Transitional Cell Carcinoma Of Urothelium Research Articles

Bladder carcinomas in patients with neurogenic bladder and urinary schistosomiasis: are they the same tumors?

The aim of our study was to evaluate and compare the expression of different immunohistochemical markers in Bladder Carcinomas (BC) in patients with Neurogenic Bladder (NB) and Urinary Schistosomiasis (US) infection. We collected tissue samples from patients with Neurogenic Bladder and Bladder Carcinoma (NBC Group) and from patients with Urinary Schistosomiasis infection and Bladder Carcinoma (SBC Group). We compared to these two groups to control samples from resection from patients with Urinary Schistosomiasis without Bladder Carcinoma (US Group); we also investigate patients' characteristics according to urothelial transitional cell carcinoma (TCC), and squamous cell carcinoma (SCC) histopathological differentiation. The expression of markers in all groups (CK7, CK14, CK20, FoxP3, GATA3, STAG2, CD3, CD8, Ki67, and P53) was analyzed using immunohistochemistry of tissue micro-array sections (TMA). Overall, 136 patients were included in the study (n = 72 in the NBC group, n = 33 in the SBC group, and n = 31 in the US group). In the TCC subgroup, the expression of CK7, CK14, CK20, and Ki67 was significantly higher compared to US controls (p 0.002; p < 0.001; p 0.036; p < 0.001). In the SCC subgroup, the expression of CK7, CK14, and CK20 was significantly higher compared to US controls (p 0.007; p < 0.001; p 0.005). Both in TCC and SCC subgroups, no difference in the expression of any tested markers was found comparing NBC and SBC groups. In US group, a significant higher expression of STAG2 was found compared to SCC subgroup (p 0.005). Based on our results, the profile of immunohistochemical biomarkers' expression in both NBC and SBC groups is similar.

Molecular determinants of recurrences of the human urothelial tumor

Background. Urothelial carcinoma (UTC) is an aggressive disease with a known propensity for frequent recurrence. It is difficult to predict the velocity of the development of UTC recur using modern means of clinical diagnostics. Therefore, the development of the capabilities of histo-morphological study of tumor tissues is of particular relevance.Materials and methods. The materials of publications (PubMed, CrossRef) for 1990-2021, devoted to the choice of biomarkers for the diagnosis of UTC, the analysis of molecular pathways, progression and metastasis, were studied. The search was carried out for the key phrases "urothelial carcinoma", "recurrent UTK", "stem cells", "biomarkers of bladder cancer", "genetic changes in urothelium", "circulating tumor DNA".Results. Cancer stem cells serve as a source of UTC recurrence after removal from the primary focus, localizing in any areas of the urothelium, as well as outside the main tumor focus and are characterized by a common genotype, but different phenotypic manifestations. To predict the recurrence of the tumour is advisable to use gene expression signatures, since the subtypes of UTC are characterized by clear gene expression profiles. A larger sample and independent dataset is needed to confirm the clinical significance of the findings. Combined biomarkers predict UTC behavior, and FGFR3 and TP53 mutations can be components for a panel for predicting UTC recurrence. The use of the liquid biopsy method with the determination of the level of circulating tumor DNA is a promising diagnostic method that needs to evaluate the results of an initiated randomized trial.Conclusion. The accumulation of knowledge base about the molecular patterns of UTC will help bridge the gap between the results of molecular genetic and clinical diagnostics. Molecular changes in the transitional cell UTC demonstrates a high potential for determining the timing of tumor recurrence, assessing disease-free survival of patients and for planning the resource base of the healthcare system.

