Ta Cell Research Articles

Early-Stage Heat- And Discharge-Induced Transformations in a Lithium-Ion Cell Monitored by an Advanced Battery Management System

Processes at the graphitic anode in lithium-ion (Li-ion) cells affect the solid-electrolyte-interphase (SEI) even when the anode temperature (Ta) is at or below 75 °C. Normal discharge may not raise Ta above 50 °C due to endothermic heat absorption by the anode. Under fast (>3C) discharge, exothermic reactions between the anode and the electrolyte increase Ta above 75 °C, even though surface-mounted temperature sensors do not measure it. Increase of Ta above 75 °C, even for one fast discharge cycle, permanently changes the cell impedance similarly to 15 months of calendar aging. In both cases, impedance measurements suggest loss of lithium ions from the electrolyte during the anode-electrolyte exothermic reaction that contributes to the growth of the SEI layer. Most battery management systems (BMS) monitor only the cell’s surface temperature (Tsurf). During fast discharge, most BMS register Tsurf < 75 °C, providing a false sense of safety, while the anode experiences unimpeded damage from reactions that may affect the SEI. An advanced Battery Internal Temperature Sensor-based—BMS (BITS-BMS) described in this work successfully monitors Ta and other intrinsic cell parameters in real time, and records heat- and discharge-induced events affecting the anode and the SEI.

Molecular subtypes of colorectal cancer in pre-clinical models show differential response to targeted therapies: Treatment implications beyond KRAS mutations.

Molecular subtypes of colorectal tumors are associated with prognosis and prediction for treatment benefit from chemotherapy. The purpose of this study was two-fold: 1) to determine the association of colorectal (CRC) molecular subtypes with response to targeted therapies in pre-clinical models and 2) to identify treatments for CRC stem-like subtype because these tumors are associated with a very poor patient prognosis. Eleven CRC cell lines were classified into molecular subtypes and tested for their response to pan-ERBB, MEK, and ERK inhibitors as single agents and in combination. All six inflammatory or TA cell lines were exquisitely sensitive to the combination of MEK and neratinib whereas all five stem-like cell lines were resistant. Growth inhibition in sensitive cell lines was greater with the combination than with either drug alone even in cell lines with KRAS mutations. The combination inhibited pERK in inflammatory cell lines but not in four out of five stem-like cell lines. MEK162 plus neratinib were synergistic in cell culture and xenograft models in inflammatory cell lines. The ERK inhibitor, SCH772984, down-regulated pERK, decreased cell viability, and was synergistic with neratinib in both inflammatory and stem-like subtypes. These results suggest that inhibition of pERK is a critical node in decreasing cell viability of stem-like CRC tumors. Our results also suggest that CRC molecular subtypes may yield predictive information and may help to identify patients who may respond to targeted inhibitors.

Very Low-Programming-Current RRAM With Self-Rectifying Characteristics

To resolve the sneak leakage problem and reduce the power consumption in crossbar RRAM arrays, a Cu/Al2O3/aSi/Ta cell with self-rectifying characteristics is developed. The cell exhibits low operating current ( $\sim $ nA), high ON/OFF ratios ( $> 100\times $ ), and pronounced nonlinearity. The use of low-programming-current RRAM elements avoids the current-driving capability bottleneck of selectors, while the integrated rectifying layer improves the RRAM operation reliability. Endurance of over 500 cycles with $\sim 100$ ON/OFF ratio was achieved without external current compliance. Even at such low programming levels, retention over $10^{4}$ s at 100 °C can still be obtained.

