Outcome of surgical treatment of patients with upper versus lower urinary tract urothelial carcinoma: stage-by-stage comparison.

OBJECTIVES: It remains controversial whether we can apply similar principles in the management of upper urinary tract urothelial carcinoma (UUT-UC) based on the behavior of bladder urothelial carcinoma (B-UC). We sought to assess whether UUT-UC and B-UC have similar biology and performed a stage-by-stage comparative analysis of outcome between the 2 groups. METHODS: A retrospective review was performed on patients who underwent nephroureterectomy for UUT-UC and radical cystectomy for B-UC from 1991 to 2006. Standard variables were collected and recurrence-free and overall survival (OS) rates were calculated. RESULTS: 280 patients with a median age of 69 years were included (99 UUT-UC treated via nephroureterectomy and 181 B-UC treated via radical cystectomy). Median follow-up was 29 months. None received neoadjuvant chemotherapy. Patients with UUT-UC presented less commonly with invasive disease compared to those with B-UC (44 vs. 77% were >pT2). Overall, 5-year OS for the B-UC group was significantly lower than for the UUT-UC group (60.8 vs. 74.5%, p = 0.02). However, when patients were stratified by stage (>pT2), patients with B-UC had similar OS compared to those with UUT-UC (54.6 vs. 60.8%, p = 0.74). CONCLUSION: Invasive UUT-UC appears to have similar tumor biology compared to B-UC. Whether we can safely extrapolate on the benefit of neoadjuvant and adjuvant strategies to patients with UUT-UC requires further investigation.

Application of Hereditary Renal Cell Carcinoma Risk Criteria to a Large Prospective Database.

AIMS: To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC). MATERIALS AND METHODS: The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion. RESULTS: Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation. CONCLUSIONS: Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing.

Natural history and management of small renal masses.

The recent stage migration observed for renal tumours is contributing to a significant increase in the diagnosis of small renal masses. This evolution has led to a significant change in the approach to renal masses. New options such as observation or energy ablation are gaining popularity in a subset of this patient population. In addition, the observed changes directly contribute to the increased use of nephron-sparing surgery. A better understanding of the various characteristics of these masses will allow for a better understanding of the natural history of these masses and for selection of the optimal therapeutic approach.

Renal cell carcinoma in the Canadian Indigenous population.

Background: Diagnosis and treatment of renal cell carcinoma (rcc) might be different in Indigenous Canadians than in non-Indigenous Canadians. In this cohort study, we compared rcc presentation and treatments in Indigenous and non-Indigenous Canadians. Methods: Patients registered in the Canadian Kidney Cancer Information System treated at 16 institutions between 2011 and 2018 were included. Baseline patient, tumour, and treatment characteristics were compared between Indigenous and non-Indigenous Canadians. The primary objective was to determine if differences in rcc stage at diagnosis were evident between the groups. The secondary objective was to determine if treatments and outcomes were different between the groups. Results: During the study period, 105 of the 4529 registered patients self-identified as Indigenous. Those patients were significantly younger at the time of clinical diagnosis (57.9 ± 11.3 years vs. 62.0 ± 12.1 years, p = 0.0006) and had a family history prevalence of rcc that was double the prevalence in the non-Indigenous patients (14% vs. 7%, p = 0.004). Clinical stage at diagnosis was similar in the two groups (p = 0.61). The disease was metastatic at presentation in 11 Indigenous Canadians (10%) and in 355 non-Indigenous Canadians (8%). Comorbid conditions that could affect the management of rcc-such as obesity, renal disease, diabetes mellitus, and smoking-were more common in Indigenous Canadians (p < 0.05). Indigenous Canadians experienced a lower rate of active surveillance (p = 0.01). Treatments and median time to treatments were similar in the two groups. Conclusions: Compared with their non-Indigenous counterparts, Indigenous Canadian patients with rcc are diagnosed at an earlier age and at a similar clinical stage. Despite higher baseline comorbid conditions, clinical outcomes are not worse for Indigenous Canadians than for non-Indigenous Canadians.

Use of targeted therapy in patients with metastatic renal cell carcinoma: clinical and economic impact in a Canadian real-life setting.