P0233ISOLATED MICROHEMATURIA IN ADOLESCENTS IS NOT ASSOCIATED WITH RENAL OR URINARY TRACT CANCER IN MIDDLE AGE

Abstract Background and Aims Chronic or persistent isolated microhematuria (microhematuria without proteinuria) is not as benign as originally thought. It has been associated with an almost 20-fold risk of developing ESRD ( End Stage Renal Disease) in adulthood. It is still unclear if this chronic glomerular bleed increases the risk of renal or urinary tract tumors, secondary to ongoing irritation and inflammation. This is a valid question, especially as an adult with long standing isolated “glomerular” microhematuria can appear with an event of macrohematuria. In order to answer these questions, we studied the association between adolescent microhematuria and renal or urinary tract tumors in adulthood. Method A retrospective study based on a cohort of 2,172,866 Jewish adolescents (60% men) aged 16-19 who underwent a mandatory physical examination between ages of 16 and 19 years from 1967 to 2007 prior to their conscription. Urothelial Transitional cell carcinoma (TCC) and Renal cell carcinoma (RCC) incidence through December 31, 2012 was identified by linkage to the national cancer registry. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) for RCC and TCC among adolescents who were diagnosed with persistent asymptomatic isolated hematuria after comprehensive medical evaluation. The models were adjusted for: Sex, age, year of birth, socio-economic status, BMI, years of education and country of origin. Results Over a median of 22 years (interquartile range of 13-31 years) of follow-up, 2007 and 1112 incident cases of TCC and RCC, respectively, occurred amongst the study population. Persistent hematuria was not associated with TCC with crude HR 1.15 (95% CI, 0.37-3.57) and adjusted HR of 1.08 (95% CI, 0.35-3.36), nor with RCC with crude HR 1.11 (95% CI, 0.28-4.457) and adjusted HR of 0.93 (95% CI, 0.23-3.75). Conclusion Isolated persistent microhematuria, while carrying a small risk of kidney disease progression, is not associated with either renal or urinary tract tumors. Screening guidelines among these patients should follow the general age and sex- matched approach.

Intravenous 5-fluoro-2\u2032-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors

PurposeFollowing promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs).MethodsPatients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis.ResultsNinety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal—though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response.ConclusionFurther study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.

An open-label, multicenter, phase IIIb study of patients with urinary tract carcinoma (UTC) (STRONG): Interim safety results for fixed-dose durvalumab (D) monotherapy (module A).

484 Background: Patients (pts) with advanced UTC who fail first-line therapy have a poor prognosis and limited treatment options, with only modest benefit from chemotherapy. D (anti-PD-L1 antibody) is approved for the treatment of metastatic urothelial carcinoma after progression on platinum-based chemotherapy. Methods: Module A of the phase IIIb STRONG study (NCT03084471) will determine the short- and long-term safety of a fixed dose of D monotherapy (1500 mg, every 4 weeks) in pts with urothelial and non-urothelial carcinoma of the UT who progressed on or after prior chemotherapy. The primary endpoint is to determine the number of pts with adverse events of special interest (AESIs). This analysis included AEs with onset date on or after the date of first dose and up to 90 days after discontinuation of study treatment. Interim results from module A are reported. Results: A total of 700 pts received D monotherapy. Median age was 68.2 yr and 79.6% were male; 88.6% had an ECOG PS 0 or 1 and 11.3% an ECOG PS 2. Most (88.4%) had urothelial (transitional cell) carcinoma. Tumor PD-L1 expression was high (tumor or immune cell membrane positivity ≥25%) in 183/436 (42%) pts with PD-L1 data. Median treatment duration was 11.7 weeks (range, 1-73). AEs of any grade were reported in 86.9% of pts (Table), and in 89.0%, 86.9%, and 78.5% of pts with ECOG PS 0, 1, or 2, respectively. The most common grade ≥3 AESI was increased lipase (1.4%). Deaths related to study treatment occurred in 10 pts (1.4%). Conclusions: Fixed-dose D monotherapy has an acceptable safety profile as second-line therapy for UTC. Long-term safety data reported here are consistent with published studies of D monotherapy. Clinical trial information: NCT03084471.

