Acknowledgments
We wish to acknowledge and thank Watson Pharmaceuticals, Inc. for their support in the publication of the Northeastern Secion – AUA 2010 Annual Meeting abstracts.
We wish to acknowledge and thank Watson Pharmaceuticals, Inc. for their support in the publication of the Northeastern Secion – AUA 2010 Annual Meeting abstracts.
Urinary tract infections (UTI) are among the most common bacterial infections in the United States. The gold standard for diagnosis is urine culture. This provides bacteria identification and sensitivity, but is labor intensive and time-consuming. As such, many UTIs are treated empirically contributing to resistance and cost. There is an urgent need for a diagnostic tool that can rapidly identify uropathogens and their sensitivities. We present the development of a PCR-based assay for Enterobacter cloacae, and evidence for its further use in the context of NanoLantern™ technology. The NanoLantern™ is a chip sensor that utilizes DNA hairpins immobilized onto a gold surface. In the presence of complementary (target) DNA, the hairpin stem is opened, exposing a quantifiable fluorophore.
A synthetic DNA hairpin, unique to Enterobacter cloacae, was immobilized onto 9 gold coated chips. Baseline fluorescence intensity was recorded. The chip was exposed to synthetic target and then imaged with a fluorescence microscope. Fluorescence intensity was recorded and compared to baseline. PCR, asymmetric PCR and linear after the exponential PCR were used to amplify the target DNA from the bacteria. The amplicon was exposed to the NanoLantern™ chip and fluorescence intensity was quantified.
Pre-synthetic target fluorescence imaging of 9 chips exposed to synthetic DNA resulted in a mean raw count of 665 (SD ± 244). Post-synthetic target fluorescence imaging of 9 chips resulted in a mean raw count of 8197 (SD ± 648), a greater than 12-fold increase in intensity. See Fig. 1.
We have demonstrated the feasibility of a novel DNA hairpin probe. Work is ongoing to develop a PCR assay and to begin testing the NanoLantern™ chip with bacteria derived amplicon and urine samples. Ultimately, these integrated assays will provide rapid analysis, as part of an automated system, to be used in the clinical setting.
P1. Fluorescence microscopy of chip pre- vs. post-target exposure.
Nox4 is a member of the NADP(H) oxidase enzyme family that transports electrons across biological membranes to produce reactive oxygen species (ROS). Loss of the von Hippel-Lindau tumor suppressor (VHL) leads to activation of hypoxia-inducible factor-2α (HIF-2α) with increased VEGF, Glut-1, TGF-α expression. We have shown that Nox4 is essential for HIF-2α transcriptional activity and that inhibition of Nox4 abrogates HIF transactivation in VHL-deficient renal cell cancer (RCC) cells. Therefore, Nox4 may serve as a therapeutic target to for RCC. To test this, we screened novel compounds with activity against Nox4 in a human VHL-deficiency renal cell carcinoma xenograft tumor model.
One million 786-O cells in 100 μl HBSS were injected subcutaneously in the left flank of 6-week-old female SCID Beige mice. Tumors were measured in two dimensions and estimated tumor weights were calculated using the formula: V (mm3) = (length × width2)/2. When tumors reached 100-150 mm3, mice were stratified into 6 equal groups of 10 mice each. Compounds, GKT137892 (100 mg/kg), GKT137928 (100 mg/Kg), GKT136901 (100 mg/Kg) or sutent (40 mg/kg) were administrated by daily gavage for 34 days. Controls arms received no gavage or gavage with vehicle only. Mice were sacrificed at 24h after last gavage, and tumors were harvested and weighed. Significance was determined by ANOVA and Student T tests.
Sutent inhibition of xenograft tumors was observed by day 1. GKT136901 treatment inhibited tumor growth by day 15. The average volume of the tumors in GKT136901-treated group was 208.36 mm3 on day 22 of treatment vs 279.26 mm3 and 275.24 mm3 for the two control groups, respectively, representing a 26% growth inhibition (p = 0.012). For compounds, GKT137892 and GKT137928, no growth inhibition was seen. No toxicity was observed for any of the drugs.
GKT136901, an inhibitor of Nox4, inhibits 786-O cell xenograft tumor growth, providing proof of principle for Nox4 as a therapeutic target for RCC. Efficacy may be further enhanced by structural alterations that improve tumor penetration.
When PSA recurs after prostatectomy, localization of prostate cancer cells by imaging is important to decide which patients should receive salvage radiation therapy (RT) as opposed to androgen deprivation therapies. However, the threshold at which prostate cancers cells must be detected for RT to be efficient is <1 ng/mL of serum PSA necessitating sensitive imaging tools. We have developed a dual transcriptional amplification system (DTSTA) that allows sensitive detection of prostate cells by non invasive imaging and tested it in a local recurrence prostate cancer model.
Adenovirus (Ad) expressing firefly luciferase (fl) under the control of a modified PSA promoter and the Two-Step-Amplification-Transcription system (Ad-PSATSTAfl) was constructed as previously described (Sato et al. 2008). We have also constructed an oncolytic adenovirus expressing viral early genes E1A and E1B under TSTA (Ad-PSATSTAE1AE1B). When the two viruses are co-administered, we named the combination DTSTA for dual-TSTA system. LAPC-9 cells expressing Renilla luciferase were implanted subcutaneoulsy or in the peritoneum (i.p., as our local recurrence model) of scid/beige mice and tumor growth was monitored in vivo by bioluminescence. Intratumoral (i.t.) reporter activity was assessed after i.p. or i.t. injections of the viruses alone or in combination.
In vitro, DTSTA infection of CWR-22Rv1 prostate cancer cells increased FL activity by 4.3-fold after 3 days when compared to Ad-PSATSTAfl alone. In vivo, i.t. injection of DTSTA in LAPC-9 tumors resulted in increased Ad-PSAPTSTAfl reporter activity by up to 25-fold (Fig. 1). Real-time PCR on tumor DNA confirmed viral genome replication in tumors infected with DTSTA. Finally, using an i.p. local recurrence after prostatectomy model, we show that DTSTAfl can detect and localize specifically prostate cancer cells.
We describe a new adenoviral based amplification system, named DTSTA, which can specifically detect prostate cancer cells by non-invasive imaging in vivo. If translated to the clinic, this nanotechnology could help treatment decision making when there is PSA recurrence after prostatectomy.
P4. Figures for P5
A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer. Given mandatory folic acid fortification of cereal grains in the United States, the potential link between prostate cancer and increased folic acid intake warrants further investigation
Determine the relationship between patient folate status and the proliferative capacity of Gleason 7 tumors in men with prostate cancer.
Serum and prostate samples from 86 patients undergoing surgery for prostate cancer and from 25 cancer-free organ donors were utilized to measure serum and/or prostate tissue folate concentrations, and assess Ki67 expression. Patients were assessed for genetic polymorphisms in methyltetrahydrofolate reductase and dihydrofolate reductase genes.
Mean serum and tissue folate levels were significantly higher in men with prostate cancer compared to cancer-free organ donors (p < 0.002 and p < 0.02, respectively) (Fig. 1). Fasting serum folate levels were positively correlated with prostate cancer tissue folate content (n = 15; Spearman Correlation r = 0.577, p < 0.03). Fasting serum folate was significantly higher in users of folic acid supplements (p < 0.05). When divided into quartiles, there were no significant differences in serum folate levels between users and non-users of supplements. Among patients with Gleason 7 disease, the mean proliferation index was 6.17 ± 3.2% and 0.86 ± 0.92% in patients in the highest (117 ± 15nM) and lowest (18 ± 9nM) quintiles for serum folate, respectively (p < 0.0001) (Fig. 2).
This is the first report of a positive correlation between serum and prostate tumor folate. Increased cancer cell proliferation in men with higher serum folate concentrations is consistent with an increase in prostate cancer incidence observed with folate supplementation. Unexpectedly, more than 25% of our patients had serum folate levels greater than 6-fold adequate. Only half of these men reported supplement use, suggesting altered folate metabolism and/or consumption of folic acid from fortified foods.
P5. Fasting serum folate concentrations (nM) in patients with prostate cancer vs. cancer-free organ donors.
P5. Representative light photomicrograph (63x) of Ki67 immunohistochemistry reveals significantly greater staining (arrows) in prostate cancer patients with high (a) vs. low (b) serum folate concentrations. Normal prostate glands from the same patients revealed no difference in Ki67 staining in patients with high (c) vs. low (d) serum folate concentrations.
Macrophage inhibitory factor (MIF) is an important chemokine influencing progression of prostate cancer. We have demonstrated that tumor hypoxia mediates many factors leading to a malignant phenotype in prostate cancer, including invasion, metastases and drug-resistance. Such hypoxia-induced phenotypes can be attenuated by manipulating nitric oxide (NO) signaling through classic, cGMP mediated pathways. The aim of this study was to determine the role of NO signalling in hypoxia-induced upregulation of MIF in prostate carcinoma cells.
MIF production by DU-145 prostate cancer cells (as well as the MDA breast cancer cell line) was determined by ELISA in different oxygen culture conditions (0.5–20% O2). The role of NO signalling in hypoxia-mediated upregulation of MIF was determined by pharmacologic inhibitors and mimics of classic NO signalling with 10 nM GTN, 100 μM L-NMMA as well as non-hydrolysable analogue of cGMP, 8-bromo-cGMP (10 nM).
These studies demonstrate that exposure of DU145 (as well as the MDA cell lines) to low oxygen tension for 24 hours consistently increased the secretion of MIF into the supernatant (1720 ± 245 ng/mL vs. 240 ± 46 ng/mL, p < 0.05). Incubation of the cell lines with the inhibitor of nitric oxide synthase L-NMMA in 20% oxygen resulted in a similar increase in MIF secretion (832 ± 66 ng/mL vs. 220 ± 33 ng/mL, p < 0.029). Restoring classical NO signalling in these cells with low concentrations of GTN or 8-bromo-cGMP was also able to significantly (p < 0.05) reverse the hypoxia-mediated increase in MIF.
These results contribute to our understanding of MIF regulation, an important chemokine linked to cancer progression in numerous cancer sites. It appears that decreased NO signalling, as a result of microenvironmental hypoxia, is at least partially responsible for increased MIF secretion by cancer cells. These results justify further in vivo investigations of the role of nitric oxide signalling and MIF action and may represent a novel target for pharmacologic therapy for prostate cancer.
For several years, fibroblast cells have been primarily used for tissue engineering but adipose-derived stem/stromal cells (ASCs) show promising potential due to their facility to obtain, their capacity to differentiate and their ability to secrete mediators. Our group previously reported on the production of a bioengineered vesical equivalent using dermal fibroblasts without exogenous matrix. The aim of this study was therefore to evaluate the possibility of engineering an autologous vesical equivalent with human ASCs in order to validate if our model can benefit from the attributes of the ASCs.
ASCs were obtained from lipoaspirated adipose tissue and fibroblasts were extracted from a dermal biopsy. These human cells were cultured with serum and ascorbic acid to stimulate the formation of extracellular matrix and obtain cell sheets. Cells were cultured with constant media motion (GyrotwisterTM, Woodbridge, NJ) during three weeks and then three cell sheets of ASCs or fibroblasts were superimposed. After 4 days of maturation allowing cell sheet fusion, human urothelial cells were seeded on top of the construction and matured at the air/liquid interface. The vesical equivalents were characterized by histology, immunofluorescence as well as mechanical and suture resistance tests.
Complete vesical equivalents were obtained with ASCs or fibroblasts. The histology clearly showed that cell sheets forming the ASC vesical equivalents featured a strong cohesion between cell sheets and were 1.8 fold thicker than the fibroblast vesical equivalents. Immunolabelings of the mature constructions showed the presence of cytokeratin 8\18, a differentiation marker for urothelial cell; and collagen 1 and 3, which are the major components of the extracellular matrix. The ASC vesical equivalents were easy to manipulate resistant enough to suture, therefore allowing the 3D reconstruction of a bladder shaped tissue engineered substitute.
Human vesical equivalents were successfully produced using either dermal fibroblasts or ASCs, without the use of exogenous scaffolding components. The ASC vesical equivalents could sustain suturing without tearing. Considering their accessibility, abundance and increased matrix production ACSs therefore represent a great cell source to further optimize our innovative model for vesical reconstruction.
The use of the DaVinci robotic surgical system in laparoscopic procedures has gained wide acceptance and popularity across all surgical disciplines. This system however requires the utilization of monopolar electrosurgery and a finite reuse of electrosurgical instruments both of which provide opportunities for stray electrical currents from capacitive coupling and/or insulation failure. We report the prevalence and magnitude of such stray currents measured in DaVinci instruments that had reached the end of their duty cycle.
We tested 30 such instruments, 6 monopolar scissors, 1 Maryland bipolar forceps, 1 monopolar hook, 5 plasma kinetic dissecting forceps, 7 prograsp forceps, 10 large needle drivers using a Valleylab Force 2 ESU at pure coag and cut waveforms in open circuit at 4 different settings (open air) at 40 w, and sequentially gel coated instruments at 40 w, 80 w and maximum ESU output (coag 120 w, cut 300 w). The magnitude of stray currents was measured by an electrosurgical analyzer (454A Dynatec, Nevada). Visual inspection did not identify insulation defects in any of the instruments.
At coag waveform in open air, 86% of instruments leaked a mean of 0.4 w (0–0.7 w). In the presence of gel coated instruments, stray currents were detected in all instruments with means and (range) of 4.2 w (1.5–7.7), 5 w (1.8–9.7), and 5 w (1.9–10.5) at 40 w, 80 w and 120 w, respectively. At cut waveform in open air, none of the instruments leaked current, while gel coated instruments leaked a mean of 2.7 w (0.6–4.3), 2.7 w (0.8–8.2) and 4 w (1.6–8.2) at 40 w, 80 w and 300 w, respectively. Compared by instrument group, the highest leakage was in PKDF (mean 4.1 w, one >8 w), followed by LND (3.3 w), PF (2.8 w), MBF (2.4 w), MCS (2.3 w), and MH (1.1 w).
At the end of their life cycle, all tested instruments showed energy leakage with one over 8 w, at >80 w of ESU power. Stray currents were higher during coag waveforms and the magnitude was not always proportionally related to ESU settings. Such stray currents may cause electrical burns to patients and/or operating room personnel.
Adjuvant therapies contribute to the successful treatment of cancer. Our previous reports have shown that combining cryoablation with cytotoxic agents enhances prostate cancer cell death. Vitamin D3 (VD3) is a natural steroidal hormone that has been shown to exhibit cytotoxic properties preferentially inducing apoptosis in a variety of human cancer cells. Human prostate cancer cells are known to be resistant to many cytodestructive agents, including cryoablation and VD3. Here, we evaluated the efficacy of VD3 combined with cryoablation on androgen insensitive human prostate cancer (PC-3 and LNCaP-HP) cell death.
Freezing and VD3 exposure to PC-3 and LNCaP-HP cells were performed using both 2D and 3D culture systems and efficacy was determined by cell viability assays. Resultant cell death and specific signaling components were determined using apoptotic inhibitors, fluorescence microscopy, protease activity assays and immunoblotting.
Exposure of LNCaP-HP cells to freezing (-15°C) or VD3 (50 uM) results in minimal cell death (15% and 10% respectively 3 days post treatment), while a complete loss of viability was observed with the combination. The synergistic effect was found to be due to a marked increase in apoptosis. Western blot analysis revealed a decrease in pro-caspase-9 and -3 between 6 and 18 hours post-exposure. Caspase activation assays confirmed the reduction in pro-caspase levels was a result of caspase activation. Protease inhibitors were incorporated into the combination protocol to determine the overall contribution of caspase activity in cell death. Inhibition of caspase-9 significantly blocked the combination induced cell death compared to cells that did not receive the inhibitor (55% vs. 21% viable, respectively). The addition of the caspase-8 inhibitor resulted in only minimal protection, indicating a specific mitochondrial-mediated event. Importantly, the combination was not effective when applied to normal prostate cells.
VD3 sensitizes CaP cells to cryoablation. The significant increase in cell death was attributed to the activation of apoptosis, specifically through mitochondrial -mediated events. The results describe a novel therapeutic model for the treatment of prostate cancer and provide support for future in vivo studies.
Investigations into the molecular-based responses of prostate cancer following cold exposure have led to the discovery of delayed-onset, apoptotic cell death within the periphery of cryolesions. The apoptotic pathway typically attributed to this delayed death is the intrinsic/mitochondrial-mediated pathway characterized by a loss of mitochondrial potential, release of cytochrome c, and activation of caspase-9. Recent studies, however, have shown that at lower temperatures within the core of the cryogenic lesion (< −20°C) a rapid programmed cell death response occurs. Using an engineered, 3-dimensional prostate tumor model, we investigated these events to determine the signaling pathway(s) responsible for the cell death as a means of developing improved molecular based approaches for the cryoablation of prostate cancer.
Human prostate cancer cells (PC3) were cultured in the 3D matrices for 7 days prior to experimentation. The tumor models were then frozen to −30 or −15°C and analyzed at various times post-thaw using fluorescence microscopy, flow cytometry, and Western blots.
Results demonstrated that the activation of apoptotic cell death occurred within 30 min of thawing at ultra low temperatures. At −30°C, ∼25% of cells were apoptotic at 30 min and by 6 hr levels had dropped near those of controls. At elevated temperatures (−15°C), the activation and progression of apoptosis was considerably delayed, peaking at ∼20% by 6 to 24 hr post-thaw. Additionally, it was determined that early onset apoptosis was regulated through a unique, caspase dependent process compared to that seen within the freeze margins. This induction was found to progress through a membrane mediated pathway associated with more severe thermal stressors as indicated by the activation of cas-pase-8 at low (−30°C) but not mild (−15°C) temperatures.
These data suggest that an apoptotic continuum exists throughout the cryolesion whereby the more severe the cryogenic stress, the faster programmed cell death is manifested. The identification of this rapid-onset apoptosis within the core of the ablative zone represents a novel finding in a region previously thought to be only necrotic. Ultimately, it is our aim to decipher the signaling pathways involved in triggering rapid-onset apoptosis such that these events can be manipulated to enhance cell death, thus improving the overall efficacy of cryosurgical procedures.
