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1.  Cancer Care Economics of Bladder Cancer: Cost-Enhancing Factors and Possible Cost Reduction 
Current opinion in urology  2008;18(5):533-539.
Purpose of review
The diagnosis and care of bladder cancer (BC) represents a significant financial burden to the population in the United States. Therapeutic advances in BC care have come at a high cost to payers, providers, and patients. This study describes the principals of economic evaluation in health care and provides recommendations for more economic use of the resources in BC care.
Recent findings
While several studies have indicated that BC is a common disease associated with substantial economic burden for patients and society, the evidence of cost-effectiveness of BC interventions is limited and of insufficient quality. In addition, very little is known about quality of life, the preferred outcome measure for economic evaluations, associated with BC states and treatments. Moreover, current clinical guideline for BC care do not incorporate economic factor when evaluating most optimal clinical pathways.
Summary
While economic studies in BC could allow us to know how the money is being spent and assist in determining more effective ways to spend it, most of the currently used interventions have not undergone economic assessment.
doi:10.1097/MOU.0b013e32830b8910
PMCID: PMC3980665  PMID: 18670280
Bladder Cancer; Cost-effectiveness; Clinical guidelines; Evidence-based medicine; Health economics
2.  A Case Series of Transformation of Teratoma to Primitive Neuroectodermal Tumor: Evolving Management of a Rare Malignancy 
Rare Tumors  2014;6(1):5268.
Primitive neuroectodermal tumor (PNET) is a pathologic diagnosis that encompasses several different tumor types, including central nervous system tumors and Ewing’s sarcomas. Teratoma, a common element of germ cell tumor (GCT), has the ability to transform to malignant PNET in a small number of patients. Making a definitive diagnosis of PNET is difficult given its deviation from elements of GCT and its non-specific pathologic findings. Establishing the diagnosis is crucial as PNETs respond poorly to standard platinum-based chemotherapy used for treatment of GCT. Primary treatment for PNET is surgical, though this is often not feasible in many patients due to extensive disease at diagnosis. As an alternative, chemotherapy regimens traditionally used for Ewing’s sarcoma, such as vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and etoposide, have shown limited efficacy in the neoadjuvant, adjuvant, and palliative settings. Future research should delineate the genetic underpinnings of PNET and develop therapeutic options accordingly.
doi:10.4081/rt.2014.5268
PMCID: PMC3977172
primitive neuroectodermal tumor; PNET; teratoma; chemotherapy
3.  Multispectral Photoacoustic Imaging of Prostate Cancer: Preliminary Ex-vivo Results 
Objective:
The objective of this study is to validate if ex-vivo multispectral photoacoustic (PA) imaging can differentiate between malignant prostate tissue, benign prostatic hyperplasia (BPH), and normal human prostate tissue.
Materials and Methods:
Institutional Review Board's approval was obtained for this study. A total of 30 patients undergoing prostatectomy for biopsy-confirmed prostate cancer were included in this study with informed consent. Multispectral PA imaging was performed on surgically excised prostate tissue and chromophore images that represent optical absorption of deoxyhemoglobin (dHb), oxyhemoglobin (HbO2), lipid, and water were reconstructed. After the imaging procedure is completed, malignant prostate, BPH and normal prostate regions were marked by the genitourinary pathologist on histopathology slides and digital images of marked histopathology slides were obtained. The histopathology images were co-registered with chromophore images. Region of interest (ROI) corresponding to malignant prostate, BPH and normal prostate were defined on the chromophore images. Pixel values within each ROI were then averaged to determine mean intensities of dHb, HbO2, lipid, and water.
Results:
Our preliminary results show that there is statistically significant difference in mean intensity of dHb (P < 0.0001) and lipid (P = 0.0251) between malignant prostate and normal prostate tissue. There was difference in mean intensity of dHb (P < 0.0001) between malignant prostate and BPH. Sensitivity, specificity, positive predictive value, and negative predictive value of our imaging system were found to be 81.3%, 96.2%, 92.9% and 89.3% respectively.