Immune Sculpting of Clonal Hematopoiesis in Advanced and Metastatic Solid Tumors

Clonal hematopoiesis (CH) is described as the phenomenon where hematopoietic cells acquire advantageous somatic mutations that result in a dominant subclonal population. These subclones are linked to various adverse outcomes such as elevated risk of hematologic malignancies and cardiovascular disease. Few studies, however, address the presence and role of CH in clinically-relevant advanced and metastatic solid tumors or how progression of CH is altered via immune selection. Here, we identified and quantified CH mutations in 883 patients with 64 different advanced solid cancer subtypes. The age of patients ranged from 1 to 96, with the average age being 66.7 years. In this cohort, whole exome sequencing (WES) of tumor and matched peripheral blood was conducted through the Englander Institute of Precision Medicine. CH was identified through mutations in the peripheral blood that were absent in the tumor. Probable SNPs were filtered using population allele frequency data from the ExAC database. Tumor mutation burden (TMB) and microsatellite instability (MSI) scores were calculated for each patient. MHC Class I alleles for HLA types A, B, C were inferred for each patient based on WES. CH was identified in 12% of patients and 19 different solid advanced and metastatic cancer subtypes and was associated with increased age (P &lt; 0.001). Cancer subtypes with the highest frequency of CH mutations were urothelial carcinoma, glioblastoma, adenocarcinoma, and transitional cell (urothelial) carcinoma. The most commonly mutated genes were DNMT3A, TET2, ASXL1, and BCOR1. We restricted further analysis to the most common CH genes: DNMT3A, TET2, and ASXL1. 60% of patients with CH had only one mutation, 13% had two mutations, and 4% had 3 or more mutations. When adjusting for covariates including tumor subtype and age, the presence of CH was suggestive of elevated MSI scores (P &lt; 0.1) but did not impact TMB. We next sought to determine if MHC class impacted susceptibility to the emergence of CH. Fisher's exact test was used to identify associations between HLA alleles and the presence of CH. We identified MHC alleles conferring hyper-susceptibility to CH development by as much as 8-fold (OR 8.0, 95% C.I. 2.1 - 39.1, P &lt; 0.001). We further identified 52 probable protective alleles. These data suggest that certain HLA alleles are significantly more permissive to CH development, while others may be protective against CH. Overall, our study is the first to systematically evaluate and suggest that patient-specific hyper-susceptibility HLA alleles impact evolutionary processes that underlie clonal sculpting leading to the emergence of CH. The presence of CH may also impact the evolution of co-occurring solid tumors, a hypothesis requiring further evaluation. This study indicates that MHC alleles and thus personal genetics place immunity-driven selective pressure for the emergence of CH, supporting the role of inherited determinants of CH. Disclosures No relevant conflicts of interest to declare.

Abstract 5065: Pharmacological modulation of inflammation and p53 signaling synergize to prevents muscle invasive bladder cancer in-vivo

Abstract Bladder cancer (BC) is the second most common genitourinary cancer and a leading cause of death globally. Muscle invasive BC (MIBC) has high mortality (&amp;gt;85% patients) leading to death within 2 years of diagnosis, if untreated. Although new treatment options were approved recently, it is still very challenging and most expensive to manage. Preventing BC is highly desirable to reduce recurrence, mortality and improve quality of life. Inactivation of p53 signaling and chronic inflammation are frequent hallmarks of MIBC. In spite of the promising chemopreventive effects of non-steroidal anti-inflammatory agents (NSAIDs), their clinical translation is hampered due to side-effects associated with their chronic intake and higher doses. Here we investigated a combinatorial approach to modulate inflammation with NSAIDs (licofelone or NO-Naproxen) and p53 signaling pathways using CP-31398 (CP) for preventing MIBC bladder in-vivo. Transgenic UPII-SV40T mice developing spontaneous MIBC were generated and fed control or experimental diets containing the licofelone (150ppm), NO-naproxen (300 ppm), CP (150ppm) alone or in combination starting at early tumor stage (6 weeks age). After 34 weeks of agent administration, mice were euthanized and urinary bladders were evaluated. Control diet fed transgenic mice developed high grade, muscle invasive, urothelial transitional cell carcinoma (TCC) leading to 3-5 fold increase in bladder weights (140.2±9.8 mg Vs 27.3±0.8 mg; p&amp;lt;0.0001) and (34.2±0.8 mg vs 14.8±0.53 mg; p&amp;lt;0.0001) in males and females compared with wild type mice. These tumors had dysregulated cell cycle and inflammation markers similar to human tumors. Treatment with licofelone, NO-Naproxen or CP alone led to significant suppression of bladder tumor. While NSAIDs had significant inhibitory effect in males (65% - 78%; p&amp;lt;0.0001) and females (31% - 34%; p&amp;lt;0.01-p&amp;lt;0.0001) compared to control group, CP had strongest tumor growth suppressive effect (80%; p&amp;lt;0.0001 and 36%; p&amp;lt;0.0001) in both genders. CP had no effect on invasion in male mice while in females ~50% inhibition was observed, while moderate effect of licofelone (12% - 42% inhibition; p&amp;lt;0.005) and NO-Naproxen (38% - 42% inhibition; p&amp;lt;0.001) was observed. Importantly, the combination of two agents led to a synergistic effect leading to significant inhibition of both tumor growth (~80% in males; p&amp;lt;0.0001 and 55% females; p&amp;lt;0.0001) and invasion ~62% inhibition (p&amp;lt;0.0001) in both genders. Molecular analysis of urothelial tumors showed inhibitory effect on proliferation and inflammatory markers (PCNA, Cyclins, p53, p21, COX2, and IL1β). Our results suggest that safer dose combination of targeted agents may yield better chemopreventive effects than higher dose of individual agents. Specifically, NSAID plus CP may be a promising combination for preventing MIBC. (Supported in part by NCI-PREVENT program - NCI-CN-53300) Citation Format: Venkateshwar Madka, Yuting Zhang, Nandini Kumar, Gopal Pathuri, Nicole Stratton, Stanley Lightfoot, Adam S. Asch, Vernon E. Steele, Altaf Mohammed, Chinthalapally V. Rao. Pharmacological modulation of inflammation and p53 signaling synergize to prevents muscle invasive bladder cancer in-vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5065.