Renal cell carcinoma (RCC) responds notoriously poor to cytotoxic chemotherapy, indicating aberrant anti-apoptotic signal activation. Meanwhile, pVHL inactivation is implicated in most RCC cases, suggesting a potential link between pVHL and RCC apoptosis. In this report, we investigate abnormal anti-apoptotic behavior in pVHL-deficient RCC cells. Our objectives are to identify the molecular mechanism involved in RCC resistance to cytotoxicity-induced apoptotic signaling and to provide information that may lead to better RCC treatment design.
HEK293, Hela, and RCC cell lines, including 786-O, RCC4, cell lines derived from these two cell lines were used in our experiments. The GST pull-down and co-IP assays were conducted to confirm protein interactions. Western blotting was performed for evaluating protein expression/activation. Kinase activity was measured by in vitro kinase assay. NF-κB activation was dedected by EMSA and luciferase reporter gene assay. RNAi techniques were applied for transient knockdown of specific protein expressions and for the construction of RNAi stable RCC cell lines. Apoptosis was assessed via FACS or fluorescence microscope.
In this study, we found that pVHL inhibits NF-κB activity by interacting with casein kinase 2α (CK2α), an I B-independent pathway. The CK2α protein level was not regulated by pVHL or hypoxia. Upon TNFα treatment, pVHL-deficient RCC cells exhibit much stronger NF-κB activation and dramatically elevated resistance to apoptosis. pVHL-deficient RCC cells also showed increased NF-κB p65 serine529 phosphorylation and enhanced association between p65 and CBP/p300. Knockdown of CK2α in pVHL-deficient RCC cells inhibited p65 ser529 phosphorylation and abnormal NF-κB activation and blunted NF-κB downstream anti-apoptotic gene expressions, which lead to restored sensitivity to TNFα-induced apoptosis. Moreover, a chemical inhibitor of CK2, 5,6-dichlororibifuranosylbenzimidazole (DRB) also showed robust inhibition of abnormal NF-κB activation in pVHL-deficient RCC cells.
Our findings suggest that pVHL regulate NF-κB anti-apoptotic pathway by suppressing CK2 kinase activity and p65 serine529 phosphorylation - a process that culminates in decreased p65/p300/CBP interaction and enhanced RCC apoptosis. This represents a novel mechanism of how pVHL inactivation reduces RCC cells susceptibility to cytotoxicity-induced apoptosis by promoting CK2 and NF-κB activations.
Recent studies demonstrate that folic acid supplementation is associated with an increased incidence of prostate cancer. We previously reported a positive correlation between serum and prostate tumor folate, and increased cancer cell proliferation in men with higher serum folate concentrations.
To determine the effect of dietary folate manipulation on prostate carcinogenesis and progression in an in vivo model of tumori-genesis.
Utilizing the subrenal prostatic recapitulation model for tissue recombination, rat urogenital mesenchyme (rUGM) was microdissected from rat embryos and combined with 10–20 mg slivers of prostate tumor or normal prostate tissue from patients with prostate cancer. Tissue recombinants were grafted beneath the renal capsule of male SCID mice. Mice were treated hormonally at the time of grafting with testosterone propionate and 17β-estradiol. Mice were randomly assigned to receive amino-acid defined diets which were folate-deficient (0 mg/kg), folate-sufficient (2 mg/kg), or excessively folate-fortified (20 mg/kg). Tissue recombinants were serially grafted and harvested after 8, 16, and 24 weeks under the renal capsule. Histological and morphological features were assessed based upon 20 fields per recombinant, with the worst histological phenotype assigned to that recombinant. Immunohistochemical analysis to detect basal cells (p63), proliferation (Ki67), DNA methylation (5-methylcytosine), and tumor aggressiveness (EZH2) was performed.
Recombinants from normal and cancerous prostate tissue formed normal, hyperplastic, focal PIN like glandular structures, and adenocarcinoma. The incidence of normal glands, hyperplasia, PIN, and adenocarcinoma in human prostate cancer tissue recombinants was 6.5%, 6.5%, 50% and 37%, respectively; incidence in normal prostate tissue recombinants was 17%, 62.5%, 18.7%, and 4.7% (Table 1). Among normal prostate tissue recombinants, excess dietary folate intake increased the incidence of PIN and adenocarcinoma when compared to recombinants grown in mice receiving a folate deficient diet (31.3% vs. 7%, respectively; p < 0.05). An increased incidence of PIN and adenocarcinoma was also observed among prostate cancer recombinants in mice with adequate or excess dietary folate intake when compared to folate deficient mice (97.6% vs. 75.3%, respectively; p < 0.05).
Adequate to excess levels of dietary folate promote prostate carcinogenesis compared to folate deficiency in an in vivo human prostate tissue recombinant model of tumorigenesis.
P12.
Epithelium (dietary folate intake mg/kg) | Normal | Hyperplasia | PIN | Small atypical foci with features of adenocarcinoma | |
---|---|---|---|---|---|
8 weeks | Normal (0) | 2/8 (25%) | 5/8 (63%) | 1/8 (13%) | 0/8 (0%) |
Tumor (0) | 1/6 (17%) | 0/6 (0%) | 3/6 (50%) | 2/6 (33%) | |
Normal (2) | 2/6 (33%) | 3/6 (50%) | 1/6 (17%) | 0/6 (0%) | |
Tumor (2) | 0/4 (0%) | 0/4 (0%) | 2/4 (50%) | 2/4 (50%) | |
Normal (20) | 0/7 (0%) | 4/7 (57%) | 3/7 (43%) | 0/7 (0%) | |
Tumor (20) | 0/11 (0%) | 0/11 (0%) | 8/11 (73%) | 3/11 (23%) | |
16 weeks | Normal (0) | 1/12 (8%) | 10/12 (84%) | 1/12 (8%) | 0/12 (0%) |
Tumor (0) | 2/16 (13%) | 3/16 (19%) | 2/16 (13%) | 9/16 (55%) | |
Normal (2) | 2/12 (17%) | 6/12 (50%) | 3/12 (25%) | 1/12 (8%) | |
Tumor (2) | 0/8 (0%) | 1/8 (12%) | 5/8 (63%) | 2/8 (25%) | |
Normal (20) | 2/7 (29%) | 4/7 (57%) | 0/7 (0%) | 1/7 (14%) | |
Tumor (20) | 0/7 (0%) | 0/7 (0%) | 6/7 (86%) | 1/7 (14%) | |
24 weeks | Normal (0) | 0 | 0 | 0 | 0 |
Tumor (0) | 1/4 (25%) | 0/4 (0%) | 1/4 (25%) | 2/4 (50%) | |
Normal (2) | 2/4 (50%) | 1/4 (25%) | 0/4 (0%) | 1/4 (25%) | |
Tumor (2) | 0/6 (0%) | 0/6 (0%) | 4/6 (67%) | 2/6 (33%) | |
Normal (20) | 0/8 (0%) | 5/8 (63%) | 3/8 (37%) | 0 | |
Tumor (20) | 0 | 0 | 0 | 0 |
PIN = prostatic intraepithelial neoplasia.
Renal cell carcinoma (RCC) causes nearly 12,000 deaths each year in America. Nox4 belongs to the NADPH oxidase family that generates reactive oxygen species (ROS). The kidney is the site of greatest abundance of the Nox4. We previously showed that Nox4 is critical to activation of HIF-2α and necessary to support the tumor phenotype of RCC cells. However, the mechanism of Nox4 induction of HIF-2α is unknown. Inactive HIF-2α is located in the cytoplasm and activation requires translocation to the nucleus where it dimerizes with ARNT and binds DNA. To determine if Nox4 is required for nuclear translocation, we localized exogenous HIF-2α by immunofluorescence in RCC cells in the presence or absence of Nox4. We further mutated key HIF-2α hydroxylation sites to measure their impact on translocation.
786-0 human kidney cancer cells with stable expression of Nox4 shRNA (KD) or a non-targeting shRNA (NS) were transiently transfected with pSNAP-HIF-2α to express wild type HIF-2α tagged at the N-terminus with SNAP. Cells were cultured 48 hr under 21% or 1% oxygen conditions and then fixed and bound to an anti-SNAP primary antibody. Nuclei were counterstained with DAPI. pSNAP-HIF-2α-PA was cloned by site directed mutagenesis of Pro531 to Ala, and pSNAP-HIF-2α-NA, was derived by mutation of Asp851 to Ala.
786-0 NS cells showed moderate nuclear HIF-2α localization at 21% O2 with a shift to 100% nuclear expression under hypoxia. With Nox4 silencing, the 786-0 KD cells demonstrated only cytoplasmic localization regardless of oxygen conditions, suggesting that Nox4 is critical to HIF-2α nuclear translocation in normoxia or hypoxia. HIF-2α-PA mutation did not alter the localization pattern at 21% or 1% O2. HIF-2α-NA mutants, however, demonstrated cytoplasmic localization under all conditions. HIF-2α staining intensity was significantly lower in KD than NS. Addition of the proteasome inhibitor, MG132 (0.1 M) increased staining intensity to levels seen in 786-0 NS.
We show for the first time that Nox4 expression is required for HIF-2α nuclear translocation in RCC cells under both hypoxic and non-hypoxic conditions. Asp851 appears to be required for Nox4-mediated translocation. We speculate that Nox4-derived ROS may inhibit FIH, the enzyme responsible for Asp851 hydroxylation, thereby triggering this “hypoxic switch” in the absence of hypoxia. Furthermore, stabilization of HIF-2α by proteasome inhibitors suggests that Nox4 protects HIF-2α from proteasomal degradation via a pVHL-independent pathway. Ongoing investigations aim to further elucidate these pathways.
Funding: ACS RSG-09-023-01-CNE
Ultrasound echo signals are affected by the geometrical deregulation of cellular architecture in neoplastic tissue and can be exploited to differentiate normal from various grades of cancerous tissue, information that is not visible in post-processed B-scan ultrasound images. We have proposed to apply an innovative approach to process raw transrectal ultrasound (TRUS) radio-frequency (RF) signals for the early detection of prostate cancer.
Ex vivo experiments have involved evaluation of a time series, through fractal and frequency analyses, of raw temporal RF ultrasound signals to differentiate tissue types in 35 human prostates obtained after radical prostatectomy. Previously described ultrasound texture features for tissue typing were included in these studies for comparison. Detailed whole mount sectioning of the prostate specimens were regarded as the gold standard and compared to probability maps created by analysis of the temporal RF signals.
Comparing the generated probability maps of prostates scanned ex vivo to the detailed pathology reports have demonstrated sensitivity and specificity values of 90% and 85% respectively, in characterizing cancerous tissue. The area under receiver operating characteristic curve for the subset of RF time series evaluation was 0.87, which increased to 0.95 when combined with other ultrasound texture features. Validation utilizing leave one patient out resulted in an area under the curve of 0.82.
These results suggest that the temporal ultrasound echo signals can be employed to differentiate different tissues in the prostate and subsequently improve cancer detection. Furthermore, we propose to train classifiers in order to visualize this information as color-coded probability maps on real-time US images and have initiated an in vivo study for men undergoing TRUS guided biopsy.
MicroRNAs (miRNAs) are a class of small RNAs that are important regulatory molecules, involved in several cell processes such as developmental timing, stem cell division, and apoptosis. Dysregulated miRNAs have been identified in several human malignancies, including bladder cancer tissue samples, and may confer a “tumor signature” that can be exploited for diagnostic purposes. We report on a prospective pilot study investigating the diagnostic capability of miRNAs in the urine of patients with urothelial cancer.
Voided urine samples were collected from 8 patients with urothelial carcinoma just prior to bladder tumor resection as well as 5 age-matched healthy control patients. Pathology demonstrated both low grade and high-grade cancer. Total RNA was isolated and quantitative reverse transcriptase-polymerase chain reaction was performed on the RNA extracts using primers for 4 miRNAs shown previously to be dysregulated in solid urothelial carcinomas with RNU6B as the endogenous control. Standard urine cytology was performed on all samples in a blinded fashion.
Two miRNAs were found to be significantly dysregulated in the urine from cancer patients with miR-A showing an average 10.42-fold decrease (p < 0.05) and miR-B showing an average 2.70-fold increase (p > 0.05) in the cancer samples compared to the normal controls. Using these 2 miRNAs, a decision-tree prediction model was generated yielding a specificity of 100% and a sensitivity of 87.5%. The sensitivity and specificity of the cytology on the same urine samples was 50% and 80% respectively.
MiRNA expression levels are altered in bladder cancer and may have diagnostic and prognostic value. This preliminary study of candidate urinary miRNA in patients with both low grade and high-grade urothelial cancer demonstrated a significantly improved diagnostic accuracy over cytology. These results provide rationale for further studies on discovery and validation of candidate miRNAs in voided urine and may potentially lead to the development of a non-invasive and sensitive test for bladder cancer diagnosis and prognosis.
Radical prostatectomy is a proven efficacious treatment locally confined prostate cancer, however rates of post operative impotency continue to range between 10–30% in contemporary series. Thus, in addition to satisfactory cancer control, accurate localization of the cavernous nerves and the contributing plexus during resection is exceedingly important during radical prostatectomy. We have developed a realtime, intraoperative tissue impedance sensor for nerve localization based on electrical impedance tomography (EIT) technology, which will serve to reduce post prostatectomy impotence
The prototype constructed consists of a probe with a needle array to interface with the tissue, and a signal generator and analysis system. The device cycles through each set of electrodes on the probe, and injects current while simultaneously computing the voltage change. Reconstruction algorithms determine nerve location based on tissue impedance properties. The system was functionally validated in an in vitro model system and following further refinement, rat sciatic nerve identification. For each trial, the probe was placed on the tissue and the device sequentially injected 5mA sinusoidal current across each of its electrodes with the resulting voltages recorded.
Each trial demonstrated the ability of the device to detect changes in impedance of different tissues. Electrodes closest to the wire in the in vitro model had the smallest voltage change, corresponding to a lower impedance value. V=0.135V for the electrodes near the wire, compared to V=0.256V for other electrodes. Localization of rat sciatic nerve was also successful demonstrating V=0.294V for the electrodes near the nerve, compared to V=0.467V for the remaining electrodes.
We have developed a realtime intraoperative tissue sensor prototype based on electrical impedance tomography which has demonstrated early proof of principle success in in vitro and small animal models of mixed tissue determination and nerve localization. With further refinements in both probe array fabrication and miniaturization as well as digital signal processing we believe this device may deliver significant benefit to procedures such as radical prostatectomy where nerve structures may be visually indeterminant but critical for preservation of function.
Evidence suggests that increases in cytokine activity may be involved in the pathogenesis of painful bladder syndrome/interstitial cystitis (PBS/IC). However, data on cytokine activity in human PBS/IC patients are lacking. This pilot study investigated the cytokine profile in human bladder tissue and urine of PBS/IC patients.
Ten PBS/IC patients (ICS definition) were enrolled in this pilot study. Human bladder (cold cup biopsy) and urine specimens were collected intraoperatively before hydrodistention (HD) under general anesthesia. Follow-up urine was also collected post-HD (mean 27 days). Specimens were compared to a control group of banked human bladder tissue and urine specimens (n = 10) from non-PBS/IC patients. A comparison of 22 cytokines was performed using multiplex analysis with a multiple antigen bead assay (Luminex 100 IS). Statistical analysis was performed using two-tailed t-tests (p ≤ 0.5).
Compared to control bladder tissue specimens; IL-16, IL-18, CTACK, ICAM-1, MCP-3, SCGFb, TRAIL and VCAM1 were significantly elevated in PBS/IC bladder tissue. When comparing the cytokine profile of control and pre-HD PBS/IC urine specimens, no significant differences were noted. However, when comparing pre-HD and post-HD urine specimens within the PBS/IC patients; MCP-3 and TRAIL were noted to be significantly decreased after hydrodistension. Standardized measures of clinical symptoms (pain, urgency and frequency (PUF) overall score [mean 25.8 ± 5.5 vs. 20.3 ± 7, p = 0.04] and PUF symptom score [mean 18.2 ± 3.2 vs. 12.2 ± 5.9; p = 0.009]) showed improvement in the pre- and post-HD comparison.
These results indicate that several cytokines are significantly elevated in PBS/IC bladder tissue. Of these cytokines, MCP-3 and TRAIL appear to significantly decrease in urine specimens in association with clinical improvement (as measured by PBS/IC symptom scores) after HD treatment in PBS/IC patients and may candidates for biomarkers. Further larger-scale studies are needed to map the cytokine profile in PBS/IC.
Cryoablation has emerged as a primary therapy to treat prostate cancer. While effective, the assumption that freezing serves as a ubiquitous lethal stress is challenged by clinical experience and experimental evidence demonstrating time-temperature related cell death dependence. The age-related transformation from an androgen-sensitive (AS) to an androgen-insensitive (AI) phenotype is a major challenge in the management of prostate cancer. AI cells exhibit morphological changes and treatment resistance to many therapies. This resistance has been linked with α6 4 integrin overexpression as a result of androgen receptor (AR) loss. As such, we investigated the influence of increased α6 4 integrin expression as a result of AR loss, on the reported increased freeze tolerance of AI prostate cancer. Further, we evaluated the targeted modulation of integrin expression in combination with cryoablation on human prostate cancer cell death.
A series of studies using AS (LNCaP LP and PC-3 AR) and AI (LNCaP HP and PC-3) cell lines were designed to investigate the cellular mechanisms contributing to variations in freezing response. Samples were frozen, thawed, and temporally assessed using fluorescence microscopy, flow cytometry and immunoblotting.
Investigation into α6 4 integrin expression revealed that AI cell lines overexpressed this protein, thereby altering morphology and increasing adhesion characteristics. For instance, following freezing to −15°C, AI cells were found to exhibit increased resistance to freezing injury compared to AS cells (55% vs. 18%, respectively). Molecular investigations revealed a significant decrease in caspase 8, 9, and 3 levels in AI cells following freezing. Inhibition of α6 4 integrin in AI samples resulted in increased caspase activity and enhanced cell death.
These studies demonstrate that integrin expression significantly influences cell tolerance to cryoablation. The data demonstrate that the inhibition of α6 4 integrin function results in a significant increase in freeze sensitivity of AI prostate cancer cells. The results show that understanding the role of androgen-receptor related integrin expression in cell response to freezing may lead to novel options for neo-adjunctive approaches to treat prostate cancer.
There remains disagreement as to whether the location of upper urinary tract cancer affects prognosis. We examined the significance of ureteral and renal pelvic upper tract urothelial carcinoma (UTUC) in a large multi-institutional study.
