Oncology Intelligence

Bladder Cancer
1:13 AM|Current Molecular Pharmacology (Volume 9 - Issue 3)|Labels: bladder cancer
With the advent of Bacille Calmette Guerin (BCG), bladder cancer was one of the earliest cancers where the concept of immunotherapy was utilized. While this is true, recent advances in the use of immunotherapy are enabling oncologists to expand the armamentarium for the treatment of bladder cancer. Unacceptable side effects and failure to produce a durable response with the use of chemotherapeutic agents in bladder cancer has led to the evaluation of more targeted and personalized approaches. Increased understanding of the underlying carcinogenesis of bladder cancer, coupled with the ability to engineer targeted agents implicated in bladder cancer associated pathways has provided new avenues for the management of this disease. Newer immunotherapeutic approaches have generated a great deal of interest in bladder cancer along with other diseases. In this article we will focus on various forms of immunotherapies that may have a therapeutic potential in bladder cancer. We will briefly review the current status of “non-targeted” immunotherapeutic agents like BCG, interferons and interleukins in bladder cancer. But the main focus of this article is to discuss the emerging role of “targeted” immunotherapeutic agents like cytotoxic T cell lymphocyte associated protein-4 blocking antibody and programmed death pathway blocking antibodies in localized or metastatic bladder cancer.
Wednesday, September 21, 2016 6:28 AM|Ben Fidler|MIT Biotech Group - Essential Biotech RSS Feed|Labels: bladder cancer, financial
Close-up Of Businesspeople Holding White Jigsaw Puzzle In Hand

Eleven Biotherapeutics became an eye-disease company several years ago, a move that allowed it to go public, raise a bunch of money, and get an eye drug all the way to a pair of late-stage clinical trials.

Both studies failed, however, which left the Cambridge, MA, company searching for a new direction—which today has been revealed as a plan to develop cancer drugs.

Eleven (NASDAQ: EBIO) has acquired a Toronto biotech called Viventia Bio. The combined company will keep the Eleven name, but take Viventia’s strategy and management team. It’ll develop a group of experimental drugs for squamous cell carcinoma, bladder, and head and neck cancers, and be run by Viventia’s president and CEO Stephen Hurly. Hurly will replace Abbie Celniker, a former Millennium Pharmaceuticals and Novartis executive and Eleven’s longtime CEO, though Celniker will remain on the company’s board of directors.

“As previously announced, Eleven performed an extensive review of our strategic alternatives, and our board of directors believes that the acquisition of Viventia offers Eleven shareholders a compelling opportunity for enhancing long-term value,” Celniker said in a statement.

In the deal, Eleven bought all of Viventia’s shares for 4,013,431 newly issued shares of Eleven common stock, representing about 16.6 percent of the company. Shares of Eleven closed at $3.37 apiece on Tuesday, and climbed about 9.5 percent in pre-market trading. The deal also includes downstream payments and royalties for Viventia’s shareholders if certain regulatory and sales targets are hit, according to a regulatory filing.

The combined company will develop fusion proteins—specifically, antibody fragments genetically fused to toxic proteins—as cancer drugs. Its most advanced drug candidates are Vicinium, which should produce data from a Phase 3 trial in high grade non-muscle invasive bladder cancer in early 2018; and Proxinium, which will begin a mid-stage trial in late-stage squamous cell carcinoma next year.

The move represents another metamorphosis for a company that’s had a few already. Eleven was formed by Third Rock Ventures and Flagship Ventures in 2010 with the idea of custom designing proteins from scratch to possess certain characteristics, like the ability to carry out a specific action on their specific biological target. The company was named after a reference to the infamous rock mockumentary “This is Spinal Tap,” when one of the band members talks of an amplifier that can be cranked up to 11, louder than 10.

In 2011 Eleven hired Celniker, a former Millennium Pharmaceuticals and Novartis executive, as CEO, and morphed into an ophthalmics company. Eleven put much of its focus behind a drug called EBI-005 (later called isunakinra), an eye drop it was developing for inflammation in ocular diseases like dry eye and allergic conjunctivitis. The company went public in February 2014, raising $50 million, and shares closed as high as $17.05 apiece a month later.

But isunakinra went on to fail each of two Phase 3 trials. That wiped out most of Eleven’s value and led it to shelve the drug altogether in January and begin evaluating strategic alternatives, considering everything from an outright sale to divesting assets one by one. Eleven sold off a technology used for drug delivery to Albumedix in January, paid off its outstanding debt to Silicon Valley Bank in March, and licensed a second eye drug, EBI-031, for diabetic macular edema, to Roche in June. Eleven has already gotten $30 million in the Roche deal, and could get up to $240 million more if the drug progresses in clinical testing.

Eleven’s chief development officer Karen Turbidy has resigned from the company following the deal, and Third Rock’s Cary Pfeffer has left the board. An entity associated with Viventia’s former executive chairman, Leslie Dan, is now Eleven’s second-largest shareholder. Third Rock had a 24.5 percent stake in Eleven as of an April proxy filing, making the Boston firm Eleven’s largest shareholder.

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Wednesday, September 21, 2016 4:12 AM|PBR - News|Labels: bladder cancer
The European Medicines Agency (EMA) validated Bristol-Myers Squibb's (BMS) type II variation application, which seeks to extend the current indications for Opdivo to include the treatment of locally advanced unresectable or metastatic urothelial carcinoma (mUC) in adults after failure of prior platinum-containing therapy.
Wednesday, September 21, 2016 3:22 AM|PharmaTimes: News RSS|Labels: bladder cancer, regulatory
Bristol-Myers Squibb's immunotherapy Opdivo has taken big step towards European approval in bladder cancer, after regulators validated the firm's marketing application, kick-starting the European Medicines Agency's centralised review process.
Wednesday, September 21, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: bladder cancer, clinical trial
Ophthalmic therapeutics company Eleven Biotherapeutics Inc. (NASDAQ:EBIO) acquired cancer company Viventia Bio Inc. (Mississauga, Ontario), which had been in the IPO queue. The combined company will retain Eleven's name and will primarily develop Viventia's pipeline. It will seek to develop oncology therapeutics based on antibody fragments genetically fused to cytotoxic proteins. Viventia CEO Stephen Hurly will be its president and CEO.In 1H18, the company expects top-line data from a Phase III study of lead candidate Vicinium (VB4-845) to treat high-grade non-muscle invasive bladder cancer (NMICB). Vicinium is a tumor-targeting antibody fragment conjugated with Pseudomonas exotoxin A. Viventia shareholders will receive 4 million newly issued Eleven shares, valued at $13.5 million based on Eleven's close of $3.37 on Tuesday, before the deal was announced. Viventia shareholders own 16.6% of the combined company, and Eleven the balance. The shareholders also are eligible for a $12.5 million milestone upon the first U.S. sale of Vicinium, $7 million tied to its first sale in Europe, and $3 million tied to its first sale in Japan. In January, Eleven's isunakinra (EBI-005) failed in a Phase III trial to treat moderate to severe allergic conjunctivitis (see BioCentury Extra, Jan. 29). Under a partnership announced in June, Roche (SIX:ROG; OTCQX:RHHBY) is developing Eleven's anti-IL-6 mAb EBI-031 to treat ocular diseases.
Tuesday, September 20, 2016 11:16 AM|Onclive Articles|Labels: bladder cancer, regulatory
The European Medicines Agency has validated a type II variation application for use of nivolumab (Opdivo) as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma who have progressed following platinum-based chemotherapy.
Tuesday, September 20, 2016 4:59 AM|Business Wire Health: Pharmaceutical News|Attachments|Labels: bladder cancer, regulatory
PRINCETON, N.J.--(BUSINESS WIRE)--$BMY #BristolMyers--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the European Medicines Agency (EMA) validated its type II variation application, which seeks to extend the current indications for Opdivo to include the treatment of locally advanced unresectable or metastatic urothelial carcinoma (mUC) in adults after failure of prior platinum-containing therapy. Validation of the application confirms the submission is complete and begins the EMA’s centralized review

Friday, September 16, 2016 4:27 PM|He Shen, Maxime Blijlevens, Nuo Yang, Costakis Frangou, Kayla E. Wilson, Bo Xu, Yinglong Zhang, Lirui Zhang, Carl D. Morrison, Lori Shepherd, Qiang Hu, Qianqian Zhu, Jianmin Wang, Song Liu, Jianmin Zhang|International Journal of Biological Sciences|Labels: bladder cancer

Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). We have previously found that amplification of chromosome 6p22 is significantly associated with the muscle-invasive rather than superficial TCC-UB. Here, we demonstrated that Sox4, one of the candidate oncogenes located within the chromosome 6p22 amplicon, confers bladder cancer stem cell (CSC) properties. Down-regulation of Sox4 led to the inhibition of cell migration, colony formation as well as mesenchymal-to-epithelial transition (MET). Interestingly, knockdown of Sox4 also reduced the sphere formation, enriched cell population with high levels of aldehyde dehydrogenase (ALDH high) and tumor formation potential. Using gene expression profiling, we further identified novel Sox4 target genes. Last, immunohistochemistry analysis of human bladder tumor tissue microarrays (TMAs) indicated that high Sox4 expression was correlated with advanced cancer stages and poor survival rate. In summary, our data show that Sox4 is an important regulator of the bladder CSC properties and it may serve as a biomarker of the aggressive phenotype in bladder cancer.