MP88-19 URINARY MICROBIOME PATTERNS APPEARS TO BE CORRELATIVE TO INTRAVESICAL RECURRENCE OF NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology V1 Apr 2016MP88-19 URINARY MICROBIOME PATTERNS APPEARS TO BE CORRELATIVE TO INTRAVESICAL RECURRENCE OF NON-MUSCLE INVASIVE BLADDER CANCER Yige Bao, Hassan Razvi, Gregory Gloor, Gregor Reid, John Denstedt, and Jeremy Burton Yige BaoYige Bao More articles by this author , Hassan RazviHassan Razvi More articles by this author , Gregory GloorGregory Gloor More articles by this author , Gregor ReidGregor Reid More articles by this author , John DenstedtJohn Denstedt More articles by this author , and Jeremy BurtonJeremy Burton More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2437AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Several studies have recently reported association between various urinary conditions. The objective of this study was to describe the urinary microbiome among bladder cancer patients, observe longitudinal urinary microbiome changes during surgery and chemotherapy, and identify microbiome patterns that are associated with frequent bladder cancer recurrences. METHODS After optimising urine sample collection, storage and processing methods for microbiome analysis, we carried out a prospective, multicenter cohort study, recruiting patients with newly diagnosed Ta, T1 or CIS transitional cell carcinoma of the bladder who underwent transurethral resection with or without intravesical instillation. Urine samples were collected at multiple time points before and after surgery as the patients were followed up for recurrence. Routine urine culture, enhanced culture, qPCR quantification and V4 16S rRNA gene sequencing were performed on urine samples for microbiome analysis. Urine samples were also analysed from gender and age-matched healthy volunteer controls. RESULTS To eliminate “background” 16S rRNA amplification we found it necessary to collect at least 20 ml of urine and store the pellet in -80 °C. We also needed to treat samples with PMA to bind any contaminating environmental DNA present. Ninety-nine patients were recruited from two medical centers and followed up for up to three years. When compared to healthy individuals, bladder cancer patients had urinary microbiome with increased alpha (within sample) diversity with a decreased proportion of “typically” commensal species. Healthy individuals generally maintained a stable urinary microbiome during the longitudinal follow up, while cancer patients’ urinary microbiome were disrupted during periods following surgery and subsequent chemotherapy, though often a restored community profile was observed in the follow up. A common urinary microbiome pattern was identified among patients with frequent recurrences compared to patients with no recurrence. CONCLUSIONS The urinary microbiome maybe indicative of likely recurrence among non-muscle invasive bladder cancer patients © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1136 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Yige Bao More articles by this author Hassan Razvi More articles by this author Gregory Gloor More articles by this author Gregor Reid More articles by this author John Denstedt More articles by this author Jeremy Burton More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

To Be(ta Cell) or Not to Be(ta cell): New Mouse Models for Studying Gene Function in the Pancreatic β-Cell.

A challenge in the pancreatic β-cell field has been to identify a promoter fragment that is active only in the β-cell compartment and inactive in other regions, such as the hypothalamic region of the brain. The presence of Cre recombinase alone in some models may also affect glucoregulation, confounding interpretation of gene function in the β-cell. A paper presented within describes the development and characterization of 2 new transgenic mice expressing Cre recombinase under the mouse insulin1 promoter that are useful for β-cell-specific gene ablation: the first is constitutive and coexpresses DsRed (Ins1-Cre-DsRed); the second allows β-cell-specific expression of the reverse tetracycline-controlled transactivator, which can be used for drug-dependent expression of a target gene of interest for overexpression studies. These novel models show robust specificity and efficiency and will be valuable tools for functional studies of gene action in β-cells, potentially alleviating current issues associated with previously available mouse lines.

390 ROLE OF KI-67 PROLIFERATION MARKER IN PREDICTING RECURRENCE OF HIGH GRADE TA & T1 BLADDER TRANSITIONAL CELL CARCINOMA

