Bladder Cancer - Volume 2, issue 4

Authors: Nandagopal, Lakshminarayanan | Sonpavde, Guru

Article Type: Review Article

Abstract: Bladder cancer is a molecularly heterogeneous disease characterized by multiple unmet needs in the realm of diagnosis, clinical staging, monitoring and therapy. There is an urgent need to develop precision medicine for advanced urothelial carcinoma. Given the difficulty of serial analyses of metastatic tumor tissue to identify resistance and new therapeutic targets, development of non-invasive monitoring using circulating molecular biomarkers is critically important. Although the development of circulating biomarkers for the management of bladder cancer is in its infancy and may currently suffer from lower sensitivity of detection, they have inherent advantages owing to non-invasiveness. Additionally, circulating molecular alterations may capture …tumor heterogeneity without the sampling bias of tissue biopsy. This review describes the accumulating data to support further development of circulating biomarkers including circulating tumor cells, cell-free circulating tumor (ct)-DNA, RNA, micro-RNA and proteomics to improve the management of bladder cancer. Show more

Keywords: Bladder cancer, circulating, biomarkers

DOI: 10.3233/BLC-160075

Citation: Bladder Cancer, vol. 2, no. 4, pp. 369-379, 2016

Authors: Russell, Christopher M. | Lebastchi, Amir H. | Borza, Tudor | Spratt, Daniel E. | Morgan, Todd M.

Article Type: Review Article

Abstract: While radical cystectomy (RC) with pelvic lymph node dissection (PLND) represents the accepted gold standard for the treatment of muscle-invasive bladder cancer, this treatment approach is associated with significant morbidity. As such, bladder preservation strategies are often utilized in patients who are either deemed medically unfit due to significant comorbidities or whom decline management with RC and PLND secondary to its associated morbidity. In a select group of patients, meeting strict criteria, bladder preservation approaches may be employed with curative intent. Trimodal therapy, consisting of complete transurethral resection of bladder tumor (TURBT), chemotherapy, and radiation therapy has demonstrated durable oncologic control …and long-term survival in a number of studies. The review presented here provides a description of trimodal therapy and the role of TURBT in bladder preservation for patients with muscle-invasive bladder cancer. Show more

Keywords: Trimodal therapy, TMT, bladder cancer, transurethral resection, radiotherapy

DOI: 10.3233/BLC-160076

Citation: Bladder Cancer, vol. 2, no. 4, pp. 381-394, 2016

Authors: Fina, Emanuela | Necchi, Andrea | Giannatempo, Patrizia | Colecchia, Maurizio | Raggi, Daniele | Daidone, Maria Grazia | Cappelletti, Vera

Article Type: Research Article

Abstract: Background: The therapeutic paradigm of metastatic urothelial carcinoma (UC) is rapidly shifting and new biomarkers are needed to enhance patient selection. Objective: Early identification of dynamic predictors of outcome may be a key to optimize the sequence of effective therapies in metastatic UC patients. Methods: Blood samples from patients receiving first-line MVAC chemotherapy were collected at baseline (T0 ) and after 2 cycles (T2 ). Samples were processed by immunomagnetic beads (AdnaTest ProstateCancerSelect kit) and the expression of EPCAM , MUC1 and ERBB2 was studied using multiplex-PCR. Circulating tumor cell (CTC) positivity and cutoffs, …obtained by receiver operator characteristic (ROC) curve analysis in healthy donors, were: ≥1 positive marker among EPCAM (≥0.40 ng/μl), MUC1 (≥0.10 ng/μl) and ERBB2 (≥0.20 ng/μl). CTC variation (T0 /T2 ) was split in favorable (+/–, –/–, –/+) and unfavorable groups (+/+). Cox regression analyses evaluated associations with clinical factors. Results: In this pilot study to assess a new CTC detection method, among 31 evaluable patients, 17 (54.8%) were CTC-positive at T0 . No association was found between CTC and objective response to MVAC. CTC dynamic changes better predicted 3-year progression-free (PFS) and overall survival (OS) compared to CTC status assessed at single time points. Unfavorable trend was univariably detrimental on 3-year PFS (10% vs. 49.2%, p  = 0.006) and OS (20% vs. 63.5%, p  = 0.017). Significance was maintained after controlling for liver metastases (p  = 0.031 and p  = 0.025 for PFS and OS) and MSKCC score (p  = 0.014 and 0.025). Conclusions: Newly described early CTC changes during chemotherapy might be useful to improve our prognostic ability. Pending validation, these results could fulfill the promise to help accelerating therapeutic sequences. Show more