Pharmacoeconomic Analysis of Vinflunine in Patients With Urothelial Transitional Cell Carcinoma Resistant to Platinum-Based Regimens

Aim. To assess the economic outcomes of using vinflunine in combination with the best supportive therapy (BST) in the treatment of patients with urothelial transitional cell carcinoma (UTCC) and ineffectiveness of chemotherapy with a cisplatin-containing combination of drugs and the inability to use immuno-oncological drugs. Methods. The economic impact assessment was carried out using cost-effectiveness analysis and budget impact analysis. Cost-effectiveness and budget impact analyses were performed in Microsoft Excel models. Results. The use of vinflunine in combination with BST in the second-line chemotherapy of UTCC, compared with using BST only, increases the life expectancy of patients – overall survival (OS) with vinflunine + BST was 6.9 months, only with BST was 4.3 months. The amount of additional costs to achieve one unit of efficiency (ICER) when using vinflunine in combination with BST amounted to 190 920 rubles for one added month of life, which is 61.7% lower compared to the reference ICER for pembrolizumab (the drug is included in the drug list). As a result of the analysis of the “impact on the budget”, it was shown that the use of therapy with vinflunine requires additional financial costs for a course of treatment in the amount of 49 639 191 руб. (57,76%) for the first year, 138 516 980 руб. (80,03%) for the second year and 263 841 866 руб. (88,91%) for the third year of the analyzed introduction of vinflunine into the structure of drug provision for patients with UTCC in the Russian Federation, based on the calculation of the need for 586 patients per year. Conclusion. Based on the analysis, it was shown that therapy with vinflunine combination with BST is a cost-effective and preferred alternative compared to BST for treating patients with urothelial transitional cell carcinoma and ineffectiveness of chemotherapy with a cisplatin-containing combination of drugs and the inability to use immuno-oncological drugs.

Analysis of HER2 mutant bladder urothelial carcinomas reveals unique mutational signature.

460 Background: Early work has described the presence of HER2 alterations in metastatic urothelial carcinomas (UC), particularly the micropapillary urothelial carcinoma (MPUC) subtype. We reviewed the genomic profiles of a large set of UC cases to further characterize HER2 altered UCs and how such alterations would suggest benefit from the expanding array of anit-HER2 therapeutics. Methods: Tissue from 2,150 UCs were assayed using hybrid capture-based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly arranged in cancer. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Results: Within the UC dataset 74.6% of cases were male (1603/2150), with a median TMB of 7 mut/Mb. 383 genomic alterations (GA) of HER2 were identified in 15.5% (334/2150) of cases which exhibited a median TMB of 8.7 mut/Mb (p &lt; 1E-5) vs patients with wildtype HER2, median TMB of 7 mut/Mb. The most frequent HER2 alterations were amplification HER2amp (45.7%, 175/383), S310F (19.8%, 76/383), and S310Y (7/6%, 29/383). Patients harbouring a HER2amp, S310 (n = 105) exhibited a median TMB of 8.7 and 12.2 mut/Mb, respectively. 42 patients presented with multiple ( &gt; 1) HER2 GA and exhibited a median TMB of 11.3 mut/Mb (p &lt; 0.1) vs patients with single HER2 GA, median TMB of 12.3 mut/Mb. Of patients with multiple HER2 alterations, 57% (24/42) harbored a HER2amp. The most common co-occuring HER2 alteration pair was an amplification and extracellular S310X alteration (38.1%, 16/42). Of these 16, the median TMB was 19.5 mut/Mb (average 22.7 mut/Mb). Morphological assessments were performed on the 24 cases harbouring a HER2amp and an additional HER2 GA. 8 cases displayed MPUC features 44.4% (8/18; 6 cases histology unavailable); of these MPUC cases, 75% (6/8), harboured a HER2 amp and S310 extracellular mutation. Conclusions: CGP of bladder urothelial (transitional cell) carcinomas reveals subclasses of HER2 altered cases. Drawing on recent advances in targeting HER2 alterations in breast cancer, dual HER2 blockade (e.g. combinations of mAB/TKI/mAB+ADC) may be needed for HER2amp cases. For cases with both HER2amp and S310 GA, neratinib monotherapy may be the agent of choice and thus may be effective in MPUC.