You have accessJournal of UrologyUrothelial Cancer: Natural History, Markers & Pathophysiology1 Apr 2013390 ROLE OF KI-67 PROLIFERATION MARKER IN PREDICTING RECURRENCE OF HIGH GRADE TA & T1 BLADDER TRANSITIONAL CELL CARCINOMA Mohamed Abdallah, Ahmed Abdelhalim, Hala Said, Tarek Abdelbakey, Nancy Assad, and Abdelaliem Eldorey Mohamed AbdallahMohamed Abdallah Quesna, Egypt More articles by this author , Ahmed AbdelhalimAhmed Abdelhalim Shibin Elkom, Macedonia More articles by this author , Hala SaidHala Said shibin elkom, Egypt More articles by this author , Tarek AbdelbakeyTarek Abdelbakey shibin elkom, Egypt More articles by this author , Nancy AssadNancy Assad shibin elkom, Egypt More articles by this author , and Abdelaliem EldoreyAbdelaliem Eldorey shibin elkom, Egypt More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1779AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Ki-67, an established proliferation marker expressed in G1, S, G2, M phases of cell cycle. We previously found an association between Ki-67 index & urothelial tumor grade, muscle invasion & positive lymph nodes. In this study, we focused on high grade non-muscle invasive urothelial tumor to predict recurrence after complete TURBT with 1 year follow up. This can aid decision of urologist either to follow up or to schedule his patient for radical cystectomy. METHODS 87 patients with high grade non-muscle invasive TCC did complete TURBT with immediate intravesical instillation of Epirubicin® 50 mg, Ki-67 index was estimated using purified rabbit polyclonal antibody raised against the C-terminal fragment of the human Ki67 nuclear antigen (Lab vision, USA). Intravesical immunotherapy by instillation of BCG & follow up cystoscopy & immunohistochemical determination of Ki-67 index at 3, 6, 9 & 12 months. RESULTS The Age of the patients (Range, Mean ± SD)45-60, 56.72 ± 4.81. The gender (Male%, Female%)86.1, 13.9.The Ki-67 index was(Range, Median)30-90,70.The table shows the recurrence rates. CONCLUSIONS The higher the Ki-67 index, the higher the probability of recurrence of high grade Ta & T1 transitional cell carcinoma of bladder with 56% recurrence with Ki-67 index 81-90% at 1 year follow up. New recurrence at 3 months 6 months 9 months 12 months total Ki-67 index 30-40% (N=15) 0 (0%) 0 (0%) 0 (0%) 2 (13.33%) 2 (13.33%) Ki-67 index 41-60% (N=21) 0 (0%) 0 (0%) 4 (19.05%) 4 (19.05%) 8 (38.1%) Ki-67 index 61-80% (N=26) 1 (3.85%) 1 (3.85%) 4 (15.38%) 4 (30.77%) 10 (38.46%) Ki-67 index 81-90% (N=25) 2 (8.0%) 4 (16%) 2 (8.0%) 6 (24.0%) 14 (56.0%) Overall recurrence at 1 year 34 (39.08%) © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e158 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohamed Abdallah Quesna, Egypt More articles by this author Ahmed Abdelhalim Shibin Elkom, Macedonia More articles by this author Hala Said shibin elkom, Egypt More articles by this author Tarek Abdelbakey shibin elkom, Egypt More articles by this author Nancy Assad shibin elkom, Egypt More articles by this author Abdelaliem Eldorey shibin elkom, Egypt More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1769 UPDATED RESULTS OF THE COMBINED PHASE I/II TRIAL OF INTRAVESICAL NANOPARTICLE ALBUMIN-BOUND PACLITAXEL IN THE TREATMENT OF BCG REFRACTORY NON-MUSCLE INVASIVE TRANSITIONAL CELL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Superficial II1 Apr 20121769 UPDATED RESULTS OF THE COMBINED PHASE I/II TRIAL OF INTRAVESICAL NANOPARTICLE ALBUMIN-BOUND PACLITAXEL IN THE TREATMENT OF BCG REFRACTORY NON-MUSCLE INVASIVE TRANSITIONAL CELL CARCINOMA James M. McKiernan, Dara D. Holder, Max Kates, Gina M. Badalato, Lamont J. Barlow, Arindam RoyChoudhury, Daniel Petrylak, and Mitchell C. Benson James M. McKiernanJames M. McKiernan New York, NY More articles by this author , Dara D. HolderDara D. Holder New York, NY More articles by this author , Max KatesMax Kates New York, NY More articles by this author , Gina M. BadalatoGina M. Badalato New York, NY More articles by this author , Lamont J. BarlowLamont J. Barlow New York, NY More articles by this author , Arindam RoyChoudhuryArindam RoyChoudhury New York, NY More articles by this author , Daniel PetrylakDaniel Petrylak New York, NY More articles by this author , and Mitchell C. BensonMitchell C. Benson New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1786AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Up to 50% of patients treated with intravesical agents for non-muscle invasive bladder cancer (NMIBC) will recur. Response rates to current second-line intravesical therapies average less than 20%. For these high risk patients, novel agents are necessary. Nanoparticle albumin-bound (nab-) paclitaxel has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy trials.It is therefore an appropriate candidate for further investigation as an intravesical agent. Results of the Phase I trial demonstrated minimal toxicity and systemic absorption during dose escalation. We now report the results of the ongoing Phase II trial. METHODS In January 2010, accrual began for the IRB approved phase II trial investigating the use of (nab-) paclitaxel for BCG refractory NMIBC. Inclusion criteria included patients with recurrent high grade (HG) Ta, T1, and Tis transitional cell carcinoma who failed at least one prior regimen of BCG. In accordance with the dosing determinations from Phase I data, 500mg of nab-paclitaxel was administered in six weekly intravesical instillations . The primary endpoint was response rate. Efficacy was evaluated by cystoscopy, biopsy, cytology, and imaging. If there was no evidence of disease, patients could elect to undergo maintenance treatment at 3, 6, 12, 18, 24 and 36 mos. Safety and toxicity profiles were monitored throughout. RESULTS As of November 1st 2011, nineteen of the targeted 29 patients had been enrolled. Three patients were withdrawn from the study: one due to non-study related pneumonia and sepsis; one withdrew consent; and one had a grade II urinary tract infection (UTI). Three patients (16%) had no evidence of disease at their initial post-treatment cystoscopy and became eligible for maintenance therapy. To date, these patients were free of disease at 5, 18 and 21 months following enrollment. Of the 16 patients who did not respond, no patient had progression of their disease. Local grade 1 toxicities were observed in 10/19 (52%) of patients, with UTIs being the most common. There was only 1 grade II complication, a Pseudomonas aeruginosa UTI. CONCLUSIONS Intravesical nab-paclitaxel has minimal toxicity and a 16% response rate in patients with non-muscle invasive disease and previous BCG failure. Completion of accrual is expected in April 2012. Long-term follow-up and quality of life will be reported at that time. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e714 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information James M. McKiernan New York, NY More articles by this author Dara D. Holder New York, NY More articles by this author Max Kates New York, NY More articles by this author Gina M. Badalato New York, NY More articles by this author Lamont J. Barlow New York, NY More articles by this author Arindam RoyChoudhury New York, NY More articles by this author Daniel Petrylak New York, NY More articles by this author Mitchell C. Benson New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Single or two instillations of pirarubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: A prospective, randomized controlled study.