Keywords: Urothelial carcinoma, circulating tumor cells, first-line chemotherapy, prognostic factors

DOI: 10.3233/BLC-160069

Citation: Bladder Cancer, vol. 2, no. 4, pp. 395-403, 2016

Authors: Rose, Tracy L. | Deal, Allison M. | Ladoire, Sylvain | Créhange, Gilles | Galsky, Matthew D. | Rosenberg, Jonathan E. | Bellmunt, Joaquim | Wimalasingham, Akhila | Wong, Yu-Ning | Harshman, Lauren C. | Chowdhury, Simon | Niegisch, Guenter | Liontos, Michalis | Yu, Evan Y. | Pal, Sumanta K. | Chen, Ronald C. | Wang, Andrew Z. | Nielsen, Matthew E. | Smith, Angela B. | Milowsky, Matthew I.

Article Type: Research Article

Abstract: Background: Trimodality bladder preservation therapy (BPT) in muscle invasive bladder cancer (MIBC) includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to radical cystectomy (RC) in appropriately selected patients, or as a treatment option in non-cystectomy candidates. Several chemotherapy regimens can be used in BPT, but little is known about current practice patterns. Objective: To describe utilization patterns of BPT and associated survival outcomes in MIBC. Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3,024 consecutive patients from 29 international academic centers from 2005 …to 2013. Patients with clinical T2-T4aN0M0 urothelial cancer of the bladder were included. Results: 265 patients received BPT. Compared with the 1,447 patients who received RC, BPT patients were older, had poorer performance status, and had more comorbidities (p  < 0.01 for all). Median overall survival (OS) was similar for patients treated with curative radiation doses in BPT and patients treated with RC (41 vs 46 months, p  = 0.33, respectively). 45% of BPT patients received concurrent chemotherapy with radiation. The most common regimens included cisplatin alone (23%), carboplatin alone (22%), gemcitabine alone (10%), paclitaxel alone (9%), and 5-FU+mitomycin (5%). There were no significant differences in survival among chemotherapy regimens. Only 10 patients (4% of BPT patients) underwent salvage cystectomy. Conclusions: In clinical practice, BPT patients have similar survival to RC patients when treated with curative radiotherapy doses. Choice of concurrent chemotherapy regimen varied widely with no clear standard. Salvage cystectomy is rarely performed. Continued research is needed on the comparative effectiveness among BPT and RC, and among chemotherapy regimens in BPT. Show more

Keywords: Transitional cell carcinoma, chemoradiotherapy, cystectomy, comparative effectiveness research

DOI: 10.3233/BLC-160072

Citation: Bladder Cancer, vol. 2, no. 4, pp. 405-413, 2016

Authors: Sui, Wilson | Matulay, Justin T. | James, Maxwell B. | Onyeji, Ifeanyi C. | Theofanides, Marissa C. | RoyChoudhury, Arindam | DeCastro, G. Joel | Wenske, Sven

Article Type: Research Article

Abstract: Introduction: Micropapillary bladder cancer (MPBC) is a variant histology of urothelial carcinoma (UC) that is associated with poor outcomes however given its rarity, little is known outside of institutional reports. We sought to use a population-level cancer database to assess survival outcomes in patients treated with surgery, radiation therapy and/or chemotherapy. Materials and Methods: The National Cancer Database (NCDB) was queried for all cases of MPBC and UC using International Classification of Disease-O-3 morphologic codes between 2004–2014. Primary outcome was survival outcomes stratified by treatment modality. Treatments included radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or adjuvant …chemotherapy (AC). Results: Overall 869 patients with MPBC and 389,603 patients with UC met the inclusion criteria. Median age of the MPBC cohort was 69.9 years (58.9–80.9) with the majority of the cohort presenting with high-grade (89.3%) and muscle invasive or locally advanced disease (47.6%). For cT1 MPBC, outcomes of RC and BPS were not statistically different. For≥cT2 disease, NAC showed a survival benefit compared with RC alone for UC but not for MPBC. On multivariable analysis, MPBC histology independently predicted worse increased risk of death. On subanalysis of the MPBC RC patients, NAC did not improve survival outcomes compared with RC alone. Conclusions: Neoadjuvant chemotherapy utilization and early cystectomy did not show a survival benefit in patients with MPBC. This histology independently predicts decreased survival and prognosis is poor regardless of treatment modality. Further research should focus on developing better treatment options for this rare disease. Show more

Keywords: Bladder cancer, micropapillary

DOI: 10.3233/BLC-160066

Citation: Bladder Cancer, vol. 2, no. 4, pp. 415-423, 2016

Authors: Erlmeier, F. | Seitz, A.K. | Hatzichristodoulou, G. | Stecher, L. | Retz, M. | Gschwend, J.E. | Weichert, W. | Kübler, H.R. | Horn, T.