Friday, September 16, 2016 10:23 AM|Ganglong Yang, Luyu Huang, Jiaxu Zhang, Hanjie Yu, Zheng Li, Feng Guan|International Journal of Biological Sciences|Labels: bladder cancer

Compartmentalization of cellular components and their associated biological processes is crucial for cellular function. Protein glycosylation provides a basis for diversity of protein functions. Diversity of glycan composition in animal cells remains poorly understood. We used differential centrifugation techniques to isolate four subcellular protein fractions from homogenate of metastatic bladder YTS1 cells, low grade nonmuscle invasive bladder cancer KK47 cells and normal bladder epithelia HCV29 cells: microsomal (Mic), mitochondrial (Mito), nuclear (Nuc), and cytosolic (Cyto). An integrated strategy combining lectin microarray and mass spectrometry (MS) analysis was then applied to evaluate protein glycosylation of the four fractions. Lectin microarray analysis revealed significant differences among the four fractions in terms of glycan binding to the lectins LCA, AAL, MPL, WGA and PWM in YTS1 cell, STL, Jacalin, VVA, LCA and WGA in KK47, and ConA, GNA, VVA and ACA in HCV29 cell. Among a total of 40, 32 and 15 N-glycans in four fractions of three cells detected by MS analysis, high-mannose and fucosylated structures were predominant, 10 N-glycans in YTS1, 5 N-glycans in KK47 and 7 N-glycans in HCV29 were present in all four fractions; and 10 N-glycans in YTS1, 16 N-glycans in KK47, and 3 N-glycans in HCV29 were present in only one fraction. Glycans in the latter category are considered potential markers for the corresponding organelles. The integrated strategy described here allows detailed examination of glycomes subcellular fraction with high resolution and sensitivity, and will be useful for elucidation of the functional roles of glycans and corresponding glycosylated proteins in distinct organelles.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: bladder cancer, clinical trial
This phase I/II trial studies the side effects and best dose of sirolimus when given together with cisplatin and gemcitabine hydrochloride and to see how well they work in treating patients with bladder cancer. Biological therapies, such as sirolimus, may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cisplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sirolimus together with cisplatin and gemcitabine hydrochloride may be an effective treatment for bladder cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: bladder cancer, clinical trial
This randomized phase II trial studies the side effects and how well postoperative intensity modulated radiotherapy works after surgery in treating patients with urothelial bladder cancer. Radiation therapy uses high energy x-rays to kill tumor cells left behind in the pelvis after surgery. It is not yet known whether surgery followed by radiotherapy is more effective than surgery alone in treating patients with urothelial bladder cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: bladder cancer, clinical trial
The objectives of this study are to assess the safety, pharmacokinetics, immunogenicity and anti-tumor activity of AGS15E in subjects with metastatic urothelial cancer who failed at least one prior chemotherapy regimen for metastatic disease.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: PD-1/PD-L1, bladder cancer, clinical trial
This is a study using pembrolizumab (MK-3475, KEYTRUDA®) for first-line treatment of participants with advanced/unresectable (inoperable) or metastatic urothelial cancer who are ineligible for cisplatin-based therapy. The primary study objective is to determine the objective response rate (ORR) in all participants, in participants whose tumors rely on programmed cell death ligand 1 (PD-L1) protein (PD-L1-positive tumors), and in participants with strongly PD-L1-positive tumors.
The main purpose of this study is to evaluate the safety and efficacy of the study drug ramucirumab in combination with docetaxel in participants with urothelial cancer who failed prior platinum-based therapy.
Wednesday, September 14, 2016 1:02 PM|Cancer News Headlines - Yahoo! News|Labels: bladder cancer, regulatory
Spectrum Pharmaceuticals Inc's experimental bladder cancer treatment apaziquone is not effective in delaying the time to recurrence of the disease, an advisory committee to the U.S. Food and Drug Administration concluded on Wednesday. Spectrum's shares fell 6.2 percent to $5.15. The committee, which convened to advise the FDA on whether to approve the drug, voted unanimously that the treatment has no more effect on the disease than a placebo over a two-year period.
Wednesday, September 14, 2016 11:10 AM|Joseph G Kattan, Celine Y Boutros, Fadi S Farhat, Georges Y Chahine, Khaled M Musallam, Marwan G Ghosn|Journal of Cancer|Labels: bladder cancer, clinical trial

Objective: Gemcitabine and platinum-based compounds represent the new standard combination therapy for bladder cancer. In this study, we evaluate the efficacy and safety of gemcitabine and carboplatin followed sequentially by paclitaxel in 27 patients with advanced transitional cell carcinoma.

Methods: This phase II multicentre study was based on the doublet gemcitabine 800 mg/m2 and carboplatin area under the concentration-time curve 2 on days 1 and 8 every 21 days for 4 cycles, followed sequentially by paclitaxel 60 mg/m2/w for 12 consecutive weeks. The disease was assessed after each sequence.

Results: Primary tumor was localized in the bladder and renal pelvis in 25 and 2 patients, respectively. Twenty patients completed all 4 cycles of the gemcitabine and carboplatin sequence. Mean number of cycles was 3.5 (range 1 to 4). Toxicities were mainly hematologic, including Grade 3 neutropenia and anemia in 3 patients. Objective response was noted in 11 pts (40.7%), including 1 complete response (CR) and 10 partial responses (PR). Three patients had stable disease and 11 progressed. Among the 20 patients, 14 received the second sequence. Mean number of paclitaxel injections was 7 (range 2 to 12). Toxicities were limited to diarrhea and neurotoxicity in 1 patient each. Objective response was documented in 6 patients (30%) (3 CR and 3 PR), including the improvement of PR into CR in 2 patients. Median duration of response was 6 months. After a median follow-up of 7 months, 21 patients died and 6 remained alive, including 2 who maintained CR and 1 PR.

Sixteen patients had locally advanced disease and 11 had metastatic disease, better prognostic was noticed with patients with locally advanced disease.

Conclusion: the sequential approach of treatment for advanced urothelial cancer using gemcitabine and carboplatine followed by paclitaxel seems to be a safer alternative to the combined triplet, but due to the limited number of patients this study failed to improve outcome. Further investigations with larger population are required.

Wednesday, September 14, 2016 11:10 AM|Andrew I. Fishman, Blake Johnson, Bobby Alexander, John Won, Muhammad Choudhury, Sensuke Konno|Journal of Cancer|Labels: bladder cancer

Although interferon (IFN) has been often used as immunotherapy for bladder cancer, its efficacy is rather unsatisfactory, demanding further improvement. Combination therapy is one of viable options, and grape seed proanthocyanidin (GSP) could be such an agent to be used with IFN because it has been shown to have anticancer activity. We thus investigated whether combination of IFN and GSP might enhance the overall antiproliferative effect on bladder cancer cells in vitro. Human bladder cancer T24 cells were employed and treated with the varying concentrations of recombinant IFN-α2b (0-100,000 IU/ml), GSP (0-100 μg/ml), or their combinations. IFN-α2b alone led to a ~50% growth reduction at 20,000 (20K) IU/ml, which further declined to ~67% at ≥50K IU/ml. Similarly, GSP alone induced a ~35% and ~100% growth reduction at 25 and ≥50 μg/ml, respectively. When IFN-α2b and GSP were then combined, combination of 50K IU/ml IFN-α2b and 25 μg/ml GSP resulted in a drastic >95% growth reduction. Cell cycle analysis indicated that such an enhanced growth inhibition was accompanied by a G1 cell cycle arrest. This was further confirmed by Western blot analysis revealing that expressions of G1-specific cell cycle regulators (CDK2, CDK4, cyclin E and p27/Kip1) were distinctly modulated with such IFN-α2b/GSP treatment. Therefore, these findings support the notion that combination of IFN-α2b and GSP is capable of additively enhancing antiproliferative effect on T24 cells with a G1 cell cycle arrest, implying an adjuvant therapeutic modality for superficial bladder cancer.

Wednesday, September 14, 2016 9:49 AM|Onclive Articles|Labels: bladder cancer, regulatory
The FDA’s Oncologic Drugs Advisory Committee voted 14-0 against approving apaziquone (EOquin; Qapzola) for intravesical instillation immediately following transurethral resection in patients with non-muscle invasive bladder cancer.
Tuesday, September 13, 2016 11:38 PM|Meng-Che Hsieh, Cheng-Hua Huang, Po-Hui Chiang, Yen-Yang Chen, Yeh Tang, Yu-Li Su|Journal of Cancer|Labels: bladder cancer

Purpose: Methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC) and gemcitabine plus cisplatin (GC) are both effective first-line chemotherapy. We explore the responsive variables of MVAC and GC for patients with metastatic urothelial carcinoma of bladder (mUCB).

Materials and Methods: Patients who were initially diagnosed to have mUCB and received MVAC or GC as metastatic first-line chemotherapy between 2000 and 2014 at Kaohsiung Chang Gung Memorial Hospital were reviewed. Totally, 130 patients were enrolled into our study. Univariable Cox proportional hazard models were constructed for OS. Hazard ratio (HR) and 95% confidence intervals (CIs) was also presented.

Results: There were 50 patients (38%) in the MVAC group and 80 patients (62%) in the GC group. The median OS was insignificantly different between MVAC and GC groups, accounting for 17.0 and 14.4 months (P = 0.214), respectively. OS of MVAC group was significantly longer with regard to age ≦ 60 years (HR: 0.38, 95% CI: 0.12-0.97, P = 0.036), pure urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015), > 1 metastatic sites (HR: 0.19, 95% CI: 0.08-0.44, P = < 0.001), and neutrophil to lymphocyte ratio > 3(HR: 0.45, 95% CI: 0.25-0.81, P = 0.006), while OS with GC group was significantly longer with regard to variant urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015).

Conclusions: Our study disclosed the predictive factors of different regimen for mUCB. These results have clinical implication for physicians who treat patients with mUCB.