LBA266 Background: Although single intravesical instillation chemotherapy immediately after transurethral resection (TUR) is the standard treatment for non-muscle-invasive bladder tumors, 40% to 80% of tumors show intravesical recurrence. In this prospective randomized controlled study, we try to evaluate the prophylactic efficacy and safety of twice intravesical instillation using pirarubicin (THP) administered immediately after TUR and on the next day following TUR by comparison with single instillation immediately after TUR. Methods: Between 2005 and 2009, 250 patients with Ta and T1 solitary bladder carcinoma were enrolled in this study. Patients were randomized into two groups. Group A patients were treated with two intravesical instillations of THP 30 mg/50 ml saline immediately after TUR and within 24 hours. Group B patients were treated with single instillation of the same dose immediately after TUR as a control group. The primary endpoint was duration to the first recurrence, and the secondary endpoint was safety. Results: The enrollment was closed on 2009, and the follow-up phase is in process. Of the 250 patients, 125 in Group A and 125 in Group B could be evaluated as full analysis set. One hundred eight male and 17 female were in Group A, on the other hands, one hundred five male and 20 female were in Group B. Eighty-six cases (69%) in group A, and 88 cases (70%) in group B were primary tumor. Fifty-seven cases (46%) in group A, and 56 cases (45%) in group B were small tumor (less than 10mm). There was no difference between backgrounds of both groups. The randomization worked well. In this ad interim report, median follow up was 48 months. Two-year recurrence-free rates were 76.8% in group A and 67.5% in group B. Adverse reactions related to instillation were observed in about 20% of the patients. These toxicities were mild and transient. Only the incidence of frequency in group A was higher than that in group B (20% vs. 8%, p=0.0106). Conclusions: Intravesical instillation of THP 30 mg twice within 24 hours after TUR was effective as prophylactic therapy for non-muscle-invasive cancer with tolerable toxicity problems.

1044 Single or two instillations of pirarubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: A prospective, randomized controlled study

1044 Single or two instillations of pirarubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: A prospective, randomized controlled study

A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer

Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen.

