Armine K. Smith

Inadequacy of Biopsy for Diagnosis of Upper Tract Urothelial Carcinoma: Implications for Conservative Management

OBJECTIVE To report changes in grade and stage between initial diagnostic and repeat biopsies or resection for urothelial carcinoma (UTUC) and investigate the consequences for endoscopic management. Ureteroscopic management of upper tract UTUC is an alternative to nephroureterectomy, which is less invasive and preserves renal function. However, concerns about potential understaging, inaccurate grading, incomplete resection, lack of effective tertiary chemoprevention, and need for ureteroscopic surveillance limits it appeal. METHODS Clinicopathological records of patients with UTUC treated at our institution were reviewed. Fifty-six patients with a histologic diagnosis of UTUC and 2 or more consecutive biopsies or biopsy followed by surgical resection were included, resulting in 65 biopsy specimens. RESULTS The median interval between diagnostic biopsy and subsequent biopsy or resection was 6 weeks (range, 1 week to 60 months). Change in grade from the diagnostic biopsy occurred in 24 of 65 biopsies (37%), including 9 in which diagnosis changed from low to high grade. Change in the stage from the diagnostic biopsy occurred in 25 of 65 biopsies (38%). Overall, 24 (43%) patients were reclassified from low-grade, noninvasive disease to high-grade and/or invasive disease. CONCLUSION A change in grade and/or stage from the diagnostic biopsy occurred in more than one third of patients with UTUC managed conservatively. Because of the short median time interval between biopsies, this finding likely represents variability in tumor sampling on biopsy. Because of the concerns of undergrading and understaging, appropriate patient selection and vigilant endoscopic surveillance are mandatory for UTUC managed endoscopically.

Role of cystitis cystica et glandularis and intestinal metaplasia in development of bladder carcinoma.

OBJECTIVES Cystitis cystica et glandularis (CCEG) and intestinal metaplasia (IM) have been suggested to represent precursors of bladder adenocarcinoma. The relationship between these entities and the subsequent development of bladder carcinoma remains unclear. METHODS We retrospectively evaluated the association among florid CCEG, IM, and bladder carcinoma. The records and imaging findings of patients with a pathologic diagnosis of florid CCEG and/or IM were reviewed for a concurrent or future diagnosis of bladder carcinoma or pelvic lipomatosis. RESULTS We identified 136 patients from 1982 to 2006 with florid CCEG (n = 117) or IM (n = 19). Of the 117 patients with CCEG, a subset was identified with concurrent mucinous adenocarcinoma (n = 1; <1%), squamous cell carcinoma (n = 4; 3%), or urothelial carcinoma (n = 34; 29%) at diagnosis. Pure IM was identified concurrently with adenocarcinoma in 2 (10%), urothelial carcinoma in 4 (21%), and urothelial carcinoma with glandular differentiation in 1 (5%) of 19 patients. Follow-up for 103 patients (75%) ranged from 7 days to 23.7 years (median 2.6 years, mean 4.4). Only 1 new case of urothelial carcinoma was identified after 3 months in 1 patient with CCEG. None of the patients in our series had associated pelvic lipomatosis. CONCLUSIONS Both florid CCEG and IM can be identified in benign bladder specimens or in conjunction with bladder carcinoma. Although IM can be associated with a concurrent diagnosis of carcinoma, we found no evidence that it increases the future risk of malignancy and our findings do not support a recommendation for surveillance cystoscopy in such patients. No association was identified between either CCEG or IM and pelvic lipomatosis.

Optimizing Orthotopic Bladder Tumor Implantation in a Syngeneic Mouse Model

PURPOSE We established a reliable technique for orthotopically implanting bladder tumor cells in a syngeneic mouse model. MATERIALS AND METHODS MBT-2 murine bladder cancer cells were transurethrally implanted in the bladder of syngeneic C3H/He mice (Jackson Laboratory, Bar Harbor, Maine). Different chemical pretreatments were used before tumor implantation, including phosphate buffered saline (control), HCl, trypsin and poly-L-lysine. MBT-2 cells (1 x 10(6) or 2 x 10(6)) were instilled into the intravesical space after chemical pretreatment. Tumor take and bladder tumor volume were determined by micro ultrasound. Bladders were harvested at the end of the study to measure bladder weight and for histopathological examination. RESULTS Bladder pretreatment with HCl in 5 preparations was discontinued due to significant adverse reactions, resulting in death in 1 mouse, and severe bladder inflammation and hematuria 3 days after pretreatment in 2. Pretreatment with phosphate buffered saline, trypsin and poly-L-lysine in 6 animals each was tolerated well without significant adverse reactions or mortality. The tumor take rate in the control, trypsin and poly-L-lysine pretreatment groups was 33%, 83% and 83%, respectively. The take rate was higher in mice instilled with 2 x 10(6) cells than in those with 1 x 10(6) cells (93% vs 73%, p <0.05). CONCLUSIONS We report a reliable, feasible method of orthotopically implanting bladder tumor cells into a syngeneic mouse model. Poly-L-lysine and trypsin are useful adjunctive pretreatment agents to improve bladder tumor uptake. This model may be suitable to evaluate treatment paradigms for bladder cancer.

Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells

Heat shock protein 90 (Hsp90) is an essential, evolutionarily conserved molecular chaperone. Cancer cells rely on Hsp90 to chaperone mutated and/or activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is frequently cytostatic in nature, and efforts to enhance the antitumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In agreement with previous data obtained using Wee1 siRNA, we show that dual pharmacologic inhibition of Wee1 tyrosine kinase and Hsp90 causes cancer cells to undergo apoptosis in vitro and in vivo. Gene expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional downregulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins, as well as activated Akt, was completely abrogated. These data support the hypothesis that Wee1 inhibition sensitizes cancer cells to Hsp90 inhibitors; they establish combined Wee1/Hsp90 inhibition as a novel therapeutic strategy; and they provide a mechanistic rationale for enhancing the pro-apoptotic activity of Hsp90 inhibitors.

Epidermoid Cyst of the Testicle

We report on a case of testicular mass with classic radiographic appearance for epidermoid cyst.

Robotic Equipment and Instrumentation

The advancement of laparoscopic robotic surgery largely depends on the development of innovative laparoscopic instrumentation. The most widely used system, the da Vinci surgical robot (Intuitive Surgical Inc., Sunnyvale, California), was introduced in 1998 and received FDA approval in 2000. Its popularity may largely be attributed to the development of EndoWrist instruments with increased degrees of freedom and improved stereoscopic vision. The electronics integrated into the system allow motion scaling of surgeon hand movement into smaller instrument tip movements in the field, reducing natural tremor of surgeon’s hands. Instruments have a total of six degrees of freedom plus grip, mimicking the up and down and side-to-side flexibility of human wrist. Recently da Vinci S system has introduced (Intuitive Surgical Inc.), which features easier docking, added system feedback and high-definition telemonitoring. Another feature of the new S system is the additional 2 inches of length of the instruments.

MP83-09 TUMOR NECROSIS FACTOR-RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) POTENTIATES THE EFFECT OF BACILLUS CALMETTE-GUÉRIN (BCG) IN UROTHELIAL CARCINOMA MODEL

Dysplasia begins by week 8 and by week 16 the majority of rats have a NMIBC phenotype with a mix of CIS, high grade Ta, and T1 disease. Beginning week 8 following the first MNU dose, rats were intravesically administered 0.3ml of BCG (n1⁄45,1 vial Tice suspended in 50ml saline), cisplatin (n1⁄45, 1mg/ml), or saline (n1⁄45) weekly for 6 total doses. All animals were sacrificed at week 16, and bladders (including tumors) were digested into single cell suspensions for flow cytometry. T lymphocyte subpopulations were then compared between the 3 groups using one-way ANOVA tests. RESULTS: After whole bladder digestion, samples yielded 1-2 million cells per bladder. Rats treated with BCG had a 42% rise in CD4+ cells compared to saline controls (51.4% vs 34.8%, p<0.001). No significant differences in FoxP3+ CD4+ cells (20.6% vs 16.4%, p1⁄40.12) or CD8+ cells (19.3% vs 16.4%, p1⁄40.28) were observed between animals receiving BCG and saline control. Animals receiving intravesical cisplatin had no significant differences in CD4+ (34.8% in cisplatin vs 29.5% in controls, p1⁄40.15), Foxp3+ CD4+ cells (13.9% vs 16.4%, p1⁄40.25), or CD8+ cells (16.4% vs 16.9%, p1⁄40.85) compared to animals receiving saline controls. CONCLUSIONS: In an immune competent murine model of bladder cancer, our analysis of lymphocytes in the bladder wall suggests that BCG induces a large increase in CD4+ effector T cells, without a significant change in Foxp3+ regulatory T cells or CD8+ T cells. This large Th1 anticancer immunosurveillance response is not seen with intravesical platinum based chemotherapy.

TARGETED CONTRAST ULTRASOUND DETECTION AND QUANTIFICATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS IN BLADDER CANCER

CONCLUSIONS: We confirmed that the FGFR3 mutations are preferentially found in low stage and low grade SUCC, typically TaG1 tumours, and that the frequency of such mutations decreases whereas the stage and the grade increase. We confirmed that the mutations of P53 and FGFR3 are globally mutually exclusive suggesting two alternative pathways in bladder carcinogenesis. Tumours carrying a non functional p53 protein have a shorter recurrence-free survival. Finally, the genotype FGFR3mt/P53wt is a significant risk factor for recurrence, but it seems to be associated with an insignificant potential of progression.