Tuesday, September 13, 2016 11:38 PM|Johannes Giedl, Anja Rogler, Andreas Wild, Marc-Oliver Riener, Thomas Filbeck, Maximilian Burger, Petra Rümmele, Carolyn Hurst, Margaret Knowles, Arndt Hartmann, Ulrike Zinnall, Robert Stoehr|Journal of Cancer|Labels: telomerase, bladder cancer

Activating mutations in the core promoter of the TERT gene have been described in many different tumor entities. In vitro models showed a two- to fourfold increase in transcriptional activity of the TERT promoter through creation of a consensus binding motif for Ets/TCF transcription factors caused by these mutations. TERT core promoter mutations are the most common mutations in bladder cancer with a frequency between 55.6% and 82.8% described so far, and are independent of stage and grade. Since limited data on molecular alterations of early-onset bladder tumors exists, we assessed the frequency of TERT core promoter mutations in early-onset bladder cancer. Two cohorts of bladder tumors (early-onset patient group; n=144 (age of onset of disease ≤45 years); unselected, consecutive group; n=125) were examined for TERT core promoter mutations. After microdissection and extraction of DNA the corresponding hotspot regions in the TERT core promoter were examined by Sanger-sequencing or a SNaPshot approach. A significantly lower frequency of TERT core promoter mutations was found in tumors from the early-onset cohort compared to the consecutive cohort (57.6% vs. 84.8%, p<0.001). Among the early-onset cohort cases younger than the cohort's median age of 39 years at disease onset showed a significantly reduced number of TERT promoter mutations (31/67, 46,3%) than cases aged between 39 and 45 years (52/77, 67.5%; p=0.012). This association was not found in the consecutive cases. Mutation status was independent of tumor stage and grade. We conclude that in tumors from early-onset bladder cancer patients TERT core promoter mutations are not as frequent as in bladder tumors from consecutive cases, but seem to play an important role there as well. In patients below 39 years of age TERT core promoter mutations are a more infrequent event, suggesting different mechanisms of tumorigenesis in these young patients.

Tuesday, September 13, 2016 11:38 PM|Yi-Ying Lee, Wen-Jeng Wu, Chun-Nung Huang, Ching-Chia Li, Wei-Ming Li, Bi-Wen Yeh, Peir-In Liang, Ting-Feng Wu, Chien-Feng Li|Journal of Cancer|Labels: STAT, bladder cancer

Background: Urothelial carcinoma (UC) commonly occurs in the urinary bladder (UB) and rarely in upper the upper urinary tract (UT). Its molecular pathogenesis, however, remains obscure. Though the constitutive phosphorylation of Signal Transducer and Activator of Transcription 5 (STAT5) is an important part of carcinogenesis generally, researchers have not systematically investigated this process specifically in relation to UC. The present study addresses this gap. Through data mining a published transcriptomic database of UBUCs (GSE32894), it identified Colony Stimulating Factor 2 (CSF2) as the stepwise upregulated gene of much significance among those related to the positive regulation of tyrosine phosphorylation of STAT5 (GO:0042523). Since the phosphorylation of STAT5, a key process in the development of UC, is closely associated with CSF2, we then examine CSF2 transcript and protein expression, justifying their association with clinicopathological features and survival in our well-established cohort of patients with UC.

Design: Laser capture microdissection in conjunction with real-time qRT-PCR are used to detect CSF2 transcript levels in 24 UBUCs and 6 non-tumor urothelium samples. We then used the H-score method to evaluate the immunohistochemistry in order to determine CSF2 protein expression in 296 UBUCs and 340 UTUCs, respectively. After correlating protein expression status with key clinicopathological features, the prognostic significance of CSF2 protein expression was determined for disease-specific survival (DSS) and metastasis-free survival (MeFS).

Results: We exclusively detected the CSF2 transcript, which was stepwise upregulated in tumor lesions (p=0.010). In both groups of UC we found overexpression of CSF2 significantly related to incremental pT status (UTUC, p=0.011; UBUC, p<0.001), as well as with perineural invasion (UTUC, p=0.002; UBUC, p=0.001). Univariate analysis found a close correlation between CSF2 overexpression and unfavorable prognosis for both DSS (UTUC, p=0.0001; UBUC, p<0.0001) and MeFS (UTUC, p=0.0001; UBUC, p=0.0002). High expression of CSF2 still remained prognostically for DSS (UTUC, p=0.015; UBUC, p=0.004) and MeFS (UTUC, p=0.008; UBUC, p=0.027) in multivariate comparison.

Conclusion: Our data showed that overexpression of CSF2 was inferred in advanced disease status and poor clinical outcomes for both UTUC and UBUC patients, suggesting that CSF2 may serve as an important prognosticator and a potential therapeutic target of UC.

Tuesday, September 13, 2016 11:38 PM|Li-Jung Ma, Wen-Jen Wu, Yu-Hui Wang, Ting-Feng Wu, Peir-In Liang, I-Wei Chang, Hong-Lin He, Chien-Feng Li|Journal of Cancer|Labels: bladder cancer

Purpose: The majority deaths of cancer patients are related to metastasis, thus genes associated with cell motility interest us. SPOCK1 was elected by data mining and serial evaluation. In addition, SPOCK1 has been reported to be highly expressed in different human cancers and been related to adverse outcomes. Therefore, we validate its prognostic significance in urothelial carcinoma (UC).

Materials and Methods: Real-time RT-PCR assay was used to detect SPOCK1 transcript level in 27 urinary tract urothelial carcinoma (UTUC) and 27 urinary bladder urothelial carcinoma (UBUC) samples. Immunohistochemistry evaluated by H-score determined SPOCK1 expressions in 340 UTUCs and 295 UBUCs. The transcript and protein expression were correlated with clinicopathological features. Further evaluations of the prognostic significance of SPOCK1 for disease-specific survival (DSS) and metastasis-free survival (MeFS) were analyzed.

Results: The expressions of SPOCK1 in UC were higher than those in normal urothelium by immunohistochemistry. The statistical analysis of clinicopathologic characteristics and immunohistochemistry showed that the higher expression of SPOCK1 was correlated to pT status (P<0.001), lymph node metastasis (UTUC, P=0.006; UBUC, P=0.033), higher histological grade (UTUC, P<0.001; UBUC, P<0.001), vascular invasion (UTUC, P<0.001; UBUC, P<0.001), perineurial invasion (UTUC, P<0.001; UBUC, P=0.001) and frequent mitosis (UTUC, P<0.001; UBUC, P=0.001). The prognosis of SPOCK1 of UC showed high SPOCK1 expression had significantly worse DSS and MeFS.

Conclusions: The investigation demonstrated that the higher expression of SPOCK1 correlates with a poor prognosis in UC.

Tuesday, September 13, 2016 11:38 PM|I-Wei Chang, Yu-Hui Wang, Wen-Jeng Wu, Peir-In Liang, Wei-Ming Li, Bi-Wen Yeh, Ting-Feng Wu, Hong-Lin He, Steven Kuan-Hua Huang, Chien-Feng Li|Journal of Cancer|Labels: bladder cancer

Background and Aims: Oncogenesis is a multistep process, resulting from the accumulations of multiple mutations. Of these mutations, self-sufficiency in growth signals, i.e., disruption of cell growth regulation, is the first episode. Nonetheless, the genes associated with cell growth dysregulation have seldom been systematically evaluated in either urothelial carcinomas of upper urinary tract (UTUC) or urothelial carcinomas of urinary baldder (UBUC). By data mining a published transcriptomic dataset of UBUCs (GSE31684), we identified the NDN gene as one of the most significant of those associated with the regulation of cell growth and found this gene is associated with advanced tumor status and metastatic disease (GO:0001558). Accordingly, we analyzed NDN transcript and protein expression with their clinicopathological significance.

Materials and Methods: We used real time RT-PCR to detect NDN transcript levels in 27 UTUCs and 27 UBUCs, respectively. Immunohistochemical study was performed to determine NDN protein (a.k.a. Necdin) expression evaluated by H-score method in 340 UTUCs and 295 UBUCs. NDN expression was further correlated with clinicopathological features and disease-specific survival (DSS) and metastasis-free survival (MeFS).

Results: NDN transcriptional level was significantly higher in UCs of both sites with stepwise more advanced pT statuses. Through immunohistochemistry, we found NDN protein expression was significantly associated with adverse clinicopathological parameters, e.g., advanced pT status, nodal metastasis, high grade histological patterns, and frequent mitotses (all P<0.05). In univariate analysis, NDN overexpression not only predicted worse DSS and MeFS in both the UTUC and UBUC groups, it also served as an independent prognostic factor for DSS and MeFS in multivariate analysis (all P<0.05).

Conclusions: NDN may play an important role in tumor progression in UC and could serve as a prognostic biomarker and a potential novel therapeutic target in UC.

Tuesday, September 13, 2016 8:19 PM|Taek Sang Kim, Jeong Hyun Oh, Hyun Yul Rhew|Journal of Cancer|Labels: bladder cancer

Objective: To evaluate the efficacy of adjuvant cisplatin-based chemotherapy for locally advanced upper tract urothelial cell carcinoma (UTUC) following radical nephroureterectomy with bladder cuff resection (RNU) in terms of survival and recurrence.

Materials and methods: Between January 2000 and January 2013, among 145 patients with upper tract urothelial cell carcinoma, a total of 65 patients with locally advanced UTUC (a diagnosis of pT3 or pT4 or pT1-2N1-3) underwent RNU. Of these 65 patients, 36 patients received at least three cycles of adjuvant gemcitabine plus cisplatin chemotherapy and the remaining 29 patient did not receive adjuvant chemotherapy. Clinical characteristics, bladder recurrence, distant metastasis, and cancer-specific survival were retrospectively reviewed.

