Evaluating the impact of the genitourinary multidisciplinary tumour board: Should every cancer patient be discussed as standard of care?

INTRODUCTION: We sought to prospectively evaluate the effectiveness of the multidisciplinary tumour board (MTB) on altering treatment plans for genitourinary (GU) cancer patients. METHODS: All GU cancer patients seen at our tertiary care hospital are discussed at MTB. We prospectively collected data on adult patients discussed over a continuous, 20-month period. Physicians completed a survey prior to MTB to document their opinion on the likelihood of change in their patient's treatment plan. Logistic regression was used to asses for factors associated with a change by the MTB, including patient age or sex, malignancy type, the predicted treatment plan, and the provider's years of experience or fellowship training. RESULTS: A total of 321 cancer patients were included. Patients were primarily male (84.4%) with a median age of 67 (range 20-92) years old. Prostate (38.9%), bladder (31.8%), and kidney cancer (19.6%) were the most common malignancies discussed. A change in management plan following MTB was observed in 57 (17.8%) patients. The physician predicted a likely change in six (10.5%) of these patients. Multivariate logistic regression did not determine physician prediction to be associated with treatment plan change, and the only significant variable identified was a plan to discuss multiple treatment options with a patient (odds ratio 2.46; 95% confidence interval 1.09-9.54). CONCLUSIONS: Routine discussion of all urologic oncology cases at MTB led to a change in treatment plan in 17.8% of patients. Physicians cannot reliably predict which patients have their treatment plan altered. Selectively choosing patients to be presented likely undervalues the impact of a multidisciplinary approach to care.

Sunitinib malate provides activity against murine bladder tumor growth and invasion in a preclinical orthotopic model.

OBJECTIVE: To evaluate the effects of sunitinib on localized bladder cancer in a mouse orthotopic bladder tumor model. METHODS: We used an established orthotopic mouse bladder cancer model in syngeneic C3H/He mice. Treatment doses of 40 mg/kg of sunitinib or placebo sterile saline were administrated daily by oral gavage. Tumor volume, intratumoral perfusion, and in vivo vascular endothelial growth factor receptor-2 expression were measured using a targeted contrast-enhanced micro-ultrasound imaging system. The findings were correlated with the total bladder weight, tumor stage, and survival. The effects of sunitinib malate on angiogenesis and cellular proliferation were measured by immunostaining of CD31 and Ki-67. RESULTS: Significant inhibition of tumor growth was seen after sunitinib treatment compared with the control. The incidence of extravesical extension of the bladder tumor and hydroureter in the sunitinib-treated group (30% and 20%, respectively) was lower than the incidence in the control group (66.7% and 55.6%, respectively). Sunitinib therapy prolonged the survival in mice, with statistical significance (log-rank test, P = .03). On targeted contrast-enhanced micro-ultrasound imaging, in vivo vascular endothelial growth factor receptor-2 expression was reduced in the sunitinib group and correlated with a decrease in microvessel density. CONCLUSION: The results of our study have demonstrated the antitumor effects of sunitinib in the mouse localized bladder cancer model. Sunitinib inhibited the growth of bladder tumors and prolonged survival. Given that almost 30% of cases in our treatment arm developed extravesical disease, sunitinib might be suited as a part of a multimodal treatment regimen for bladder cancer.

In vivo targeted contrast enhanced micro-ultrasound to measure intratumor perfusion and vascular endothelial growth factor receptor 2 expression in a mouse orthotopic bladder cancer model.

PURPOSE: We evaluated the feasibility of using targeted contrast enhanced micro-ultrasound imaging to assess intratumor perfusion and vascular endothelial growth factor receptor 2 expressions in a mouse orthotopic bladder cancer model. MATERIALS AND METHODS: We created an orthotopic mouse model by implanting MBT-2 murine bladder cancer cell lines in the bladder of syngeneic C3H/He mice (Jackson Laboratory, Bar Harbor, Maine). Successful tumor implantation was confirmed by transabdominal micro-ultrasound imaging on post-implantation day 11. Contrast enhanced micro-ultrasound imaging was done on days 14 and 21. Vascular endothelial growth factor receptor 2 targeted contrast agent was prepared by adding biotinylated anti-vascular endothelial growth factor receptor 2 monoclonal antibodies to streptavidin coated microbubbles. The targeted contrast agents were injected via the retro-orbital route. We quantified intratumor perfusion, vascular endothelial growth factor receptor 2 endothelial expression and blood volume in real time. RESULTS: In the initial study intratumor perfusion data and vascular endothelial growth factor receptor 2 expression could only be measured in 10 of 14 mice (71%) due to motion artifact. We modified our technique by applying an elastic band over the lower abdomen to minimize body wall movement. After the modification complete images were acquired in all mice at 2 consecutive imaging sessions. Measurements were made of intratumor perfusion and in vivo vascular endothelial growth factor receptor 2 expression. No adverse effects occurred due to anesthesia or the ultrasound contrast agent. CONCLUSIONS: Targeted contrast enhanced micro-ultrasound imaging enables investigators to detect and monitor vascular changes in orthotopic bladder tumors. It may be useful for direct, noninvasive, in vivo evaluation of novel anti-angiogenesis therapeutic agents. With the modified technique target enhanced contrast ultrasound can be applied in an orthotopic bladder cancer model.

Transabdominal micro-ultrasound imaging of bladder cancer in a mouse model: a validation study.

