Derya Tilki

Urine Markers for Detection and Surveillance of Non-Muscle-Invasive Bladder Cancer

CONTEXT Bladder cancer diagnosis and surveillance includes cystoscopy and cytology. The limitation of urinary cytology is its low sensitivity for low-grade recurrences. As of now, six urine markers are commercially available to complement cystoscopy in the detection of bladder cancer. Several promising tests are under investigation. OBJECTIVE In this nonsystematic review, we summarize the existing data on commercially available and promising investigational urine markers for the detection of bladder cancer. EVIDENCE ACQUISITION A PubMed search was carried out. We reviewed the recent literature on urine-based markers for bladder cancer. Articles were considered between 1997 and 2011. Older studies were included selectively if historically relevant. EVIDENCE SYNTHESIS Although different studies have shown the superiority of urine markers regarding sensitivity for bladder cancer detection as compared with cytology, none of these tests is ideal and can be recommended unrestrictedly. CONCLUSIONS Urine markers have been studied extensively to help diagnose bladder cancer and thereby decrease the need for cystoscopy. However, no marker is available at present that can sufficiently warrant this. Several urinary markers have higher but still insufficient sensitivity compared with cytology. Urinary cytology or markers cannot safely replace cystoscopy in this setting. To identify an optimal marker that can delay cystoscopy in the diagnosis of bladder cancer, large prospective and standardized studies are needed.

Soft Tissue Surgical Margin Status is a Powerful Predictor of Outcomes After Radical Cystectomy: A Multicenter Study of More Than 4,400 Patients

PURPOSE We evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder. MATERIALS AND METHODS We retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen. RESULTS Positive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p <0.001). Actuarial 5-year recurrence-free and cancer specific survival probabilities were 62.8% +/- 0.8% and 69% +/- 0.8% for patients without soft tissue surgical margins vs 21.6% +/- 3.1% and 26.4% +/- 3.3% for those with positive soft tissue surgical margins (p <0.001). On multivariable analyses adjusting for the effect of standard clinicopathological features and adjuvant chemotherapy positive soft tissue surgical margin was an independent predictor of disease recurrence and cancer specific mortality (HR 1.52 and HR 1.51, p <0.001, respectively). Soft tissue surgical margin retained independent predictive value in subgroups with advanced disease such as pT3Nany, pT4Nany or Npositive. CONCLUSIONS Positive soft tissue surgical margin is a strong predictor of recurrence and eventual death from urothelial carcinoma of the bladder. Soft tissue surgical margin status should always be reported in the pathological reports after radical cystectomy. Due to uniformly poor outcomes patients with positive soft tissue surgical margins should be considered for studies on adjuvant local and/or systemic therapy.

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy.

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

Discrepancy between clinical and pathological stage: External validation of the impact on prognosis in an international radical cystectomy cohort

Study Type – Prognosis (case series) Level of Evidence 4

Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Angiogenesis and Invasion of Human Urinary Bladder Cancer

Here, we show that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in umbrella cells of bladder urothelium but is down-regulated in superficial bladder cancer, such as histologic tumor stage a (pTa) and transitional cell carcinoma in situ (pTis). Concurrently, CEACAM1 is up-regulated in the endothelia of adjacent angiogenic blood vessels. Mimicking the CEACAM1 down-regulation in the urothelium, CEACAM1 was silenced in bladder cancer cell lines 486p and RT4 using the small interfering RNA technique. CEACAM1 down-regulation was confirmed at the protein level by Western blot analyses. CEACAM1 silencing leads to a significant up-regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D in quantitative reverse transcription-PCR. Correspondingly, supernatants from the CEACAM1-overexpressing bladder cancer cell lines reduce, but those from CEACAM1 silencing induce endothelial tube formation and potentiate the morphogenetic effects of VEGF. These data suggest that the epithelial down-regulation of CEACAM1 induces angiogenesis via increased expression of VEGF-C and VEGF-D. Inversely, CEACAM1 is up-regulated in endothelial cells of angiogenic blood vessels. This in turn is involved in the switch from noninvasive and nonvascularized to invasive and vascularized bladder cancer. CEACAM1 appears to be a promising endothelial target for bladder cancer therapy.