Conclusion:
Our preliminary results of ex-vivo human prostate study suggest that multispectral PA imaging can differentiate between malignant prostate, BPH and normal prostate tissue.
doi:10.4103/2156-7514.119139
PMCID: PMC3814905  PMID: 24228210
Multispectral; photoacoustic; prostate
4.  Age and Racial Differences among PSA-Detected (AJCC Stage T1cN0M0) Prostate Cancer in the U.S.: A Population-Based Study of 70,345 Men 
Frontiers in Oncology  2013;3:312.
Purpose: Few studies have evaluated the risk profile of prostate-specific antigen (PSA)-detected T1cN0M0 prostate cancer, defined as tumors diagnosed by needle biopsy because of elevated PSA levels without other clinical signs of disease. However, some men with stage T1cN0M0 prostate cancer may have high-risk disease (HRD), thus experiencing inferior outcomes as predicted by a risk group stratification model.
Methods: We identified men diagnosed with stage T1cN0M0 prostate cancer from 2004 to 2008 reported to the surveillance, epidemiology, and end results (SEER) program. Multivariate logistic regression was used to model the probability of intermediate-risk-disease (IRD) (PSA ≥ 10 ng/ml but <20 ng/ml and/or GS 7), and high-risk-disease (HDR) (PSA ≥ 20 ng/ml, and/or GS ≥ 8), relative to low-risk disease (LRD) (PSA < 10 ng/ml and GS ≤ 6), adjusting for age, race, marital status, median household income, and area of residence.
Results: A total of 70,345 men with PSA-detected T1cN0M0 prostate cancer were identified. Of these, 47.6, 35.9, and 16.5% presented with low-, intermediate-, and high-risk disease, respectively. At baseline (50 years of age), risk was higher for black men than for whites for HRD (OR 3.31, 95% CI 2.85–3.84). The ORs for age (per year) for HRD relative to LRD were 1.09 (95% CI 1.09–1.10) for white men, and as 1.06 (95% CI 1.05–1.07) for black men. Further, among a subgroup of men with low PSA (<10 ng/ml) T1cN0M0 prostate cancer, risk was also higher for black man than for white men at baseline (50 years of age) (OR 2.70, 95% CI 2.09–3.48). The ORs for age (per year) for HRD relative to LRD were 1.09 (95% CI 1.09–1.10) for white men, and as 1.06 (95% CI 1.05–1.07) for black men.
Conclusion: A substantial proportion of men with PSA-detected prostate cancer as reported to the SEER program had HRD. Black race and older age were associated with a greater likelihood of HRD.
doi:10.3389/fonc.2013.00312
PMCID: PMC3870291  PMID: 24392353
prostate cancer; race; age; population-study; SEER; screen-detected
5.  Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression 
BMC Urology  2012;12:21.
Background
Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate) has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium. We speculated that inhibition of angiogenesis by valproate might be mediated by this anti-angiogenic protein.
Methods
Bladder cancer cell lines UMUC3 and T24 were treated with valproate or another histone deacetylase inhibitor, vorinostat, in culture for a period of three days. Proliferation was assessed by alamar blue reduction. Gene expression was evaluated by reverse transcription of RNA and quantitative PCR.
Results
Proliferation assays showed treatment with valproate or vorinostat decreased proliferation in both cell lines. Histone deacetylase inhibition also increased relative expression of thrombospondin-1 up to 8 fold at 5 mM valproate.
Conclusions
Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.
doi:10.1186/1471-2490-12-21
PMCID: PMC3487994  PMID: 22898175
Bladder cancer; Valproic acid; Thrombospondin-1, Urothelial carcinoma; Gene expression
6.  Role of frozen section analysis of testicular/paratesticular fibrous pseudotumours: a five-case experience 
Background:
Fibrous pseudotumours of the testicular and paratesticular tissues are fibroinflammatory reactive lesions that can clinically mimic neoplasms. Very little is known about the role of frozen section analysis (FSA) for these lesions in terms of intraoperative surgical management.