We collected and pooled a database of 700 patients with UTUC who underwent radical nephroureterectomy. Univariate and multivariate models examined the effect of tumor location on recurrence-free (RFS) and cancer-specific survival (CSS) rates. Collected variables included age, gender, race, presence of lymphovascular invasion, concomitant carcinoma in situ, pathological stage/nodal status, lymph node dissection and type of surgery (open vs. laparoscopic).
The median follow-up for patients alive was 42 months (IQR: 20–76). With regards to location, 34% of tumors were ureteral, 59% pelvic and 7% were multifocal. Tumor location was significantly associated with lymphovascular invasion (p = 0.035), pathological stage (p = 0.014), race (p < 0.001), tumor necrosis (p = 0.017) and type of surgery (p = 0.038). It was, however, not associated with age (p = 0.206), gender (p = 0.858), grade (p = 0.511), lymph node dissection (p = 0.259), number of nodes resected (p = 0.084), nodal status (p = 0.422), concomitant CIS (p = 0.296), or follow-up duration (p = 0.508). On multivariate analyses adjusting for age, gender, race, surgical type, stage, grade, nodal status, lymphovascular invasion and concomitant CIS, ureteral tumor location when associated with multifocal disease remained an independent predictor of both RFS (p = 0.004) and CSS (p = 0.035).
Contrary to recent data, our results show that ureteral tumor location in association with multifocal disease is an independent prognostic factor for both RFS and CSS.
Data are scarce on literature describing surgical outcomes in elderly patients undergoing treatment for renal cell carcinoma (RCC). The goals of this study were to determine overall- and cancer-specific survival, use of radical versus partial nephrectomy, and complication rates in elderly patients with RCC.
532 patients who underwent extirpative surgery for clinically diagnosed RCC between 1994 and 2009 were identified using a single-institution IRB-approved database. Of these patients, 127 (24%) were 75 years of age or older. These patients were further separated into groups based on surgical type and incidence of complications and were stratified by gender, tumor stage, and tumor grade. Preoperative and postoperative creatinine clearances and length of stay were compared among the groups. Cox proportional hazard modeling and Kaplan-Meier analyses were used to determine overall- and cancer-specific survival among the cohorts.
Older patients were more likely to undergo laparoscopic radical than partial nephrectomy than their younger counterparts (p = 0.003), and had longer average hospital stays (4.0 vs. 2.7 days, p < 0.001). Older patients were 3.4 times more likely to experience an immediate (within 24 hours) complication (95% CI 1.37–8.30, p = 0.008), and there was a trend toward a higher overall complication rate in elderly patients. Complication rates, however, were similar after radical or partial nephrectomy. Calculated creatinine clearance in the radical nephrectomy group (18.9 mL/min/m2) decreased more than in the partial nephrectomy group (8.0 mL/min/m2, p < 0.0001). Despite this, there was no significant difference in overall or cancer-specific survival between younger and older patients. Median length of followup were 13.3 (0–135) and 19.2 (0–164) months for younger and older patients, respectively (Fig. 1).
Extirpative surgery is safe in elderly patients with RCC. The risk of immediate complications is increased in older than younger patients, but risk appears unrelated to type of surgery. Partial nephrectomy should be advocated when feasible in order to maintain renal function.
P20.
The established role of partial nephrectomy in the management of renal cancer is removal of the entire tumor with negative margins and preservation of normal parenchyma. We investigated whether renal cortical tumors can be differentiated from normal parenchyma by NIRF of intravenous (IV) ICG during laparoscopic partial nephrectomy.
Thirteen patients undergoing laparoscopic partial nephrectomies had intraoperative NIRF imaging of their 13 renal cortical tumors. Following renal exposure, 4–10cc (2.5mg/ml) of ICG was injected intravenously and NIRF was detected using SPY Scope™ system (Novadaq Technologies Inc, Canada). ICG uptake and deposition was recorded.
Average age of patients undergoing laparoscopic partial nephrectomy using intraoperative SPY Scope™ was 53.6 years (30–76) and mean follow up was 7.8 months (2–11). Tumor size averaged 3.2 cm (0.9–6.5). Tumors were peripheral and exophytic in 8 and hilar in 5 patients. Average R.E.N.A.L. nephrometry score was 7.7 (5–11). A total of 13 lesions were found in 13 patients, 11 solid and 2 cystic. All malignant tumors (clear cell (6) and chromophobe (3) carcinomas) were seen as hypo or non-fluorescent areas clearly demarcated from highly fluorescent normal parenchyma. Oncocytoma (1) was seen as mildly hypofluorescent, with minimal difference between the tumor and surrounding tissue. AML (1) and benign cysts (2) were characterized as having increased fluorescence compared to the normal parenchyma. All surgical margins were negative. No immediate allergic or systemic side effects occurred and no postoperative changes in kidney function were observed.
Laparoscopic NIRF after IV ICG permits accurate intraoperative detection of renal cortical tumors during partial nephrectomy. This modality has unique properties that may allow urologists to decrease positive surgical margins rates, diagnose additional lesions, and spare unnecessary resection of normal parenchyma, thereby preserving renal function.
Percutaneous needle core biopsy is becoming established in the management of small renal masses(SRMs) that were <4cm in diameter, mainly solid and enhancing. Numerous series have reported success rates of ≥80% with excellent accuracy. Indeterminate or non-diagnostic results continue to be a problem. We present our results of a large biopsy series with outcomes of these non-diagnostic biopsies.
A prospective database of patients undergoing SRM biopsy was analyzed. Pathology reports of “indeterminate” included insufficient material, normal kidney or non renal tissue. We have recently recommended repeat biopsy in these cases. The success rate and pathological findings were analyzed.
Three hundred and forty-five(345) biopsies were performed from 2000 to 2008 inclusive. The biopsy was diagnostic in 278 cases(80.6%) and non-diagnostic in 67 (19.4%). Among diagnostic biopsies, 221(79.8%) were malignant, 94.1% of which were renal cell carcinoma(RCC). Histologic subtyping and grading of RCC was possible in 88% and 63.5% of cases respectively. Seventeen of the non-diagnostic (25.3%) were taken at the time of radiofrequency ablation. Repeat biopsy was performed in 12 of the 67 non-diagnostic cases and a diagnosis was possible in 10 (83.3%). Eight lesions wee malignant and 2 were oncocytic neoplasms. Larger tumor size and a more solid nature were found to predict for success of repeat biopsy. Minor complications were experienced in 10.4% of cases but no major bleeding or tumor seeding was experienced.
Percutaneous biopsy can be performed safely and accurately for the investigation of SRMs. In those cases in which the biopsy is indeterminate, repeat biopsy can be performed with a similar success rate as for initial biopsy which provides a diagnosis in the majority of these patients.
Non-surgical management (NSM) represents a treatment option for select individuals with small renal masses. We examined the patterns of NSM patients with histologically proven renal cell carcinoma within the 17 registries of the Surveillance, Epidemiology, and End Results (SEER) database
Between 1988 and 2006, 26 844 individuals with histologically proven small renal masses were identified within the 17 SEER registries database. Trends, proportions, and multivariable analyses assessed the use of NSM relative to other types of treatment modalities.
Overall, 2191 (8.2%) individuals were managed non-surgically. The rate of NSM increased from 5.7 to 8.0% over the study period (X2 trend, p = 0.003). The majority of the individuals who were non-surgically managed were aged 80 years and older (32.8%) vs. 30.4% in 70–79-year-olds vs. 18.6% in 60–69-year-olds vs. 10.9% in 50–59-year-olds vs. 7.4% in individuals younger than 50 years old. Most were male (62.8%) and Caucasian (79.2%). In multivariable analyses, African American patients were twice as likely to be treated non-surgically relative to Caucasians (p < 0.001). Multivariable logistic regression showed that NSM relative to other types of treatment was 15 times more likely in octogenarians, 1.3 times more likely in males, 2.2 times more likely in African Americans, and 1.4 times higher in contemporary years (all p <0.001)
Non-surgical management of histologically proven small renal masses gained in popularity over the past decade. In accordance with the National Comprehensive Cancer Network guidelines, it is mostly offered to individuals with limited life expectancy and its use accounts for up to only 8% of all patients with small renal masses.
Cytoreductive nephrectomy (CNT) may improve survival of patients with metastatic RCC (mRCC). However, it may be associated with higher morbidity and mortality rates relative to nephrectomy in non-mRCC patients. We assessed the perioperative outcomes of CNT in patients with mRCC and compare these to the outcomes of individuals who underwent a nephrectomy for non-mRCC in a large population-based dataset.
Between 1988 and 2008, 1985 and 27 037 patients underwent a nephrectomy for respectively mRCC and non-mRCC in the state of Florida. We examined patient characteristics, complications and perioperative mortality rates of patients with mRCC who underwent a CNT and we compared those with the characteristics and outcomes of individuals with non-mRCC.
Relative to non-mRCC individuals, a larger proportion of mRCC patients were males (67.9 vs. 61.6%; p < 0.001) and represented emergency admissions (27.5 vs. 19.4%; p < 0.001). Length of stay was statistically significantly longer in patients with mRCC relative to their non-mRCC counterparts (9.5 vs. 6.7 days; p < 0.001). The overall complication rate was also higher in mRCC patients (29.6 vs. 22.8%; p < 0.001). Specifically, the rates of accidental intraoperative lacerations (5.6 vs. 3.6%; p < 0.001), postoperative cardiac complications (4.2 vs. 2.4%; p <0.001), vascular complications (2.5 vs. 0.8)%; p < 0.001), respiratory complications (8.4 vs. 6.4%; p = 0.001), hemorrhage (2.6 vs. 1.4%; p < 0.001), and postoperative infections (2.0 vs. 1.4%; p = 0.02) were higher in patients with mRCC. Perioperative in-hospital mortality rate was also higher in mRCC patients (3.0 vs. 1.2%; p < 0.001). In multivariable logistic regression models, after adjusting for patient age, gender, race, insurance type, average annual surgical and hospital volume, mRCC was a statistically significant predictor of any complication type (OR: 2.7 [95% CI: 2.0–3.5]; p < 0.001), and predicted higher perioperative mortality (OR: 1.4 [95% CI: 1.3–1.6]; p < 0.001).
Nephrectomy in individuals with mRCC is associated with higher complication and perioperative mortality rates relative to nephrectomy performed in patients with non-mRCC. This information should be included in informed consent. Moreover, careful patient selection is critical to minimize morbidity and mortality after CNT.
Although surgical resection is still the gold standard therapy for localized renal tumors, patients with multiple bilateral tumors and/or significant comorbidities present a clinical challenge. Percutaneous radio frequency ablation (RFA) provides an alternative to minimize morbidity in selected patient cohort. The goal of the current study was to evaluate the role of RFA in the management of renal tumors in an academic center.
A retrospective chart review of all renal tumor patients treated with RFA was performed. Patients were followed with CT and/or MRI according to their renal function. Procedure success was assessed by the absence of tumor enhancement and progression on imaging.
From 2005, a total of 27 patients (19 males and 8 females) with 32 renal tumors underwent CT guided RFA under general anesthesia by a single operator. Median tumor size was 2.8 cm (mean 3.1, range: 1.4–5.4 cm). Five patients required a 2nd RFA procedure. Patients received from 1 to 5 ablations per tumor. Median age was 72 years (range 39–95). All patients had either solitary kidney, bilateral disease or considered unfit for surgery due to significant comorbidities. Mean patient follow-up was 2.7 years. A total of 24 (88%) patients had no evidence of disease. One patient had no response and a nephrectomy was performed. Two (7%) patients had residual disease and are followed up. Post-RFA complications were; minor bleeding and hematoma (n = 5), worsening renal functions (n = 2) of which one required permanent dialysis, pneumothorax (n = 2), splenic injury (n = 1), hepatic puncture (n = 1), duodenal fistula (n = 1), urinoma (n = 2), perirenal abscess and emphysematous pyelonephritis (n = 1), renal cortical infarction (n = 1), deep cutaneous burn (n = 1), wrist drop (n = 1) and psoas injury (n = 1).
Even though RFA can be a reasonable successful management modality for a selected patient cohort with renal tumors, it can still carry a significant risk for serious complications.
Little data exist about clinical outcomes in octogenarians who undergo surgery for renal cell carcinoma (RCC). The goal of this study was to determine overall and cancer-specific survival, and the use of partial versus radical nephrectomy in elderly patients.
Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, 60,693 patients in the years 1988 and 2005 were identified who underwent either partial or radical nephrectomy for RCC. Patients were separated into two groups - those younger than age 80, and those 80 years of age or older - and were stratified by the aforementioned variables. Chi-squared and Kaplan-Meier analyses were used to determine differences amongst the cohorts in terms of surgical approach and overall and cancer-specific survival.
Four-thousand two-hundred twenty seven patients (7.5%) were over the age of 80. Octogenarians were more likely to undergo radical nephrectomy than their younger counterparts (87% vs. 92%, p < 0.0001). At a median follow-up of 37 months (range 0–215) in patients <80 years, and 27 months (range 0–203) in patients ≥80 years, octogenarians were more likely to die of all causes (HR 2.32, 95% CI 2.22–2.42, p <0.001) than their younger counterparts. Octogenarians were also more likely to die of RCC (HR 1.33, 95% CI 1.23–1.43, p < 0.001), but at a lower hazard ratio than for overall mortality. These cancer-specific differences in survival persisted throughout individual pathologic stages, with the exception of pathologic stage pT4 and metastatic disease. Octogenarians who underwent partial nephrectomy were 0.39 times less likely to die of RCC (95% CI 0.26–0.60, p < 0.001) than older patients who underwent radical nephrectomy.
Octogenarians who undergo partial nephrectomy have improved overall and cancer-specific survival than those who undergo radical nephrectomy, yet they are less likely to undergo partial nephrectomy than their younger counterparts. Octogenarians experience a decreased overall and cancer-specific survival benefit from extirpative surgery than younger patients. This data should be considered when treating the renal mass in the “elderly” patient.
Open partial nephrectomy (OPN) and laparoscopic radical nephrectomy (LRN) may be underutilized. We explored the rates of the two surgeries relative to open radical nephrectomy (ORN) in a large population-based database.
Between 1998 and 2008, a total of 17690 nephrectomies for non-metastatic renal cell carcinoma were performed in the state of Florida. Of these, 2528 (14.3%), 1379 (7.8%) and 13783 (77.9%) respectively represented OPN, LRN and ORN. We examined the proportion of patients who underwent a OPN, LRN and ORN throughout the study period. Multivariable logistic regression analyses addressed predictors of either OPN or LRN after adjusting for patient age, gender, race, Charlson comorbidity index, insurance type and year of surgery.
Overall the rate of OPN increased from 8.1 to 18.7% over the study period vs. from 0.2 to 12.3% for LRN (χ2 trend: p < 0.001). OPN and LRN rates ranged respectively from 9.6 to 25.1% and from 0.3 to 12.2% in individuals 70 years-old. Similarly, OPN and LRN rates ranged from 13.0 to 24.2% and from 0.3 to 11.7% in the highest annual hospital volume tertile vs. from 4.7 to 14.7% and from 0.2 to 10.4% in the lowest annual hospital volume tertile. In multivariable logistic regression analyses, high hospital volume and high surgical volume were independent predictors of the use of OPN and of the use of LRN (p < 0.001).
OPN and LRN are performed significantly less frequently than ORN. Both hospital and surgical volume represented important determinants of OPN and LRN use. This implies that the likelihood of being treated with either OPN or LRN is the highest when the surgery is performed at high volume centers and by high volume surgeons.
Open partial nephrectomy (OPN) has gained an increasingly important role in the surgical management of patients with renal cell carcinoma (RCC). We examined the differences in length of stay and complication rates between OPN and open radical nephrectomy (ORN) in patients with non-metastatic RCC.
Overall, 2528 (15.5%) OPNs and 13783 (84.5%) ORNs were performed in the state of Florida for non-metastatic RCC between 1998 and 2008. We examined the proportion of patients who underwent LRN vs. ORN throughout the study period, as well as the perioperative outcomes of the two surgical procedures.
The rate of OPN constantly increased from 8.1 to 21.3% over the study period (chi-square trend: p < 0.001). Patients treated with OPN were statistically significantly younger (mean age: 61.6 vs. 64.7 years; p < 0.001) and had a lower Charlson comorbidity index (CCI) (61.6 vs. 57.4% patients with CCI=0; p < 0.001) than patients treated with ORN. Length of stay (LOS) was statistically significantly shorter in patients treated with OPN (mean LOS: 5.3 vs. 6.0 days; p < 0.001). Total hospital charges were also lower in OPN patients (mean hospital charges: 36680 vs. 39330$; p < 0.001). The proportion of patients with postoperative complications was comparable between the two surgeries (22.8 vs. 23.3% for respectively OPN and ORN; p = 0.7). Similarly, no statistically significant differences were recorded for specific complications, except for higher blood transfusions rates in ORN patients (11.8 vs. 9.1%; p < 0.001). In multivariable logistic regression models addressing the overall complication rate, after adjustment for patient age, gender, race, CCI, insurance type, average annual hospital and surgical volume, type of surgery (OPN vs. ORN) did not achieve the independent predictor status (OR: 1.03 [95% CI: 0.93–1.15]; p = 0.5).
Despite higher surgical complexity of OPN, the length of stay and complication rates associated with this type of surgery are not more elevated than those recorded for ORN. In consequence, OPN should be given high priority when it is indicated.
We assessed the rate of metastatic renal cell carcinoma (mRCC) at diagnosis in a large population-based tumor registry.
Between 1988 and 2006, 87 842 patients were identified within 17 Surveillance, Epidemiology and End Results (SEER) registries with tissue-proven diagnosis of RCC of all stages. We examined the rates of mRCC at diagnosis throughout the study period. Multivariable logistic regression models examined the impact of year of diagnosis quartiles (1988–1992 vs. 1993–1997 vs. 1998–2002 vs. 2003–2006) on mRCC rates after adjusting for patient age, gender, race and socioeconomic status.
The overall rate of mRCC was 19.1% and it decreased from 23.8% in the first year quartile to 16.5% over the study period (2 trend: p < 0.001). The decrease in mRCC rates was more pronounced in females (−8.6%) than in males (−6.9%), in older individuals (−12.3% in ≥80 years) than in younger patients (−7.0% in <50 years), in African-American (−9.7%) than in Caucasian patients (−7.3%), and in patients within the highest socioeconomic status quartile (−8.9%) relative to individuals within the lowest socioeconomic status quartile (−7.3%). In multivariable logistic regression models more advanced age (p < 0.001), male gender (p < 0.001), race other than Caucasian and African-American (p = 0.02) and lower socioeconomic status (p < 0.001) represented independent predictors of mRCC diagnosis. Finally, more contemporary year of diagnosis remained the foremost predictor of lower rate of mRCC at initial diagnosis (p < 0.001).