Results: The mean age of the 65 patients was 60.4 (range, 37-87) years and the median follow-up period was 34 (range, 12-114) months. Patent demographics were not statistically different between the two groups. During the follow-up period, 14 patients (21.5%) experienced distant metastasis; 8 (8/36, 22.2%) patients who had undergone adjuvant chemotherapy and 6 (6/29, 20.7%) patients who did not. Bladder recurrence was noted in 17 patients (26.2%), 5 (5/36, 13.9%) of whom received adjuvant chemotherapy while the remaining 12 (12/29, 41.4%) did not. Kaplan-Meire and multivariate analysis showed that the incidence of bladder recurrence was significantly higher in patients who did not undergo adjuvant chemotherapy, and cancer specific survival was not significantly associated with adjuvant chemotherapy.

Conclusions: Adjuvant chemotherapy for locally advanced UTUC can prevent bladder recurrence, but has a minimal effect on cancer-specific survival.

Friday, September 9, 2016 1:21 AM|Hiroshi Fukuhara, Yasushi Ino, Tomoki Todo|Cancer Science|Labels: bladder cancer, clinical trial
Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T-Vec (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1 (HSV-1) armed with GM-CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T-Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX-594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM-CSF-expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild-type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third-generation oncolytic HSV-1, is ongoing in glioblastoma patients. G47∆ was recently designated as a “Sakigake” breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast-track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor-specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients. Oncolytic virus therapy is rapidly emerging as a new approach of cancer treatment. This review depicts this new trend of cancer therapy, in which the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor specific viral replication. It is likely that cancer patients will be able to choose oncolytic virus therapy freely as a treatment option in the very near future.
Monday, September 5, 2016 10:35 PM|Masaya Yonemori, Naohiko Seki, Hirofumi Yoshino, Ryosuke Matsushita, Kazutaka Miyamoto, Masayuki Nakagawa, Hideki Enokida|Cancer Science|Labels: bladder cancer
Our recent study of the microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that two miRNA, microRNA-139-5p/microRNA-139-3p were significantly downregulated in BC tissues. The aim of this study was to investigate the functional roles of these miRNA and their modulation of cancer networks in BC cells. Functional assays of BC cells were performed using transfection of mature miRNA or small interfering RNA (siRNA). Genome-wide gene expression analysis, in silico analysis and dual-luciferase reporter assays were applied to identify miRNA targets. The associations between the expression of miRNA and its targets and overall survival were estimated by the Kaplan–Meier method. Gain-of-function studies showed that miR-139-5p and miR-139-3p significantly inhibited cell migration and invasion by BC cells. The matrix metalloprotease 11 gene (MMP11) was identified as a direct target of miR-139-5p and miR-139-3p. Kaplan–Meier survival curves showed that higher expression of MMP11 predicted shorter survival of BC patients (P = 0.029). Downregulated miR-139-5p or miR-139-3p enhanced BC cell migration and invasion in BC cells. MMP11 was directly regulated by these miRNA and might be a good prognostic marker for survival of BC patients. miR-139-3p that used to be considered as non-functional miRNA (passenger strand) may actually have tumor suppressive function as well as miR-139-5p (guide strand). miR-139-3p/5p may function as tumor suppressors simultaneously through targeting MMP11 that has oncogenic funtion.
Monday, September 5, 2016 6:00 PM|Graham G Giles|British Journal of Cancer - Issue - science feeds|Labels: bladder cancer

Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case–control study

British Journal of Cancer 115, 664 (06 September 2016). doi:10.1038/bjc.2016.237

Authors: Pierre-Antoine Dugué, Maree T Brinkman, Roger L Milne, Ee Ming Wong, Liesel M FitzGerald, Julie K Bassett, Jihoon E Joo, Chol-Hee Jung, Enes Makalic, Daniel F Schmidt, Daniel J Park, Jessica Chung, Anthony D Ta, Damien M Bolton, Andrew Lonie, Anthony Longano, John L Hopper, Gianluca Severi, Richard Saffery, Dallas R English, Melissa C Southey & Graham G Giles

Wednesday, August 31, 2016 11:00 PM|Mai, Kien T.; Ball, Christopher G.; Belanger, Eric C.|Applied Immunohistochemistry & Molecular Morphology - Current Issue|Labels: bladder cancer
imageBackground: We investigated the clinical and pathologic significance of a subgroup of noninvasive papillary urothelial carcinomas (UCs) expressing reactivity to urothelial basal cell markers. Design: In total, 302 consecutive cases of noninvasive papillary UC were evaluated immunohistochemically with cytokeratin 5 (CK5)/CD44. Any UC that was reactive for greater than 25% thickness of the urothelium was designated as basal-like urothelial carcinoma (BUC); remaining UC cases were designated as non-BUC. The follow-up period was up to 3 years. Historical review of UC was extended for up to 3 retrospective years. Results: Among 302 noninvasive UC, BUC was identified in 33 of 256 (12.9%) low-grade UC and 8 of 46 (17%) high-grade UC (P=0.041). Immunoreactivity for CD44 was similar to that of CK5, but displayed weaker and more diffuse staining. CK20 was reactive in 9 cases, primarily high-grade BUC. Other basal cell markers (34bE12, p63, bcl2, and EP4) were found to be neither sensitive nor specific in detecting UC with high CK5 expression. In comparison with non-BUC, BUC was associated with increased multifocality, larger tumor size, higher recurrence rate, and more frequent upgrading and stage progression. In the follow-up period of 3 years, distant metastasis occurred in 6 cases of which 5 were in the BUC subgroup. Conclusions: Our results showed that noninvasive papillary BUC represents a small subset associated with increased risk of tumor recurrence and progression. The aggressive behavior is likely associated with basal-like features of BUC, as seen in carcinomas with basal cell features in other body sites.
Tuesday, August 30, 2016 12:11 PM|Unknown Author|Urology Times - bladder cancer (RSS 2.0)|Comments|Labels: bladder cancer, clinical trial

Bladder Ca drug-device combination begins second phase Ib trial

TARIS Biomedical has announced the initiation of a second phase Ib clinical trial of its drug-device combination product, TAR-200 (GemRIS [Gemcitabine Releasing Intravesical System]). The trial will focus on patients with nonmuscle-invasive bladder cancer (NMIBC). Researchers will assess whether continuous, local exposure to gemcitabine via TAR-200 is safe and tolerable in patients with intermediate-risk NMIBC. TAR-200 is designed to release gemcitabine continuously into the bladder over 7 days. The open-label study will be conducted at multiple sites in Europe and expects to enroll up to 30 patients who have been diagnosed with NMIBC but have not yet had transurethral resection of bladder tumors.

Injectable agent ablates tumor cells in localized prostate Ca study

Sophiris Bio Inc. recently announced successful biopsy results from all 18 patients enrolled in the phase IIa proof-of-concept study of topsalysin (PRX302) in localized prostate cancer. Topsalysin, an inactivated pore-forming protein that is injected into the prostate, showed the ability to ablate tumor cells in 50% of the patients tested 6 months after treatment. Topsalysin was administered once locally to patients, with no serious adverse effects and no new safety signals reported. The phase IIa study was an open-label study at the University College London. Results of this stage support advancing topsalysin into a phase II study to optimize delivery and confirm dosage, Sophiris Bio said.

Next: New Surgical robot sold in Europe; FDA submission planned


New surgical robot sold in Europe; FDA submission planned

TransEnterix, Inc. has announced the first global sale of its ALF-X Surgical Robotic System to a hospital in Milan, Italy. TransEnterix has indicated the multi-port robotic system is for use in urology, general surgery, gynecology, and thoracic surgery. The system is able to provide the surgeon with haptic feedback and eye-sensing camera control. Although not currently available in the U.S., TransEnterix said it is actively preparing a submission for FDA clearance.

Study shows feasibility of detecting PCa in urine with proprietary kit

BioLight Life Sciences Ltd. completed a feasibility clinical study designed to detect prostate cancer cells in urine specimens using its CellDetect technology. CellDetect is designed to provide a diagnosis of cancerous and precancerous cells, based on a combination of color and morphology, by utilizing a proprietary kit containing unique extract and dyes, according to BioLight Life Sciences. The study illustrated the feasibility of identifying intact cells originating from the prostate in urine samples following prostate massage. In the study, 18 samples were tested and researchers were able to diagnose each case in the study, while an external reviewer identified most of the prostate cancer cases. The CellDetect technology is being developed by a subsidiary of BioLight, Micromedic Technologies.

Next: Phase III patient visits completed for HSDD study


Phase III patient visits completed for hypoactive sexual desire study

Palatin Technologies has announced that the last patient visits in two phase III clinical trials of bremelanotide for treatment of female hypoactive sexual desire disorder (HSDD) have been completed. Bremelanotide is delivered subcutaneously via an auto injector pen as an on-demand, as-needed treatment. Each phase III study is a multicenter, randomized, placebo-controlled, parallel-group, 8-month trial with an open label-extension phase. Palatin expects to go through data verification and database lock in late September.

IBM develops lab-on-a-chip tech; will test its use in prostate cancer

IBM said it has developed a new lab-on-a-chip technology that can separate biological particles at the nanoscale level—a technology could help physicians diagnose cancer and other diseases before symptoms appear. IBM is working with a team from New York’s Icahn School of Medicine at Mount Sinai to continue development with plans to test the device on prostate cancer patients. Using exosomes, the IBM team is able to obtain data from easily accessible bodily fluids. The device is able separate bioparticles by size down to 20 nanometers in diameter. Researchers can detect and separate those particles in order to gain information about the presence and state of disease.

Next: Journal publishes new protocoll for prostate risk ID


Journal publishes new protocol for prostate risk identification

The Journal of Urology has published the initial results supporting the development of Exact Imaging’s PRI-MUS (prostate risk identification using micro-ultrasound) protocol. The paper appears in the August 2016 issue. According to Exact Imaging, the protocol aims to set a new standard to facilitate micro-ultrasound-based visualization and stratification of prostate tissue imaging and to best instruct real-time targeting of suspicious regions using the micro-ultrasound platform.