Testate Amoebae Examined by Confocal and Two-Photon Microscopy: Implications for Taxonomy and Ecophysiology

Testate amoebae (TA) are a group of free-living protozoa, important in ecology and paleoecology. Testate amoebae taxonomy is mainly based on the morphological features of the shell, as examined by means of light microscopy or (environmental) scanning electron microscopy (SEM/ESEM). We explored the potential applications of confocal laser scanning microscopy (CLSM), two photon excitation microscopy (TPEM), phase contrast, differential interference contrast (DIC Nomarski), and polarization microscopy to visualize TA shells and inner structures of living cells, which is not possible by SEM or environmental SEM. Images captured by CLSM and TPEM were utilized to create three-dimensional (3D) visualizations and to evaluate biovolume inside the shell by stereological methods, to assess the function of TA in ecosystems. This approach broadens the understanding of TA cell and shell morphology, and inner structures including organelles and endosymbionts, with potential implications in taxonomy and ecophysiology.

A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCG-refractory and BCG-intolerant patients

PurposeA Phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of the immunotoxin VB4-845 in patients with nonmuscle-invasive bladder cancer (NMIBC) refractory to or intolerant of bacillus Calmette–Guerin (BCG). Secondary objectives included evaluation of the safety, tolerability, pharmacokinetics, immunogenicity, and efficacy of VB4-845.Patients and methodsSixty-four patients with Grade 2 or 3, stage Ta or T1 transitional cell carcinoma or in situ carcinoma, either refractory to or intolerant of BCG therapy, were enrolled. Treatment was administered in ascending dose cohorts ranging from 0.1 to 30.16 mg. After receiving weekly instillations of VB4-845 to the bladder via catheter for 6 consecutive weeks, patients were followed for 4–6 weeks post-therapy and assessed at week 12.ResultsAn MTD was not determined, as a dose-limiting toxicity was not identified over the dose range tested. VB4-845 therapy was safe and well tolerated with most adverse events reported as mild; as a result, no patients were removed from the study in response to toxicity. By the end of the study, the majority of patients had developed antibodies to the exotoxin portion of VB4-845. A complete response was achieved in 39% of patients at the 12-week time point.ConclusionsVB4-845 dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. Although an MTD was not determined at the doses administered, VB4-845 showed evidence of an antitumor effect that warrants further clinical investigation for the treatment of NMIBC in this patient population.

Chitosan Increases α6 Integrinhigh/CD71highHuman Keratinocyte Transit-Amplifying Cell Population

Abstract － Glycosaminoglycans (GAGs) and chitosan have been used as matrix materials to support the dermal part of skin equivalent which is used for both pharmacological and toxicological evaluations of drugs potentially used for dermatological diseases. However, their biological roles of GAGs and chitosan in the skin equivalent are still unknown. In the present study, we evaluated whether GAGs and chitosan directly affect keratinocyte stem cells (KSCs) and their transit-amplifying cells (TA cells). Among supporting matrix materials, chitosan significantly increased the number of α6 integrin high /CD71 high human keratinocyte TA cells by 48.5%. In quantitative real-time RT-PCR analysis, chitosan significantly increased CD71 and CD200 gene transcription whereas not α6 integrin. In addition, the level of the gene transcription of both keratin 1 (K1) and K10 in the chitosan-treated human keratinocytes was significantly lower than those of control, suggesting that chitosan inhibit keratinocyte differentiation. We also found that N-acetyl-D-glucosamine (NAG) and β-(1-4)-linked D-glucosamine (D-glc), two components of chitosan, have no effect on the expression of CD71, K1, and K10, suggesting that each monomer component of chitosan is not enough to regulate the number of epidermal keratinocyte lineage. Conclusively, chitosan increases keratinocyte TA cell population which may contribute to the cellular mass expansion of the epidermal part of a skin equivalent system.Keywords: Chitosan, Keratinocyte stem cells, Transit-amplifying cells, CD71, K1, K10

Stage pT0 at Radical Cystectomy Confers Improved Survival: An International Study of 4,430 Patients