OBJECTIVES: To validate the use of transabdominal micro-ultrasound imaging (MUI) in an orthotopic murine bladder cancer model. The current in vivo imaging systems for murine bladder cancer include magnetic resonance imaging, bioluminescent and fluorescent imaging, and intravesical ultrasound. METHODS: We implanted murine bladder tumor-2 tumor cells into C3H/He female mice. Mice underwent MUI before, and every 3 days after instillation of tumor cells. Three mice were killed at every MUI session. Bladder tumors were measured and tumor volumes were calculated during MUI and gross stereomicroscopy. Bladders were harvested and examined under gross stereomicroscopy to confirm the presence, location, and size of bladder tumors, and were prepared for histology review. RESULTS: Overall, 15 of 33 (45%) mice were confirmed to have tumors, using MUI, gross stereomicroscopy, and histology. Measurements of tumor size by MUI and gross microscopy had a high correlation coefficient (r = 0.97). MUI identified all tumors that were present on final histology. The smallest confirmed tumor on MUI was detected at 0.52 mm(3), and mean tumor volume was 0.95 mm(3). No tumors that were not detected first using MUI were found on final histology. CONCLUSIONS: Transabdominal MUI is a valuable tool to use for translational studies involving orthotopic mouse bladder cancer models. MUI provides real-time, high resolution in vivo images of bladder tumors. Tumor presence can be confirmed with a high degree of accuracy pertaining to tumor volume before initiation of treatment. In addition, tumor growth or regression can be followed up in vivo longitudinally.

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.

Mouse orthotopic models for bladder cancer research.

Bladder cancer is a common malignancy in the urinary tract. Despite different therapeutic options, recurrence and progression of urothelial carcinoma after treatment is not uncommon. Novel therapeutic options of bladder cancer are urgently needed. The preclinical evaluation of new treatments requires an animal tumour model that mimics the human counterpart. To date, various animal orthotopic bladder cancer models have been described, but the reported rate of tumour 'take' is 30-100%. The establishment of reliable and reproducible animal models remains an ongoing challenge. We review different kinds of mouse models of orthotopic bladder cancer used in urothelial cancer studies, the methods of implantation, and the reported rate of tumour take. Significant progress has been made recently in noninvasive small animal-imaging in tumour models. It is now possible for researchers to investigate the effects of studied agents by monitoring of in vivo tumour growth directly and noninvasively, as well as measuring a wide range of tumour-related variables in small animals. We summarize the recent development in small-animal imaging for tumour detection and quantification.

Novel enhanced lung-colonizing variant of murine MBT-2 bladder cancer cells.

OBJECTIVES: To develop an enhanced lung-colonizing variant of murine bladder cancer that will allow the mechanism of metastasis to be studied more readily. METHODS: We implanted murine bladder tumor cells (MBT-2) into the leg muscles of C3H mice. We developed variant cells from a lung metastasis nodule. We compared the MBT-2 cells and variant cells (MBT-2V) in vivo by evaluating lung nodule formation, survival, in vitro adhesion, and migration-invasion assays. Zymography and semiquantitative reverse transcriptase-polymerase chain reaction analyses were also performed to characterize the metastatic ability of both cells. RESULTS: MBT-2 and MBT-2V cells were tumorigenic when injected intramuscularly into C3H mice, but MBT-2 cells had little potential to metastasize compared with MBT-2V cells. Metastases were observed in the lungs of mice injected in the tail vein with MBT-2 and MBT-2V cells. Mice receiving MBT-2V cells had significantly shorter survival (P <0.01) and more lung nodules (245 versus 106, P <0.0001) than those receiving MBT-2 cells. In vitro study revealed that MBT-2V cells exhibited more adhesion, greater migration, and more invasiveness than did MBT-2 cells. Pathologic examination revealed the tumors from MBT-2V cells to be more aggressive than those from MBT-2 cells. MBT-2V also showed significantly greater matrix metalloproteinase-9 expression. CONCLUSIONS: We generated an enhanced lung-colonizing variant of MBT-2 cells. Our MBT-2V cells showed more aggressive and invasive metastatic ability than that of the MBT-2 cells. Zymography and reverse transcriptase-polymerase chain reaction analyses indicated that matrix metalloproteinase-9 might be associated with the metastatic ability of MBT-2V cells.

Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model.

OBJECTIVES: To evaluate the antitumor effect of intravesical cationic liposome-mediated interleukin-12 (IL-12) gene delivery in an orthotopic murine bladder cancer model, and to investigate the immunologic memory against tumors between IL-12 gene therapy and bacille Calmette-Guérin (BCG) therapy. METHODS: Orthotopic murine bladder tumors were established by implanting 5 x 10(5) MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical IL-12 gene therapy was evaluated at varying doses: 0 microg (control) and 3, 5, and 10 microg (n = 8 for each group). Intravesical treatments were performed every 3 days and repeated six times beginning 5 days after tumor implantation. To compare the long-term, tumor-specific immunity between IL-12-treated mice (n = 18) and BCG-treated mice (n = 20), the animals surviving at day 60 and 10 new control mice were rechallenged with MBT-2 cells and received no additional treatment. On day 120, all surviving mice were killed and underwent necropsy. RESULTS: In the IL-12 groups at doses of 0, 3, 5, and 10 microg, 0, 2, 3, and 3 mice survived, respectively. Mice in the 5-microg and 10-microg IL-12 groups survived significantly longer than did the control group. All mice cured by IL-12 treatment successfully rejected the rechallenge with MBT-2 cells; however, mice cured by BCG and the new control mice died of the rechallenged bladder tumors. CONCLUSIONS: Intravesical IL-12 gene therapy, which induced long-lasting tumor-specific immunologic memory compared with BCG therapy, improved survival in an orthotopic bladder cancer model.