FDA committee will meet to discuss nasal spray for nocturia

On Oct. 19, 2016, the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee will discuss the efficacy and safety of a new drug application for Serenity Pharmaceuticals, LLC’s desmopressin nasal spray, 0.75 mcg/0.1mL and 1.5 mcg/0.1 mL. The application has been submitted for the proposed treatment of adult-onset nocturia. The FDA’s Center for Drug Evaluation and Research will provide a live webinar of the meeting free of charge.

Next: Results of study on system to aid intertility diagnosis


Study yields promising results of system to aid infertility diagnosis

Fertility and Sterility has published an article demonstrating the clinical utility of Aytu BioScience’s MiOXSYS System, which assesses the level of oxidative stress in semen as an aid in diagnosing male infertility. MiOXSYS measures oxidation-reduction potential (ORP), which Aytu BioScience says provides a more comprehensive measure of oxidative stress by accounting for both known and unknown oxidants and antioxidants in the sample. Results of the study indicate strong correlation of ORP, as measured with MiOXSYS, across different sample preparations, suggesting that ORP can be measured accurately irrespective of sample type and time, according to the company. Aytu BioScience is currently pursuing an approval pathway from the FDA.

Trial tests drug that may stop bladder cancer resistance to chemo

A clinical trial has been launched to test whether a drug is able to stop bladder cancers from becoming resistant to chemotherapy. Guadecitabine (SGI-110) will be used in combination with chemotherapy in the study from Cancer Research UK’s Centre for Drug Development and the Experimental Cancer Medicines Centre network. The first part of the multicenter trial will administer small doses of the treatment to between three and 36 advanced solid tumor patients to find the most effective dose and to ensure the drug is safe. Upon completion of the first phase, the drug will be tested in 20 bladder cancer patients to test its effectiveness. Guadecitabine is a type of DNA methyltransferase inhibitor and blocks molecules that can modify DNA.

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Sunday, August 14, 2016 10:05 PM|Frantzi, M., van Kessel, K. E., Zwarthoff, E. C., Marquez, M., Rava, M., Malats, N., Merseburger, A. S., Katafigiotis, I., Stravodimos, K., Mullen, W., Zoidakis, J., Makridakis, M., Pejchinovski, M., Critselis, E., Lichtinghagen, R., Brand, K., Dakna, M., Roubelakis, M. G., Theodorescu, D., Vlahou, A., Mischak, H., Anagnou, N. P.|Clinical Cancer Research recent issues|Labels: bladder cancer, biomarker diagnostic

Purpose: Urothelial bladder cancer presents high recurrence rates, mandating continuous monitoring via invasive cystoscopy. The development of noninvasive tests for disease diagnosis and surveillance remains an unmet clinical need. In this study, validation of two urine-based biomarker panels for detecting primary and recurrent urothelial bladder cancer was conducted.

Experimental Design: Two studies (total n = 1,357) were performed for detecting primary (n = 721) and relapsed urothelial bladder cancer (n = 636). Cystoscopy was applied for detecting urothelial bladder cancer, while patients negative for recurrence had follow-up for at least one year to exclude presence of an undetected tumor at the time of sampling. Capillary electrophoresis coupled to mass spectrometry (CE-MS) was employed for the identification of urinary peptide biomarkers. The candidate urine–based peptide biomarker panels were derived from nested cross-sectional studies in primary (n = 451) and recurrent (n = 425) urothelial bladder cancer.

Results: Two biomarker panels were developed on the basis of 116 and 106 peptide biomarkers using support vector machine algorithms. Validation of the urine-based biomarker panels in independent validation sets, resulted in AUC values of 0.87 and 0.75 for detecting primary (n = 270) and recurrent urothelial bladder cancer (n = 211), respectively. At the optimal threshold, the classifier for detecting primary urothelial bladder cancer exhibited 91% sensitivity and 68% specificity, while the classifier for recurrence demonstrated 87% sensitivity and 51% specificity. Particularly for patients undergoing surveillance, improved performance was achieved when combining the urine-based panel with cytology (AUC = 0.87).

Conclusions: The developed urine-based peptide biomarker panel for detecting primary urothelial bladder cancer exhibits good performance. Combination of the urine-based panel and cytology resulted in improved performance for detecting disease recurrence. Clin Cancer Res; 22(16); 4077–86. ©2016 AACR.

Friday, August 12, 2016 12:58 PM|Derre, L., Cesson, V., Lucca, I., Cerantola, Y., Valerio, M., Fritschi, U., Vlamopoulos, Y., Burruni, R., Legris, A.-S., Dartiguenave, F., Gharbi, D., Martin, V., Vaucher, L., Speiser, D. E., Romero, P., Jichlinski, P., Nardelli-Haefliger, D.|Clinical Cancer Research Online First Articles|Labels: bladder cancer, clinical trial

Purpose:Treatments with cancer-vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T-cells in the bladder and tumor-regression in murine bladder-cancer models. Here we determined whether an adjuvanted cancer-vaccine can be safely administered with concomitant standard intravesical Bacilus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle-invasive bladder cancer (NMIBC). Experimental Design:In a non-randomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer-vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine-injections or BCG-instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG-instillations. Results:The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AE were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T-cells were induced in blood, irrespective of BCG treatment. Interestingly, such T-cells were only detected in urine upon BCG-induced T-cell infiltration. Conclusions:Cancer-vaccines including strong adjuvants can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T-cells in the bladder upon BCG provides proof principle evidence that cancer-vaccines with local immunostimulation may be beneficial.

Friday, August 12, 2016 12:06 AM|Keishiro Fukumoto, Eiji Kikuchi, Shuji Mikami, Koichiro Ogihara, Kazuhiro Matsumoto, Akira Miyajima, Mototsugu Oya|Cancer Science|Labels: bladder cancer
Tumor budding has been defined as an isolated single cancer cell or a cluster composed of fewer than five cancer cells scattered in the stroma. It is a strong predictor for lymph node metastasis in T1 colorectal cancer. We introduced this concept to T1 non-muscle invasive bladder cancer and evaluated whether tumor budding could have a prognostic impact on the clinical outcome. We identified 121 consecutive patients with newly diagnosed T1 bladder cancer between 1994 and 2014 at Keio University Hospital. All slides were re-reviewed by a dedicated uropathologist. Budding foci were counted under ×200 magnification. When the number of budding foci was 10 or more, tumor budding was defined as positive. The relationship between tumor budding and clinical outcomes was assessed using a multivariate analysis. The median follow-up was 52 months. Tumor budding was positive in 21 patients (17.4%). Tumor budding was significantly associated with T1 substaging, tumor architecture and lymphovascular invasion. The 5-year progression-free survival rate in T1 bladder cancer patients with tumor budding was 53.8%, which was significantly lower than that in patients without tumor budding (88.4%, P = 0.001). A multivariate Cox regression analysis revealed that tumor budding was independently associated with stage progression (P = 0.002, hazard ratio = 4.90). In a subgroup of patients treated with bacillus Calmette-Guérin instillation (n = 88), tumor budding was also independently associated with stage progression (P = 0.003, hazard ratio = 5.65). Tumor budding may be a novel indicator for predicting stage progression in T1 bladder cancer, and would likely be easily introduced in clinical practice. Tumor budding is the important prognostic factor in patients with colorectal cancer, which is easy to evaluate and doesn't need immunohistochemical staining. Tumor budding may be a novel indicator for predicting stage progression in T1 non-muscle invasive bladder carcinoma.
Monday, August 1, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: PD-1/PD-L1, bladder cancer, clinical trial

Results from a phase II study indicate that the PD-L1 inhibitor atezolizumab, recently approved for advanced bladder cancer that's refractory to standard platinum chemotherapy, is effective as first-line therapy for this disease. Durable responses to atezolizumab were seen in nearly a quarter of the study patients, who were all ineligible to receive cisplatin.

Thursday, July 28, 2016 7:56 AM|Heo, J. H., Jin, H. A., Kang, Y. H., Kim, K. H., Hong, S. J., Han, K. S.|Cancer Research recent issues|Labels: PD-1/PD-L1, bladder cancer
Background: Immunotherapy based on BCG has been a standard therapy to prevent recurrence and progression in bladder cancer. Activation of immune checkpoints by binding PD-1 to its ligands, PD-L1, is vital for physiologic regulation of immune system.Tumor cells can co-opt the PD-1 pathway to escape from immunosurveillance mechanism. We investigated expression of immune checkpoints and their effects on T cells in bladder cancer.Methods: A panel of transitional cell carcinoma cell lines (UC-3,T24,KU1919 and 253J) and normal human bladder urothelial cells (SVHUC1) were used to evaluate expression of immune checkpoints. Western blot analysis was used for protein expressions from cell lines and qPCR for RNA expression from human bladder tissues. Human bladder cancer/normal paired tissues were obtained at two time points; surgical resection and then after BCG immunotherapy. Immunohistochemical staining was performed to assess infiltration and distribution of CD4+ and CD8+ T cells in bladder tumor tissues and normal bladder tissues. Immune cells were isolated and T cells were isolated by FACS sorting after immune cell isolation from tumor/normal tissues.Results: PD-L1 proteins were highly expressed in bladder cancer cell lines compared to normal bladder epithelial cell line (SVHUC1). In paired human samples (cancer and normal tissues), PD-L1 were also highly expressed in bladder cancer tissues compared with paired normal tissues. Real time RT-PCR confirmed the high expression of PD-L1 in bladder cancer tissues. Interestingly, normal epithelial tissues regenerated after surgical resection of the tumor and BCG immunotherapy had low PD- after surgical resection and BCG immunotherapy while recurred tumor showed high expression of PD-L1. Isolation of TIL and immunohistochemical staining with CD4/CD8 showed that T cells were more infiltrated in bladder cancer tissues compared to paired normal tissues. Mouse bladder tumor model expressing PD-L1 showed increased CD3+CD4+ T cells and Treg cells.Conclusion: PD-L1 are highly expressed in bladder cancer. CD3+CD4+ T cells and Treg cells are highly infiltrated in human and mouse bladder cancer tissues. Our data suggest that PD-L1 might be involved in tumor recurrence after BCG immunotherapy and might be a novel targets in bladder cancer.Citation Format: Jun Hyeok Heo, Hyun A. Jin, You Hyun Kang, Ki Hong Kim, Sung Joon Hong, Kyung Seok Han. Expression of PD-L1 and BCG immunotherapy in non-muscle invasive bladder cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A16.
Wednesday, July 27, 2016 11:11 AM|ELLINGER, J., SCHNEIDER, A.-C., BACHMANN, A., KRISTIANSEN, G., MULLER, S. C., ROGENHOFER, S.|Anticancer Research recent issues|Labels: bladder cancer