We describe the cancer related outcome in patients with pT0 bladder urothelial carcinoma at radical cystectomy who did not receive preoperative chemotherapy in a large multicenter series. We also compared outcomes in patients with pT0 bladder urothelial carcinoma to those in patients with other stages and assessed the effect of clinical stage on outcome. We reviewed the records of 4,430 patients treated with radical cystectomy for bladder urothelial carcinoma without neoadjuvant chemotherapy at 12 centers in the United States, Canada and Europe. Of the patients 228 (5.1%) had pT0 disease at radical cystectomy. Clinical stage was cTa or cTis in 13.6% and cT1 in 29.8% of these patients, and disease was muscle invasive (cT2-4a) in 56.2%. Metastasis developed to regional lymph nodes in 17 cases (7.5%). At a median 48.2-month followup 15 patients (6.6%) had died of bladder cancer. Five-year recurrence-free and cancer specific survival estimates were 89.7% (95% CI 85.3-93.1) and 93.1% (95% CI 88.9-95.6), respectively. Disease-free and cancer specific survival in pT0 cases was similar to that in pTa/pTis cases but significantly better than in pT1 or pT2 cases. On multivariate analysis increased disease recurrence and cancer specific mortality risks were significantly associated with lymph node metastasis (each p <0.001) and female gender (p <0.001 and 0.013, respectively). Although stage pT0 at radical cystectomy confers a benefit in survival, some patients experience disease recurrence and eventual death. Identifying these patients may help tailor postoperative decision making in patients with pT0.

Phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of BCG-refractory non-muscle-invasive bladder cancer.

4542 Background: Up to 50% of patients treated with intravesical agents for non-muscle-invasive bladder cancer will recur. Response rates to current second line intravesical therapies average less than 20%. For these high risk patients, novel agents are necessary. Our previous phase I trial showed docetaxel to be a safe and efficacious agent for intravesical therapy. Nanoparticle albumin-bound (nab-)paclitaxel has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy and was therefore deemed an appropriate candidate for further investigation as an intravesical agent. Methods: This phase I trial began enrollment on 1/1/08, and the primary endpoint was reached as of 1/1/10. Inclusion criteria included recurrent high grade (HG) Ta, T1 and Tis transitional cell carcinoma failing at least one prior regimen of BCG. 6 weekly instillations of nab-paclitaxel were administered beginning at a dose of 150 mg at a concentration of 5mg/ml in normal saline with a dose escalation model used until a maximal deliverable dose (MDD) of 500 mg/100ml was achieved. The primary endpoints were dose-limiting toxicity (NCI common toxicity criteria grade 3 or 4 toxicity) and MDD; the secondary endpoint was response rate. Efficacy was evaluated by cystoscopy with biopsy, cytology, and CT imaging. Results: 18 patients were enrolled and received dose levels of 150, 225, 300, 375, 450, and 500 mg. One patient demonstrated measurable systemic absorption of nab-paclitaxel at the 450 mg dose as measured by HPLC assays (16.8 ng/mL; median detected level after standard intravenous administration: 18,000 ng/mL). 56% (10/18) of patients experienced grade 1 local toxicities, with dysuria being the most common. No grade 2, 3 or 4 drug related local toxicities have been encountered. 28% (5/18) of patients had no evidence of disease at their post-treatment cystoscopy. One patient had disease progression at the time of recurrence. Conclusions: Intravesical nab-paclitaxel exhibited minimal toxicity and systemic absorption in the first ever human intravesical dose escalation trial. A larger phase II prospective clinical trial at the 500mg dose level has been initiated. No significant financial relationships to disclose.

Loss of Heterozygosis on IFN-α Locus is a Prognostic Indicator of Bacillus Calmette-Guerin Response for Nonmuscle Invasive Bladder Cancer

We evaluated the role of loss of heterozygosity on the interferon-alpha locus to predict the response to bacillus Calmette-Guerin therapy in patients with nonmuscle invasive bladder cancer. A total of 117 consecutive patients were selected, including 77 with nonmuscle invasive bladder cancer and 40 controls. Loss of heterozygosity on the interferon-alpha locus (chromosome 9p21) was assessed in blood and urine samples before transurethral resection. All patients underwent transurethral resection and then 6 weekly bacillus Calmette-Guerin instillations. Those with nonmuscle invasive bladder cancer were assigned to groups 1 and 2 with and without loss of heterozygosity on the interferon-alpha locus, respectively. Of the 77 patients with nonmuscle invasive bladder cancer 39 (50.6%) had loss of heterozygosity on the interferon-alpha locus (group 1) and 38 (49.4%) had no alteration (group 2). Only 1 of 40 controls showed loss of heterozygosity on the interferon-alpha locus. At the end of followup 13 patients in group 1 and 27 in group 2 were alive without recurrence. We noted a significant difference between loss of heterozygosity on interferon-alpha and followup status (dF 01, LR 11.252, p = 0.003). Kaplan-Meier analysis revealed a significant difference in recurrence probability (response to bacillus Calmette-Guerin) and loss of heterozygosity on interferon-alpha (p <0.0001). On multivariate analysis loss of heterozygosity (HR 4.09, 95% CI 2.59-6.28, p = 0.002), grade (grade 3 HR 3.31, 95% CI 1.38-3.35, p = 0.03) and the number of lesions (3 or greater HR 2.31, 95% CI 1.38-3.25, p = 0.03) were independent predictors of the bacillus Calmette-Guerin response. This study highlights the predictive value of loss of heterozygosity analysis on interferon-alpha in patients with nonmuscle invasive bladder cancer treated with bacillus Calmette-Guerin.