Our findings are highly encouraging and suggest that a larger proportion of patients will harbor curable or highly treatable stages of RCC. Conversely, an increasingly smaller proportion of mRCC will hopefully contribute to the overall RCC patient population. The increased use of imaging studies may represent an explanation for the observed results.
Recently, nephron-sparing surgery (NSS) has become the preferred treatment for small renal masses. Open and laparoscopic partial nephrectomy can preserve renal function and have become the gold-standard for oncological outcomes. Percutaneous radiofrequency ablation (RFA) and cryotherapy ablation are non-ischemic, minimally-invasive procedures that can be performed as outpatient procedures without general anesthesia. We present our five-year experience at Albany Medical Center in patients treated with curative intent and in difficult cases in which we believed percutaneous ablation was preferred.
This is a retrospective review of consecutive cases of radiofrequency or cryotherapy ablation of renal masses performed at our center. Pre-operative data including demographics, body mass index (BMI), comorbidities, renal function, and biopsy results were recorded. Follow-up information consisted of last available imaging, date of last follow-up, and latest GFR, calculated by the Modification of Diet in Renal Disease equation. Change in GFR was calculated for all patients. We defined curative intent as a procedure performed for an initial presentation of stage T1a renal cell carcinoma (RCC). Recurrence was defined as an enhancing lesion on CT or MRI when a confirmatory biopsy was not obtained.
From January 2005 to December 2009, our center performed 52 percutaneous ablation procedures for renal masses. Thirty-eight (73%) were cryoablation procedures. Median patient age was 73.5 years, median BMI 30.5, and median tumor size was 2.5 cm (range 1.6–7.3 cm). Fifty-eight percent of patients were obese, including 30% who were morbidly obese. Forty-one patients (79%) had stage T1a disease and 37 (71%) were treated with curative intent. Sixty-three percent had biopsyproven RCC, and an additional five patients had a previous history of RCC. Of patients treated with curative intent, 32 (86%) had no evidence of disease at a median follow-up of 12 months. No patients with normal renal function pre-operatively developed renal insufficiency, and only four patients had a decrease in GFR by more than 10. There were two major complications early in our series with RFA including a bowel perforation, and development of acute renal failure in a patient with a solitary kidney. There was one major complication of bilateral pleural effusions following cryotherapy.
Percutaneous ablation of renal masses resulted in short-term oncological outcomes that approach reported success rates of NSS with no effect on renal function. For patients with advanced age, morbid obesity or history of RCC, percutaneous ablation provides a relatively safe surgical option.
The increased use of percutaneous radiofrequency ablation (RFA) for the treatment of small renal tumors has presented new challenges for safe and effective tumor control. Adjacent organs such as the colon, liver, and spleen may interfere with a clear window for probe placement. Patient habitus may prevent the typical prone positioning during treatment. Nearby renal cysts or arterial branches may also create a heat-sink effect, lowering temperatures at the treatment site and possibly reducing the effectiveness of cancer control. We report our experience with techniques to overcome these concerns.
Twenty-two cases employing atypical treatment approaches during percutaneous RFA of renal tumors were identified from hospital records and retrospectively reviewed. All patients were treated with the LeVeen CoAccess™ Electrode System and RF 3000® Radiofrequency Ablation System (Boston Scientific, Natick, MA). Electrodes were placed under computed tomography (CT) guidance. All lesions were biopsied immediately before treatment. Patients were monitored in the hospital overnight for complications. Preoperative and postoperative images were reviewed for treatment effectiveness and complications.
Atypical treatment characteristics included injection of sterile water between organs (hydrodisplacement) to facilitate probe placement (13 patients), supine or lateral positioning (4 patients), transhepatic approach (3 patients), transrenal approach (1 patient), and arterial embolization or cyst aspiration prior to percutaneous embolization (1 patient each). Mean length of follow up was 19.2 months, and mean tumor size was 2.3 cm. There were no immediate complications. Three biopsies were non-diagnostic. Renal function remained unchanged for all patients reviewed. There was no evidence of disease recurrence or progression from the treated lesion. One patient underwent subsequent nephrectomy due to concern for recurrent disease but the tumor was entirely necrotic on final pathology, and another patient had bilateral nephrectomy prior to renal transplant.
Percutaneous RFA of small renal tumors can be accomplished safely, even in cases that were previously not amenable to a standard approach. These techniques may facilitate cancer control in an extended number of patients who would otherwise be high-risk surgical candidates.
Treatment of renal AML is indicated for symptomatic lesions and those at a high risk of bleeding (size over 4 cm). SAE is a minimally invasive treatment option that may prevent spontaneous bleeding, preserve renal function, and obviate the need for surgery. Despite demonstration of cessation of blood flow during initial treatment, repeat angiography for lesions that enhance on follow up imaging may demonstrate alternative feeding vessels that can be embolized. Here we report our experience with SAE of classic AML over the past twenty years.
Patients who had received SAE for AML from 1989–2009 were identified and analyzed. Patient data recorded included age, gender, tumor size, type of embolization material used, treatment complications, renal function before and after treatment, and need for future surgical management. The diagnosis of AML was based on radiologic features.
Eight SAE treatments were performed in six patients at an average age of 46.2 years. One had tuberous sclerosis and five were female. Prior to treatment the mean tumor size was 6.5 cm. Average length of follow up was 15 months. The mean reduction in tumor size was 1.1 cm on follow up imaging. Varying combinations of absolute ethanol, microparticles, and embolization coils were used. Two patients had incomplete embolization discovered at repeat angiography, which was done for stable lesion size and continued enhancement on follow up CT. These patients underwent repeat SAE. Minor complications developed in 2 patients – one had renal arterial vasospasm requiring intra-arterial administration of nitroglycerin, while another developed transient flank pain and fevers following treatment. Renal function was unchanged after primary and repeated SAE. Three patients eventually underwent partial or radical nephrectomy, either due to concern for malignancy or because lesion size remained stable and there was continued concern about spontaneous hemorrhage. All three demonstrated hypovascular AML on final pathology with an average size of 8.8 cm.
SAE and repeated SAE are safe methods of treatment for patients with renal AML. If follow up imaging demonstrates continued enhancement or increasing tumor size, repeat SAE may be indicated. Otherwise, in our experience hypovascular AML is the typical pathologic finding if subsequent partial or radical nephrectomy is performed. This may indicate that despite stability in lesion size, a completely embolized AML may no longer be at a high risk of bleeding.
Laparoscopic surgery has been shown to portend a number of advantages over open surgery in terms of more rapid recovery and decreased morbidity. Despite this, there is a great deal of clinical variability in patients’ post-operative recovery. The purpose of this study is to objectively quantify the recovery of health-related quality of life (HRQL) in patients undergoing laparoscopic nephrectomy, and determine which factors are predictive of a more expedited recovery.
Patient recovery was prospectively measured among patients undergoing laparoscopic simple (n = 12), radical (n = 42) and donor (n = 95) nephrectomy. All procedures were performed using a 3- or 4-trocar, transperitoneal fully-laparoscopic technique with intact specimen extraction using impermeable sacs for simple and radical nephrectomy, and hand extraction for donor nephrectomy. Post-operative recovery and quality of life were measured using the Postoperative Recovery Scale (PRS) administered preoperatively, immediately postoperatively and as an outpatient at 4, 8, 12, and 16 weeks postoperatively. ANOVA and Pearson’s Chi Squared tests were performed on demographic data, and multivariate logistic regression analysis was used to calculate odds ratios for factors predictive of recovery.
There were statistically significant differences at baseline with respect to age (p = 0.02), gender (p < 0.01), body mass index (BMI; p = 0.03), surgical side (p < 0.01) and activity-based lifestyle (p = 0.04) across the three groups. Minimal adverse events were seen. Factors predictive of a more expedited recovery include age less than 50 years (OR: 2.1, p < 0.01), BMI <30 kg/m2 (OR: 1.7, p < 0.01), active lifestyles (OR: 1.3, p < 0.01) and those patients undergoing nephrectomy for benign or malignant indications rather than for organ donation (OR: 1.4, p < 0.01). There was a significant delay in the donor group versus the non-donor group with respect to the median number of days both groups took to recover 75% and 90% of their baseline PRS scores (11 days, p = 0.02; 20 days, p = 0.02, respectively).
Predictive factors of recovery from laparoscopic nephrectomy include age, BMI, lifestyle and surgical indication. The differences between HRQL recovery following donor versus non-donor laparoscopic nephrectomy is significant, and suggests the possible interplay of underlying psychological factors.
Laparoscopic nephrectomy requires 3 to 5 small incisions for port placement. Specimen extraction requires elongation of one of those small incisions. Transumbilical laparoendoscopic single-site (U-LESS) surgery employs only one small paraumbilical incision for multiple instrument entry and specimen extraction with advantages to further minimize minimally-invasive surgery. In this report, we present our experience and technique of U-LESS nephrectomy and bilateral nephrectomy.
Patients were positioned in a modified lateral decubitus position. A 2.5 to 5 cm skin incision (based on the size of the specimen) was made along the skin crease of the umbilicus. A 12-mm port and two 5-mm small-profile conventional ports were placed through separate fascial insertion along the incision. No specially designed single port device was used. The instruments used in these procedures including10-mm flexible tip HD EndoEye and 5-mm 30 degree EndoEye laparoscope (Olympus), articulating laparoscopic Marilyn dissector and Therma Seal (Novare), 5-mm LigaSure (Valleylab), and a set of conventional laparoscopic instruments. Renal arteries and veins were controlled with large Hem-o-lok clips or Endo GIA vascular staplers. For bilateral nephrectomies, repositioning was required after one side was done and both kidney specimens were extracted at the end of the entire procedure.
From November 2008 to January 2010, a total of 16 cases (6 male and 10 female) with age ranging from 8 to 81 yrs (Median 45) were performed, including nonfunctioning atrophic kidneys (7 cases) and kidney masses (9 cases, one of these cases was palliative due to known C-spine metastasis). All kidney masses were not suitable for partial nephrectomy. Three of these cases were bilateral nephrectomies. All cases were performed uneventfully without needs for additional port placement. Operative times for unilateral nephrectomy ranged from 60–203 minutes, with an average of 155 minutes. Operative times for the three bilateral nephrectomies were 320, 163, and 239 minutes, respectively. Estimate blood loss ranged from 5–150 cc, with an average of 51 ml. Hospital stay ranged from 1–4 days (median 2 days). The length of followup ranged from 2–15 months and no short-term complications were observed in our patients.
U-LESS nephrectomy and bilateral nephrectomies can be safely performed for selected patients with currently available laparoscopic instruments though with increased technical challenges.
Percutaneous nephrolithotomy (PCNL) is the gold standard therapy for large renal calculi. The optimal puncture site for collecting system access remains controversial, with many suggesting increased morbidity from supracostal puncture. We report a retrospective review of 318 consecutive PCNL cases over a sixty-month time period performed by two surgeons in a teaching environment.
Perioperative data was collected on 318 consecutive PCNL cases performed for intra-renal nephrolithiasis from May 2004 to June 2009; patient anatomic anomalies, calyceal diverticuli, endopyelotomy, antegrade ureteroscopy, and patients failing to return for follow-up were excluded. Patient demographics, stone, operative, post-operative and follow-up data were collected. Complications were assessed using the Clavien system and stone outcomes were assessed with KUB x-rays and CT scans. Successful treatment outcome was defined as stone free or sand-like (1mm or less) particles on CT scan.
318 patients undergoing PCNL in the prone-flexed position (57.9% male) with a mean age of 52.9 years (SD 14.4) and mean BMI 27.8 kg/m2 (SD 6.0) were analyzed. Sixteen (5.4%) of the tracts were above the 11th rib, 120 (40.8%) were above the 12th rib and 158 (53.7%) were infracostal. Multiple tracts were used in 16 (5%) of patients. There were no significant differences between patients undergoing supracostal versus infracostal puncture with respect to side, stone area, number of tracts, number of stones, or the presence of staghorn or struvite calculi, although there was a trend to larger stones and more staghorn calculi in the supracostal group. Success rates in the supracostal group (89.8%) were equivalent to the infracostal group (94.1%). Complication rates across groups were low, with no significant difference in complications between the supracostal and infracostal puncture groups, respectively, across Clavien grade I (12 vs. 1), grade II (4 vs. 11), grade IIIa (4 vs. 0), grade IIIb (2 vs 0), and grade IVa (1 vs 2), p = 0.067. All four (2.6%) Clavien grade IIIa complications in the supracostal group were pleural complications requiring chest drain insertion. No patients required a blood transfusion or angioembolisation.
When indicated, supracostal access can provide excellent outcomes, particularly for patients with complex stone disease while obviating the need for multiple tracts or retreatment. Although complications, particularly pleural, occur more frequently in those patients undergoing supracostal puncture, the incidence is low and acceptable considering the significant advantages in this patient population.
Patients known to have previous nephrolithiasis are regularly followed in Stone Clinic with frequent imaging to rule out recurrences. Recently, there has been increasing awareness and concerns among both patients and health care professionals regarding long term risks from radiation exposure in follow-up of patients with benign disease. The aim of the present study was to quantify the yearly effective radiation doses associated with the follow-up of patients with nephrolithiasis in Stone Clinic at a single institution.
Retrospective chart review of 56 patients attending the Stone Clinic at a single academic centre between January and September 2009 was performed. Number and modality of diagnostic imaging studies in the previous 2 years were collected. Effective radiation exposure doses (reported in mSV) were calculated from the Dose Length Product values reported with each CT scan performed since November 2007. Radiation exposure from Kidney Ureter Bladder Plain Films (KUBs), Intravenous Pyelograms (IVPs) and fluoroscopic examinations were estimated from previous published data.
A total of 38 males and 18 females with a mean age of 49 years (range: 21–78 years) were included in this study. 137 KUBs, 9 IVPs, 47 fluoroscopic examinations and 73 CTs were reviewed. Median yearly calculated effective radiation exposure dose was 36.87mSV (Mean: 33.86, range: 1.7 – 54.59 mSV) in 2008 and 21.64 mSV (mean 22.42, range: 1.4–77.27 mSV) in 2009. A total of 7 (12.5%) patients received a calculated effective radiation exposure dose >50 mSV per year. Mean effective radiation exposure dose was significantly higher in 2008 when compared to 2009, but did not correlate with stone location, age or sex of the patient.
Currently there are no guidelines on imaging modality or frequency in follow-up of patients with nephrolithiasis. A significant portion of patients are receiving effective radiation doses that exceed the current occupational radiation hazard limits. Therefore, urologists should be cognizant of the radiation exposure of patients when ordering imaging studies for follow-up of patients with benign disease.
Percutaneous nephrolithotomy (PCNL) is the treatment of choice in patients with large stone burden or when other modalities of treatment are not successful. The stone-free rates after PCNL have ranged from 70% to 85%. At the same time, the use of second look nephroscopy is assumed to increase stone-free rate. However, the predictors of having residual stones post PCNL have not been studied previously. Our objective is to evaluate the preoperative and perioperative factors associated with residual stones after PCNL. Our hypothesis is the use of second look nephroscopy is associated with improved outcome.
Data were extracted from an institutional review board-approved retrospective review of 230 procedures performed at our institution between January 2000 and December 2008. PCNL was performed by two endourologists with similar training and experience. Second look nephroscopy was done in patients who were not stone-free after the initial procedure. Outcome was defined as stone-free status after initial PCNL or second look nephroscopy while overall stone-free status is after subsequent additional procedures. Stone-free status was defined based on complete absence of stones on subsequent radiological imaging. The assessed parameters were age, sex, body mass index (BMI), stone size, number, and location, history of genitourinary anomaly or surgery, staghorn stones, prior surgery for the same stone, access location, and use of specific lithotripters. A sub-analysis was performed in patients with residual stones after the initial procedure to evaluate the role of second look nephroscopy. Univariate and multivariate analyses were performed using Pearson Chi-square, two-tailed t, and Fisher’s Exact tests. All variables were considered statistically significant at p < 0.05
Mean age and BMI were 54.15 years and 29.59 kg/m2 respectively. Univariate analysis revealed that stone diameter (p < 0.0001), complete staghorn stones (p < 0.001), and upper pole stones (p < 0.0001) were associated with having more residual stones while prior extracorporeal shockwave lithotripsy (p < 0.037) and holmium laser use (p < 0.01) were associated with improved stone-free status. In a sub-analysis of patients who had residual stones after the initial procedure, second look nephroscopy was associated with improved overall stone-free status (p < 0.019) in comparison to patients who did not have a second-look.
Preoperative and perioperative parameters can predict outcome of PCNL. Second look nephroscopy is associated with improved stone clearance. These results indicate that further studies with larger sample size are needed to construct preoperative prediction models.
Perinephric hematoma formation is a potentially serious complication of extracorporeal shock wave lithotripsy (SWL), with a reported incidence of between 0.2% and 30%. The aim of this study was to determine the incidence of and evaluate the risk factors for the development of clinically apparent post SWL renal hematoma with the latest generation shock wave lithotripter.
From April 2006 to September 2008, 3351 SWL treatments were performed using the Storz Modulith SLX-F2. Data was collected prospectively for patient age, body mass index, gender, stone size, stone location, number of shock waves, energy level, shock frequency, medications and the existence of hypertension and/or diabetes mellitus. A case-control analysis was then conducted to compare risk factors.
Following SWL treatment, 12 patients developed clinically apparent renal hematomas for an overall incidence of 0.3%. All patients were male and 8 (66%) of the affected patients had known hypertension. Pre-operative use of drugs with antiplatelet effect was associated with a greater risk of perinephric hematoma (p = 0.047).
The incidence of clinical apparent hematomas following SWL with the SLX-F2 was 0.3%. Statistical significant risk factors for perinephric hematoma included male gender and use of drugs with antiplatelet effect.
Shock wave lithotripsy (SWL) is considered a standard treatment for upper tract stones less than 10 mm in diameter, whereas stones larger than 20 mm are best treated by percutaneous nephrolithotomy (PCNL). The treatment of stones between these sizes remains controversial. We review our modern series of SWL, RIRS and PCNL outcomes for intermediate-sized upper tract calculi.