Background/Aim: Alterations of global histone modification levels have been identified in various tumor entities, including bladder cancer (BCA). Our study was designed to investigate the value of global histone acetylation levels as diagnostic and prognostic biomarker for BCA patients. Materials and Methods: A tissue microarray with formalin-fixed paraffin-embedded tissues (271 BCA and 29 normal urothelial samples) was used to determine global histone acetylation levels (histone H3 acetylation (H3Ac); histone H3 lysine 18 acetylation (H3K18Ac); histone H4 acetylation (H4Ac)). Results: Global H3Ac levels were decreased in BCA patients, whereas H3K18Ac and H4Ac levels were similar in both groups. All studied histone acetylation markers were lower in muscle-invasive BCA compared to non-muscle invasive BCA and normal urothelial tissue, thereby indicating a possible prognostic relevance. Conclusion: Global histone acetylation levels undergo quantitative alterations during bladder cancer progression and could be helpful to identify patients at risk for early cancer recurrence.

Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: bladder cancer

A distinct mutational signature is linked to NER pathway mutations and smoking in urothelial tumors.

Thursday, June 30, 2016 10:05 PM|Sweis, R. F., Spranger, S., Bao, R., Paner, G. P., Stadler, W. M., Steinberg, G., Gajewski, T. F.|Cancer Immunology Research recent issues|Labels: PD-1/PD-L1, bladder cancer

Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1–targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non–T-cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report that T-cell–inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8+ T-cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell–inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. β-Catenin, PPAR-, and FGFR3 pathways were activated in non–T-cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance. Cancer Immunol Res; 4(7); 563–8. ©2016 AACR.

Wednesday, June 29, 2016 6:00 PM|Mahir Maruf, Sam J. Brancato, Piyush K. Agarwal|Cancer Biology & Medicine|Labels: bladder cancer
Intravesical Bacillus Calmette-Guérin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer.Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment ofurothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies includerecombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emergingimmunotherapeutics in the treatment of nonmuscle invasive bladder cancer.
Friday, June 17, 2016 3:15 PM|News-Medical.Net Bladder Cancer News Feed|Comments|Labels: bladder cancer, biomarker diagnostic
Somatic mutations in the helicase-encoding ERCC2 gene are associated with response to neoadjuvant cisplatin-based chemotherapy in patients with muscle-invasive urothelial bladder carcinoma.
Monday, June 6, 2016 2:12 PM|Unknown Author|Urology Times - bladder cancer|Comments|Labels: PD-1/PD-L1, bladder cancer, biomarker diagnostic, clinical trial, regulatory

FDA approval of a new form of immunotherapy as well as a companion diagnostic test will have a significant impact on patients with the most common type of bladder cancer in the U.S., a leading urologic cancer expert says.  

Related: Genetics of two bladder cancer variants analyzed

In May, the FDA approved atezolizumab (TECENTRIQ) for treatment of locally advanced or metastatic urothelial carcinoma (mUC) that has progressed during or following platinum-based chemotherapy, or has worsened within 12 months of receiving platinum-based chemotherapy before or after surgery.

The FDA also approved VENTANA PD-L1 (SP142) Assay (developed by Roche and available through LabCorp) as a complementary diagnostic for atezolizumab. The assay measures PD-L1 expression in the bladder cancer tissue and has an immune cell scoring algorithm that can help urologists and others identify potentially good candidates for atezolizumab treatment.

Also see: Bladder cancer tests: What factors impact results?

Atezolizumab, the first and only anti-PD-L1 cancer immunotherapy approved by the FDA, was granted an accelerated, or conditional, approval because it helps to fill an unmet need. The drug is the first FDA-approved treatment for people with this specific type of bladder cancer in more than 3 decades, according to a press release from Genentech.

Next: "Finally, now, we have a second-line therapy"


Peter Black, MDDr. BlackAtezolizumab is a major breakthrough for patients with bladder cancer and a sign of more good things to come, University of British Columbia, Vancouver urologist Peter Black, MD, told Urology Times.

Have you read: Study weighs impact of BCG shortage on outcomes

“Cisplatin-based combination chemotherapy has been the standard of care for advanced bladder cancer for at least 25 years. When it fails, there are no good alternatives,” said Dr. Black, who is a principal investigator for a Genentech-co-sponsored trial evaluating atezolizumab. “Finally, now, we have a second-line therapy. And this is only the first step. Hopefully, we will be able to use this drug earlier in the care of bladder cancer patients as more trials are completed. It is also noteworthy that this drug was approved first for its use in bladder cancer.”

There is, however, some controversy over the companion assay, according to Dr. Black.

“While the response rate is greatest in patients with high PD-L1 expression, it is still encouraging in patients lacking PD-L1 expression. And these response rates are not yet firmly established,” Dr. Black said. “Developing markers to predict response to atezolizumab and other similar drugs will be very important as the field moves forward—the PD-L1 assay is not the final word.”

The approval of atezolizumab was based on IMvigor 210, an open-label, multicenter, two-cohort phase II study in which researchers studied the drug’s safety and efficacy in patients with locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression. More than 300 patients whose disease had progressed during or following platinum-based chemotherapy treatment or who had disease progression within 12 months of treatment with a platinum-based neoadjuvant or adjuvant chemotherapy regimen received a 1,200-mg intravenous dose of atezolizumab on day one of 21-day cycles until unacceptable toxicity or either radiographic or clinical progression.

Also see - The Affordable Care Act: How it has impacted men’s health

Researchers reported that, in a subset of 59 subjects with disease progression following neoadjuvant or adjuvant platinum-containing therapy, atezolizumab shrank tumors in 22% of those patients. The median follow-up was 14.4 months.

Next: Data presented at ASCO


Full results from IMvigor 210 Cohort 1 and updated results from IMvigor 210 Cohort 2 were presented at the recently concluded American Society for Clinical Oncology annual meeting in Chicago. Cohort 1 consisted of patients who had received no prior therapies for locally advanced or metastatic urothelial cancer and who were ineligible for first-line cisplatin-based chemotherapy, according to a press release from Genentech. Cohort 2 consisted of patients whose disease progressed during or following previous treatment with a platinum-based chemotherapy regimen (second-line or later). The primary outcome was objective response rate (ORR).

Read: States attempt to limit importance of MOC

In Cohort 1, ORR was 24%. Median overall survival (OS) was 14.8 months, and 12-month landmark OS was 57%. In the updated Cohort 2 results, the researchers observed an ORR of 16%, with median OS of 7.9 months and 12-month landmark OS of 37%.

Possible atezolizumab side effects include pneumonitis, hepatitis, colitis, issues affecting the pituitary, thyroid, adrenal glands, and pancreas, neuropathy and meningoencephalitis, ocular problems, severe infections, and severe infusion reactions.

“It is still only a minority of patients who show an objective response to atezolizumab and the other PD1/PD-L1 inhibitors, but many of those who do respond have durable responses,” Dr. Black said. “The durability of response is the really exciting part. Otherwise, we need to continue searching for additional treatments for those who do not respond.”

Genentech plans to offer patient assistance programs for people taking TECENTRIQ. Doctors can contact Genentech Access Solutions at (888) 249-4918 or get more information at

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Monday, June 6, 2016 3:33 AM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: bladder cancer
The immune checkpoint blockade drug nivolumab reduced tumor burden in 24.4 percent of patients with metastatic bladder cancer, regardless of whether their tumors had a biomarker related to the drug's target, according to clinical trial results from The University of Texas MD Anderson Cancer Center.
Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: EGFR, bladder cancer

HER2 or ERBB3 alterations are predictive of afatinib response in refractory urothelial carcinomas.

Tuesday, May 24, 2016 3:00 PM|Cancer|Cancer via|Comments|Labels: bladder cancer
Precis Bladder cancer is well known to preferentially afflict men. However, women are significantly more likely to die of the disease even when corrected for stage, tumor characteristics, and age. In this issue of Cancer, Rose and colleagues highlight concerning disparities in bladder cancer treatment and outcomes between the sexes. See also pages 000–000. (Source: Cancer)
Friday, May 20, 2016 5:00 AM|Renal and Urology News|Latest articles from Renal and Urology News Bladder Cancer|Labels: PD-1/PD-L1, bladder cancer, regulatory
Atezolizumab received accelerated FDA approval for patients whose disease has progressed despite platinum-based chemotherapy.
Wednesday, May 18, 2016 12:58 PM|Christina Kelly|ASCO - FDA|Labels: PD-1/PD-L1, bladder cancer, regulatory
May 18, 2016

On May 18, 2016, the U. S. Food and Drug Administration gave accelerated approval to atezolizumab injection (Tecentriq, Genentech, Inc.) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody.