Two instillations of epirubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: a prospective, randomized controlled study

Although transurethral resection (TUR) is the standard treatment for non-muscle-invasive bladder tumors, 40-80% of tumors recur in spite of complete resection. To evaluate the efficacy, dose effectiveness and safety of early short-duration intravesical instillation therapy using epirubicin (EPI) administered immediately after TUR and on the next day following TUR. Between 1995 and 2001, 303 patients with Ta and T1 non-muscle-invasive bladder carcinoma were enrolled in this study. Patients were randomized into three groups. Group A patients were treated with two intravesical infusions of EPI 20 mg/40 ml saline immediately after TUR and within 24 h. Group B patients were treated with EPI 50 mg/100 ml on the same schedule as group A. Group C patients were treated by TUR alone as a control group. The primary endpoint was a duration to the first recurrence. Of the 303 patients, 79 in Group A, 84 in Group B, and 77 in Group C could be evaluated for recurrence. Median follow-up was 44 months. Median recurrence-free survival durations for Groups A, B, and C were 24, 38, and 13 months, respectively. The difference between Groups B and C was statistically significant (p = 0.04). Adverse reactions related to instillation were observed in about 30% of the patients. These reactions included micturition pain and frequency. These toxicities were mild and transient. Intravesical instillation of EPI 50 mg twice within 24 h after TUR was effective as prophylactic therapy for non-muscle-invasive bladder cancer with tolerable toxicity problems.

Abstract A84: Serum VEGF is an independent prognostic factor in superficial bladder cancer

Abstract Background: Superficial bladder cancer (SBC) is a precursor of muscle-invasive, potentially life-threatening bladder cancer. Given the field cancerization effect and the risk of recurrence and progression, SBC appears the most suitable target for bladder cancer systemic chemoprevention. However, new risk biomarkers are demanded to select at-risk subjects and to conduct efficient clinical chemoprevention trials. Angiogenesis represents a key step for tumor progression and metastatic spread in solid tumors. Vascular Endothelial Growth Factor (VEGF) is the most known angiogenic factor and is involved in early stages of bladder carcinogenesis. VEGF expression, either as tissue or soluble form, has been consistently reported to be higher in SBC than in invasive bladder cancer. Purpose: We analyzed the prognostic value of serum VEGF on progression and mortality in patients (pts) with Ta and T1 transitional cell carcinoma of the bladder after a median follow-up time of 13.7 years. Methods: We used clinical, DNA flow cytometry and serum biomarker data from a chemoprevention trial of the synthetic retinoid fenretinide in 99 pts with SBC that was initiated at the National Institute for Cancer Research in Genoa in 1993. Serum aliquots at baseline and after 12 months from randomization were available for 62 subjects, 29 allocated in the fenretinide and 33 in the control arm, respectively. Study endpoints were the change of VEGF levels after 1 year of treatment and the prognostic value of baseline VEGF on progression-free survival (PFS), bladder cancer-free survival (BCFS), overall survival (OS) and cancer-free survival (CFS). Results were adjusted for age, sex, smoking habits, treatment, tumor stage, tumor grade, tumor history, DNA index and baseline VEGF levels. A Cox model for OS was used to test the prognostic effect of all factors on study. Results: No significant difference on the change of VEGF levels were observed between the two treatment arms. Kaplan Meier curves showed that the highest quintile of VEGF (&amp;gt; 350 pg/mL) at baseline defined two groups with different prognosis: at a median follow-up time of 13.7 years, 8 patients out of 12 (67%) died in the high VEGF group versus 11 of 50 (22%) in the low VEGF group (Log Rank p=0.0008); 6 of 12 (50%) and 7 of 50 (14%) died from any cancer type, respectively (p=0.002); 3 of 12 (25%) and 0 of 50 died from bladder cancer, respectively (p=0.0001). This effect was observed also in PFS analysis: 3 pts out of 12 (25%) progressed to invasive cancer in the high VEGF group versus 2 of 50 (4%) in the low VEGF group (Log Rank p=0.007); in the Cox model, high VEGF levels (&amp;gt;350pg/mL) and smoking habit (ever vs. never) were the only significant risk factors for OS with hazard ratios of 4.9 (95% CI: 1.7–14.4) and 12.0 (95% CI: 1.5 to 97.4), respectively. Conclusions: High serum VEGF levels is an independent risk factor for OS, BCS and PFS in our cohort of SBC pts. Given the relevant role of VEGF in early stages of bladder carcinogenesis, it may represent a biomarker of at-risk subjects and an attractive target to be validated in future intervention trials for chemoprevention in pts with SBC. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A84.