Data from patients treated with SWL, RIRS and PCNL from June 2005 to June 2009 were reviewed. Analysis was restricted to those patients with a pre-treatment non-contrast CT scan conducted at our centre demonstrating an upper tract calculus measuring an area between 100 and 300 mm2. Demographic, stone, patient, treatment and follow-up data were collected from a prospective database and review of CT and KUB imaging performed by two independent urologists and one radiologist. Data was analyzed with Chi square analysis and ANOVA where appropriate.
137 patients were referred with non-staghorn calculi with an area between 100–300 mm2. Across groups, there were 89 males (65.0%), 61 right-sided stones (44.5%), and an overall mean age of 53.1 years (SD 14.2) and BMI of 29.0 kg/m2 (SD 6.6). 53 (38.7%) patients were treated with SWL, while 41 (29.9%) and 43 (31.4%) underwent RIRS and PCNL, respectively. Mean stone area was higher in the PCNL group at 211.1 mm2 (SD 56.8), compared with 172.6 mm2 (SD 58.2) for the SWL group and 162.9 mm2 (SD 54.9) for the RIRS group (p < 0.001). Stone density, measured by Hounsfield units (HU) on CT, were significantly higher for SWL patients (1008 HU, SD 244) versus 786 HU (SD 289) for RIRS and 837 HU (SD 326), p = 0.002. Single treatment success rates were significantly better for PCNL at 95.3%, versus 87.8% for RIRS and 60.4% for SWL, p < 0.001. However, when up to two SWL treatments were administered, the success rate improved to 79.2%, thus removing any significant difference between the success of the three treatment modalities (p = 0.66). Auxiliary treatments were more common after SWL (42.3%) vs. 9.8% and 7.0% in the RIRS and PCNL groups, respectively.
Although success rates are significantly higher with single treatment PCNL and RIRS when compared to SWL, when allowing for up to two SWL treatments there was no significant difference between treatment modalities. Thus, SWL is a reasonably successful treatment alternative for patients not fit for or not wishing a general anesthetic, provided they accept a higher number of treatments.
Percutaneous nephrolithotomy (PCNL) is the gold standard for management of large renal stones. Traditionally, patients are admitted post-operatively with a large-bore nephrostomy tube, which is removed after a normal nephrostogram on post-operative day two. Although tubeless PCNL has been described previously, there have been no reports of ambulatory tubeless PCNL. The aim of the present study was to assess the safety and feasibility of ambulatory tubeless PCNL. Here the initial 10 patients are presented.
The initial series of 10 patients undergoing ambulatory tubeless PCNL was included in the present study. Patient information including age, sex, fluoroscopy time, operating room time, stone size (using largest diameter), and Hounsfield Units (HU) were collected prospectively and analyzed retrospectively. Furthermore, number of needle punctures, number of tracts, and stone free status were ascertained. Amount of narcotic administered in the recovery room (mg morphine equivalents), amount of time spent in recovery room (minutes), amount of narcotics used at home, and complications were recorded and documented. Criteria for same day discharges were: single tract, stone free status, adequate pain control, and satisfactory post-operative chest X ray and CBC. All patients had antegrade double J stents placed intra-operatively. Male patients were discharged home with Foley catheter. Follow-up office visit was done on post operatively 2 days for trial of void and removal of the flank dressing. Double J stents were removed a week later cystoscopically.
Out of the 10 patients undergoing ambulatory PCNL, 2 had established nephrostomy tracts. The rest of the 8 patients had nephrostomy tract established intra-operatively by the urologist. The median operating and fluoroscopy times were 83.5 and 4.45 minutes, respectively. The median stone diameter was 20 mm with a median of 800 HU. Patients spent a median of 240 minutes in the recovery room and received a median of 19.25 mg of morphine equivalents. There were no intra-operative complications and none of the patients required transfusions. There were two post-operative complications. The first was a Deep Vein Thrombosis requiring anticoagulation. The second was re-admission for multi-resistant E. Coli UTI requiring intravenous antibiotics.
In highly-selected patients, ambulatory tubeless PCNL is safe and feasible. More patients are needed to verify criteria for patients undergoing ambulatory approach.
Minimizing radiation exposure during urologic procedures has gained importance recently. Traditionally, percutaneous nephrolithotomy (PCNL) has been associated with the highest radiation exposure in endourologic procedures. Therefore, the aim of the present study was to document radiation exposure during a contemporary series of PCNL and to determine factors influencing fluoroscopy time.
All patients with large renal stones presenting for PCNL between July 31, 2009 and November 20th, 2009 were included in the study. Patient information including age, sex, fluoroscopy time (seconds), operating room time (minutes), stone size (using largest diameter in mm), and stone density measured in Hounsfield Units (HU) were collected prospectively and analyzed retrospectively. Linear regression was used to determine whether fluoroscopy time varied with length of surgery, stone size and stone density.
There were a total of 19 patients with a median age of 51yrs old (14 males and 5 females). Median OR time was 85 minutes and the median fluoroscopy time was 317 s (5.28 minutes) (range 127–720 s). Median stone size was 25 mm with a median of 800 HU. Length of fluoroscopy was independent of the length of surgery (p > 0.05) and stone size (p > 0.05). There was a trend towards less fluoroscopy time with denser stones (−19s/100HU). However, this did not reach statistical significance (p = 0.06). This could be due to the small sample size.
Urologists should be cognizant of radiation exposure during PCNL. More patients are needed to verify whether fluoroscopy times decrease with higher stone densities.
Posterior tibial nerve stimulation (PTNS) is a relatively new approach used to treat medically refractory overactive bladder. However, its efficacy and poststimulation effects are not yet fully recognized. The goals of this study were to therefore test the efficacy of different stimulation parameters and to determine the post-stimulation effects of PTNS.
Ten females cats anesthetized with alpha-chloralose underwent PTNS via a nerve cuff electrode. Initially, the bladder was infused with saline via a urethral catheter to a volume about 100–120% of bladder capacity in order to induce rhythmic bladder contractions. Short duration (2–3 minutes) PTNS of 5 Hz or 30 Hz at various voltages was then applied to suppress the isovolumetric bladder contractions. After the effective stimulation parameters were determined, PTNS (5Hz or 30 Hz) was applied for 30 minutes to inhibit the rhythmic bladder contractions. CMG was then performed 5 times in the ensuing 1–1.5 hours without PTNS in order to determine the post-stimulatory effect on the micturition reflex. Finally, PTNS was applied during CMG to determine its maximal inhibitory effect on bladder activity.
PTNS at both 5 Hz and 30 Hz significantly (p < 0.05) inhibited iso-volumetric bladder contractions at a stimulation intensity 2–3 times that of the threshold (T) voltage—the minimum voltage required for inducing toe movement at 5 Hz. After continuous 30 minute PTNS, bladder capacity was significantly (p < 0.05) increased to 134±2.1% (30 Hz) and 137.8 ± 1.2% (5 Hz) of the control capacity. There was no significant difference between 5 Hz and 30 Hz stimulation. In the post-stimulation period, PTNS at 5 Hz further increased bladder capacity to 177 ± 10% of control capacity.
This study demonstrated that PTNS could significantly inhibit bladder activity at both low (5 Hz) and high (30 Hz) stimulation frequencies. Furthermore, continuous 30 minute PTNS could induce a post-stimulation inhibitory effect on the bladder lasting 1–1.5 hours, supporting the clinical observation of PTNS having a long-lasting inhibitory effect on bladder overactivity.
The POWER Registry was established as an observational registry measuring standard of care practices assessing safety and efficacy of type 1 mesh products to treat female pelvic prolapse, across different specialties with sites from USA and New Zealand. This report is from one local center with one surgeon that participated in this registry.
Eligible patients are adult females with at least one AMS product implanted for prolapse repair and no other restrictions on product type. Prolapse was quantified via Baden-Walker measurement in this center. The serial follow-up period was for two years.
Patients were enrolled from May 2005 and the study was completed in August 2009. During this period 170 patients were enrolled in this center. The median procedure time was 78 min (53–123 IQR). Areas of prolapse repair included cystocele (89%), rectocele (49%), vault (45%), and enterocele (6%). The rates of concomitant hysterectomy and incontinence repair were 52% and 90%, respectively. More than 95% percent of patients were Caucasian. Mean patient age was 60 years and mean gravidity was 2.8 with 1.33 standard deviation (range 0–8). The mean intra-operative complication rate was 1.2%. Most patients (83%) were free of prolapse device-related events. Conversely 17% of patients experienced at least one prolapse device-related event and one with bladder perforation during insertion requiring closure as a serious event, but with no subsequent issues. In another, the insertion needle was noted in the bladder, and after repositioning, did not requir bladder repair. The most frequent event, mesh extrusion through the vaginal mucosa, occurred in 6.5% of all patients. All of them were satisfactorily managed with estrogen cream and/or trimming and secondary closure. Mesh erosion involving the urethra/bladder did not occur. Incontinece issues were noted in 3.5% of patients. Other events included healing issues, pain, granuloma formation (4%), and dehiscence (2.4%).
In 63 patients who completed 19–24 months follow-up, the anterior prolapse significantly improved at least one grade (ΔBW Cystocele −1.94, p < 0.001). Similar improvement was seen in the posterior area (ΔBW Rectocele −1.12, p < 0.001, ΔBW Vault −1.69, p < 0.001, and Δ BW Enterocele −0.13 p < 0.001).
Standard of care outcomes using minimally invasive, type 1 mesh for treating prolapse exhibited a good safety profile with low complication rates and good efficacy. The most common prolapse device-related complication was mesh extrusion through the vaginal mucosa that was satisfactorily managed with no subsequent or long-standing issues.
Pelvic floor reconstruction with mesh graft is a currently popular procedure to correct the vault prolapse and cystocele. Most of the commercial products are designed with only a “one-size-fits-all female patient” in mind. Since the pelvic size and shape of each individual is different, “one-size” product will not fit every female patient exactly. It is suggested that this is the possibe cause of recurrent prolapse (incompletely fit a larger pelvis) and mesh erosion/extrusion (bunched up mesh to fit a smaller pelvis). Using 3D pelvic CT scan with cystogram, the pelvic size and shape is able to exactly measured and the mesh can be tailoring to fit each individual’ s pelvis. The above complications can be avoided.
Twenty femal patients with vault prolapse and grade III or IV cystocele were studies past 2–3 years. A 3D pelvic CT scan with cystogram is performed. The pelvic size is measured by Vitea 2,3D processing software (Fig. 1). A 15x15 cm polypropylene mesh (pore size 1121,w-66 c-90) is tailoring according the above measurement (Fig. 2). The mesh is anchoring into the sacrospinous ligament and each side of Arch Tendinous Pelvic Fascia (ATPF) by Capio devic. The normal posterior urethrovesical angle is also resorted by anchoring the mesh to the insertion area of ATPF to the pelvic ramus. The mesh also sutured to peri-urethral ligament to correct hypermobility of the urethra.
All twenty patients have not recurrent proplase. No erosion or extrusion of mesh are observed. Pelvic muscular pain occured in 4 patients and usually resolved in three months. Two patients developed ureteral obstruction from the procedure and had lysis procedure. Ureteral obstruction can be prevented with ureteral catheter placement prior to the procedure.
The pelvic floor reconstruction with individual customized mesh graft can provided a better result than the one-size-fit mesh graft. More study is needed.
P45.
P45. Comparison of the effect of using pulsatile renal perfusion vs. cold preservation on delayed graft function in DCD kidneys.
Urinary diversion (with or without cystectomy) as a treatment modality for end-stage classic ulcerative interstitial cystitis (IC) has been reported to be beneficial. Diversion with cystectomy for non-ulcerative IC fails to benefit the majority of patients and can add significant morbidity. Recent reports suggest that simple urinary diversion without cystectomy could benefit non-ulcerative IC patients. Simple diversion could improve IC symptoms by preventing bladder stretching and removing chemical irritation from urine. We offered a trial of bilateral percutaneous nephrostomy tubes with Fogarty ureteral occlusion balloons to four patients with refractory non-ulcerative IC to determine if their symptoms would significantly decline enough to be offered a simple diversion.
Four female patients, who fulfilled the National Institute of Arthritis, Diabetes, Digestive, and Kidney Diseases criteria for non-ulcerative IC and who had failed previous medical and intravesical treatments, underwent placement of bilateral 8 French percutaneous nephrostomies with 4 French Fogarty ureteral occlusion balloons. Pre- and post-procedure pain scores were reviewed for each patient. Three patients had significant reduction of pain scores and subsequently underwent ileal conduit urinary diversion (2 open, 1 robotic assisted laparoscopic approach).
Mean duration of disease at time of nephrostomy placement was 7 years (range 5–11). Mean duration of nephrostomy placement was 27 days (range 9–50). Mean decrease in pain scores at time of nephrostomy removal was 5.3 (range 3–8). Mean time between nephrostomy placement and ileal conduit urinary diversion was 154 days (range 103–227). Mean hospital length of stay after diversion was 18 days (range 6–29). At six month postoperative visits, patients were re-evaluated. One patient (age = 63) had complete resolution of pelvic symptoms with pain score = 0. One patient (age = 32) went back to her pre-nephrostomy pain score of 9; her pain is exacerbated by bowel movements and she continued on extensive narcotic regimen and intravesical therapy. One patient (age = 27) intermittently has pre-nephrostomy pain scores but at six month visit was using significantly less narcotics for symptom control and was overall pleased with surgical outcome.
Patients who suffer from refractory non-ulcerative IC present a treatment challenge for urologists. Therapy with irreversible urinary diversion can be beneficial but long term success is not easily predicted by a preoperative trial of bilateral nephrostomy tubes with ureteral occlusion balloon catheters. Our limited series suggest that further criteria may need to be fulfilled prior to a patient being eligible for simple diversion.
To compare the results of a low trans-scrotal mid-raphe orchidopexy in patients with palpable undescended testes (UDT), to a high-scrotal incision (Bianchi) and to the conventional inguinal approach.
We used a retrospective cohort study design. All orchidopexies performed between 2003 and 2009 with a minimum of 3-month follow-up were included. All palpable UDT that could be brought down manually into the upper third of the scrotum under general anaesthesia, were then reviewed (group 1: high-scrotal incision, group 2: low-scrotal incision) and compared to the inguinal two-incision technique (group 3). We excluded cases who had undergone previous inguinal surgery or with concomitant surgeries. We comprehensively reviewed the charts and focused on the following outcomes: operative time, success as defined by mid or lower scrotal position of the testicle, and complications at 6–12-weeks and 1-year after surgery.
A total of 286 orchidopexies were performed in 214 patients with palpable UDT. In group 1, a high-scrotal incision was performed in 44 patients for 60 UDT (success 59/60, 98%) with one recurrence. A modification to the technique was adopted and since 2005, patients in group 2 had a trans-scrotal orchidopexy through a single low-scrotal incision on the median raphe. It was performed in 81 patients for 125 UDT. All testes except 1 (99%) were located in a good position within the scrotum. In group 3, a standard inguinal two-incision orchidopexy was performed in 89 patients for 101 UDT (success 100%). The mean operative time for unilateral UDT was significantly shorter for the low trans-scrotal orchidopexy (mean 28 min vs. mean 37 min; p < 0.001) than for the inguinal orchidopexy but equivalent to a high scrotal incision (27 min; p = 0.59). One patient approached by high-scrotal incision required conversion to a traditional inguinal approach. All patent processes vaginalis were ligated, regardless of their size. In all 160 children followed at 1 year, no long term atrophy or secondary reascent were observed. Postoperative complications included transient postoperative scrotal hematoma in a single patient from group 1 and 2 wound infections in group 3.
Low trans-scrotal mid-raphe orchidopexy appears to be an excellent alternative to the high-scrotal incision or the standard inguinal orchidopexy for low palpable UDT especially for bilateral cases. Scrotal orchidopexy is simple, safe, and effective in selected cases.
The use of a renal perfusion pump vs. cold storage for the preservation of kidneys obtained from donors after cardiac death (DCD) is controversial. Herein, we examine the impact of using renal perfusion pumps on delayed graft function and graft survival using a systematic review.
The PUBMED database was searched and reference lists from 1960 to 2009 were consulted. Randomized controlled trials as well as prospective and retrospective cohort studies that compared delayed graft function and graft survival were included. Studies excluded from review were unable to discriminate between DCD and neurologically deceased donor (NDD) deaths. Eleven studies that followed a total of 3377 participants qualified for review. Statistical analysis was carried out using the random effects criteria and odds ratios calculated using the Cochrane database software.
We found that perfusion pumped kidneys from DCD donors had reduced DGF rates vs. kidneys that were placed in cold storage (Fig. 1) (p = 0.008; odds ratio 0.4, CI 0.20–0.82). In addition, graft function at 1 year post-transplantation favored perfusion pumped kidneys (p = 0.04, odds ratio 1.96, CI 1.02–3.77). No differences in primary nonfunction rates between groups were noted.
This review supports the use of perfusion pumps for DCD kidney transplantation with respect to delayed graft function rates and graft survival.
P48.
Urologic malignancies are common after heart transplantation, with prostate cancer (CaP) being the most common solid tumor. To date, there are no studies comparing the aggressiveness of urologic malignancies in heart transplant recipients (HTR).
We retrospectively reviewed our institution’s transplant database to identify patients diagnosed with urologic malignancies following heart transplantation between January 1980 and January 2010. Prostate cancer was detected after routine screening with both digital rectal exam (DRE) and prostate-specific antigen (PSA), whereas renal cell carcinoma (RCC) and bladder cancer (CaB) were diagnosed either incidentally on imaging or upon evaluation for hematuria. Data was analyzed using descriptive statistics.
Among 1250 HTR, 12 patients were found and treated based on elevated PSA levels. One additional CaP case was incidentally discovered on transurethral prostate resection and not treated. Of the 12 CaP patients that were treated, 5 underwent prostatectomy, 6 had radiation, and 1 received both radiation and hormone ablation therapy. The mean time between transplantation and CaP diagnosis was 65 ± 33 months. Nine patients (75%) were biochemically free of recurrence at a mean of 49 months. Three (25%) are alive with disease. No patients died from CaP at a mean follow up of 45 ± 30 months. Four patients were diagnosed with CaB. Three (75%) are dead with disease: 2 after cystectomy were aborted due to metastatic disease and 1 after chemotherapy and radiation. Mean interval between transplantation and CaB diagnosis was 54 ± 33 months. At a mean follow up of 42 ± 46 months, 3 mortalities were attributed to CaB. Two patients were diagnosed with RCC and surgically treated. The mean interval between transplantation and RCC diagnosis was 66 ± 29 months. At a mean follow up of 54 ± 15 months, there was 1 mortality (Table 1).