Introduction: Outside of randomized controlled clinical trials, the understanding of the effectiveness and costs associated with targeted therapies for metastatic renal cell carcinoma (mrcc) is limited in Canada. The purpose of the present study was to use real-world prospective data to assess the effectiveness and cost of targeted therapies for patients with mrcc. Methods: The Canadian Kidney Cancer Information System, a pan-Canadian database, was used to identify prospectively collected data relating to patients with mrcc. First- and subsequent-line time to treatment termination (ttt) was determined from therapy initiation time (sunitinib or pazopanib) to discontinuation of therapy. Kaplan-Meier survival curves were used to estimate the unadjusted and adjusted overall survival (os) by treatment. Unit treatment cost was used to estimate the cost by line of treatment and the total cost of therapy for the management of patients with mrcc. Results: The study included 475 patients receiving sunitinib or pazopanib in the first-line setting. Patients were treated mostly with sunitinib (81%); 19% of patients were treated with pazopanib. The median ttt in the first line was 7.7 months for patients receiving sunitinib and 4.6 months for those receiving pazopanib (p < 0.001). The adjusted os was 32 months with sunitinib and 21 months with pazopanib (hazard ratio: 1.61; p < 0.01). The total median cost of first- and second-line treatments was $56,476 (interquartile range: $23,738-$130,447) for patients in the sunitinib group and $46,251 (interquartile range: $28,167-$91,394) for those in the pazopanib group. Conclusions: For the two therapies, os differed significantly, with a higher median os being observed in the sunitinib group. The cost of treatment was higher in the sunitinib group, which is to be expected with longer survival.

In vivo modulation of macrophage tumoricidal activity by oral administration of the liposome-encapsulated macrophage activator CGP 19835A.

The present study evaluated the in vivo biological activity of synthetic muramyl tripeptide, CGP 19835A, when encapsulated into phosphatidylcholine liposomes (POPC-19835A) and administered as an p.o. immunomodulator to BALB/c mice. Liposomes were rapidly absorbed in the intestine and reached the systemic circulation within 4 h. Alveolar macrophages harvested from the lungs of mice 24 h after a single p.o. feeding of POPC-19835A were tumoricidal toward syngeneic murine renal cell carcinoma target cells. Repeated daily feedings with POPC-19835A generated sustained activation of the alveolar macrophages. Activation of peritoneal macrophages to the tumoricidal state required at least three daily feedings of POPC-19835A. In vitro studies demonstrated the release of tumor necrosis factor alpha and interleukin 6 by macrophages activated by POPC-19835A in the presence of gamma-interferon. Interleukin 1 and nitric oxide were not induced in macrophages by this liposomal preparation. Daily administration of POPC-19835A after i.v. injection of renal cell carcinoma tumor in BALB/c mice inhibited the development of experimental lung metastasis and confirmed the potential role of long-term therapy with this new p.o. immunomodulator.

Intravesical liposomal muramyl tripeptide phosphatidylethanolamine treatment of human bladder carcinoma growing in nude mice.

The present study evaluated the in vivo activity of synthetic lipophilic muramyl tripeptide phosphatidylethanolamine (MTP-PE) when encapsulated into liposomes (phosphatidylcholine-phosphatidylserine, 7:3 molar ratio) and administered intravesically to athymic nude mice with human transitional cell carcinoma 253J-V cells growing in their bladder. Intravesical liposome-MTP-PE was effective in eradicating the human tumors implanted orthotopically in nude mice. Following therapy, activated macrophages were found in the bladders of liposome-MTP-PE-treated mice but not in control mice. In vitro activation of murine macrophages with liposome-MTP-PE increased their cytotoxicity against the 253J-V cell line used in these experiments. This effect was enhanced by cotreatment with interferon-gamma (IFN-gamma). Furthermore, cotreatment of macrophages with both liposome-MTP-PE and IFN-gamma resulted in the secretion of both tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Liposome-encapsulated MTP-PE shows promise as an effective therapeutic agent for bladder carcinoma.

Links between Fer tyrosine kinase expression levels and prostate cell proliferation.