Safety of Vinflunine in Patients with Advanced Urothelial Carcinoma Refractory to Platinum-based Chemotherapy: A Prospective Pilot Study.

Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

Abstract LB-118: A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation

Abstract Regulatory T (Treg) cells play an important role in modulating the tumor microenvironment, leading to the suppression of anti-tumor immune responses. Tumor Tregs could be targeted by taking advantage of the differential expression of immune checkpoints on these cells as compared to other T cell subsets. While the elevated expression of checkpoints such as CTLA-4 on Tregs compared to conventional T cells is well-characterized, less is known about the collective landscape of Treg specific checkpoint expression specific in the tumor microenvironment. We identified a network of Treg-associated checkpoint markers including those previously associated with Treg function (CTLA4, ICOS) as well as several additional checkpoints (BTLA, LAG3, TIGIT, TNFRSF9) by characterizing the expression of 28 checkpoint molecules across 7,608 bulk tumor samples (31 tumor types) from TCGA. We then utilized whole transcriptome RNA sequencing of purified peripheral and tumor Treg cell populations across 4 different tumor types (glioblastoma multiforme, prostatic adenocarcinoma, urothelial transitional cell carcinoma, renal clear cell carcinoma) to characterize the Treg specific expression of checkpoint molecules. Peripheral and tumor Tregs demonstrate differential checkpoint expression landscapes, with tumor Tregs uniquely discriminated by collective expression of TNFRSF9 (4-1BB), HAVCR-2 (TIM-3), and LAG-3. This discriminatory signature was conserved across the 4 profiled tumor types, was associated with changes in Treg biology, and was confirmed in published data from three additional cancer cohorts (breast, colorectal, and non-small-cell-lung cancers). Furthermore, normalized TNFRSF9 expression in TCGA was also associated with a worse survival outcome, suggesting that elevated Treg TNFRSF9 expression may be a poor prognostic factor across a wide range of tumors. Taken together, these data highlight the potential of targeting TNFRSF9 expressing Tregs in the tumor as a novel immunotherapeutic approach for several types of cancer. Citation Format: Zachary T. Freeman, Daniel H. Hovleson, Alexander T. Pearson, Jingyi Zhai, Ali Ghasemzadeh, Thomas R. Nirschl, Hui Jiang, Scott A. Tomlins, Charles G. Drake. A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-118.

Dose escalation results from a first-in-human, phase 1 study of the glucocorticoid-induced TNF receptor-related protein (GITR) agonist AMG 228 in patients (Pts) with advanced solid tumors.

2521 Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this open label, first in human, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and maximum tolerated dose (MTD) and recommended phase 2 dose of AMG 228 in pts with advanced solid tumors. Methods: Pts with refractory advanced colorectal cancer (n = 13), squamous cell carcinoma of head and neck (n = 10), non–small cell lung cancer (n = 2), urothelial transitional cell carcinoma (n = 4), and melanoma (n = 1) received AMG 228 IV Q3W. Dose escalation was in two stages: single-pt cohorts until AMG 228-related grade &gt; 2 adverse events (AEs), efficacy, or 90 mg dose reached (4 cohorts: 3, 9, 30, and 90 mg), followed by rolling six design (n = 2 to 6) until MTD or highest planned dose of 1200 mg reached (5 cohorts: 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and AEs and PK. Additional endpoints were objective response (RECIST 1.1) and evidence of biological activity. Results: In total, 30 pts (median age 63 y) were treated (3, 9, 30, and 90 mg, n = 1; 180 mg, n = 6; 360 mg, n = 4; 600 mg, n = 6; 900 mg, n = 4; 1200 mg, n = 6). Twenty-seven (90%) pts had treatment-emergent AEs; the most common were hypophosphatemia (23%), fatigue (23%), anemia (23%), nausea (20%), and pyrexia (20%). No DLTs occurred; the MTD was not reached. AMG 228 exposure was dose-related, with PK profiles at low doses (3 to 90 mg) consistent with target mediated drug disposition; doses &gt; 360 mg achieved serum levels needed for 95% receptor occupancy on activated PBMCs. No evidence of T cell activation was observed despite complete target coverage in both tumor and peripheral blood. Among 29 evaluable pts, none had an objective response. Conclusions: In this population of pts with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), showing favorable PK. However, no clinical or immunological activity was observed in this limited number of pts. Clinical trial information: NCT02437916.