Methods:
We recently experienced 5 patients with testicular/paratesticular fibrous pseudotumours in whom frozen sections were used to demonstrate its non-neoplastic nature prior to the decision for radical surgery.
Results:
In 2 cases, FSA resulted in testicular-sparing surgery. In contrast, the remaining 3 cases ultimately underwent radical orchiectomy, due to questionable viability of the testicle involved by inflammatory/infiltrative lesions and in 1 case a slight possibility of lymphoproliferative malignancy.
Conclusion:
Urologists should be aware of this entity and its gross features, such as firm masses and diffuse fibrous proliferation encasing the testicle to help determine intraoperative management. In select cases, intraoperative FSA is helpful in obviating radical orchiectomy.
doi:10.5489/cuaj.10144
PMCID: PMC3148395  PMID: 21806893
7.  Phase II Study of Intravesical Therapy with AD32 in Patients with Papillary Urothelial Carcinoma or Carcinoma in situ (CIS) Refractory to Prior Therapy with Bacillus Calmette-Guerin (E3897): A Trial of the Eastern Cooperative Oncology Group 
Urologic oncology  2008;27(5):496-501.
SUMMARY
Objectives
Assess the safety and effectiveness of AD32, a doxorubicin analogue with little systemic exposure when administered intravesically, in patients with recurrent or refractory superficial urothelial carcinoma (formerly called transitional cell carcinoma [TCC]), or carcinoma in situ (CIS), who have failed prior BCG-based immunotherapy.
Methods
Eligible patients received 6 weekly doses (800mg) of intravesical AD32 and were evaluated at 12-week intervals for 24 months or until date of worsening disease. Primary analysis was the proportion of all patients recurrence-free at 12 months. Treatment-related and GU-specific toxicities were also examined. All participating institutions submitted the protocol for Institutional Review Board (IRB) approval.
Results
The study was halted due to unavailability of study drug after accrual of 48 of a planned 64 patients; 42 were included in the analysis. Of these, 28 (67%) were still alive after median follow-up of 61.1 months. Of 21 TCC patients, 18 (85.7%) experienced disease recurrence (median time to recurrence, 5.3 months). Of the 5 CIS patients with complete response (CR), 3 (60%) experienced disease recurrence; (median time to recurrence, 37.3 months). Recurrence-free rates at 12 and 24 months were 20% (90% CI, 7.8%, 36.1%) and 15% (90 CI, 4.9%, 30.2%), respectively, for patients with TCC and 80% (90% CI, 31.4%, 95.8%) at both intervals for CIS patients with CR. Infection was the most common treatment-related toxicity; no grade 4 or higher toxicity was observed. The most common GU-specific toxicity was increased frequency/urgency.
Conclusions
AD32 is safe and active for treatment of recurrent or refractory superficial bladder carcinoma. The agent awaits more complete characterization when drug production problems can be solved.
doi:10.1016/j.urolonc.2008.05.004
PMCID: PMC2743955  PMID: 18639470
AD32; superficial transitional cell carcinoma; urothelial carcinoma; carcinoma in situ; bladder; intravesical
8.  Treatment of Non-Muscle Invading Bladder Cancer: Do physicians in the United States Practice Evidence Based Medicine? : The use and economic implications of Intravesical Chemotherapy after Transurethral Resection of Bladder Tumors 
Cancer  2009;115(12):2660-2670.
Background
Phase III clinical trials performed primarily outside the United States (U.S.) demonstrate that intravesical instillation of chemotherapy immediately following transurethral resection of a bladder tumor (TURB) decreases recurrence rates. We sought to determine whether U.S. urologists have adopted this practice, and its potential effect on costs of bladder cancer (BC) care.