As in the generalized population, routine PSA testing and DRE appear to be beneficial as screening for CaP in HTR. In our experience, both CaB and RCC appear to be uncommon, but aggressive in HTR. Given the limited number of patients in this cohort, no definitive conclusions can be made. However, patients with signs or symptoms of CaB or RCC should be evaluated in a timely fashion.
P49. Urologic Malignancy in Heart Transplant Recipients
Cancer type | Clinical Stage | Gleason Score/or Grade1 | Treatment | Outcome | Transplant-cancer interval (months) | Follow-up after cancer (months) | |
---|---|---|---|---|---|---|---|
1 | Prostate | T2bNxMx | 3+4=7 | RRP2 | Alive, NED5 | 104 | 60 |
2 | Prostate | T1cNxMx | 3+4=7 | Radiation | Dead, NED5 | 55 | 42 |
3 | Prostate | T2bNxMx | 3+4=7 | RRP2 | Alive, NED5 | 67 | 111 |
4 | Prostate | T2bNxMx | 3+4=7 | RAP3 | Alive, NED5 | 91 | 29 |
5 | Prostate | T1cNxMx | 3+4=7 | Radiation | Dead, NED5 | 61 | 61 |
6 | Prostate | T2aNxMx | 4+4=8 | Radiation | Alive, with tumor | 23 | 59 |
7 | Prostate | T1cNxMx | 3+4=7 | Radiation | Alive, NED5 | 110 | 14 |
8 | Prostate | T1cNxMx | 3+4=7 | RRP2 | Dead, NED5 | 18 | 51 |
9 | Prostate | T2bNxMx | 4+5=9 | XRT + Hormone Tx4 | Alive, with tumor | 50 | 11 |
10 | Prostate | T1cNxMx | 3+4=7 | Radiation | Dead, NED5 | 43 | 71 |
11 | Prostate | T1aNxMx | 2+3=5 | No Tx4 | Alive | 47 | 61 |
12 | Prostate | T1cNxMx | 3+3=6 | RRP2 | Alive, NED5 | 125 | 3 |
13 | Prostate | T1cNxMx | 3+3=6 | Radiation | Alive, with tumor | 47 | 13 |
14 | Bladder | T2bNxMx | High Grade | Chemo & radiation | Dead, with disease | 97 | 40 |
15 | Bladder | T1NxMx | Low Grade | TURBT, intavesical BCG | Alive, NED5 | 52 | 107 |
16 | Bladder | T3aNxM0 | High grade | attempted radical cystoprostatectomy (unresectable) | Dead, with disease | 50 | 17 |
17 | Bladder | T4aNxM1 | High Grade | attempted radical cystoprostatectomy (metastatic) | Dead, with disease | 16 | 4 |
18 | Renal | T1aNxMx | Intermediate Grade | partial nephrectomy | Alive, NED5 | 86 | 64 |
19 | Renal | T2NxMx | High Grade | radical nephrectomy - -> chemo/XRT | Dead, recurrance | 45 | 43 |
Grade (Fuhrman grade for RCC)
RRP (radical retropubic prostatectomy)
RAP (robotic assisted prostatectomy)
Tx (treatment)
NED (No evidence of disease)
Patients with testicular cancer undergo therapeutic regimens that are known to have deleterious long-term effects. We hypothesized that these patients may have an increased baseline risk for secondary malignancies, and that radiotherapy may further increase their risk of developing certain cancers. We explored the rates of secondary bladder cancer, leukemia and lymphoma, due to their association with ionizing radiation, in testicular cancer patients.
We retrospectively searched the SEER database for all patients diagnosed with primary testicular cancer between 1973 and 2006. Within this cohort, we calculated rates of secondary leukemia, lymphoma and bladder cancer via International Code diagnostique-oncology-3 (ICD-O-3) codes. Secondary malignancies were included only if they were diagnosed after the testicular cancer. We calculated overall cohort rates, and cancer rates specifically in those patients that received radiotherapy.
Between 1973 and 2006, there were 20 300 patients diagnosed with a testicular cancer. The median age of diagnosis was 33 years. They were followed for a total of 285 077 person-years, and their median follow up was 13.0 years. Of all patients with testicular cancer, 8590 (43%) received some form of radiation therapy. They were followed for a total of 124 684 years, and their median follow up was 14 years. Of all patients, 139 developed lymphoma or leukemia, and 99 developed bladder cancer. Of those patients who received radiotherapy, 76 developed lymphoma or leukemia, and 56 developed bladder cancer. The calculated rates of lymphoma-leukemia were 48.9 and 61.01 cases per 100 000 persons per year, for all testicular cancer patients and those that received radiotherapy, respectively. These rates were 15.3% and 44% higher than national cancer institute published rates. The calculated rates of bladder cancer were 34.7 and 44.0 cases per 100 000 persons per year, for all testicular cancer patients and those that received radiotherapy, respectively. These rates were 6.5% lower and 19% higher than national averages.
We acknowledge that the limitation of this study was that we were unable to discern who received chemotherapy. However, in our analysis patients with testicular cancer had an increased rate of leukemia and lymphoma, which was augmented by radiotherapy. Thus, patients should counselled accordingly as to the risks of radiotherapy, and should be closely followed for life given the potential development of secondary malignancy.
No data are available regarding the use of retroperitoneal lymph node dissection (RPLND) across all stages of non-seminomatous germ cell testicular tumors (NSGCTT) in the community. We examined the rates of RPLND use in this patient subset in a large population-based cohort.
Between 1988 and 2006, 9633 patients with NSGCTT were treated with or without an RPLND within 17 Surveillance, Epidemiology and End Results (SEER) registries. Analyses focused on annual trends (1988–1992, 1993–1997, 1998–2002, 2003–2006) and univariable and multivariable logistic regression models, stratified according to disease stage. Analyses were adjusted for patient age, race (white, black, other), socio-economic status (low vs. high) and SEER region.
Overall 2620 (27.2%) of 9633 NSGCTT patients underwent an RPLND (1988–1992: 34.7%, 1993–1997: 29.5%, 1998–2002: 27.6%, 2003–2006: 22.2%; X2 trend p < 0.001). In patients with stage I NSGCTT, the overall rate of RPLND was 22.4% (1988–1992: 18.4%, 1993–1997: 23.5%, 1998–2002: 32.4%, 2003–2006: 25.7%; X2 trend p < 0.001). In patients with stage II NSGCTT the rate of RPLND was 50.1% (1988–1992: 20.9%, 1993–1997: 18.5%, 1998–2002: 31.8%, 2003–2006: 28.8%; X2 trend p = 0.003). Finally in patients with stage III NSGCTT the overall rate of RPLND was 13.1% (1988–1992: 15.0%, 1993–1997: 19.0%, 1998–2002: 32.3%, 2003–2006: 33.6%; X2 trend p = 0.983). In multivariable logistic regression models that focused on stage I patients, year of surgery (p < 0.001) and SEER registry (p < 0.001) represented independent predictors of RPLND. In patients with stage II, year of surgery (p = 0.01) remained an independent predictor of RPLND.
Population based trends indicate a decreasing rate of RPLND use. This decrease is most apparent in stage I patients where a 55.1% drop was recorded. It may be attributable to wider use of surveillance and/or chemotherapy. Less pronounced decrease was also recorded in stage II patients (19.1% drop) and is attributable to the wider use of chemotherapy as monotherapy. The RPLND rates did not change for stage III patients.
A previous report (Journal Urology; Bridges P, Sharif R, Razzaq A, Guinan P; 1998) indicated that Black Americans have worse survival after the diagnosis of testicular cancer (TC) than their White counterparts. We re-examined the association between race and survival in a large population-based dataset.
Between 1998 and 2006, 2221 men were diagnosed and treated for metastatic Testicular Germ Cell Tumors (TGCT) (Seminoma and Non-Seminoma). Analyses focused on the association between Black American race and overall mortality (OVM) and consisted of univariable and multivariable Cox Regression models. Analyses were adjusted for age, year of diagnosis (1988–1995, 1996–2000, 2001–2003, 2004–2006), affluence level (low, high), income level (low, high), education level (low, high), histological subtype (Seminoma, Non-seminoma,) type of intervention (orchiectomy ± RPLND, no surgical intervention) and SEER registry.
Of 2221 patients with metastatic TGCT, 80 (3.6%) were Black Americans, 2019 (90.9%) were White Americans and 122 (5.3%) were from other ethnicities. The 5-year OVM was 38.0%, 25.0% and 27.8% for respective Black Americans, White Americans and Other Ethnicities (Black vs. White; p = 0.018, Other vs. White; p = 0.3, Black vs. Other p = 0.3). Black American race was associated with a 1.6-fold and 1.5-fold higher overall mortality when compared to White Americans in univariable and multivariable analyses respectively.
Overall mortality rate is 1.6 and 1.5-fold higher in Black American patients with metastatic TGCT relative to White Americans. This disparity in overall mortality rate relative to White American patients with TGCT deserves attention.
The use of androgen deprivation therapy (ADT) in prostate cancer is associated with increased fracture risk. Previously we demonstrated in a Phase III trial that toremifene, a selective estrogen receptor modulator (SERM), significantly decreased fracture incidence in men receiving ADT. Similar to other SERMs, there was an increase in venous thromboembolic events (VTEs). This risk appeared to stratify to men ≥80 years of age. VTEs occurred in 1.5% and 2.5% of men <80, ≥80 respectively. To identify a patient population with the greatest benefit/risk profile we assessed the effect of toremifene in men <80 years.
In this analysis of men <80 years of age receiving ADT for prostate cancer, 430 men received toremifene 80 mg and 417 received placebo (orally daily). All subjects were on ADT for ≥6 months, had a serum PSA ≤4 ng/mL, were ≥70 years of age or were at or below WHO thresholds for spine or hip (BMD). The primary endpoint was new vertebral fractures. Secondary endpoints included fragility fractures and bone mineral density (BMD).
Toremifene 80 mg demonstrated a 79.5% relative risk reduction in the incidence of new vertebral fractures (CI0.95: 29.8%–94.0%;p < 0.005). The absolute reduction was 3.8% (4.8% placebo, 1.0% toremifene). Toremifene 80 mg significantly increased BMD at all sites measured (p < 0.001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p < 0.001 for all comparisons). Venous thromboembolic events occurred in 2.1% of the toremifene patients compared to 1.0% (p = 0.26) of the placebo patients. Other adverse events were similar between groups.
In men <80 years receiving ADT for prostate cancer, toremifene significantly decreased the incidence of new vertebral fractures. Toremifene also significantly improved BMD, bone turnover markers, and breast pain and tenderness. The risk of VTE was lower than in the overall study population. These results suggest an improved benefit/risk profile in men <80 years receiving ADT.
Predicting the time to recovery of urinary continence after radical prostatectomy (RP) remains an impossible task. The causes for the challenge are the multifactorial nature of incontinence, some of which have been studied at length and others not studied thoroughly. Patient’s age, urinary function & the degree of neurovascular bundle preservation have been shown as independent predictors of post-RP urinary continence. To evaluate the role of reconstructing the posterior aspects of the rhabdosphincter (RS) for a more rapid recovery of continence after robotic assisted radical prostatectomy (RARP); two age matched groups were compared at 90 and 180 days after catheter removal.
110 patients were matched from two consecutive series, one with RARP reconstruction of the RS & one without. The patients were matched regarding age, nerve sparing and baseline continence. The patients were evaluated using a QOL questionnaire score for continence. At 3 and 6 months after catheter removal mean QOL scores and number of pads/day of both sets were compared. The procedure involved restoring the continuity of the severed ends of the Denonvillers’ fascia.The preserved reflection of the Denonvilliers’ fascia dorsal to the bladder neck was sutured to the distal end at the urethral stump, attached to the posterior rhabdosphincter.
No significant difference in age, preoperative quality of life (QOL) scores & nerve preservation between both sets was found between both sets of patients (p-value 0.99, 0.84 & 0.65 respectively). However a significant difference between both sets was observed in the mean QOL scores and number of pads used at 3 and 6 months (p values <0.001). Fisher’s exact also showed a significant difference between the frequency of pad use among both sets at 3 months and 6 months (p-values are <0.0001).Regression analysis of all the variables on QOL scores recorded that reconstruction of the RS, time & their interaction had a significant positive impact on postoperative continence, (p-values <0.0001, <0.0001 and 0.028, respectively).
With elimination of other variables affecting postoperative continence, posterior reconstruction of the RS could be considered an effective technique for early continence recovery after RARP.
Sipuleucel-T is an investigational autologous active cellular immunotherapy. Three Phase 3 studies in metastatic castration-resistant prostate cancer (CRPC) provided evidence of survival prolongation, and a randomized trial in androgen dependent prostate cancer (ADPC) demonstrated an increase in PSA doubling time. We now describe the safety profile of sipuleucel-T across these 4 studies.
Patients were randomized (2:1) to receive 3 intravenous (IV) doses of sipuleucel-T or placebo in the outpatient setting at 2-week intervals at medical oncology and urology sites. Patients on the ADPC trial were eligible for a single booster infusion following PSA ≥3.0 ng/mL. The safety population included 904 patients (601 sipuleucel-T: 303 placebo) who underwent at least 1 leukapheresis.
The majority of patients were Caucasian (90.6%) and had a baseline ECOG performance status of 0 (83.4%); the median age was 70. 93% of patients in the safety population received all 3 infusions. Adverse events (AEs) seen more commonly in sipuleucel-T patients were chills (53.1%), pyrexia (31.3%), headache (18.1%), myalgia (11.8%), influenza-like illness (9.7%), and hyperhidrosis (5.0%). The majority of these AEs occurred ≤1 day following infusion, were mild or moderate, and resolved in ≤2 days. AEs following booster infusion were comparable to the initial infusions. Grade 3 acute infusion reactions (AIRs), including chills, pyrexia, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, myalgia, nausea, and vomiting, occurred in 3.5% of sipuleucel-T and 0% of placebo patients. The incidence of Grade 3 AIRs was 0.8%, 2.1%, and 1.3% following the 1st, 2nd, and 3rd infusions of sipuleucel-T, respectively. AIRs were treated with acetaminophen, IV H1 and H2 blockers, and IV meperidine. No Grade 4 or 5 AIRs were observed. There was no evidence of an increased incidence of autoimmune events or secondary malignancies. Cerebrovascular events (CVEs) occurred in 3.5% of sipuleucel-T and 2.6% of placebo patients or 2.010 (95% CI: 1.25, 3.08) and 1.50 (95% CI: 0.65, 2.96) per 100 person-years, respectively (P = 0.48). No evidence of a difference in the time to onset of CVEs or in the incidence of non-neurologic arterial or venous vascular events was observed.
Sipuleucel-T is well tolerated in both the CRPC and ADPC settings. Acute infusion reactions can be managed in the outpatient setting.
The therapeutic benefit of pelvic lymph node dissection (PLND) at radical prostatectomy is still under debate. The overall effect of standard or extended node dissection on prostate cancer survival outcomes are complicated by variation in patient populations and study outcomes in most retrospective reviews. We report our findings of therapeutic effect of PLND for Ontario patients after radical prostatectomy.
The information sources for the study included electronic clinical data such as the Ontario Cancer Registry (OCR) and supplemented through an extensive chart review conducted by trained abstractors according to a standardized protocol. We used a retrospective case-cohort approach to assess the effect of lymph node removal on prostate cancer-specific mortality. A parent study population included a random sample of 1703 patients treated for cure in Ontario between 1990 and 1998, as well as 591 cases selected based on death from their prostate cancer within 10 years of diagnosis. From this group 313 patients meeting inclusion criteria for this study were identified. A Cox-proportional hazards model was used to determine the association between number of lymph nodes removed and risk of prostate cancer death, considering baseline disease characteristics, treatment and age as potential confounders. In a secondary analysis, the results were stratified based on nodal status.
The crude hazard ratio (HR) showed a marginally statistically significant reduced risk of prostate cancer mortality as the number of LN removed via PLND increased (HR: 0.92, 95% CI: 0.84–1.01). None of the variables considered as confounders caused a change in the LN hazard ratio of greater than 10% and therefore were not included in the adjusted model. Stratification based on pathological nodal status did not significantly (>10%) change the HR.
These results seem to confirm a trend to therapeutic benefit of greater node removal with reduced prostate cancer mortality although the study was slightly underpowered. In this case-control study design of mostly low-to-intermediate risk patients in Ontario, the possible therapeutic benefit of PLND was found to be independent of pathological nodal status.
There are many novel techniques to treat localized prostate cancer. Almost all use prostate volume as a cut-point to obtain better results. Imaging methods (computed tomography, magnetic resonance, ultrasound) may have a wide measurement variability between each other. We have compared reports of trans-rectal ultrasound (TRUS) and digital rectal examinations (DRE) with the actual dimensions and weight of prostate specimens after radical prostatectomy; other than the usual “ellipsoid shaped formula,” we also used a new “bullet shaped formula” for validation.
During 18 months, three dimensions (height, width and length) were obtained from 150 fresh specimens after radical prostatectomy and before formalin fixation. The prostate gland was also weighted. In this study, those values were compared with transrectal ultrasound measurements. Each TRUS measurement was compared to fresh specimen dimensions to evaluate which were more susceptible to errors. Clinical patterns were analyzed to verify the main reasons of error.
Median age was 61 years old. Gleason score 6 or 7 was observed in 44.7% and 42.0%, respectively. Clinical stage T1c or T2a was present in 88.7% of cases. Laparoscopic or open radical prostatectomy was done in 64% and 34% of cases, respectively. When evaluating the DRE data, there was a clear tendency by the clinician to overestimate small (<40 g) and underestimate big prostates (>60 g). The overall rate of precise measurements (error less than 10%) was 21.3%, 22.0% and 31.3% for DRE, TRUS (ellipsoid shaped formula) and TRUS (bullet shaped formula). The “bullet shaped formula” got results closer to the actual volume when compared to “ellipsoid shaped formula” and DRE. The dimension with fewer errors was width. When correlating subgroups with error or not and clinical-pathological features (PSA, Gleason score, margins, extracapsular extension, clinical stage), no predictor for inaccuracy during TRUS could be identified.
