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Colin P N Dinney

Publications and source records attributed to Colin P N Dinney.

At least 19 recordsLinked to original sources
PubMed2006

Schedule dependent efficacy of gefitinib and docetaxel for bladder cancer.

PURPOSE: We determined the sequence specific efficacy of gefitinib and docetaxel treatment for bladder cancer. This combination was selected because it is currently under study in a phase II clinical trial. MATERIALS AND METHODS: In vitro antiproliferative effects of gefitinib, docetaxel and a combination were determined in the 4 bladder cancer cell lines 253J B-V, UM-UC-3, KU-7 and UM-UC-13 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle analysis was analyzed using flow cytometry and propidium iodide labeling. Epidermal growth factor receptor downstream signaling was assessed by Western blot analysis. In vivo nude mice were injected subcutaneously with 253J B-V cells and treated with placebo, gefitinib, docetaxel, docetaxel followed by gefitinib or gefitinib followed by docetaxel. Tumor kinetics were established. RESULTS: Gefitinib demonstrated antiproliferative effect against 253J B-V cells (50% inhibitory concentration less than 0.5 muM) but no apoptotic effect in vitro, whereas docetaxel demonstrated antiproliferative and apoptotic effects. When gefitinib and docetaxel were combined, gefitinib enhanced the apoptotic and antiproliferative effects of docetaxel only when gefitinib was administered following docetaxel pretreatment. Apoptosis increased from 45% to 66%. In vivo there were significant differences in tumor weight in mice treated with combination therapy vs gefitinib or docetaxel alone. Importantly improved efficacy was observed when docetaxel was followed by gefitinib administration compared with gefitinib followed by docetaxel (mean tumor weight 42 vs 93 mg, p = 0.022). Sequence specific efficacy was not observed in UM-UC-3, UM-UC-13 and KU-7 cells, which are resistant to gefitinib. CONCLUSIONS: Docetaxel followed by gefitinib demonstrated sequence specific efficacy against gefitinib sensitive bladder cancer compared with gefitinib followed by docetaxel or either drug alone. Accordingly gefitinib administration concurrently or after chemotherapy might be the sequence of choice and it should be considered for future clinical trials.

Animals↗
PubMed2006

Chylous ascites after post-chemotherapy retroperitoneal lymph node dissection: review of the M. D. Anderson experience.

PURPOSE: We determined the clinical presentation, risk factors and optimal treatment of chylous ascites that develop after retroperitoneal lymph node dissection in patients with testicular cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of 329 patients who underwent post-chemotherapy retroperitoneal lymph node dissection at our institution, of whom 23 (7%) had chylous ascites postoperatively. Clinical and pathological parameters were entered into a database. RESULTS: Mean patient age at chylous ascites presentation was 32.1 years. On univariate and multivariate logistic regression analyses increasing amounts of preoperative chemotherapy (OR 1.24) and intraoperative blood loss (OR 1.33) were predictive of chylous ascites. The clinical presentation of chylous ascites consisted of abdominal fullness and distention in all patients. Initial treatment was paracentesis alone or combined with total parenteral nutrition in 77% of patients. An abdominal drain was used for persistent ascites in 10 patients. In patients treated conservatively the rate of resolution of chylous ascites was 77%. Only 23% of patients required peritoneovenous shunt placement. However, shunt use was associated with an 80% surgical revision rate. CONCLUSIONS: Conservative treatment resolves most cases of postoperative chylous ascites. An abdominal catheter drain should be considered for significant or recurring chylous ascites. When a peritoneovenous shunt is required, it may be needed for an extensive period for resolution and there are significant complications associated with its use. Increasing amounts of preoperative chemotherapy and operative blood loss raise the likelihood of chylous ascites.

Adult↗
PubMed2006

Upper urinary tract tumors with nontransitional histology: a single-center experience.