In our cloning strategy to identify tyrosine kinases implicated in the regulation of prostate growth, the dog fer cDNA was obtained and shown to be highly homologous to known fer cDNAs. Using a polyclonal Fer antibody directed against a C-terminal peptide, we studied its associations with cortactin, beta-catenin and p120Cas in human prostate carcinoma PC-3 cells. In contrast to previous reports, no interactions were observed. To assess its functional role, fer cDNA constructs were transfected in PC-3 cells. Antisense clones exhibiting a marked diminution of Fer expression had a reduced growth rate (doubling time of 29 vs. 42 h) and were unable to form colonies in soft agar. In agreement with these results, Fer protein expression was linked to human prostatic proliferative diseases, with enhanced levels in extracts from cancer tissues as compared to those from normal and hyperplastic ones, and was also expressed in the human prostate carcinoma cell lines DU145 and LNCaP. In the dog model, Fer expression was up-regulated in dividing versus resting prostate epithelial cells in vitro, and also in vivo when basal cell hyperplasia and metaplasia was induced by estrogen after castration. Minimal effects were observed when renewing the luminal epithelium with androgens. Taken together, these results show that Fer expression is associated with prostate cell proliferation and enhanced in prostate cancer.

Determination of (R)- and (S)-ketoprofen in human plasma by liquid chromatography/tandem mass spectrometry following automated solid-phase extraction in the 96-well format.

A sensitive and selective method was developed for the determination of (R)-ketoprofen ((R)-kt) and (S)-ketoprofen ((S)-kt) in human plasma using chiral liquid chromatography/tandem mass spectrometry (LC/MS/MS). Plasma samples spiked with stable-isotope-labeled [(13)C(1), (2)H(3)]-(R and S)-ketoprofen, for use as the internal standards, were prepared for analysis using automated solid-phase extraction (SPE) in the 96-well microtiter format. The enantiomers were separated on an (R)-1-naphthylglycine and 3,5-dinitrobenzoic acid (Chirex 3005) 250x2.0 mm i.d. analytical column, equipped with a 30x2.0 mm i.d. guard column using isocratic mobile phase conditions. The (R)- and (S)-kt levels were quantifiable from 0.05 to 2500 ng ml(-1) by constructing two separate curves from calibration standards covering the same range. The first curve ranged from 0.05 to 100 and the second from 100 to 2500 ng ml(-1). A concentration of 0.05 ng ml(-1) of either enantiomer was easily detected using a 1 ml plasma sample volume. The average method accuracy, evaluated at four levels over an extended period, was better than +/-3% over the entire range. The precision for the same set of quality control samples ranged from 4.0 to 7.0 % RSD (n = 24). The method was applied to the evaluation of pharmacokinetic parameters in human plasma obtained from volunteers who received 25 mg of kt by peroral administration of Actron caplets or by topical administration of Oruvail gel.

Thirty-day mortality rates and cumulative survival after radical retropubic prostatectomy.

OBJECTIVES: To assess the 30-day mortality rate and overall survival after radical retropubic prostatectomy (RRP). METHODS: Identification of all RRPs performed in the Province of Quebec between January 5, 1988 and January 16, 1996 was accomplished through the Quebec Healthcare Plan Database. RESULTS: Four thousand nine hundred ninety-seven RRPs were performed by 104 urologists. Overall, 451 deaths were recorded: 32 occurred during the first 30 days (0.6% 30-day mortality rate). A significant decrease in the 30-day mortality rate, from 2.45% to 0.5%, was recorded during the span of the study. The year of surgery, patient age, and hospital type were statistically significant short-term mortality variables (life table analysis). Patient age and year of surgery determined the cumulative survival probability (univariate and multivariate Cox analysis). Cumulative survival at 31 months of follow-up increased from 88.2% in 1988 to 98.1% in 1995. Men 75 years old and older were at a clear disadvantage with regard to survival probability compared with their younger counterparts. CONCLUSIONS: In this population-based analysis of RRP outcomes, we demonstrated a significant improvement in short- and long-term outcomes, as evidenced by a decrease in the 30-day mortality rate and an improved cumulative survival, recorded over the span of the study. The recorded outcome trends may be explained by improved patient selection and optimal management. Although we are unable to determine cancer-specific outcomes, the results of this analysis should prove valuable to urologists and patients until there are results from randomized trials.

Predictors of positive tuberculin skin test results in a jail population.