Article Type: Research Article

Abstract: Introduction: Immunological pathways are relevant for the effectiveness of conventional cytotoxic chemotherapy. Recently, checkpoint inhibition of the PD-1/PD-L1 axis has been shown to be therapeutically relevant in urothelial carcinoma. Objective: To monitor PD-L1 expression on tumor cells and intratumoral infiltration with CD8 positive lymphocytes during perioperative chemotherapy for urothelial cancer and to evaluate their use as potential predictive markers for chemotherapy. Patients and Methods: Sixty-four patients with muscle-invasive urothelial cancer were included in the analysis. Twenty-two patients received preoperative chemotherapy and 42 were treated in an adjuvant setting for locally advanced disease or lymph node …metastases. PD-L1 status and the density of infiltration with CD8-positive cells were assessed by immunohistochemistry and analysed for their association with survival (adjuvant group) and response to chemotherapy (preoperative group). For PD-L1 positivity we used a cutoff of 10% positive tumor cells. Results: In the adjuvant group, 11 of 42 patients (26.2%) had PD-L1 positive tumor cells. Twenty-six of 42 (61.9%) patients were highly infiltrated with CD8 + lymphocytes. There was no significant evidence of an association with overall survival for PD-L1 status nor for CD8 infiltration density (p  = 0.63 and 0.71). In the preoperative group, eight of the 22 (36.4%) patients were PD-L1 positive and 13 (59%) were highly infiltrated with CD8 + lymphocytes before chemotherapy. There was no evidence of associations with response or survival. Eight patients showed a pathological response to preoperative treatment. These had a significantly longer overall survival than non-responders (p  = 0.01). In the preoperative group the pre-treatment expression of the immunologic markers could be compared to the post-treatment status. Only one patient showed a changed PD-L1 status and three patients a changed CD8 status. Conclusions: The tumoral expression of PD-L1 in urothelial carcinoma does not seem to be largely influenced by chemotherapy. Our data do not provide evidence that tumoral expression of PD-L1 and CD8 are useful as prognostic or predictive markers. Small sample size is the major limitation of our study. Show more

Keywords: PD-L1, perioperative chemotherapy, bladder cancer

DOI: 10.3233/BLC-160067

Citation: Bladder Cancer, vol. 2, no. 4, pp. 425-432, 2016

Authors: Zuk, Keegan | Jensen, Derek | Gills, Jessie | Wyre, Hadley | Holzbeierlein, Jeffrey M. | Lopez-Corona, Ernesto | Lee, Eugene K.

Article Type: Research Article

Abstract: Background: The “July effect” is the potential effect that new and recently promoted residents have on patient care during the first months of the academic year. Literature suggests that the July effect may worsen patient outcomes and lead to systemic inefficiencies. Objective: We evaluate the July effect on mortality, morbidity, and efficiency outcomes in patients undergoing radical cystectomy. Methods: A chart review was performed in patients who underwent radical cystectomy between January 2008 and April 2012. Demographic information was abstracted from patient charts and outcomes compared between operations performed in July, September, and November (first month …of each resident’s university rotation) to the remainder of the year. Outcomes of interest included mortality, complications, and markers of efficiency (operative time, length of hospital stay, and estimated blood loss). Results: Two hundred and fifty one patients were included in the analysis. There were no major differences in mortality or morbidity between the July, September, November group and the rest of the year. Multivariable analysis demonstrates a trend for operations performed in the months of July, September, and November to be associated with longer OR times 2.06 (0.99–4.27), p  = 0.053. Length of hospital stay and estimated blood loss were no different between the two groups. Conclusions: These data demonstrate no increase in mortality or morbidity during the early academic period. Additionally, while there is a trend for OR time to be longer in the early group, length of hospital stay and estimated blood loss were no different. These data may be used as an impetus to continue to investigate technical/clinical teaching practices, strategies to assess resident progression, and to initiate protocols to support residents early in the academic year in efforts to prevent inefficiencies. Show more

Keywords: Radical cystectomy, July effect, efficiency markers

DOI: 10.3233/BLC-160059

Citation: Bladder Cancer, vol. 2, no. 4, pp. 433-439, 2016

Authors: Chandrasekar, Thenappan | Pugashetti, Neil | Durbin-Johnson, Blythe | Dall’Era, Marc A. | Evans, Christopher P. | deVere White, Ralph W. | Yap, Stanley A.