OBJECTIVES: To review our experience with patients with upper urinary tract tumors of nonurothelial origin. Upper urinary tract tumors of nonurothelial origin are uncommon entities. To our knowledge, no series of patients with these neoplasms has been published in the past decade. METHODS: We reviewed the records at the University of Texas M. D. Anderson Cancer Center from 1990 to 2004 to identify patients with primary nonurothelial tumors of the upper urinary tract. We reviewed the patient records to collect data on tumor subtype, treatment, recurrence, and survival. RESULTS: Sixteen patients (1.9% of our database of patients with upper urinary tract tumors) were identified; 12 had squamous cell carcinoma, 2 had adenocarcinoma, 1 had sarcomatoid carcinoma, and 1 had small cell carcinoma. The tumors were located in the renal pelvis in 10 and the ureter in 6. Of the 16 patients, 15 had been treated with nephrectomy or nephrouterectomy and 1 with chemotherapy and radiotherapy. Fifteen of the tumors were pathologic Stage T3 or worse. Ten patients received adjuvant chemotherapy. Of the 16 patients, 9 died (1 of unknown causes), 4 were alive without disease, 2 were alive with disease, and 1 was alive at last follow-up with the disease status unknown. The median follow-up was 30.1 months, the median overall survival time was 11.3 months, and 1-year survival rate was 46%. The median recurrence-free survival time and 1-year recurrence-free survival rate were 5.8 months and 38%, respectively. CONCLUSIONS: Primary nonurothelial carcinomas of the renal pelvis and ureter are rare. Our analysis suggests a poor prognosis for most patients with these pathologic types, probably resulting from the advanced stage at diagnosis and poor responses to systemic therapy.

Carcinoma↗
PubMed2006

Immediate versus staged urethrectomy in patients at high risk of urethral recurrence: is there a benefit to either approach?

OBJECTIVES: To compare treatment-related outcomes of immediate and staged urethrectomy in patients at high risk of urethral recurrence. METHODS: We retrospectively identified 76 male patients with cystectomy for transitional cell carcinoma of the bladder who had undergone urethrectomy in the absence of established urethral recurrence. Concomitant cystoprostatectomy and urethrectomy was performed in 57 patients and staged urethrectomy in 19 patients. The criteria for staged urethrectomy were the presence of a positive urethral margin or established transitional cell carcinoma of the urethra in the cystectomy specimen. The mean interval from cystectomy to staged urethrectomy was 4.7 months (range 1.4 to 14). RESULTS: The most common pathologic finding of the urethrectomy specimens was prostatic duct involvement (31.6%) in the immediate urethrectomy group and Stage pT0 in the delayed urethrectomy group (73.7%). No statistically significant difference in disease-specific survival was noted between the immediate and staged groups (P = 0.14). Similarly, no difference was noted in postoperative complication rates or total operative blood loss (P = 0.77 and P = 0.64, respectively). However, a slight benefit for immediate urethrectomy was noted in the total duration of hospitalization (P = 0.01). The presence of local or distant recurrence was a predictor of disease-specific survival (P = 0.02 and P = 0.02, respectively). CONCLUSIONS: Immediate and staged urethrectomy appear to be similar in surgical morbidity and disease-specific survival. A benefit was noted for the immediate group in the total duration of hospitalization. The development of local or distant recurrence was a predictor of poor survival.

Adult↗
PubMed2006

Therapy of invasive bladder cancer.

Effective treatment of invasive bladder cancer depends upon an understanding of the natural history of this disease and careful clinical staging. Radical cystectomy offers acceptable long-term survival for most individuals with organ-confined disease, but those with more advanced tumors or those associated with adverse features may benefit from the addition of neoadjuvant chemotherapy.

Combined Modality Therapy↗
PubMed2006

The case for early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma.

PURPOSE: Micropapillary bladder carcinoma is a rare variant of UC. Due to paucity of data regarding treatment outcomes, patients with nonmuscle invasive micropapillary UC often receive intravesical therapy in an attempt at bladder preservation. MATERIALS AND METHODS: We reviewed the records of all patients evaluated at our institution who had micropapillary UC of the bladder. Of these, 44 had nonmuscle invasive disease at presentation and form the basis of this report. RESULTS: Mean patient age was 64.3 years (range 45 to 81) with a male-to-female ratio of 13:1. Stage distribution at presentation was 5 Ta (11%), 4 CIS (9%) and 35 T1 (80%). Median CSS was 81 months. Kaplan-Meier estimates of 5 and 10-year CSS rates were 64% and 26%, respectively. Intravesical BCG therapy was attempted in 27 patients (61%). Of these 27 patients, 67% (18 of 27) had progression (cT2 or greater), including 22% in whom metastatic disease developed. Only 19% of patients (5 of 27, all T1) remain disease-free with an intact bladder at a median followup of 30 months. A total of 30 patients (68%) underwent cystectomy. Among patients who underwent cystectomy after progression (18), median CSS was 61.7 months with no patient surviving 10 years, whereas among those undergoing cystectomy as initial therapy (12), median survival was not reached and the 10-year CSS rate was 72%. CONCLUSIONS: Intravesical BCG therapy appears to be ineffective against micropapillary UC. Our results suggest that the optimal treatment strategy for nonmuscle invasive micropapillary UC is radical cystectomy performed before progression.