Methods
Using 1997–2004 MEDSTAT claims data, we identified patients with newly diagnosed BC who underwent cystoscopic biopsy or TURB, and those who received intravesical chemotherapy within one day after TURB. Economic consequences of this treatment compared to TURB alone were modeled using published efficacy estimates and Medicare reimbursements. We used a time horizon of 3-years and assumed that this treatment was given for all newly diagnosed low risk BC patients.
Results
Between 1997 and 2004, we identified 16,748 patients with newly diagnosed BC, of whom 14,677 underwent cystoscopic biopsy or TURB. Of these, only 49 (0.33%) received same day intravesical instillation of chemotherapy. From 1997 through 2004, there has been little change in the use of this treatment. We estimated a 3-year savings of $538 to $690 (10 to12%) per patient treated with TURB and immediate intravesical chemotherapy compared with TURB alone, reflecting a yearly national savings of $ 19.8 to $24.8 million.
Conclusion
Instillation of intravesical chemotherapy immediately after TURB has not been embraced in the U.S. Adopting this policy would significantly lower the cost of BC care.
doi:10.1002/cncr.24311
PMCID: PMC2769205  PMID: 19455607
Intravesical therapy; Bladder Cancer; Evidence Based Medicine; Transurethral resection of bladder tumor
9.  Commentary: the role of cytologic analysis of voided urine in the work-up of asymptomatic microhematuria 
BMC Urology  2009;9:13.
Microscopic hematuria is a common finding in patients presenting to both primary care doctors as well as urologists. Sources of microscopic hematuria include infection, stones, inflammatory disorders as well as cancer of the genitourinary tract, particularly urothelial cancer. A primary focus in the urologic workup of hematuria is to rule out cancer. This is done using radiographic studies as well as procedures such as cystoscopy and bladder biopsy. As the authors state in their article titled "The utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria", cytologic analysis of voided urine, though attractive due to its noninvasive nature, has been found to have the neither the sensitivity, cost-effectiveness, nor the ease of administration necessary to replace more invasive diagnostics in the evaluation of microscopic hematuria.
doi:10.1186/1471-2490-9-13
PMCID: PMC2753578  PMID: 19744318
10.  Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1 
BMC Urology  2008;8:7.
Background
Steroid hormones influence mitogenic signaling pathways, apoptosis, and cell cycle checkpoints, and it has long been known that incidence of bladder cancer (BC) in men is several times greater than in women, a difference that cannot be attributed to environmental or lifestyle factors alone. Castration reduces incidence of chemically-induced BC in rodents. It is unclear if this effect is due to hormonal influences on activation/deactivation of carcinogens or a direct effect on urothelial cell proliferation or other malignant processes. We examined the effect of castration on BC growth in UPII-SV40T transgenic mice, which express SV40 T antigen specifically in urothelium and reliably develop BC. Furthermore, because BC growth in UPII-SV40T mice is exophytic, we speculated BC growth was dependent on angiogenesis and angiogenesis was, in turn, androgen responsive.
Methods
Flat panel detector-based cone beam computed tomography (FPDCT) was used to longitudinally measure exophytic BC growth in UPII-SV40T male mice sham-operated, castrated, or castrated and supplemented with dihydrotestosterone (DHT). Human normal bladder and BC biopsies and mouse bladder were examined quantitatively for thrombospondin-1 (TSP1) protein expression.
Results
Mice castrated at 24 weeks of age had decreased BC volumes at 32 weeks compared to intact mice (p = 0.0071) and castrated mice administered DHT (p = 0.0233; one-way ANOVA, JMP 6.0.3, SAS Institute, Inc.). Bladder cancer cell lines responded to DHT treatment with increased proliferation, regardless of androgen receptor expression levels. TSP1, an anti-angiogenic factor whose expression is inhibited by androgens, had decreased expression in bladders of UPII-SV40T mice compared to wild-type. Castration increased TSP1 levels in UPII-SV40T mice compared to intact mice. TSP1 protein expression was higher in 8 of 10 human bladder biopsies of normal versus malignant tissue from the same patients.
