Bladder Cancer - Volume 1, issue 1

Authors: Lerner, Seth P. | Theodorescu, Dan

Article Type: Editorial

DOI: 10.3233/BLC-159001

Citation: Bladder Cancer, vol. 1, no. 1, pp. 1-1, 2015

Authors: Raghavan, Derek

Article Type: Review Article

Abstract: Invasive, clinically non-metastatic bladder cancer has a cure rate of only 50% , when all T stages are considered. The pattern of relapse is dominated by systemic spread, provided that optimal surgery is practiced. Occult metastases are thus most likely to be present at first presentation. For more than 30 years, therapeutic strategies have focused on the use of systemic chemotherapy before, during or after loco-regional therapy to produce cure. More aggressive surgery and more precise radiation techniques in addition to improved chemotherapy have also been tested to improve cure rates. Genetic analysis has focused on prediction and prognostication, without …yet having a major impact on outcomes. New agents have been tested in the neoadjuvant and adjuvant setting, but have not yet proven superior to standard algorithms, such as neoadjuvant MVAC chemotherapy. Many studies have tested ineffective metastatic regimens in the neoadjuvant setting without success, giving rise to the maxim that ignoring logical rules of investigation will not advance clinical practice. Leveraging molecular prognostication and immune responsiveness of urothelial cancer may produce the next era of progress. Five simple rules are proposed to guide the development of future studies. Show more

Keywords: Invasive, bladder cancer, chemotherapy, neo-adjuvant, adjuvant, chemo-radiation, bladder preservation, geneexpression, P53, gemcitabine, paclitaxel, MVAC, CMV, PD-L1, c-MET gene

DOI: 10.3233/BLC-150010

Citation: Bladder Cancer, vol. 1, no. 1, pp. 3-13, 2015

Authors: Buchwald, Zachary S. | Efstathiou, Jason A.

Article Type: Review Article

Abstract: Recently, immunotherapy with checkpoint inhibitors has been showing promise in clinical trials for stage IV bladder cancer. Herein, we review the literature regarding the role for radiation therapy, the role for immunotherapy, and the potential synergy of these treatments combined in bladder cancer. There is ample pre-clinical data in a number of different tumor models, coupled with a growing body of clinical evidence in melanoma and other malignancies to suggest combining radiation and immunotherapy could lead to substantial advances in treatment outcomes for bladder cancer. Yet, these data for bladder cancer remain at the pre-clinical stage, and further study is …needed. Show more

Keywords: Immunotherapy, radiation therapy, bladder cancer, checkpoint inhibitor, BCG, bladder-sparing therapy

DOI: 10.3233/BLC-150014

Citation: Bladder Cancer, vol. 1, no. 1, pp. 15-27, 2015

Article Type: Short Communication

DOI: 10.3233/BLC-159002

Citation: Bladder Cancer, vol. 1, no. 1, pp. 29-30, 2015

Authors: Jevons, Sarah J. | Green, Angela | Lunter, Gerton | Kartsonaki, Christiana | Buck, David | Piazza, Paolo | Kiltie, Anne E.

Article Type: Research Article

Abstract: Background: Germline mutations in DNA damage signalling and repair genes predispose individuals to cancer. Rare germline variants may also increase cancer risk and be predictive of outcomes following cancer treatments, but require high-throughput sequencing (HTS) for detection in large cohorts. Objective: To use a dual indexing system on a HTS platform to detect novel variants in CtIP (RBBP8) which may be associated with clinical outcomes following radiotherapy treatment for bladder cancer. Methods: …All exons and flanking introns of CtIP were amplified from germline DNA from bladder cancer patients using seven primer pairs by automated long-range PCR. Amplicons were pooled, fragmented and ligated to adaptor sequences. One of 96 tag sequences was introduced at each end by PCR. Sequencing was performed on a single flow cell of an Illumina MiSeq. Reads were mapped by Stampy and variants called by Platypus. For phasing experiments, target regions were amplified and cloned for Sanger sequencing. Results: Of 201 samples, 160 were successfully amplified. Eleven CtIP variants were called, within the exons and 15 bp adjacent intronic DNA, including eight known variants from the 1000 Genomes project, plus three previously unreported variants now confirmed by Sanger sequencing. In two individuals, phasing experiments showed two variants of interest to be on separate alleles, likely to result in stronger impairment of gene function. Conclusions: We have demonstrated proof of principle for dual indexing on 160 samples on one MiSeq flow cell sequencing surface, and show that for the CtIP gene multiplexing of up to 720 samples would provide sufficient coverage to achieve >98% detection power for rare germline variation, reducing HTS costs substantially. Show more