Aged↗
PubMed2006

Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: a contemporary review of the M. D. Anderson Cancer Center experience.

PURPOSE: Partial cystectomy is a surgical option for select patients diagnosed with urothelial carcinoma. We review our experience with partial cystectomy for muscle invasive urothelial carcinoma to assess local control and survival rates. MATERIAL AND METHODS: From 1982 to 2003 a total of 37 patients with muscle invasive urothelial carcinoma underwent partial cystectomy with curative intent. Reviewed data included history of superficial tumors, presence of variant histology, tumor location, clinical stage, pathological stage, presence of carcinoma in situ, adjuvant therapy and disease status. RESULTS: The 5-year overall, disease specific and recurrence-free survival rates were 67%, 87% and 39%, respectively. Mean followup was 72.6 months (range 6 to 217). Of the 37 patients 19 (51%) did not have tumor recurrence, 9 (24%) had superficial recurrence in the bladder that was treated successfully and 9 (24%) had recurrence with advanced disease. A total of 24 patients (65%) had an intact bladder with no evidence of disease after a median of 53 months. There were 6 patients (16%) who died of bladder cancer, 3 of whom died of late recurrence of muscle invasive cancer (41, 44 and 138 months after partial cystectomy). On multivariate analysis higher pathological stage (HR 3.4, p = 0.04) was associated with shorter recurrence-free survival. A history of superficial tumors (p <0.01) and clinical stage (p = 0.01) was associated with advanced recurrence-free survival. The use of adjuvant chemotherapy (HR 0.18, p = 0.03) was associated with prolonged advanced recurrence-free survival, however adjuvant chemotherapy did not impact overall survival. CONCLUSIONS: Partial cystectomy provides adequate local control of muscle invasive bladder cancer in select patients. Because late recurrence is not uncommon and is potentially life threatening, lifelong followup with cystoscopy is recommended.

Adult↗
PubMed2006

Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: Time to change the treatment paradigm?

OBJECTIVE: To evaluate factors associated with disease recurrence and survival in patients undergoing nephroureterectomy for upper urinary tract transitional cell carcinoma (UUT-TCC) in one centre over an 18-year period. PATIENTS AND METHODS: The records of patients who had a nephroureterectomy for UUT-TCC at our institution from 1986 to 2004 were reviewed for clinical, pathological and treatment period data. Cox's proportional hazards regression model was used to test the statistical significance of several potential prognostic factors for recurrence and survival. RESULTS The median overall duration of follow-up was 2.5 years for 184 patients. Significant prognosticators for disease-specific survival (DSS) by univariate analysis were tumour stage (P < 0.01), tumour grade (P < 0.01), node-positive disease (P < 0.01), multifocality (P = 0.03), previous cystectomy (P < 0.01) and synchronous bilateral UUT-TCC (P = 0.02). On multivariate analysis, only tumour stage (P = 0.03) and grade (P = 0.01) correlated with DSS. The median recurrence-free survival duration was 2.4 years. In 44 patients, the disease recurred outside the bladder; 15 (8.2%) had local recurrence, 20 (10.9%) distant metastasis, and nine (4.9%) both local and distant recurrence. Bladder tumours occurred in 40 (26.1%) patients with no previous cystectomy. The evaluation of treatment outcome during three periods of the study showed no significant effect on DSS. CONCLUSION: Tumour stage and grade correlated with DSS in this cohort, with no improvement in outcome over the 18-year period assessed. Patients with high-stage and high-grade disease continue to fare poorly, suggesting a need for changing the treatment protocol. Judiciously applying a multimodal approach to the management of high-risk patients by incorporating neoadjuvant chemotherapy and surgical resection might provide, for the first time, the opportunity to improve patient outcome.