Long-term Clinical Outcomes of a Phase I Trial of Intravesical Docetaxel in the Management of Non–muscle-invasive Bladder Cancer Refractory to Standard Intravesical Therapy

To report the long-term clinical outcomes and durability of response after treatment with induction intravesical docetaxel. Most novel agents used to treat bacillus Calmette-Guerin refractory high-grade non-muscle-invasive (NMI) bladder cancer are evaluated only after short follow-up periods. Our previously published phase I trial demonstrated that docetaxel is a safe agent for intravesical therapy with minimal toxicity and no detectable systemic absorption. We sought to determine long-term clinical outcomes after treatment with intravesical docetaxel. Eighteen patients with recurrent Ta (n = 7), T1 (n = 5), and Tis (n = 6) transitional cell carcinoma who experienced treatment failure with at least 1 prior intravesical therapy completed the phase I trial. Docetaxel was administered as 6 weekly intravesical instillations using a dose-escalation model terminated at 0.75 mg/mL. Efficacy was evaluated by interval cystoscopy with biopsies when indicated, cytology, and computed tomography imaging. Follow-up consisted of quarterly cystoscopy, cytology, computed tomography, and biopsy when indicated. With a median follow-up of 48.3 months, 4 patients (22%) have demonstrated a complete durable response and currently remain disease-free without further treatment. Three patients (17%) had a partial response, defined as a single NMI recurrence with no further therapy for bladder cancer. Eleven patients (61%) failed treatment, and required another intervention. One patient developed stage progression. No delayed toxicities were noted. The median disease-free survival time was 13.3 months. After 4 years of follow-up without maintenance therapy, intravesical docetaxel has demonstrated the ability to prevent recurrence in a select number of patients with refractory NMI bladder cancer and warrants further investigation.

A single‐institution experience with induction and maintenance intravesical docetaxel in the management of non‐muscle‐invasive bladder cancer refractory to bacille Calmette‐Guérin therapy

To analyse the durability of response for patients with non-muscle-invasive bladder cancer (NMIBC) refractory to bacille Calmette-Guérin (BCG) therapy and treated with intravesical docetaxel in a combined induction and maintenance regimen. A previous phase I trial showed docetaxel to be safe for intravesical therapy, with no systemic absorption and minimal toxicity after six weekly instillations for patients with BCG-refractory NMIBC. In that trial, docetaxel gave a 56% complete response (CR) rate at 12 weeks, but the durability was only 22%. Thus a second group of patients was treated with a 6-week induction and then given monthly maintenance therapy with intravesical docetaxel. Thirteen patients with BCG-refractory Ta, T1, or Tis transitional cell carcinoma were treated. Induction therapy was administered as six weekly intravesical instillations of 75 mg followed by single-dose monthly maintenance therapy for nine additional instillations in patients who had a CR. The initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy, and urine cytology. The follow-up consisted of quarterly cystoscopy with biopsy and cytology, and periodic imaging. The median follow-up was 13 months; 10 of 13 patients had a CR after induction, and six have remained disease-free during the follow-up. Of those in who the treatment failed, six had transurethral resection of the tumour and one a cystectomy. All 10 initial responders completed at least three instillations of maintenance therapy to date (median nine instillations), of whom six have remained recurrence-free. Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a selected group of patients with BCG-refractory NMIBC, and might decrease the overall risk of recurrence in high-risk NMIBC.