Keywords: Biomarkers, bladder cancer, CtIP , dual indexing, next generation sequencing, radiotherapy, RBBP8

DOI: 10.3233/BLC-150007

Citation: Bladder Cancer, vol. 1, no. 1, pp. 31-44, 2015

Authors: Dancik, Garrett M. | Theodorescu, Dan

Article Type: Research Article

Abstract: Background: Approximately half of patients with muscle invasive bladder cancer succumb to their disease. Previous work identified cell cycle related genes as a prognostic class of gene expression biomarkers in bladder cancer and found a specific 31-gene cell cycle proliferation (CCP) signature predicted outcome across multiple bladder cancer cohorts. However, the prognostic value of the CCP signature specifically in muscle invasive tumors was not evaluated. Objective: To determine the prognostic value of cycle related genes in patients with muscle invasive bladder cancers. Method: …We collected all publicly available gene expression data for patients with high-grade, muscle invasive bladder cancer (8 cohorts, N = 458). We evaluated the CCP signature and two larger cell cycle gene sets: 1826 genes with a Gene Ontology (GO) annotation of “cell cycle” (GO-CCS) and 124 genes belonging to the “cell cycle” pathway in the KEGG pathway database (KEGG-CCS). An independently derived a sex identification gene signature (SIS) was developed as a positive control. Results: While SIS distinguished males from females in all cohorts with information about patient sex, the CCP signature was not prognostic in any of the cohorts we analyzed, and the GO-CCS and KEGG-CCS were never prognostic in more than 2 independent cohorts. Furthermore, neither the CCP, GO-CCS, nor KEGG-CCS signatures were consistently enriched in prognostic genes while SIS was enriched with genes associated with sex in all cohorts. Conclusions: Our findings suggest that cell cycle related genes have limited prognostic value in patients with high-grade, muscle invasive tumors. Their usefulness in predicting progression of noninvasive disease and patient response to chemotherapy remains to be determined. Show more

Keywords: Cell cycle, gene expression, bladder neoplasms

DOI: 10.3233/BLC-150012

Citation: Bladder Cancer, vol. 1, no. 1, pp. 45-63, 2015

Authors: Steinberg, Ryan L. | Thomas, Lewis J. | O’Donnell, Michael A. | Nepple, Kenneth G.

Article Type: Research Article

Abstract: Background: Bacillus Calmette-Guerin (BCG) is the most effective intravesical therapy for non-muscle invasive bladder cancer (NMIBC), but patients can fail or supply shortages can develop. For BCG failures, radical cystectomy is recommended. However, in patients who desire bladder preservation or are poor surgical candidates, alternative salvage intravesical therapies should be explored. Objective: To determine whether dual sequential intravesical gemcitabine and docetaxel is effective in treating NMIBC. Methods: We evaluated our initial experience with 45 patients treated with intravesical gemcitabine and docetaxel between June 2009 and May 2014. Patients were treated with 6 weekly instillations of gemcitabine …(1 gram of gemcitabine in 50 ml of sterile water) followed immediately by docetaxel (37.5 mg of docetaxel in 50 mL of saline). Treatment success was defined as no bladder cancer recurrence and no cystectomy. Intention-to-treat analysis was performed using the Kaplan Meier method. Results: Forty-five patients received treatment with a median overall follow-up of 15 months. Median follow up for treatment success was 6 months in all patients and 13 months for responders. Five patients were unable to tolerate a full induction course. Treatment success was 66% at first surveillance, 54% at 1 year, and 34% at 2 years after initiating induction. Ten patients received cystectomy (median of 5.6 months from starting induction) with no positive margins or lymph nodes on final pathology. Conclusions: Sequential dual intravesical gemcitabine and docetaxel can salvage some patients in a challenging NMIBC cohort. Show more

Keywords: Urinary bladder neoplasms, instillation, bladder, docetaxel, gemcitabine, salvage therapy

DOI: 10.3233/BLC-150008

Citation: Bladder Cancer, vol. 1, no. 1, pp. 65-72, 2015

Authors: Flack, Chandra K. | Monn, M. Francesca | Kaimakliotis, Hristos Z. | Koch, Michael O.