Aged↗
PubMed2005

Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells.

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways, such as phosphatidylinositol-3 kinase/Akt and Ras/mitogen-activated protein kinase (MAPK), have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the urogenital tumors. To investigate the mechanism of resistance to EGFR inhibition in bladder cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-3beta (GSK-3beta). We found that the resistance to the antiproliferative effects of gefitinib, in vitro as well as in vivo in nude mice models, was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-3beta activation and degradation of its target cyclin D1 were indicators of a high cell sensitivity to gefitinib. Further analysis of one phenotypic sensitive (253J B-V) and resistant (UM-UC13) cell lines revealed that platelet-derived growth factor receptor-beta (PDGFRbeta) activation was responsible for short circuiting the EGFR/MAPK pathway for mitogenic stimuli. However, invasion as well as actin dynamics were efficiently reduced by EGFR inhibition in UM-UC13. Chemical disruption of signaling pathways or of PDGFR kinase activity significantly reduced the inactive pool of cellular GSK-3beta in UM-UC13 cells. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in bladder cancer. Although this uncoupling may arise through different mechanisms, we suggest that the resistance of bladder cancer cells to EGFR blockade can be predicted early in the course of treatment by measuring the activation of GSK-3beta and of nuclear cyclin D1.

Antineoplastic Agents↗
PubMed2005

Correlation between annual volume of cystectomy, professional staffing, and outcomes: a statewide, population-based study.

BACKGROUND: The association between high procedure volume and lower perioperative mortality is well established among cancer patients who undergo cystectomy. However, to the authors' knowledge, the association between volume and perioperative complications has not been studied to date and hospital characteristics contributing to the volume-outcome correlation are unknown. In the current study, the authors studied these associations, emphasizing hospital factors that contribute to the volume-outcome correlation. METHODS: Multiple-variable models of inpatient mortality and complications were developed among all 1302 bladder carcinoma patients who underwent cystectomy between January 1, 1999 and December 31, 2001 in all Texas hospitals. General estimating equations were used to adjust for clustering within the 133 hospitals. Data were obtained from hospital claims, the 2000 U.S. Census, and databases from the Center for Medicare and Medicaid Services and the American Hospital Association. RESULTS: Complications were reported to occur in 12% of patients, 2.2% of whom died. Mortality was higher in low-volume hospitals compared with high-volume hospitals (3.1% vs. 0.7%; P < 0.001); mortality in moderate-volume hospitals was reported to be intermediate (2.9%). After adjustment for advanced age and comorbid conditions, treatment in high-volume hospitals was associated with lower risks of mortality (odds ratio [OR] = 0.35; P = 0.02) and complications (OR = 0.53; P = 0.01). Hospitals with a high registered nurse-to-patient ratio also had a lower mortality risk (OR = 0.43; P = 0.04). CONCLUSIONS: Mortality after cystectomy was found to be significantly lower in high-volume hospitals, regardless of patient age. Referral to a hospital performing greater than 10 cystectomies annually is indicated for all patients. However, patients with poor access to a high-volume hospital may derive similar benefit from treatment at a hospital with a high-registered nurse-to-patient ratio. This finding requires further confirmation.

Adult↗
PubMed2005

Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade). Synergistic induction of apoptosis occurred within 4 to 6 hours in cells treated with TRAIL plus bortezomib and was associated with accumulation of p21(WAF-1/Cip-1) (p21) and inhibition of cyclin-dependent kinase (cdk) activity. Roscovitine, a specific cdk1/2 inhibitor, also sensitized cells to TRAIL. Silencing p21 expression reduced levels of DNA fragmentation by 50% in cells treated with bortezomib and TRAIL, confirming that p21 was required for the response. Analysis of the TRAIL pathway revealed that caspase-8 processing was enhanced in a p21-dependent fashion in cells exposed to TRAIL and bortezomib as compared with cells treated with TRAIL alone. Thus, all downstream components of the pathway (Bid cleavage, cytochrome c release, and caspase-3 activation) were amplified. These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy.

Apoptosis↗
PubMed2005

Clinical applications for targeted therapy in bladder cancer.