The approval was based on a multicenter, single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma.  Patients entering this trial had disease progression during or following a platinum-containing chemotherapy regimen or within 12 months of treatment with a neoadjuvant or adjuvant platinum-containing regimen.  The study excluded patients who had a history of autoimmune disease or required systemic immunosuppressive medications.  Tumor specimens were required in all patients.  All patients received an intravenous infusion of atezolizumab, 1200 mg, every 3 weeks.  Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DoR).

Visceral metastases were present in 78% of patients and 40% of patients had received greater than or equal to 2 prior regimens in the metastatic setting.  Nineteen percent (19%) of patients had progressed following neoadjuvant or adjuvant therapy.   

The confirmed ORR by independent review was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response duration ranged from 2.1+ to 13.8+ months.  Of the 46 responders, 37 patients had an ongoing response for greater than or equal to 6 months and 6 for greater than or equal to12 months.  Tumor specimens were evaluated using the Ventana PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses.  Patients were considered PD-L1 positive if PD-L1 stained tumor-infiltrating immune cells occupied greater than or equal to 5% of the tumor area. Of the 310 patients, 32% were classified as having PD-L1 expression of greater than or equal to  5% (defined as PD-L1 stained tumor-infiltrating immune cells [ICs] covering greater than or equal to  5% of the tumor area).  The remaining 68% of patients were classified as having PD-L1 expression of less than 5% (PD-L1 stained tumor-infiltrating ICs covering less than 5% of the tumor area).  The confirmed ORR was 26.0% (95% CI: 17.7, 35.7) in 100 patients whose specimens had PD-L1 expression of greater than or equal to 5% and 9.5% (95% CI: 5.9, 14.3) in 210 patients whose specimens had PD-L1 expression of less than 5%.  Response durations in these subgroups were similar to those noted above in all treated patients. 

The most common adverse reactions of atezolizumab (greater than or equal to 20% of patients) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation.  Grade 3-4 adverse events were seen in 50% of patients.  Infection and immune-related adverse events such as pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, diabetes, pancreatitis, and dermatitis/rash were also seen with atezolizumab.    

The recommended dose of atezolizumab is 1200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. Testing of PD-L1 expression in tumor specimens is not required for the use of atezolizumab, but may guide in patient selection.  The Ventana PD-L1 (SP142) Assay is approved for PD-L1 testing on tumor-infiltrating immune cells. 

This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of September 12, 2016.  Atezolizumab received Breakthrough Therapy Designation for this indication and the application was granted Priority Review.  A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

Full prescribing information is available at:

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Tuesday, May 17, 2016 9:25 AM|Zhang, H., Prado, K., Zhang, K. X., Peek, E. M., Lee, J., Wang, X., Huang, J., Li, G., Pellegrini, M., Chin, A. I.|Clinical Cancer Research Online First Articles|Labels: bladder cancer

Purpose: The transcriptional regulation mediating cancer cell differentiation into distinct molecular subtypes and modulating sensitivity to existing treatments is an enticing therapeutic target. Our objective was to characterize the ability of the forkhead/winged transcription factor FOXP3 to modulate the differentiation of bladder cancer. Experimental Design: Expression of FOXP3 was analyzed by immunohistochemistry in a tumor microarray of 587 samples and overall survival in a subset of 187 patients following radical cystectomy. Functional assays were performed in SW780 and HT1376 cell lines in vitro and in vivo, and gene expression profiling performed by RNA-Seq. Validation was undertaken using gene expression profiles of 131 patients from The Cancer Genome Atlas (TCGA) consortium in bladder cancer. Results: FOXP3 expression correlates with bladder cancer stage and inversely with overall survival, with biased expression of the FOXP33 isoform. Functional assays of FOXP33 demonstrated resistance to chemotherapy in vitro, while subcutaneous xenografts overexpressing FOXP33 developed larger and more poorly differentiated bladder cancers. RNA expression profiling revealed a unique FOXP33 gene signature supporting a role in chemotherapy resistance. Accordingly, knockdown of Foxp3 by small interfering RNA in HT1376 cells conferred sensitivity to cisplatin- and gemcitabine-induced cytotoxicity. Validation in TCGA dataset demonstrated increased expression of FOXP3 in subtypes II-IV and skewing of molecular subtypes based on FOXP33-specific gene expression. Conclusions: (i) Biased expression of the FOXP33 isoform in bladder cancer inversely correlates with overall survival, (ii) FOXP33 induces a unique gene program that mediates cancer differentiation, and (iii) FOXP33 may augment chemotherapy resistance.

Wednesday, May 11, 2016 3:00 AM|Renal and Urology News|Latest articles from Renal and Urology News Bladder Cancer|Labels: CDK, bladder cancer
Researchers found elevated incidences of upper tract urothelial carcinoma (UTUC) in patients with CKD.
Tuesday, May 10, 2016 6:30 AM|Renal and Urology News|Latest articles from Renal and Urology News Bladder Cancer|Labels: bladder cancer
Therapy used in less than 5% of cases, even in those with higher clinical stage.
NY-ESO-1 antigen is a cancer-testis antigen that is exclusively expressed in several types of cancer, aside from expression in the normal testis and placenta. This antigen is considered an ideal target for cancer immunotherapy. Cholesteryl pullulan (CHP) is a novel antigen delivery system. Complexes of CHP and NY-ESO-1 antigen (CHP-NY-ESO-1) present multiple epitope peptides to both the MHC class I and class II pathways. MIS416 is a non-toxic microparticle adjuvant that activates immune responses via NOD-2 and TLR9 pathways. (Source: The Journal of Urology)
Monday, March 28, 2016 12:24 PM|The Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
The objective of the current multi-center, blinded study was to validate this capability in a large clinical trial. (Source: The Journal of Urology)
Monday, March 28, 2016 12:24 PM|The Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: PD-1/PD-L1, bladder cancer
Programmed cell death protein (PD-1) expressed on active T cells, and its ligand PD-L1 expressed on the surface of cancer cells, complementarily down-regulate T cell activation and are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the rule of PD-1 expression on clinical outcome have not been investigated. (Source: The Journal of Urology)
Monday, March 28, 2016 12:24 PM|The Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer, clinical trial
UGT1A, a major phase II drug metabolism enzyme, is known to play an important role in preventing bladder cancer initiation by detoxifying carcinogenic compounds. However, the role of UGT1A in the development and progression of upper urinary tract urothelial carcinoma (UUTUC) has not been fully investigated. In the current study, we aim to determine the expression status of UGT1A in UUTUC and its prognostic significance. (Source: The Journal of Urology)

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Optimal patient selection for adjuvant chemotherapy has not been clarified in upper urinary tract urothelial cancer (UTUC). We aimed to develop a risk model to select candidates for adjuvant chemotherapy after radical nephroureterectomy (RNU). (Source: The Journal of Urology)
Monday, March 28, 2016 12:24 PM|The Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer, biomarker diagnostic
Diffusion-weighted MRI (DWI) is a functional imaging technique that derives image contrast from differences in the motion of water molecules in tissues. The extent of the water molecule diffusion within the tissue can be quantitatively calculated as an apparent diffusion coefficient (ADC) value from DWI. We investigate the role of ADC value as an imaging biomarker for preoperative risk stratification of upper tract urothelial carcinoma (UTUC) patients. (Source: The Journal of Urology)
The predictive impact of primary tumor location for patients with upper-tract urothelial carcinoma (UTUC) on the presence of concomitant urothelial carcinoma of the bladder is still contentious. We precisely evaluated the association between tumor location and concomitant presence of urothelial carcinoma of the bladder, along with urothelial recurrence free survival (URFS) in patients with UTUC. (Source: The Journal of Urology)
Monday, March 28, 2016 12:24 PM|The Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
Accurate grading and staging of upper tract urothelial carcinoma (UTUC) often proves challenging secondary to inadequate tissue sampling during endoscopic biopsy. Furthermore, accurate knowledge of tumor biology would allow tailored treatment for patients who are not candidates for nephroureterectomy (NU) or who could benefit from minimally invasive therapy. MicroRNAs (miRNA) are promising cancer biomarkers measurable in tissue, serum and urine; however, miRNA profiling of UTUC tumors remains largely unexplored. (Source: The Journal of Urology)
Epigenetic silencing as a consequence of aberrant hypermethylation of the tumor suppressor gene RASSF1A is crucial to oncogenesis. However, little is known about the predictive role of RASSF1A methylation in postoperative upper tract urothelial carcinoma (UTUC). We analyzed the methylation status of the RASSF1A promoter in UTUC and retrospectively investigated whether the RASSF1Apromoter methylation status provides prognostic information after surgeries. (Source: The Journal of Urology)
Carcinoma in situ (CIS) of the bladder is a flat, high-grade lesion that poses heightened risk of progression to muscle invasion. However, no biomarker is currently available to reliably predict this progressive step. Identification of the molecular drivers of CIS progression in humans has been hampered in part by the limited amount of fresh materials suitable for whole transcriptome analysis. (Source: The Journal of Urology)
Monday, March 28, 2016 12:24 PM|The Journal of Urology|MedWorm: Carcinoma in Situ|Comments|Labels: bladder cancer, clinical trial
Imiquimod is a toll like receptor agonist with proven anti-tumor activity as a topical treatment for skin cancer. Vesimune® 0.4% is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non-muscle-invasive bladder cancer in a phase 1 clinical trial. Herein we report the results of a phase 2 clinical trial assessing the safety and activity of intravesical Vesimune®. (Source: The Journal of Urology)