Article Type: Research Article

Abstract: Objective: To evaluate the clinicopathologic and functional outcomes of a modified Vescica ileale Padovana (VIP) neobladder technique. Methods: Data for 160 patients at a single institution who underwent radical cystectomy and orthotopic VIP neobladder creation between 1998 and 2013 were analyzed. Modified VIP technique involved longitudinal opening of the small bowel close to the anterior mesenteric border instead of along the true anti-mesentery. This allowed for creation of a dependent neourethral funnel and a large serosal surface for ureteral anastomosis, distant from any suture lines. Results: Mean age for the entire cohort was …59.5, with 9% female and 64% with muscle invasive disease prior to cystectomy. Within 30 days of surgery, 16 patients (10%) developed a Clavien grade 3-4 complication and there were no deaths. Ninety-six percent reported minor or no daytime urinary leakage at 12 months, and 70% reported minor or no nighttime urinary leakage. Two- and five-year overall survival rates were 84.2% and 72.6% , respectively. Seven patients developed a ureteral stricture (4%), three (2%) had bladder neck contractures, two (1%) experienced urethral recurrence, and there were no vesicovaginal fistulas. Conclusions: This modified VIP neobladder technique achieves favorable functional, survival, and recurrence outcomes similar to other published orthotopic continent diversions. Its near spheroidal shape lowers internal pressure, allowing for improved continence at physiologic filling capacity, and its offset bowel opening helps prevent unnecessary stretch to the native urethra, even in large individuals. The widened uretero-enteric anastomosis site distant from bowel suture lines contributes to decreased stricture rates and its placement on the dome of the neobladder facilitates endoscopic access should strictures occur. Finally, lack of posterior overlapping suture lines also mitigates the risk of fistulae formation in females should anterior vaginal wall excision or entry be unavoidable. Show more

Keywords: Cystectomy, urinary diversion, urinary bladder neoplasms, urinary reservoirs, continent, treatment outcome, quality of life

DOI: 10.3233/BLC-140002

Citation: Bladder Cancer, vol. 1, no. 1, pp. 73-79, 2015

Authors: Joo, Kwan Joong | Li, Hongtao | Zhang, Xiaoliu | Lerner, Seth P.

Article Type: Research Article

Abstract: Purpose: Despite recent improvements, resistance to traditional immunotherapy or chemotherapy is still common in patients with bladder cancer. We constructed an oncolytic virus from herpes simplex virus type II (HSV-2), which selectively targets tumor cells with an activated Ras signaling pathway. We evaluated the antitumor effect of this oncolytic HSV-2 (FusOn-H2) against bladder cancer, and compared with that of a first generation oncolytic virus derived from HSV-1 (Baco-1). Materials and methods: We established bladder tumor at the orthotopic site in C3H/He mice using the MBT-2 cells. Baco-1 or FusOn-H2 was instilled into the bladder through the urethra …respectively. Tumor volume and weight were recorded by the end of the experiment. Animal spleens were also collected to determine if any anti-tumor immunity was elicited during virotherapy in this syngeneic bladder cancer model. Results: Two instillations of the oncolytic HSVs into bladder of tumor-bearing mice almost completely eradicated the tumor in majority of tumor bearing mice. The results of tumor-specific cytotoxic T lymphocyte activity assay showed that tumor destruction by oncolytic viruses in vivo, especially by the FusOn-H2, induced potent anti-tumor immune responses. Conclusion: Oncolytic virus derived from HSV-2 has potent anti-tumor activity against bladder cancer. Oncolytic effect of this virus in vivo induces tumor specific cellular immunity that further enhances the overall anti-tumor activity. Translating this novel virotherapy into the clinic could present an alternative intravesical therapy strategy for patients with bladder cancer. Show more

Keywords: Urinary bladder neoplasms, herpes simplex virus, oncolytic virus, ras gene

DOI: 10.3233/BLC-150013

Citation: Bladder Cancer, vol. 1, no. 1, pp. 81-90, 2015

Authors: Rozanski, Alexander T. | Benson, Cooper R. | McCoy, Jacob A. | Green, Charles | Grossman, H. Barton | Svatek, Robert S. | Shah, Jay B.