The purpose of this analysis was to determine the prevalence and predictors of positive tuberculin skin tests (TSTs) in a jail population. TST results and demographic data were obtained for 996 male inmates of a Connecticut jail who were tested following identification of a case of multidrug-resistant Mycobacterium tuberculosis (MDR-TB). Inmates were predominantly young (median age, 26 years) and Black (51%) and were born in the United States (96%). Overall 109 (11%) inmates had positive TST results. TST positivity was strongly associated with being born outside the United States (adjusted odds ratio [aOR] = 11.3, 95% confidence interval [95% CI] 4.9-25.8), being Puerto Rican born (aOR = 3.7, 95% CI 1.9-7.4), and increasing age (15-24 years aOR = l [referent]; 25-34 years aOR = 2.1 95% CI 1.2-3.5; 35-44 years aOR = 4.3 95% CI 2.4-7.7; > or = 45 years aOR = 6.4 95% CI 2.8-14.6). The combination of being U.S.-born and Black was also associated with increased rates of positive TSTs. The prevalence of TST positivity was > 10% for all age groups of inmates born outside the United States or Puerto Rico and for Puerto Rican-born inmates aged > or = 25 years and U.S.-born inmates aged > or = 35 years. Analysis of routinely collected TST data allows predictors of TST positivity to be identified and may help determine population subgroups for whom anergy screening and preventive therapy should be considered.

Spot urine osmolality, age and bladder capacity as predictors of response to desmopressin in nocturnal enuresis.

The objective of the current study was to find a cost-effective way of correlating spot urine osmolalities, bladder capacity and age in patients with monosymptomatic nocturnal enuresis with response to treatment with desmopressin (Minirin, DDAVP). A total of 35 children fulfilled the entry criteria and were included in the study. Constipation was eliminated in these children by appropriate enema treatment and diet adjustment prior to enrollment. Urine samples were collected at home at times that would best reflect fluctuations in plasma vasopressin levels (08:00, 16:00 and 22:00) over three consecutive 24-hour periods. Maximal functional bladder capacity was determined from the largest voided volume. A 2-week dose-titration treatment period with intranasal desmopressin was then conducted. With doses of desmopressin being increased by 10 micrograms every 3 days. Response to desmopressin treatment was then assessed and factors that were observed to be markers of a favourable response were noted. Of the 35 children, 27 demonstrated a complete response to desmopressin treatment, at doses of 10-30 micrograms. Spot urine osmolalities were not predictive of the response to desmopressin (P > 0.1). In contrast, there was a significant correlation between a high maximum functional bladder capacity and response to desmopressin (P = 0.006). Age was also predictive of a good response to desmopressin treatment (P = 0.008).

Relationship between initial PSA density with future PSA kinetics and repeat biopsies in men with prostate cancer on active surveillance.

The objective of our study is to examine the correlation between PSA density (PSAd) at the time of diagnosis with PSA velocity (PSAV), PSA doubling time and tumour progression, on repeat biopsy, in men with prostate cancer on active surveillance. Data from 102 patients with clinically localized prostate cancer on active surveillance in the period between 1992 and 2007, who had the necessary parameters available, were collected. PSAd was calculated and correlated with PSAV, PSA doubling time (PSADT), Gleason score at diagnosis and local progression on repeated biopsies. PSAV was 0.64 and 1.31 ng ml(-1) per year (P = 0.02), PSADT of 192 and 113 months (P = 0.4) for PSAd below and above 0.15, respectively. The rate of detecting high Gleason score (≥ 7) at diagnosis was 6 and 23% for PSAd below and above 0.15, respectively. A total of 101 patients underwent at least a second biopsy and the incidence of upgrading was 10 and 31% for PSAd below and above 0.15, respectively (P = 0.001). Although low PSAd is an accepted measure for suggesting insignificant prostate cancer, our study expands its role to indicate that PSAd < 0.15 may be an additional clinical parameter that may suggest indolent disease, as measured by future PSAV and repeat biopsy over time.

The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types.

