ng/mL and mean Tmax was 1.79 (1.89) hours after instillation. Mean apparent t½ following instillation was 1.27 (0.63) hours. Mean total systemic exposure to mitomycin up to 6 h post-instillation was 20.30 (19.69) ng h/mL. At 6 h post-instillation, mitomycin plasma concentrations of 5/6 participants were < 2 ng/mL. There were no clinically important adverse events or changes in laboratory values in any participant after a single instillation of UGN-101.ConclusionThe reverse thermal gel formulation of UGN-101 is associated with higher concentration and extended dwell time of mitomycin in contact with the urothelium of the upper urinary tract while limiting systemic absorption of mitomycin.RegistrationNCT02793128; registered June 8, 2016.