Abstract 5241: Nitric oxide-releasing naproxen prevents muscle invasive bladder cancer

Abstract Bladder cancer is the second most common and a leading cause of death among genitourinary cancers worldwide. Particularly, untreated muscle invasive bladder cancer has high mortality (&amp;gt;85% patients) leading to death within 2 years of diagnosis. Preventing this deadly form is highly imperative since the currently available options to patients with invasive disease remained essentially unchanged and no effective drugs have been approved in past two decades. Several non-steroidal anti-inflammatory agents (NSAIDs) have shown promising chemopreventive activity in many cancers. The common adverse events with NSAIDs, especially gastrointestinal (GI) morbidities, including complications in both upper and lower GI tract drives the need for development of safer agents. To overcome this various nitric oxide (NO)-linked NSAIDs have been synthesized. Here we investigated the NO-releasing Naproxen (NO-Naproxen) with proven anti-inflammatory and GI protecting effects for its efficacy in preventing bladder cancer. Transgenic mouse model (UPII-SV40T; n = 30/group) that develop muscle invasive urothelial tumors were generated, genotyped and fed modified AIN-76A diet containing NO-naproxen (0, 300 and 600 ppm) starting at 6 weeks of age. At 40 weeks age, control (0 ppm) and experimental diet (300 and 600 ppm) fed mice were euthanized and urinary bladders were analyzed. Control diet fed male and female transgenic mice developed high grade, invasive transitional cell carcinoma (TCC) of bladder resulting in significant increase in bladder weights (140.2±9.8 mg; p&amp;lt;0.0001 and 34.2+0.8 mg; p&amp;lt;0.0001 respectively) compared with wild type mice (27.3±0.8 mg and 14.8±0.53 mg). These tumors had a significant disregulation of proliferation, cell cycle markers and antioxidant enzymes similar to human tumors. NO-Naproxen administered mice had normal body weight gain; and gross tissue analysis and showed no signs of overt toxicities. Treatment of transgenic mice with NO-Naproxen led to significant suppression of bladder weight in both genders (up to 58% in males, p&amp;lt;0.0001; up to 21% in females, p&amp;lt;0.005) compared to control group. While there was no dose-dependent increase in tumor inhibition, mice on NO-Naproxen diet had developed significantly less muscle invasive tumors suggesting inhibitory effect of treatment on disease progression. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 54%; p&amp;lt;0.005) and females mice (up to 85%; p&amp;lt;0.0001) of the experimental diet groups. Molecular analysis of urothelial tumors via real-time PCR, IHC and/or western blotting showed inhibitory effect of NO-Naproxen on proliferation and inflammatory markers (PCNA, Cyclins, COX2, and IL1b) and showed modulation of antioxidant enzymes (CAT, GPx, GST, NQO1, and SOD3). Our results suggest that NO-Naproxen may be a promising agent for preventing urothelial TCC and warrants further investigation. (Supported in part by NCI-CN53300) Citation Format: Venkateshwar Madka, Altaf Mohammed, Qian Li, Yuting Zhang, Stanley Lightfoot, Xue-Ru Wu, Vernon Steele, Levy Kopelovich, Chinthalapally V. Rao. Nitric oxide-releasing naproxen prevents muscle invasive bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5241.

Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo.

Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P < 0.0001). Similarly, CP showed approximately 77% (P < 0.0001) suppression of tumor weight. The combination of low-dose rapamycin and CP led to approximately 83% (P < 0.0001) inhibition of tumor weight. There was no significant difference in tumor weights between rapamycin and CP treatments (P > 0.05). However, there was a significant difference between 8 ppm rapamycin and the combination treatment. Tumor invasion was also significantly inhibited in 53% (P < 0.005) and 66% (P < 0.0005) mice after 8 ppm and 16 ppm rapamycin, respectively. However, tumor invasion was suppressed in 73% (P < 0.0001) mice when CP was combined with 8 ppm rapamycin. These results suggest that targeting two or more pathways achieve better treatment efficacy than a single-agent high-dose strategy that could increase the risk of side effects. A combination of CP and rapamycin may be a promising method of inhibiting muscle-invasive urothelial transitional cell carcinoma.