In addition to new tumour antigens, new prognostic and diagnostic markers are needed for common cancers. In this study, we report the expression of Dickkopf-1 (DKK1) in multiple common cancers. This constitutes a comprehensive analysis of the DKK1 expression profile. Dickkopf-1 expression was evaluated by classical and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbant assay for protein determination, in cancer lines and clinical specimens of several cancer origins. For breast cancer, expression was correlated with clinicopathological parameters. Dickkopf-1 expression was confirmed in several cancer cell lines derived from breast and other common cancers. Dickkopf-1 protein secretion was documented in breast, prostate and lung cancer lines, but was negligible in melanoma. Analysis of DKK1 expression in human cancer specimens revealed DKK1 expression in breast (21 out of 73), lung (11 out of 23) and kidney cancers (six out of 20). Interestingly, DKK1 was preferentially expressed in oestrogen and progesterone receptor-negative tumours (ER(-)/PR(-); P=0.005) and in tumours from women with a family history of breast cancer (P=0.024). Importantly, DKK1 protein production was confirmed in multiple breast cancer specimens that were positive by RT-PCR. This work establishes DKK1 as a potential prognostic and diagnostic marker for cohorts of breast cancer patients with poor prognosis. Dickkopf-1 may also become a relevant candidate target for immunotherapy of different cancers.

Direct comparison of ELISPOT and ELISA-based assays for detection of individual cytokine-secreting cells.

A direct comparison was made between the insoluble ELISPOT, solubilized ELISPOT, and ELISA assays, to detect cytokine secretion by cells, using sterile ELISA plates and commercially available monoclonal antibodies. We evaluated the IL-6 secretion by resident peritoneal macrophages of BALB/c mice and the secretion of IL-2, IL-4, IL-5, and IL-6 by the murine T helper clone, D10.G4.1 cells. Our results demonstrated that ELISPOT can detect cytokine secretion at the single cell level in either adherent or nonadherent cells. The level of detection by ELISPOT was 10 to 200 times more sensitive than ELISA performed on culture supernatants. We also demonstrated that the solubilized ELISPOT can detect cytokine secretion by cells with greater sensitivity than conventional ELISA. These ELISPOT assays can be used to characterize the cytokine secretion pattern of different cell populations in a simple, reproducible, and reliable manner.

Natural history of renal masses followed expectantly.

PURPOSE: An increasing number of incidental renal masses have been detected with increasing use of ultrasonography, computerized tomography and magnetic resonance imaging. We investigated the natural history of incidentally detected renal masses. MATERIALS AND METHODS: A total of 24 patients were included in this retrospective analysis. Average patient age was 68.3 years (range 29 to 83). The 16 males and 8 females were followed with abdominal imaging for a mean and median followup of 31.6 and 24 months, respectively (range 8 to 86). Patients elected to be observed because of age, poor medical condition or the presence of a mass in a solitary kidney. The majority of patients (22 of 24) were asymptomatic at diagnosis. Two patients were followed with bilateral renal masses, and 2 with T3b tumors. Of the 20 patients with incidental solitary renal masses, 6 were at the upper pole, 9 were mid polar and 5 lower pole. Mean maximum diameter of lesions was 3.3 cm (median 2.7, range 0.9 to 10). Growth rate was calculated based on diameter and tumor volume. RESULTS: Of the 24 patients only 5 demonstrated tumor growth during the surveillance period. No metastasis developed in any patients. Mean tumor growth rate observed in the 5 patients was 0.49 cm per year or 7.3 cc per year. Of the 24 patients 4 underwent surgery after surveillance because of apparent tumor growth or per patient request. Pathology revealed renal cell carcinoma in all 4. CONCLUSIONS: Tumor growth of renal masses is often limited. Most of our patients did not demonstrate significant growth when followed expectantly. Without tumor growth the risk of metastasis seems limited.

The risk of upper tract recurrence following cystectomy in patients with transitional cell carcinoma involving the distal ureter.

PURPOSE: Risk factors for the development of an upper urinary tract transitional cell carcinoma following radical cystectomy are identified. MATERIALS AND METHODS: The records of 430 patients who underwent cystectomy for transitional cell carcinoma of the bladder between 1981 and 1988 were retrospectively reviewed. RESULTS: Upper tract tumors developed in 11 patients (2.6%) at a median of 40 months after radical cystectomy. Of the potential risk factors evaluated only the presence of transitional cell carcinoma within the distal ureter showed a statistically significant correlation with upper tract recurrence (p = 0.001). Six of the 11 recurrent neoplasms were asymptomatic. Among the patients with upper urinary tract recurrence 5 died of disease, 4 had no evidence of disease and 2 were alive with cancer. CONCLUSIONS: Patients with distal ureteral involvement at cystectomy are at a high risk for upper tract recurrence. These patients should be monitored with routine upper tract cytology and imaging studies.