Article Type: Research Article

Abstract: Objective: To evaluate the patterns of impact of neoadjuvant chemotherapy (NAC) on renal function across the initial year following treatment for muscle-invasive bladder cancer (MIBC) with radical cystectomy (RC). Methods: We reviewed the charts of 241 patients who underwent RC for urothelial carcinoma of the bladder between 2003-14 at our institution. Renal function was evaluated at multiple time points (pre-chemotherapy, pre-operatively, post-operatively, 6–12 months follow-up), and then classified by CKD staging. Univariable and multivariable logistic regression analyses were performed to determine relationship between NAC and change in CKD stage. Results: Of the 241 patients who underwent …RC for urothelial carcinoma of the bladder, 66 (27%) received NAC and 175 (73%) did not. In multivariable analysis, NAC was significantly associated with a decrease of at least one CKD stage from baseline to post-op (p  = 0.009), but not to the 6–12 months follow-up time point (p  = 0.050). The loss of GFR in the NAC cohort occurs up-front with chemotherapy, but the peri-operative course is similar to those who underwent cystectomy alone. Of the 15 NAC patients (26.8%) who were Stage 3 CKD prior to chemotherapy, none progressed to a higher stage CKD. Conclusion: NAC is associated with an initial decline in GFR, which then remains stable through the first year following RC. Despite an initial insult, patients receiving NAC are not vulnerable to further deterioration. When appropriately selected, NAC does not appear to result in a clinically significant deterioration of renal function. Show more

Keywords: Urinary bladder neoplasms, renal insufficiency, acute kidney injury, neoadjuvant therapy, antineoplastic agents

DOI: 10.3233/BLC-160071

Citation: Bladder Cancer, vol. 2, no. 4, pp. 441-448, 2016

Authors: Hoffmann, Michèle J. | Koutsogiannouli, Evangelia | Skowron, Margaretha A. | Pinkerneil, Maria | Niegisch, Günter | Brandt, Artur | Stepanow, Stefanie | Rieder, Harald | Schulz, Wolfgang A.

Article Type: Research Article

Abstract: Background: Cell culture models of normal urothelial cells are important for studying differentiation, disease mechanisms and anticancer drug development. Beyond primary cultures with their limitations in lifespan, interindividual heterogeneity and supply, few conditionally immortalized cell lines with limited applicability due to partial transformation or impaired differentiation capacity are available. We describe characteristics of the new spontaneously immortalized cell line HBLAK derived from a primary culture of uroepithelial cells. Objective: To characterize utility and limitations of HBLAK cells as an urothelial cell culture model. Methods: Differentiation markers were investigated by immunofluorescence and RT-PCR, genetic changes by standard …karyotyping, array-CGH, PCR, RT-PCR and exome sequencing; expression of p53 and p21 by Western blotting. Results: HBLAK cells proliferated for >50 passages without senescing. They expressed cytokeratins of basal urothelial cells. Terminal differentiation markers appeared only after induction of differentiation by specific protocols. The karyotype was stable, with few chromosomal changes, especially gains of chromosomes 5 and 20 and a chromosome 9p21 deletion resulting in p16INK 4A loss. A C228T TERT promoter mutation was present, but no other mutation typical of urothelial carcinoma. TP53 was wild-type and the cell cycle was arrested in response to genomic stress. Conclusions: HBLAK cells retain some differentiation potential and respond to cytotoxic agents similar to normal urothelial cells, but contain genetic changes contributing to immortalization in urothelial tumors. HBLAK may be valuable for evaluating the tumor specificity of novel cancer drugs, but may also be applied as an urothelial in vitro carcinogenesis model. Show more

Keywords: Immortalization, normal urothelial cells, bladder cancer, cell culture model, telomerase, urothelial differentiation, CDKN2A, p53

DOI: 10.3233/BLC-160065

Citation: Bladder Cancer, vol. 2, no. 4, pp. 449-463, 2016

Authors: Soloway, Mark S.

Article Type: Case Report

DOI: 10.3233/BLC-169012

Citation: Bladder Cancer, vol. 2, no. 4, pp. 465-466, 2016