Does the Extent of Lymphadenectomy in Radical Cystectomy for Bladder Cancer Influence Disease-Free Survival? A Prospective Single-Center Study

BACKGROUND Controversy exists regarding the optimal extent of lymphadenectomy and the number of lymph nodes to be retrieved at radical cystectomy (RC). OBJECTIVE To compare the disease-free survival of patients with standard lymphadenectomy (endopelvic region composed of the internal, external iliac, and obturator groups of lymph nodes) versus extended lymphadenectomy (up to the level of origin of the inferior mesenteric artery) at RC in a prospective cohort of patients at a single, high-volume center. DESIGN, SETTING, AND PARTICIPANTS Prospective data were collected from 400 consecutive patients treated with RC for bladder cancer by two high-volume surgeons at Mansoura Urology and Nephrology Center. Of the 400 patients, 200 (50%) received extended lymphadenectomy and the other 200 (50%) underwent standard lymphadenectomy at RC. The patients did not receive any neoadjuvant or adjuvant therapy. MEASUREMENTS Patient characteristics and outcomes are evaluated. RESULTS AND LIMITATIONS Median patient age for the entire group was 53.0 yr. Ninety-six patients (24.0%) had lymph node metastases. Median follow-up was 50.2 mo. Estimates of 5-yr disease-free survival in the extended lymphadenectomy group were 66.6% compared with 54.7% for patients with standard lymphadenectomy (p = 0.043). Extended lymphadenectomy was associated with better disease-free survival after adjusting for the effects of standard pathologic features (p = 0.02). When restricting the analyses to lymph node-positive patients, patients with extended lymphadenectomy had much better 5-yr disease-free survival compared with patients with standard lymphadenectomy (48.0% vs 28.2%; p = 0.029). The study was nonrandomized. CONCLUSIONS Extended lymphadenectomy is associated with better disease-free survival for bladder cancer patients with endopelvic lymph node involvement and should be considered in these patients.

Vascular wall as a reservoir for different types of stem and progenitor cells.

Tissue regeneration and several diseases such as tumor and atherosclerosis depend on new vessel formation by both angiogenesis and vasculogenesis. Endothelial cells (ECs) are widely considered to be the active cellular component in these processes, followed by contractile cells such as pericytes and smooth muscle cells. The best known sources providing these cell types or their progenitors are ECs lining the vessel lumen and bone marrow. As easily evident, the vessel wall was recognized as being a passive player to a great extent except ECs of the vascular intima. Particularly, the vascular adventitia has been considered as a passive layer rather than an active part of the vessel wall. But results provided during the last few years have led to a revision of this classical view because of an apparent stem cell niche function of the vascular adventitia. This review aims to sum up findings identifying the vessel wall as an important stem cell reservoir and discusses its impact on health and disease.

Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model

Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P<0.005). In conclusion, autophagy is as an important mechanism of resistance to ARSI in CRPC. Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway and the suppression of mTOR pathway. Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in vitro and in vivo, implying the therapeutics potential of autophagy inhibitors in the antiandrogen-resistance setting.

18F-Fluoroethylcholine PET/CT Identifies Lymph Node Metastasis in Patients with Prostate-Specific Antigen Failure After Radical Prostatectomy but Underestimates Its Extent

BACKGROUND The detection of lymph node metastases (LNMs) is one of the biggest challenges in imaging in urology. OBJECTIVE To evaluate the accuracy of combined 18F-fluoroethylcholine (FEC) positron emission tomography (PET)/computed tomography (CT) in the detection of LNMs in prostate cancer (PCa) patients with rising prostate-specific antigen (PSA) level after radical prostatectomy. DESIGN, SETTINGS, AND PARTICIPANTS From June 2005 until November 2011, 56 PCa patients with biochemical recurrence after radical prostatectomy underwent bilateral pelvic and/or retroperitoneal lymphadenectomy based on a positive 18F-FEC PET/CT scan. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The findings of PET/CT were compared with the histologic results. RESULTS AND LIMITATIONS Median PSA value at the time of 18F-FEC PET/CT analysis was 6.0 ng/ml (interquartile range: 1.7-9.4 ng/ml). In 48 of 56 (85.7%) patients with positive 18F-FEC PET/CT findings, histologic examination confirmed the presence of PCa LNMs. Of 1149 lymph nodes that were removed and histologically evaluated, 282 (24.5%) harbored metastasis. The mean number of lymph nodes removed per surgical procedure was 21 (standard deviation: ± 18.3). A lesion-based analysis yielded 18F-FEC PET/CT sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 39.7%, 95.8%, 75.7%, and 83.0%, respectively. A site-based analysis yielded sensitivity, specificity, PPV, and NPV of 68.4%, 73.3%, 81.3%, and 57.9%, respectively. Patients with negative PET/CT did not undergo surgery, thus sensitivity, specificity, and negative predictive value on a patient basis could not be calculated. CONCLUSIONS A positive 18F-FEC PET/CT result correctly predicted the presence of LNM in the majority of PCa patients with biochemical failure after radical prostatectomy but did not allow for localization of all metastatic lymph nodes and therefore was not adequately accurate for the precise estimation of extent of nodal recurrence in these patients.

Quality of life and perioperative outcomes after retroperitoneoscopic radical nephrectomy (RN), open RN and nephron-sparing surgery in patients with renal cell carcinoma

To prospectively evaluate health‐related quality of life (HRQoL) and perioperative outcomes in patients with T1 and T2 renal cell carcinoma (RCC) after retroperitoneoscopic radical nephrectomy (RRN), open RN (ORN) or open nephron‐sparing surgery (NSS).