Abstract 4653: Modulation of mTOR and p53 signaling using rapamycin plus CP-31398 inhibits growth and progression of urothelial carcinoma in-vivo

Abstract Bladder cancer is the second most common genitourinary cancer worldwide. Despite multidisciplinary treatment advances, muscle-invasive bladder cancer continues to have high mortality. Since dysregulation of p53 and mTOR signaling in urothelium is associated with tumor initiation, growth and invasiveness, we investigated whether up-regulation of TP53 plus inhibition of mTOR additively or synergistically inhibits tumor growth and progression in vivo. Transgenic UPII-SV40T male mice (n = 15/group) were generated, genotyped and fed control or experimental diets containing the mTOR inhibitor rapamycin (8 or 16 ppm) and/or the p53 stabilizing agent CP31398 (150 ppm) starting at 6 weeks of age. After 34 weeks, control diet fed transgenic mice developed urothelium-specific high-grade, invasive transitional cell carcinoma (TCC) with significant increase in bladder weights (140.2 ± 9.8 mg; p&amp;lt;0.0001) compared with wild type (27.3 ± 0.8 mg). Rapamycin (8 or 16 ppm) reduced tumor weight by ∼ 67% or 77% and CP31398 decreased it by &amp;gt;70%. The combination of CP31398 with 8 ppm rapamycin decreased tumor weight by ∼83% (16.47 ± 5.4 mg; p&amp;lt;0.0001). Rapamycin (8 or 16 ppm) suppressed tumor invasion by 53% (p&amp;lt;0.005) or 66% (p&amp;lt;0.0005). CP-31398 alone failed to inhibit tumor invasion; however its combination with low-dose rapamycin inhibited tumor invasion &amp;gt;71% (p&amp;lt;0.0001). Molecular analysis of tumors via real-time PCR, IHC and western blotting showed synergistic inhibition by the drug combination of tumor growth and invasion with suppression of mTOR signaling (mTOR, pmTOR, raptor, rictor, Akt, pAkt); induction of p53 expression; and decreased expression of proliferation (PCNA), cell cycle regulators (cyclin D1, cyclin A), pro-survival molecules (Hif1a, Vegf) and androgen receptor. The combination of CP-31398 and rapamycin appears to be a promising approach for preventing urothelial TCC invasion. (Supported in part by NCI-CN53300) Note: This abstract was not presented at the meeting. Citation Format: Venkateshwar Madka, Altaf Mohammed, Qian Li, Yuting Zhang, Laura Biddick, Jagan M.R. Patlolla, Stanley Lightfoot, Xue-Ru Wu, Vernon Steele, Levy Kopelovich, Chinthalapally V. Rao. Modulation of mTOR and p53 signaling using rapamycin plus CP-31398 inhibits growth and progression of urothelial carcinoma in-vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2015-4653

Cost-effectiveness and budget impact analysis of vinflunine used in the treatment of patients with urothelial transitional cell carcinoma resistant to platinum-based regimens

As of now, vinflunine is the only second-line chemotherapy drug showing an advantage over the best maintenance therapy in a Phase III randomized study treating patients with urothelial transitional cell carcinoma. Due to the advent of this drug, it was relevant to make a pharmacoeconomic analysis comparing therapy with vinflunine in combination with the best maintenance therapy and the latter only. A budget impact analysis showed that the use of the new drug required additional expenditures. The ICER reflecting the cost of one additional year of life and estimating vinflunine therapy as cost-effective was determined by the results of a cost-effectiveness analysis.

Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice.

Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.

Epidemiology of post-transplant malignancy in Chinese renal transplant recipients: a single-center experience and literature review.