Conclusion
FPDCT allows longitudinal monitoring of exophytic tumor growth in the UPII-SV40T model of BC that bypasses need for chemical carcinogens, which confound analysis of androgen effects. Androgens increase tumor cell growth in vitro and in vivo and decrease TSP1 expression, possibly explaining the therapeutic effect of castration. This effect may, in part, explain gender differences in BC incidence and implies anti-androgenic therapies may be effective in preventing and treating BC.
doi:10.1186/1471-2490-8-7
PMCID: PMC2374790  PMID: 18433501
11.  Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator 
BMC Urology  2004;4:3.
Background
Interstitial cystitis (IC) is a chronic bladder disorder of unknown etiology. Antiproliferative factor (APF), a peptide found in the urine of IC patients, has previously been shown to decrease incorporation of thymidine by normal bladder epithelial cells. This study was performed to determine the effect of APF on the cell cycle of bladder epithelial cells so as to better understand its antiproliferative activity.
Methods
Explant cultures from normal bladder biopsy specimens were exposed to APF or mock control. DNA cytometry was performed using an automated image analysis system. Cell cycle phase fractions were calculated from the DNA frequency distributions and compared by two-way analysis of variance (ANOVA).
Results
APF exposure produced statistically significant increases in the proportion of tetraploid and hypertetraploid cells compared to mock control preparations, suggesting a G2 and/or M phase cell cycle block and the production of polyploidy.
Conclusions
APF has a specific effect on cell cycle distributions. The presence of a peptide with this activity may contribute to the pathogenesis of interstitial cystitis through disruption of normal urothelial proliferation and repair processes.
doi:10.1186/1471-2490-4-3
PMCID: PMC411044  PMID: 15068487
12.  Inducible expression of catalytically active type 1 serine/threonine protein phosphatase in a human carcinoma cell line 
Background
One of the major cellular serine/threonine protein phosphatases is protein phosphatase type 1 (PP1). Studies employing many eukaryotic systems all point to a crucial role for PP1 activity in controlling cell cycle progression. One physiological substrate for PP1 appears to be the product of the retinoblastoma susceptibility gene (pRB), a demonstrated tumor suppressor. The growth suppressive activity of pRB is regulated by its phosphorylation state. Of critical importance is the question of the in vivo effect of PP1 activity on pRB and growth regulation. As a first step towards addressing this question, we developed an inducible PP1 expression system to investigate the regulation of PP1 activity.
Results
We have established a cell line for inducing protein expression of the type 1, alpha-isotype, serine/threonine protein phosphatase (PP1α). A plasmid encoding a fusion protein of the catalytic subunit of PP1α with a 6-histidine peptide (6His) and a peptide from hemagluttinin (HA) was transfected into the UMUC3 transitional cell carcinoma cell line, previously transfected with the reverse tetracycline transactivator plasmid pUHD172-1neo. A stable cell line designated LLWO2F was established by selection with hygromycin B. 6His-HA-PP1α protein appeared in cell lysates within two hours following addition of doxycycline to the culture medium. This protein localizes to the nucleus as does endogenous PP1α, and was shown to associate with PNUTS, a PP1-nuclear targeting subunit. Like endogenous PP1α, immunocomplexed 6His-HA-PP1α is active toward phosphorylase a and the product of the retinoblastoma susceptibility gene, pRB. When forcibly overexpressing 6His-HA-PP1α, there is a concomitant decrease in endogenous PP1α levels.
Conclusions
These data suggest the existence of an autoregulatory mechanism by which PP1α protein levels and activity remain relatively constant. RT-PCR analyses of isolated polysome fractions support the notion that this putative autoregulatory mechanism is exerted, at least in part, at the translational level. Implications of these findings for the study of PP1α function in vivo are discussed.
doi:10.1186/1475-2867-3-12
PMCID: PMC183861  PMID: 12914669
Type 1 protein phosphatase; retinoblastoma protein; serine/threonine dephosphorylation; phosphatase activity; inducible protein expression

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