The tremendous amount of data accumulated through genomics, proteomics, and metabolomic technologies has not led to a definitive understanding of the mechanisms underlying cancer. The challenge remains as to how to integrate all of the relevant knowledge and data in a systematic manner so that researchers can gain the knowledge needed to devise the best therapeutic and diagnostic strategies. Human transitional cell carcinoma of the bladder is genetically heterogeneous, and it is surrounded by a complex tissue microenvironment involving vasculature, stromal cells, and connective tissue. One of the most challenging problems facing cancer researchers is the lack of correlation between in vitro cell lines and animal tumor models and human in vivo tumors. A few promising approaches are being devised that will help address this issue in the coming years. One such approach is the measurements of molecular levels of receptors, ligands, pathways components, and so on, directly in human tumors through in vivo imaging, or through proteomic profiling, as it has been proposed as standard protocol for cancer diagnostics and therapeutics.

Antineoplastic Agents↗
PubMed2004

Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells.

Immunomodulators such as Bacillus Calmette-Guerin and interferon are clinically active in transitional cell carcinoma of the bladder, but their mechanisms of action remain unclear. Here we investigated the effects of IFNalpha on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and apoptosis in a panel of 20 human bladder cancer cell lines. Six (30%) displayed significant DNA fragmentation in response to increasing concentrations of IFNalpha (10-100,000 units/mL). In these lines IFNalpha induced early activation of caspase-8, and DNA fragmentation was blocked by a caspase-8-selective inhibitor (IETDfmk), consistent with the involvement of death receptor(s) in cell death. IFNalpha stimulated marked increases in TRAIL mRNA and protein in the majority of IFN-sensitive and IFN-resistant cell lines. A blocking anti-TRAIL antibody significantly inhibited IFN-induced DNA fragmentation in four of six IFN-sensitive cell lines, confirming that TRAIL played a direct role in cell death. Bortezomib (PS-341, Velcade), a potent TRAIL-sensitizing agent, increased sensitivity to IFNalpha in two of the IFN-resistant cell lines that produced large amounts of TRAIL in response to IFN treatment. Our data show that IFN-induced apoptosis in bladder cancer cells frequently involves autocrine TRAIL production. Combination therapy strategies aimed at overcoming TRAIL resistance may be very effective in restoring IFN sensitivity in a subset of human bladder tumors.

Antineoplastic Agents↗
PubMed2004

Regional effects of an antivascular endothelial growth factor receptor monoclonal antibody on receptor phosphorylation and apoptosis in human 253J B-V bladder cancer xenografts.

Vascular endothelial growth factor (VEGF) is a key angiogenic factor in a variety of solid tumors, making it one of the most attractive therapeutic targets. VEGF promotes the proliferation, survival, and differentiation of vascular endothelial cells by stimulating autophosphorylation and activation of VEGF receptor-2 (VEGFR-2, fetal liver kinase-1, and kinase insert domain-containing receptor). We developed fluorescence-based, quantitative methods to measure total VEGFR-2, VEGFR-2 phosphorylation, apoptosis, and microvessel density and size within whole tumor cross-sections using a laser scanning cytometer. Using these methods, we characterized the effects of DC101, a blocking antibody specific for murine VEGFR-2, on orthotopic human 253J-BV bladder tumors growing in nude mice. Basal levels of receptor phosphorylation were heterogeneous, with approximately 50% of endothelial cells positive for phosphorylated VEGFR-2 at baseline. DC101 therapy resulted in a 50% decrease in overall VEGFR-2 phosphorylation and a 15-fold and 8-fold increase in endothelial cell (CD31-positive) and tumor cell apoptosis, respectively. DC101 also decreased overall tumor microvessel density, but it mostly affected smaller CD105-negative microvessels located in the periphery of the tumor. Intriguingly, anti-VEGFR-2 therapy resulted in increased mean vessel size and an increase in overall VEGFR-2 levels. Increases in total VEGFR-2 levels were localized to the tumor core and were associated with increased expression of the oxygen-sensitive transcription factor, hypoxia inducible factor-1alpha. These data suggest that VEGFR inhibitors preferentially target discrete populations of tumor endothelial cells associated with the smaller peripheral blood vessels. Thus, agents that target a single receptor (e.g., VEGFR-2) may not be sufficient to completely inhibit tumor angiogenesis.

Animals↗