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Saturday, March 26, 2016 4:00 PM|The Kaohsiung Journal of Medical Sciences|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
In this study, we sought to identify predictors of bladder recurrence and overall survival after simple partial cystectomy. We included 27 patients with bladder tumor who received simple partial cystectomy without pelvic lymph node dissection between March 2000 and September 2013. Adjuvant chemotherapy or radiation therapy was prescribed according to the pathological results. Parameters were compared on the basis of bladder recurrence and overall survival. During a mean follow-up time of 39 months, five patients (18.5%) experienced bladder recurrence. An older age, a higher pathological stage, positive surgical margins, and distant metastases were significant predictors of overall survival (p = 0.031, p = 0.001, p = 0.001, and p = 0.011, respectively). Meanwhile, previous bladder ...
Friday, March 25, 2016 10:58 AM|International Journal of Radiation Biology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: HIF, bladder cancer
CONCLUSIONS: HIF1α and LDH5 are markers of poor outcome in patients with bladder cancer treated with radiotherapy. Blockage of anaerobic metabolism may prove of importance in clinical radiotherapy. PMID: 27010533 [PubMed - as supplied by publisher] (Source: International Journal of Radiation Biology)
Friday, March 25, 2016 5:35 AM|Minerva Urologica e Nefrologica|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
Authors: Redrow GP, Matin SF Abstract Upper tract urothelial carcinoma (UTUC) is a rare but highly morbid genitourinary malignancy. In 2014 approximately 15000 new cases were diagnosed in the United States. It accounts for approximately 5-10% of all urothelial cell carcinomas, and 10% of renal tumors. Recent research has increased understanding of the epidemiology of this disease, including several high-risk populations. Environmental exposure to tobacco as well as aristolochic acid, and other carcinogens significantly increase the development of UTUC. Additionally, the genetic condition of hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch Syndrome (LS) is linked to development of UTUC. Advances in imaging, ureteroscopy, cytological techniques and pathologic...

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Monday, March 21, 2016 4:00 PM|Indian Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
Conclusion: Expression of miR129, miR205 and miR200a in the normal-looking mucosa of bladder cancer patients was significantly higher than the normal mucosa of a HC. This may help in predicting recurrence and formulating the follow-up strategy. (Source: Indian Journal of Urology)
Sunday, March 13, 2016 11:08 AM|Oncotarget|MedWorm: Transitional Cell Carcinoma|Comments|Labels: HPSE, bladder cancer
Authors: Gross-Cohen M, Feld S, Naroditsky I, Nativ O, Ilan N, Vlodavsky I Abstract While the pro-tumorigenic function of heparanase is well taken, the role of its close homolog, heparanase 2 (Hpa2) in cancer is by far less investigated. Utilizing immunohistochemical analysis we found that Hpa2 is expressed by normal bladder transitional epithelium and its levels are decreased substantially in bladder cancer. Notably, tumors that retain high levels of Hpa2 were diagnosed as low grade (p=0.001) and low stage (p=0.002), suggesting that Hpa2 is required to preserve cell differentiation and halt cell motility. Indeed, migration of 5637 bladder carcinoma cells was attenuated significantly by exogenous addition of purified Hpa2, and over expression of Hpa2 in 5637 cells resulted in small...

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Friday, March 11, 2016 4:00 PM|Diagnostic Cytopathology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
ConclusionThis study analyzed the nuclear and nucleolar volume to establish an index for discrimination of benign and malignant urothelial cells, providing possible additional information in urine cytology. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc. (Source: Diagnostic Cytopathology)
Thursday, March 10, 2016 4:00 PM|Urologic Oncology|MedWorm: Carcinoma in Situ|Comments|Labels: bladder cancer
CONCLUSION: That EZH2 status of noninvasive and invasive cancer correlated in individual patients suggests that EZH2 may be a marker of lineage. EZH2 may offer diagnostic utility, particularly in flat urothelial CIS vs. benign urothelium. The present study supports that EZH2 expression in bladder cancer is not predictive of oncologic outcome. PMID: 26976725 [PubMed - as supplied by publisher] (Source: Urologic Oncology)
Saturday, March 5, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Transitional Cell Carcinoma|Comments|Labels: RAS, bladder cancer
While pharmacoepidemiologic and laboratory studies have supported the hypothesis that the antidiabetic drug metformin may be useful in treating or preventing cancer, there is limited evidence to suggest which specific cancer sites may be particularly sensitive. Sensitivity likely is determined both by features of tumor pathophysiology and by pharmacokinetic factors. We used UPII-mutant Ha-ras transgenic mice that develop hyperplasia and low-grade, papillary urothelial cell carcinoma to determine whether metformin has activity in a model of superficial bladder cancer. Metformin significantly improved survival, reduced urinary tract obstruction, reduced bladder weight (a surrogate for tumor volume), and led to clear activation of AMP α kinase and inhibition of mTOR signaling in neoplas...
Tuesday, March 1, 2016 4:00 PM|The Journal of Urology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
(Source: The Journal of Urology)
Wednesday, February 17, 2016 7:36 AM|Expert Review of Anticancer Therapy|MedWorm: Carcinoma in Situ|Comments|Labels: bladder cancer
Authors: Sharma P, Zargar-Shoshtari K, Sexton WJ Abstract The most effective intravesical regimen for the treatment of non-muscle invasive bladder cancer (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) has still not been identified or optimized to minimize recurrence-free survival and prevent progression reliably and consistently. Valrubicin, however, is a cytotoxic chemotherapeutic agent that is used as an intravesical agent for BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Here we analyze the literature regarding the treatment of non-muscle invasive urothelial malignancies with intravesical valrubicin for refractory bladder cancer, present our opinion on i...
Sunday, January 31, 2016 4:00 PM|Urologic Oncology: Seminars and Original Investigations|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
Hydrogen sulfide (H2S) is a newly discovered gas transmitter. It is synthesized by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MPST). Endogenous hydrogen sulfide has never been studied in bladder cancer. (Source: Urologic Oncology: Seminars and Original Investigations)
Monday, January 25, 2016 4:00 PM|Tumor Biology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer, biomarker diagnostic
Abstract Neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase (MMP)-9, and NGAL/MMP-9 complex have been evaluated as diagnostic markers of several cancers, but results for bladder cancer are scanty. We evaluated these proteins in urine and serum of 89 patients with histologically confirmed bladder cancer and 119 cancer-free controls from a case-control study. Urinary concentrations were standardized on creatinine level. The performance of these proteins as cancer biomarkers was evaluated through the receiver operating characteristic (ROC) analysis. Urinary level of NGAL, MMP-9, and NGAL/MMP-9 complex was higher in current smokers, whereas no impact of dietary habits was observed. After adjusting for tobacco smoking, urinary concentration of MMP-9 was indepen...
Sunday, January 24, 2016 4:00 PM|Cancer Biomarkers : Section A of Disease Markers|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer, biomarker diagnostic
CONCLUSIONS: The association between podoplanin concentration and clinicopathological features indicates that it might be useful while making therapeutic decisions. PMID: 26835590 [PubMed - as supplied by publisher] (Source: Cancer Biomarkers : Section A of Disease Markers)
Thursday, January 21, 2016 3:19 AM|Urologia Internationalis|MedWorm: Transitional Cell Carcinoma|Comments|Labels: bladder cancer
Conclusion: Dispensing from adjuvant intravesical BCG treatment is associated with increased overall- and disease-specific mortality in patients with T1 high-grade transitional cell carcinoma of bladder. This observation confirms that adjuvant BCG instillation is a crucial part of treatment in this patient population.Urol Int (Source: Urologia Internationalis)

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Saturday, January 16, 2016 10:54 AM|Molecular Medicine Reports|MedWorm: Transitional Cell Carcinoma|Comments|Labels: AKT, bladder cancer
Authors: Zheng SS, Gao JG, Liu ZJ, Zhang XH, Wu S, Weng BW, Wang YL, Hou SC, Jiang B Abstract The aim of the present study was to investigate the effect of fatty acid synthase complex (FASN) on the migration capacity of bladder transitional cell carcinoma (BTCC) cells and the involvement of matrix metalloproteinase‑9 (MMP‑9) via targeting of phospho‑AKT (p‑AKT). FASN‑specific small‑interfering RNA (FASN‑siRNA) was used to inhibit FASN gene expression in the 5637 and 253J BTCC cell lines. The knockdown efficiency of FAM‑conjugated FASN‑siRNA was confirmed by fluorescence microscopy. The migratory abilities of BTCC cells were assessed using a Transwell assay. Furthermore, protein and mRNA expression of FASN, p‑AKT, AKT, and migration‑associated protein MMP‑9 w...
Wednesday, January 13, 2016 4:00 PM|Urologic Oncology|MedWorm: Carcinoma in Situ|Comments|Labels: bladder cancer
Authors: Steinberg RL, Thomas LJ, Nepple KG Abstract Intravesical Bacillus Calmette-Guérin (BCG) remains the standard of care in the treatment of bladder carcinoma in situ and as adjuvant therapy after thorough transurethral resection of high-grade non-muscle-invasive bladder cancer. Despite BCG therapy, in up to 40% of patients it would recur and 60% to 70% of those would fail repeat BCG induction be deemed BCG unresponsive. For such patients, cystectomy remains the preferred treatment option per the American Urological Association and European Association of Urology, though some patients would be medically unfit or refuse radical surgery. Further intravesical therapy for bladder-preservation therapies may preserve quality of life in these patients and in some cases can be curati...
Tuesday, January 5, 2016 4:00 PM|Cancer Prevention Research|MedWorm: Transitional Cell Carcinoma|Comments|Labels: mTOR, bladder cancer
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 ...

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Tuesday, January 5, 2016 4:00 PM|Therapeutic Advances in Urology|MedWorm: Carcinoma in Situ|Comments|Labels: bladder cancer
Conclusion: Based on analysis of available published data, MCNA offers a durable response for a small proportion of patients that have failed prior intravesical therapy. There still exists a large unmet need for nonsurgical treatment options for patients with NMIBC who have failed adjuvant intravesical therapies. (Source: Therapeutic Advances in Urology)

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