Article Type: Research Article

Abstract: Background: The ability to accurately determine tumor stage in bladder cancer is critical because it impacts the management paradigm and overall prognosis. There is often discrepancy between clinical and pathologic staging. Historically, exam under anesthesia (EUA) has been recommended to assist in the staging of bladder cancer. Objective: In this era of modern imaging technology, we sought to determine if EUA still contributes meaningfully to the local staging of bladder cancer. Methods: We retrospectively reviewed the charts of 1898 patients from 1994–2013 in our radical cystectomy database at MD Anderson Cancer Center. There …were 414 patients that had complete information including EUA and whose surgery was performed by one of two surgeons and included in the final analysis. Univariate and multiple logistic regression models were generated to determine the ability of EUA, imaging, and other patient characteristics to predict pathological fat extension at the time of cystectomy. Results: 38% of patients had≥pT3 disease at the time of cystectomy. 30.9% of patients had findings on EUA suggestive of T3 disease and 28.7% had radiologic findings suggestive of T3 disease. In a model including age, BMI, ethnicity, year of operation, and neoadjuvant chemotherapy among other factors, the only factors predictive of pT3 disease were EUA and imaging (p = 0.002). The combination of EUA and imaging improved the accuracy of clinical staging compared to either modality alone. Conclusions: Despite modern advances in imaging, EUA contributes meaningfully to accurate determination of local bladder cancer stage. Show more

Keywords: Bladder cancer, clinical staging, exam under anesthesia, modern imaging

DOI: 10.3233/BLC-150006

Citation: Bladder Cancer, vol. 1, no. 1, pp. 91-96, 2015

Authors: Niegisch, Günter | Hulsbergen - van de Kaa, Christina | Ploeg, Martine | Hendricksen, Kees | Witjes, J. Alfred

Article Type: Research Article

Abstract: Background: A second primary tumors of the urethra (urethral recurrence) after radical cystectomy has been reported to be more infrequent in patients with ileal orthotopic (neobladder) compared to incontinent diversions. Objective: To investigate whether an altered immunogenic environment of urethral tissue is induced by urethro-ileal anastomosis. Methods: Between 10/2008 and 12/2009 urethral biopsies of 19 patients (9 neobladder patients, 10 control patients without urethra-ileal anastomosis) were evaluated by conventional histopathological examination and immunohistochemistry for T- (CD3/CD5, CD4, CD8) and B-cell markers …(CD20/22, CD79a, CD138). After semi-quantitative assessment, relative cell fractions (B vs. T cells) and subclasses (T4-helper vs. T8-killer cells vs. B cell clones, plasma cells) in neobladder vs. control patients were studied. Unpaired t-test was used for statistical analysis. Results: Of 19 included patients, 16 were eligible for analysis (7x neobladder, 9x controls). All neobladder patients had undergone cystectomy for UBC. Comparing relative fractions of cells positive for T- and B-cell markers in NB and CO patients, no statistical differences were observed. In 4/7 neobladder patients relative fraction of CD79a positive B-cells was higher than relative fraction of CD3/CD5 positive T-cells (B/T-ratio 1.3). B cells were predominantly CD138 positive plasma cells (5/7 NB patients). Relative B-cell fraction was lower than T-cell fraction in 7/9 control patients (B/T-ratio 0.6). Neither CD 138 positive plasma cells nor CD22 positive B cell clones were predominant. T-helper and CD8 positive T-killer cells were equally distributed in both neobladder (CD4/CD8-ratio: 2.1) and control patients (CD4/CD8-ratio: 1.9). Conclusions: Comparing neobadder and control patients the distribution of B- and T-cells was statistically not different. However, a trend towards an increased presence of B-cells in urethral tissues of NB patients that could become relevant in a larger study might be suggestive for an immunological response induced by connecting urethral and ileal tissue. Show more

Keywords: Orthotopic diversion, neobladder, urethral recurrence, cancer immunology, radical cystectomy, second primary tumors of the urethra

DOI: 10.3233/BLC-140001

Citation: Bladder Cancer, vol. 1, no. 1, pp. 97-103, 2015