The prostate measurements obtained using TRUS are often inaccurate. However, the bullet-shaped formula demonstrated better volume measurement accuracy. The height and length dimensions have a larger degree of error. The DRE tend to aggregate the cases between 30 and 60 g, under or overestimating the others. In light of the findings, further caution is necessary when using prostate volume as main criteria to include or exclude non-surgical treatments as therapeutic choice for localized prostate cancer.
Recently authors in the breast cancer domain have shown that in patients with metastases, primary tumor pathological characteristics do not predict outcomes as well as previously thought. Thus, we analyzed classical predictors of disease progression in a mets-only cohort from time of distant recurrence after prostatectomy. Moreover, we report the chronologic history of progression from RP to metastatic disease to death, and assess competing risks of death in this unique group of patients.
Between 1954 and 1997, 1004 consecutive patients underwent radical prostatectomy at Virginia Mason Medical Center in Seattle, Washington. Kaplan Meier survival analysis were used to analyze time to metastases (METS) and death. Univariate and multivariate Cox regression models addressed the prognostic significance of METS on death and PC-specific death. Washington State death certificates were obtained to assess cause of death.
Of all patients, 99 (9.9%) had METS. The actuarial METS-free survival for all 1004 men was 81% (95% confidence interval [CI], 78–84%) 20 years after surgery. Median time to METS after surgery was not reached for the entire cohort. Of all patients, METS were predictive of PC-specific death on univariate (HR=27.3, p<0.001) and multivariate (HR=10.0, p < 0.001) Cox Regression. Of those with documented biochemical recurrence (BCR), median time from BCR to METS was 2.7 years (95% CI, 2.5–3.0). Of those with METS, median time from surgery to METS was 6.7 years (95% CI, 5.6–7.7), and mean time from METS to death was 5.0 years (95% CI, 4–5.9). Of those with METS, only pre-op PSA was predictive (HR=1.1, p < 0.05) of PC-specific death on Cox regression. On multivariate analysis, PSA was no longer significant (p = 0.05). However, PSA was predictive of overall death on adjusted analyses, but pathological Gleason was not. Of all patients with METS, 77 (77.7%) died. Of those, 71% were PC-specific, 10.4% cardiovascular, 5.2% pulmonary, 4% lung cancer, and 12% other.
The minority of men will develop metastatic disease. The risk of metastases was predicted by classical pathological predictors. However, once men develop metastases, their risk of dying of their disease is unrelated to their initial grade and stage. In addition, the median time from mets to death in our study was shorter than reported in previous studies and maybe due to later time of diagnosis of mets for some in the pre-PSA era. Finally, a third of patients will die of competing risks, which is important to recognize when planning treatment for these men.
Post chemotherapy retroperitoneal lymph node dissection (pcRPLND) for residual retroperitoneal disease is the standard of care for non-seminomatous germ cell tumours. The management of men whose retroperitoneal disease completely responds(CR) by imaging to chemotherapy is more controversial. Some centres recommend RPLND to remove microscopic disease that may progress to late relapse. We have retrospectively evaluated our experience with the management of patients who presented with retroperitoneal(RP) metastases and who underwent initial chemotherapy.
The charts of the 305 consecutive patients from the Princess Margaret Hospital Testis Tumor Clinic who presented to the clinic with RP adenopathy and received initial chemotherapy were reviewed.
Of these 305 men, 131(42.9%) achieved a CR in the RP as assessed by imaging(defined as residual adenopathy <1 cm in maximal axial dimension) and were observed. Nine(6.8%) later relapsed and all were salvaged(6 RPLND only, 2 salvage chemotherapy+RPLND, 1 RPLND+chemotherapy). Full bilateral pcRPLND with postganglionic sympathetic nerve preservation where possible was done in 144 men with residual RP disease. Thirty(30) did not achieve an initial response of whom 50% died of disease.
Our experience in unique in that we report the outcomes of all men who present with RP adenopathy managed by initial chemotherapy and not just those who either undergo RPLND or are managed expectantly. In our total experience, 42.9% achieved a CR in the RP. Without further therapy (pcRPLND), only 6.8% of these patients relapsed and all were salvaged. Our experience strongly supports continuing surveillance as opposed to surgery in this population of CR after chemotherapy.
Surgery and radiation are both standard treatment options in the management of localized or locally extensive prostate cancer. Few direct comparisons of these 2 modalities have been performed. Coinciding with the opening of the Ottawa Prostate Cancer Assessment Center the aim of this study is to analyze the surgical outcomes of patients treated at the Ottawa Hospital. A parallel analysis will be performed by radiation oncology in patients treated with radiotherapy.
Between April 1995 and October 2007, 570 patients underwent open radical prostatectomy (RP) at the Ottawa Hospital - Civic Campus. Of these, 434 did not receive pre-operative androgen ablation, had complete clinical data, and thus were included in analysis. Two definition of biochemical recurrence (BCR) were considered, PSA >0.2 ng/mL and PSA >0.4 ng/mL. Additionally, patients receiving post-operative radiotherapy or hormones were considered primary treatment failures.
Five and Ten year recurrence free survival was 79% (95% CI 73–84%) and 72% (95% CI 62–80%) with BCR >0.2 ng/mL compared to 82% (95% CI 77–87%) and 80% (95% CI 73–86%) with BCR >0.4. Clinical stage, pre-treatment PSA and biopsy Gleason sum were significant predictors of disease recurrence.
These results provide local validation of the effectiveness of Radical Prostatectomy in the management of men with localized prostate cancer. We await the results of men treated with radiotherapy during this time period. This information can be used to counsel patients being evaluated in the Prostate Cancer Assessment Center.
Radical prostatectomy accounts for approximately one-half of the $1.7 billion cost of prostate cancer treatment. Utilization of robotic-assisted laparoscopic prostatectomy (RALP) has increased rapidly. The cost efficacy of RALP remains undetermined.
To perform a comparative cost-analysis of RALP and open radical prostatectomy (RRP).
We retrospectively reviewed all patients undergoing RALP (n = 25) or RRP (n = 55) by one of four surgeons at a single institution over a 3 month period. Hospital length of stay (LOS), operative time, hospital charges, reimbursement, and direct and indirect hospital costs were analyzed and compared. Ratio of costs-to-charges (RCC) rates was applied to each charge amount to calculate costs. Detailed cost information was obtained according to charge origin.
Mean LOS between patients undergoing RALP (1.2 ± 0.5 days) and RRP (1.6 ± 0.6 days) was comparable (p > 0.05). Mean OR time was 48% longer in patients undergoing RALP (277.5 ± 97 minutes) compared to RRP (187 ± 86 minutes). Mean total costs for RALP exceeded the total costs for RRP by 71% ($13,992 vs. $8,180; p < 0.05). Most of the difference was due to surgical supply and operating room costs ($11,425 RALP vs. $4,054 RRP; p < 0.05). Total nursing costs were significantly greater for RRP than for RALP ($2,240 vs. $834; p < 0.05). 36% of the total costs associated with robotic prostatectomy were related to the robotic technique ($2000 direct, $3000 indirect). The ancillary, cardiology, imaging, administrative, laboratory and pharmacy costs were not significantly different.
In this single institution analysis, total actual costs associated with RALP were significantly greater than costs for RRP. Higher operating room costs account for the increased cost of RALP. These data require validation among a larger cohort.
The prostate gland is dependent on male steroids (androgens) for its development, adult maintenance and function. Androgen action in prostate cells requires the presence of the androgen receptor (AR) protein, a nuclear transcription factor that is conditionally active only when bound to an active androgen. Previously, others have shown that the AR expressed in prostate stromal cells is necessary for prostate development whereas AR expression in the epithelial cells of the tissue is not needed for prostate formation. Since AR is known to be involved in prostate cancer development and progression, all past work on defining AR regulated gene expression has focused on studies of prostate epithelial or cancer cells. Here, we attempted to define the gene products that are regulated by the AR in prostate stromal cells.
Using human WPMY-1 prostate derived stromal cells as a model, we first tested whether AR is expressed in these cells and whether it is able to activate androgen-inducible gene expression. Using Western blotting, we showed that parental WPMY-1 cells express 100-fold lower AR protein when compared to prostate cancer (LNCaP) cells. Additionally, WPMY cells do not activate reporter gene expression from androgen-inducible promoters unlike LNCaP cells. Therefore, we created a stable WPMY-1 variant (WPMY-AR) that overexpresses AR protein by transduction with an AR expressing lentivirus; this cell variant strikingly upregulates reporter gene expression from the androgen-sensitive probasin gene promoter. Then we undertook gene expression profiling using the Affymetrix ST 1.0 gene chips and compared gene expression in vehicle treated WPMY-AR vs androgen (dihydrotestosterone) treated WPMY-AR (72 hrs).
One hundred and eighteen genes were found to be upregulated by androgen whereas 367 genes were downregulated by androgens in this paradigm.
The GO characterization of upregulated genes using the David Program showed a major class of genes in the “Developmental Signaling” category and some of the particular genes that were upregulated suggest that androgen stimulated WPMY-AR cells stimulate expression of genes involved in Wnt and BMP signaling suppression that might be consistent with a program of differentiation initiated by androgen signaling from prostate stromal cells.
Chronic non-bacterial prostatitis (NIH classification-type III) is a recurrent and bothersome condition with symptoms that may interfere with normal acitivities. It may be associated with pelvic floor muscle dysfunction that may be directly or indirectly attributing to some of these symptoms. Literature search failed to find any study indicating the use of pelvic floor release osteopathic technique to manage this condition. The purpose of this pilot study was to know if this treatment has any role in the management of symptomatic and recurrent chronic non-bacterial prostatitis, in addition to medical and other conservative managements.
Institutional IRB approval was obtained prior to enrollment. All patients presenting to one of the author’s Urology practice with the above condition were given the option of participating in this study and were enrolled after consent. All patients had more than 3 episodes of prostatitis and had received medications including antibiotics, anti-inflammatory drugs, and alpha-blockers and had cystoscopic evaluation with prostatic massage in the past. None of them had taken pentosan polysulfate (“Elmiron”) or gabapentin (“Neurontin”) or other related medications. Patient also had been instructed to avoid prostate irritants, regular sexual activity and to avoid strenuous exercise or work. At initial visit, in addition to pelvic and rectal examination, thorough osteopathic evaluation and urinalysis and culture were performed. All patients completed International Prostatitc Symptom (IPS) and Pelvic pain and Urgency/Frequency Patient Symptom Scale (PUF) scores at initial visits and at subsequent follow-ups. The release treatments were performed weekly for 4 weeks and then on alternate weeks until patient was satisfactorily better or for a total of eight treatments. The technique involved application of direct passive force to levator ani and coccygeus muscles to allow relaxation and provide improvement of symptoms both directly and indirectly.
A total of 6 eligible patients were enrolled. Two patients dropped out after one and 3 treatments and were lost for follow-up. Remaining 4 patients either reported 75 to 100% better with their bothersome symptoms and/or showed significant reduction in symptom scores, especially PUF score reduction of more than 50%. These patients had 4 to 8 treatments (mean of 5.4).
This pilot study has shown the possible role of osteopathic pelvic floor muscle release in selected patients with chronic non-bacterial prostatitis (type III) to improve their symptoms. However, a large scale study using control group may be needed before this treatment is being widely used.
The Urological Surgery field has been growing vigorously throughout the past two decades. New procedures, mainly in the area of minimally invasive surgery were added to urologists’ routine. However, it still lacks a reliable classification to report surgical complications. The Clavien Classification has shown to be accurate and trustworthy when applied to General Surgery operations. Briefly, instead of taking into account the complication per se, this classification gives scores (I to V) mainly considering the medications and procedures applied to fix such complications. The most important strength of this system is that it is standardized and has been well validated. We assessed the agreement rate among urologists applying this classification to actual scenarios. Considering that usually residents and fellows are in charge of reporting surgical complications, we have also compared Clavien scores given by fully trained urologists to scores given by residents or fellows.
During 12 months, consecutive surgical complications were prospectively recorded from four centers, composing the major areas of urological practice. Among these, twenty cases were selected to compile a survey. The cases were distributed in order to include a broad spectrum of frequent complications. After a briefing and explanation session concerning the classification, the survey was applied to 16 full trained urologists and 16 urology residents/fellows. During the presentation, each subject had the same amount of time to answer the questionnaire. Concordance rates were recorded for each scenario separately and as a pool of scores.
Twenty scenarios and 32 subjects were included, totalizing 640 scores. Concordance rates for each scenario ranged from 45.2% to 100%. The mean concordance rate was 83.4%. Four out of 20 scenarios had concordance rates below 80%. In two scenarios, the scores given by residents/fellows were significantly lower when compared to scores given by fully trained urologists (p < 0.05). The same tendency was shown when all scenarios were collapsed and evaluated as a group.
The Clavien Classification has shown to be reliable when applied to urological procedures. In a small proportion of scenarios, the interpretation might diverge among urologists. In those cases, residents and fellows have the trend to underestimate the severity of the complication when compared to fully trained urologists.
To report early results of PVP using LBO laser aiming to identify any clinical difference to KTP laser in prostates <80 gm.
A total of 186 men with symptomatic benign prostatic hyperplasia with prostate size <80 gm underwent photoselective laser vaporization of the prostate using KTP (n = 84) between (October 2004–April 2007) or LBO (n = 104) between (July 2007 – January 2010). Functional follow up included measurement of maximum urinary flow rate (Qmax), post void residual urine (PVR), international prostate symptom score (IPSS), quality of life (QoL), and prostate specific antigen (PSA). Follow-up evaluations were done for the patients during their visits at 1, 3 and 6 and 12 months postoperatively.
Operative data, complications, catheter removal and hospital stay were also recorded.
Base line characteristics of both groups were similar. Mean pre-operative prostate volume was 44.25 ± 13.3 and 45.5 ± 16.3 cc in KTP group and LBO group, respectively. KTP required more operating time than LBO (59.4 vs 50.6 minutes, p = 0.02)
All functional parameters improved significantly compared to base line values in both groups. There was no difference in IPSS, QoL, Qmax, PVR and percentage of PSA reduction between the two groups at 1,3, 6 and 12 months postoperatively. At 12 months follow-up, the IPSS improved by 60.1%, QoL improved by 61.1%, Qmax increased by 141.2% and PVR decreased by 69.2% in KTP group. In LBO group, the IPSS improved by 69.6 %, QoL improved by 65.7%, Qmax increased by 120.9% and PVR decreased by 72.7%. There were no significant differences regarding intra-operative and postoperative complications in both groups.
Despite some technical differences, KTP and LBO have comparable perioperative safety and produce similar early functional results for men with symptomatic benign prostatic hyperplasia in prostates <80 gm. However, KTP requires a longer operating times than LBO.
LUTS was originally coined by Walsh referring to unexplained lower urinary tract symptoms on which 5 alpa reductase inhibitor was reported to have only a placebo effect. The term has eventually evolved to include a host of inflammatory conditions: male interstitial cystitis, Chronic Pelvic Pain Syndrome, etc. Previous investigators have tried to establish reflux as the initiating factor by injecting radio-active carbon particles and scintiscanning the urethra while others have designed digital graphics but have not received adequate acceptance. Our team utilized real-time gray scale and spectral Doppler technology revealing voiding urethral regurgitation as an initiating factor in LUTS/male interstitial cystitis/CPPS, etc.
Medical records of patients with urethral, perineal, testicular, bladder and pelvic pains with dysuria, obstructive symptoms, e.g. hesitancy, dribbling, slow stream, incomplete emptying and irrigative, e.g. frequency, urgency were reviewed. Initially, 30 patients were worked-up routinely with negative yields. Our team then tested voiding urethral Doppler using external 7 Mhz transducer which showed regurgitation on spectral Doppler due to a distal urethral web shown on real-time gray scale ultrasound and direct visualization. Resection of the web was undertaken after initial satisfactory outcome with the first group.
403 patients with LUTS and sonographically detected voiding urethral regurgitation (Fig. 1) from a gray scale ultrasound and direct vision visualized distal urethral web (Fig. 2) underwent resection of the web supplemented by antibiotics per microbiology and alpha blockers/5ARI per urodynamics/lower urinary ultrasound/cystoscopy. 386 reported satisfactory results while 16 were unsatisfactory. 5 were female with irreversible interstitial cystitis from a distal urethral ring of Lyon (Fig. 3) reported in J Urol (Vol 63, 1965). 16 were younger females in whom development of IC was avoided by early intervention with age-specific urethrotomy.
This is a clinical report and not a randomized placebo-controlled study on 403 patients with new sonographically detected voiding urethral regurgitation from a distal urethral web, resection of this was followed by satisfactory outcome. In the female, early transurethral incision by age-specific urethrotomy of the distal ring of Lyon prevented development of IC.
Source of Funding: none
To evaluate the efficacy and tolerability of combined multiple anticholinergic therapy in the treatment of refractory overactive bladder (OAB).
Twenty-three patients (14 female, 9 male) followed at a referral neurourology clinic were identified in retrospective chart review. Charts of patients with diagnoses of overactive bladder, urgency, frequency, urge incontinence, or mixed incontinence, with office visits within the last 2 years were reviewed. Inclusion criteria were patients on multi-drug therapy after failing dose-escalated monotherapy. All patients had overactive bladder with urge incontinence (n = 13) or without incontinence (n = 10), and had undergone urodynamic studies (n = 21). Patients were all treated with combined double, triple, or quadruple anticholinergic therapy (tolterodine 4 to 8 mg, oxybutynin 10 to 20 mg, oxytrol patch 3.9 mg, solifenacin 5 to 10 mg, darifenacin 7.5 to 15 mg, trospium 20 to 60 mg, imipramine 75 mg, and/or flavoxate 300 mg) after failing monotherapy. Mean age was 64 years (range 33–86). Mean age at start of therapy was 60 years (range 22–85). Combined drug therapy was given and patients were followed for mean of 5 years (range 1–15).
Continence improved in all 23 patients. 19 patients (83%) had significant improvement in their symptoms, including 3 patients (13%) with resolution of symptoms. Four patients (17%) had mild improvement. 18 patients (78%) received double drug therapy. 4 patients (17%) received triple therapy. 1 patient (4%) was maintained on quadruple therapy. Mean post-void residual (PVR) was 31.5 mL, with 9 patients (39%) with PVR of 0. Incontinence events decreased to 23.8% of baseline incontinence on monotherapy. 3 patients (13%) could not tolerate the addition of a second anticholinergic (dry mouth, nausea, headache) and stopped treatment despite symptom relief. 4 patients (17%) were tried on 2 or more different combinations of double therapy before being maintained on the most efficacious therapy.