This study investigated the incidence and types of post-transplant malignancy in Chinese renal transplant recipients and the risk factors associated with malignancy. Data from 3,462 patients who underwent renal transplantation at Beijing Friendship Hospital were combined with data from 26 previous reports describing malignancy rates in 27,170 Chinese renal transplant recipients. Between 1974 and 2014, 179/3,462 (5.17 %) patients who underwent renal transplantation at our center developed malignancy. The most common site of malignancy was the urinary system, and the most common type was urothelial transitional cell carcinoma. Combined data from our center and previous reports showed malignancy in 671 (2.19 %) Chinese renal transplant recipients. The ten most common malignancies were urothelial transitional cell carcinoma (n = 283), hepatocellular carcinoma (n = 68), gastrointestinal cancer (n = 63), renal cell carcinoma (n = 42), lymphoma (n = 42), lung cancer (n = 28), breast cancer (n = 19), skin cancer (n = 18), Kaposi's sarcoma (n = 12), and cervical cancer (n = 10). The incidence of post-transplant malignancy in renal transplant recipients was lower in China than the reported rates in other countries, and the most common sites of malignancy were the urinary and digestive system. The relative frequency of malignancy sites differed between northern and southern China. Renal transplant recipients on long-term immunosuppressive therapy should receive careful follow-up, including annual or biannual screening for malignancy in high-risk individuals.

Can We Improve the Biopsy Quality of Upper Urinary Tract Urothelial Tumors? Single-Center Preliminary Results of a New Biopsy Forceps

Objective: Our aim was to evaluate the biopsy quality of upper urinary tract urothelial transitional cell carcinoma with a new biopsy forceps (BIGopsy®, Cook Medical) compared to a classic biopsy forceps (Piranha®, Boston Scientific). Patients and Methods: From December 2009 to December 2011, 20 patients with upper urinary tract urothelial transitional cell carcinoma underwent conservative treatment endoscopically. All lesions were evaluated and biopsied with 3 Fr cup forceps using both types of forceps (BIGopsy and Piranha). A single pathologist blindly analyzed the specimens in order to determine the optimal biopsy for each patient. Specimen histopathology results were graded; however, they were staged if the lamina propria was not invaded (T1) or if the tumor was detected at the lamina propria (T1+). Results: Of the 20 upper urinary tract lesions, 12 (60%) were in the renal pelvis, 3 (15%) in the upper calyx, 1 (5%) in the middle calyx, 1 (5%) in the lower calyx, 1 (5%) in the upper third of the ureter and 2 (10%) in the middle third of the ureter. We did not detect T1 in all biopsies. One patient had no valid biopsies by both forceps. A diagnosis of urothelial carcinoma was made in 17 BIGopsy biopsies compared to 7 Piranha biopsies. Conclusion: Despite the limited number of cases, our study demonstrated the advantage of the new forceps (BIGopsy) in obtaining a valid biopsy of upper urinary tract urothelial tumors. Therefore, we recommend it in evaluating this pathology for optimal treatment.

How to manage intravenous vinflunine in cancer patients with renal impairment: results of a pharmacokinetic and tolerability phase I study

Vinflunine (VFL) ditartrate, a novel tubulin-targeted inhibitor, is registered for the treatment of patients with advanced or metastatic urothelial transitional cell carcinoma. This phase I study assessed the effect of renal impairment on the pharmacokinetics and tolerability of VFL. VFL was infused in patients with advanced/metastatic solid tumours once every 3 weeks with anticipated dose reduction on the first cycle stratified according to the creatinine clearance (CLcr ) values. Pharmacokinetic data were collected on the first two cycles in renally impaired patients (CLcr ≤ 60 ml min(-1) ) and were compared with a control cohort of patients (CLcr > 60 ml min(-1) ). Thirty-three patients (46-86 years) were treated, 13 in group 1 (40 ml min(-1) ≤ CLcr ≤ 60 ml min(-1) ) and 20 in group 2 (20 ml min(-1) ≤ CLcr < 40 ml min(-1) ). The renal dysfunction induced a mean decrease in VFL clearance of 12% in group 1 and 28% in group 2, compared with the control group. The anticipated dose reduction given in renally impaired patients (i.e. 280 mg m(-2) and 250 mg m(-2) in groups 1 and 2, respectively) yielded similar drug exposure to control patients. The tolerance profile of VFL in patients with renal dysfunction was similar to that observed in patients with CLcr > 60 ml min(-1) . In conclusion, the recommended doses of intravenous VFL administered once every 3 weeks in cancer patients with renal impairment are 280 mg m(-2) when CLcr is between 40 and 60 ml min(-1) and 250 mg m(-2) when CLcr is between 20 and <40 ml min(-1) .