Eighty-three percent of OAB patients refractory to single drug therapy responded successfully to combination anticholinergic therapy. These included the newer generation selective receptor drugs. Long term followup in our study showed durable effect, improved quality of life, satisfaction, and tolerability. Side effects were comparable to single drug therapy. Combination anticholinergic therapy may be an efficacious, non-invasive treatment option for refractory OAB.
Combined data of 2 placebo-controlled phase 3 studies showed that silodosin significantly improved International Prostate Symptom Score (IPSS) and peak urinary flow rate (Qmax) in patients with symptoms of benign prostatic hyperplasia (BPH). In this post hoc analysis, we evaluated the relationship between estimated prostate volume (PV) and symptom improvement.
PV was estimated from prostate-specific antigen (PSA) levels as described (Roehrborn et al. J Urol. 1999;53:581–589). Changes from baseline to week 12 (with last observation carried forward) were compared between patients with estimated PV <30 mL and those with estimated PV ≥30 mL, using ANCOVA with baseline as the covariate.
Of 466 patients who received silodosin (mean age, 65 years), 450 provided PSA data at baseline (range of estimated PV, 18.4 to 76.8 mL); of those, 100 patients had an estimated PV <30 mL. The 2 subgroups had similar baseline values for IPSS and Qmax (Table 1). Silodosin-mediated reduction in IPSS from baseline to week 12 tended to be slightly greater in patients with larger estimated PV, but the mean difference between the 2 PV subgroups was not statistically significant (Table). Mean changes in Qmax from baseline to week 12 were ≥2.3 mL/sec in both subgroups, indicating that silodosin provided clinically important improvement in Qmax, regardless of estimated prostate volume.
Silodosin provided improvements in IPSS and Qmax in patients with estimated PV <30 mL and in those with estimated PV ≥30 mL.
P68. Change from Baseline (CFB) in IPSS and Qmax by Estimated PV
<30 mL (N=100) | ≥30 mL (N=350) | ||
---|---|---|---|
IPSS | Baseline, mean ± SD | 21.0 ± 5.2 | 21.4 ± 5.1 |
CFB to wk 12, mean ± SD | −5.4 ± 6.4 | −6.7 ± 6.7 | |
Adj. mean difference (95% CI) | −1.2 (−2.6, 0.2) | ||
Qmax, mL/sec | Baseline, mean ± SD | 8.9 ± 2.4 | 8.7 ± 2.6 |
CFB to wk 12, mean ± SD | 3.3 ± 5.4 | 2.3 ± 4.1 | |
Adj. mean difference (95% CI) | −1.1 (−2.0, −0.1) |
Funding: Watson Pharma, Inc. provided funding for this research.
Vitamin D deficiency has been reported to be prevalent in the general population in the United States. Vitamin D has been associated with numerous health benefits ranging from bone health to cancer prevention. An emerging group of individual urologists consider themselves, and are perceived as “Men’s Health” experts. Since Vitamin D deficiency is a significant men’s health concern, a prospective analysis (Vitamin D 3 levels checked by blood samples) of 100 consecutive male patients was performed in a general urology practice. Vitamin D deficiency was detected in 74% of the patients tested. Urologists, particularly those interested in providing more comprehensive men’s health care to patients, should consider testing for Vitamin D levels as part of their evaluation of new and established male patients. Treatment is simple, inexpensive, and effective. This simple modification in urology practice can augment the urologist’s role in providing more comprehensive care as a “Men’s Health” specialist.
Patients undergoing active surveillance for prostate cancer may be subject to multiple prostate biopsies. Prior studies suggest that prostate needle biopsy (PNB) and vasectomy may cause erectile dysfunction (ED). We explored the relationship between a prior PNB or vasectomy and rates of ED.
We reviewed a prospectively organized database of 890 patients who underwent transrectal ultrasound (TRUS)-guided PNB. ED was modeled as a categorical variable as either any, moderate-severe, or severe based on International Index of Erectile Function (IIEF) scores. Binary logistic regression was used to analyze the predictive ability of PNB and vasectomy. They were adjusted for age in multivariate analysis.
Median age and IIEF score were 63 years and 19 points, respectively. According to IIEF scores, 22%, 11%, 15%, 34% had severe, moderate, mild-moderate, and mild ED, respectively. 18% had no ED. Vasectomy status was available in 391 patients, of whom 41% had prior vasectomy. On univariate analysis, age (OR=1.1, p < 0.001), prior PNB (OR=1.83, p < 0.002) and prior vasectomy (OR=0.41, p < 0.001) were all associated with moderate-severe ED. Only age (OR=1.1, p < 0.001) and vasectomy (OR=0.39, p < 0.002) were predictive for severe ED. On multivariate analysis, age was predictive for moderate-severe (OR=1.08, p < 0.001) and severe (OR=1.09, p < 0.001) ED, while vasectomy was protective against moderate-severe (OR=0.41, p < 0.001) and severe (OR=0.41, p < 0.003) ED. PNB status was no longer significant (p > 0.05) after adjustment for other covariates.
Age is a strong predictor of ED. Prior vasectomy is associated with a reduced risk of ED. Prior PNB, after adjustment for other variables, does not increase the risk of ED. Patients should be re-assured that PNB does not cause ED. Furthermore, ED was common in this cohort, and thus patients undergoing definitive therapy for prostate cancer should expect ED post treatment due to prior dysfunction.
The most widely-accepted explanation for the development of abnormal collagen deposits in the tunica albuginea covering of the penis, known as Peyronie’s disease (PD) is that it follows aberrant wound healing after penile injury. It is suggested that following trauma to the erect penis, probably during sexual intercourse, microscopic tears develop in the tunica albuginea. Contemporary data suggests incidence in 5–9% of men, as “tunical scarring” results in development of penile plaques and subsequent penile curvature or other deformity during erection and in some, erectile dysfunction. On the other hand, data to support the involvement of penile trauma in precipitating PD are inconclusive. Interestingly, while the testes have a similar tunica albuginea covering to that of the penis, testicular injury (direct trauma) does not seem to result in tunical scarring. The aim of this study was to clarify the prevalence of penile injury in a large contemporary cohort of patients diagnosed with PD.
Patients were evaluated between January 2008 and February 2010 and diagnosed with PD based on history, genitourinary examination and high resolution penile ultrasound (US). Penile US was used to confirm the penile plaques sites, size, and presence/absence of calcification. If erectile function was compromised, color penile US was done. Patients were questioned for injury events (self and/or partner stimulation) to the erect penis prior to the development of penile deformity. Institutional approval was obtained.
The 450 consecutive patients included in this study had a mean age of 52y and duration of disease prior to presentation of 1.1 y. Plaque distribution was primarily dorsal or dorso-lateral. Calcification of the penile plaques was present in 18% (n = 81) of patients, while only 15% (n = 67) of patients reported history of penile injury. There were no significant differences between the patients with and without history of penile injury regarding age, penile plaque size, site and presence of calcification.
This large prospective series condirms recent evolving data that penile injury does not appear to be the primary cause of PD; potential causes may include immunological or inflammatory disorders, or as yet unidentified causes.
Surgeons endeavour to reconstruct lower genitourinary anomalies early in childhood. Considerable success is achieved in restoring functionality but these individuals must make various lifestyle adjustments to cope with numerous challenges. Such patients managed in a Community Urology practice over the past 20 years were studied to identify these challenges and the strategies used in their management. Results of treatment as they affect sex, sexuality and procreation were examined in 4 cases.
Records from hospitals and Physicians’ offices were reviewed for demographic data, surgical procedures and diagnostic imaging studies performed and follow up patterns. Parents when available were interviewed. For this report, complex anomalies were those who had more than 2 attempts at corrective surgery.
The 4 cases identified out of 15 and lessons learned are presented (1) Baby born with cloacal anomaly, imperforate hymen and solitary left kidney. After numerous surgeries she got married, conceived twice, 2 living sons delivered by caesarean section. Tubal ligation achieved birth control. At 40, she is happily married and grateful for mother’s and family support. (2) Baby boy born with complex hypospadias had numerous surgeries in early life. In his late teens, required further surgeries to correct multiple urethral diverticulae, strictures and stones. Graduated from University and got married. Currently challenged by oligospermia and fertility issues at 26. (3) Baby born with urethral duplication and genital anomaly. With parental consent, baby was raised as a girl. At age 14, she requested for a gender re assignment. With the support of the parents, the urologist and the legal system her request was granted. (4) Baby born with Bladder Exstrophy. Multiple reconstructive surgeries achieved good cosmesis and functionality. At 25, she is in a sexual relationship, carrying out self catheterization with occasional UTIs.
Complex lower urogenital anomalies can present challenges and long term lifestyle adjustments. Parental support, excellent reconstructive surgeries, ongoing urological/medical care in adulthood can produce good results. Patient’s cooperation and resilience are paramount.
Lymphadenectomy is important for staging and prognostication penile squamous cell carcinoma (PPSCC). The AJCC system stage IV includes any number or size of positive nodes, however it is unclear if the number of positive nodes may strongly affect the outcome of these patients. Therefore we examined the effect of the number of positives nodes in pT1–4 N1–3 M0 on cancer-specific survival after surgery for PPSCC.
We relied on a cohort of 330 patients with pT1–4 N1–3 M0 PPSCC identified in the 1996 to 2006 Surveillance, Epidemiology and End Results (SEER) database. Survival analyses relied on Kaplan-Meier plots and difference in survival rates were assessed using the log-rank test. Stratification was made according to the number of positive nodes (0 vs. 1 vs. 2 vs. 3 vs. >3). The same analysis was redone in the sub cohort of pT2.
Of all patients, 129 (39.1%) were pT1, 133 (40.3%) pT2, 57 (17.3%) T3 and 11 (3.3%) T4 PPSCC. Nodal status was as follows: N0 162 (49.1%), N1 73 (22.1%), N2 50 (15.2), N3 45 (13.6%). Number of positive nodes range from 0 to 18 (median 1). In survival analysis, similar cancer-specific survival rates were recorded among patients with positives nodes, regardless the number of nodes (log-rank p>0.05, all). For example, at 1 years after surgery cancer-specific survival in pT1–4 patients with N0 vs. 1 node vs. 2 nodes vs. 3 nodes vs. >3 nodes were respectively, 97.4% vs. 81.3% vs. 81.6% vs. 78.0%. For pT2 lesions, at 1 year, survival rates were 98.6% vs. 77.1% vs. 80% vs. 77.4%.
Similar cancer-specific survival rates were recorded across all N+ patients. Moreover, the number of positive nodes did not seem to affect cancer-specific survival at any stage. Therefore, efforts should be made to make earlier diagnosis and deliver definitive therapy promptly.
The objective of this study was to compare clinical and pathologic outcomes of radical cystectomy for muscle-invasive bladder cancer in relation to prior history of superficial transitional cell carcinoma.
Retrospective data collection from 2287 patients managed by radical cystectomy for transitional cell carcinoma of the bladder from the Canadian Bladder Cancer Network were analyzed. Patients with clinical stage T2 or more were included and divided into two groups: (1) patients with prior history of superficial transitional cell carcinoma of the bladder (356 patients), and (2) patients with clinical muscle-invasive cancer de novo (785 patients). Variables analyzed included patient age, gender, pathologic stage, adjuvant chemotherapy, tumour recurrence and survival.
Both groups were nearly equal in the mean age and gender distribution, with mean age of 67.2 and 66.7 years, and 79.7% and 79.5% of patients being men in groups 1 and 2, respectively. The presence of preoperative hydronephrosis was 20.8% and 32.6% (P 0.0007) for groups 1 and 2, respectively. The incidence of higher pathological stage (T3 or T4) was 36.3% and 58% (p < 0.0001), positive lymph nodes was 20.1% and 28.8% (P 0.002) and lymphovascular invasion was 31.7% and 46.2% (p = 0.0001) for groups 1 and 2, respectively. The incidence of adjuvant chemotherapeutic treatment was 15.5% and 23.3% (p = 0.002) for groups 1 and 2, respectively. The overall survival (OS) and the disease specific survival (DSS) at 5 years was 62% and 70% for group 1 and 51% and 60% for group 2 respectively. At 10 years, 46% and 66% for group 1 and 35% and 49% for group 2, respectively (p [log-rank] = 0.0001 and 0.0002 respectively). In multivariate analysis, studying factors affecting OS, DSS and tumour recurrence, the presence of previous superficial bladder tumor was found to be associated with a significant reduced risk of mortality and tumor recurrence (Hazard ratio of 0.7 for all risks).
Our retrospective study suggests that patients with superficial transitional cell carcinoma of the bladder that progress to muscle-invasion and require radical cystectomy appear to have better pathologic and clinical outcome than patients presenting with clinical muscle-invasive disease de novo.
We sought to examine stage at radical cystectomy (RC), as well as cancer-specific mortality (CSM) rates in non-bilharzial squamous cell carcinoma (SCC) RC patients relative to patients with urothelial carcinoma (UC) RC of the urinary bladder within a large population-based cohort. We hypothesized that SCC histological subtype fares a worse survival than UC patients.
Of 12311 RC cases, we identified 614 (5.0%) SCC versus 11697 (95.0%) UC individuals within 17 Surveillance, Epidemiology, and End Results (SEER) registries, between 1988 and 2006. Differences in the rates of CSM were assessed using the cumulative incidence plots that control for non-cancer related mortality. Univariable and multivariable competing-risks regression models addressed the effect of histological subtype at RC for prediction of CSM. Covariates consisted of age, gender, year of diagnosis, race, pathological T and N stages, as well as tumor grade.
After accounting for other-cause mortality, the cumulative CSM rates at 5 years were 40.3 and 35.1% for SCC vs. UC patients (p < 0.001, Gray). For the same time point, the CSM rates in organ confined (OC) disease were 25.0 and 19.8% for SCC vs. UC patients (p = 0.2, Gray) and 46.3 and 49.3% respectively for the same groups of patients in non-organ confined (NOC) disease (p = 0.8, Gray). In multivariable competing-risks regression models, SCC was not associated with a statistically significantly higher rate of CSM than UC histological subtype (p = 0.06, Gray). Similarly, SCC was unassociated with a higher risk of CSM after stratification according to OC and NOC disease (p = 0.2 and p = 0.1, Gray).
SCC is rare, and more frequently associated with non-organ confined disease. After accounting for non-cancer related mortality, which was never previously done with Cox regression models, SCC was not statistically significantly related to a worse prognosis than UC subtypes.
Local infiltration with CD8+ effector T cells (CTLs) correlates with good prognosis in different forms of cancer. In contrast, tumor infiltration with Treg cells, predicts poor outcomes. In the current study, we determined the feasibility of selectively promoting CTL into bladder cancer, with concomitant local suppression of Treg-attracting chemokines.
Chemokine expression in untreated tumors and ex-vivo-cultured tumor explants from patients with bladder cancer was analyzed by RT-PCR (Taqman) and ELISA. The ability of CTLs and Tregs to migrate towards the differentially-treated tumors was tested in chemotaxis chambers.
We observed that in the absence of activation bladder cancer explants produced only marginal levels of Teff-attracting chemokines. While BCG alone was an effective inducer of IL-8, a known inducer of neutrophil infiltration, it failed to induce local production of CXCR3 lig-ands (MIG and IP-10) or RANTES (CCR5 ligand), the chemokines able of attracting CTLs, TH1 and NK cells, the immune cells desirable in cancer settings. However, it’s combination with IFNa and TLR3- or TLR4 ligands, such as poly-I:C or LPS allowed for strong elevation of the above chemoattractants.
Our data indicate the possibility to correct the BCG-induced pattern of inflammatory chemokines in bladder cancer lesions, using a modified BCG-based intravesical therapy. Our upcoming clinical trials will determine whether such tumor-selective chemokine modulation can enhance the local production of the desirable chemokines in situ and may enhance antitumor effectiveness of BCG-based treatments, by directing the desirable types of immune cells (CTLs, as well as CXCR3-and CCR5-bearing Th1 and NK cells) to tumors and limiting local Treg attraction.
Supported by 1PO CA132714
Adverse event reporting is highly variable and nonstandardized in the urological literature. We sought to better characterize complications and identify risk factors for complications in patients after robot-assisted radical cystectomy (RARC) using a standardized reporting methodology.
Utilizing a prospectively maintained, single institution database, we identified and retrospectively reviewed 156 consecutive patients who underwent RARC with at least 90 days of follow up. All complications were analyzed and graded according to the Modified Clavien system and were also defined and stratified by organ system. Univariate and multivariate logistic regression models were used to define predictors of complications. Cox proportional hazard modeling and Kaplan-Meier survival analysis were used to correlate complication grade and overall mortality.
Median age was 90 years (IQR 61–76), and median BMI was 28 (IQR 25–32). Overall, sixty-five percent (102/156) of patients experienced a postoperative complication at a median followup of 9 months. Fifty-two percent (81/156) of patients experienced a complication within 90 days of surgery. Overall, the highest grade of complication was grade 1 in 30 (19%), grade 2 in 34 (22%), and grade 3–5 in 38 patients (24%). Twenty-one percent (33/156) of patients required hospital readmission within 90 days of surgery. Gastrointestinal, infectious, and genitourinary complications were most common (31%, 25%, and 13%, respectively). An association was found between BMI and likelihood of having a grade 3–5 complication on univariate and multivariate analysis. When patients were stratified by highest Clavien grade, no difference was found in overall survival (Cox HR 0.98, 95% CI 0.64–1.50).
When reported using strict guidelines, surgical morbidity after RARC is significant, but the majority of complications are low grade. The highest complication grade, however, did not impact overall mortality. Stringent reporting of complications after RARC is essential to appropriately counsel patients, assess quality surgical care, and allow meaningful comparisons between open radical cystectomy series and institutions.
The prognostic significance of advanced age on cancer-specific mortality (CSM) after nephroureterectomy (NU) for invasive upper urinary tract urothelial cancer (UTUC) is controversial. We assessed the effect of advanced age on CSM after NU in a large population-based cohort.
We relied on 2824 patients, who were treated with NU for UTUC in 9 Surveillance, Epidemiology, and End Results registries, between 1988 and 2004. Using the most significant cut-off values, age was stratified into three strata: ≤59 years vs. 60 to 79 years vs. ≥80 years. Differences in the rates of CSM were assessed using cumulative incidence plots that account for other-cause mortality. Univariable and multivariable competing-risks regression models were used to assess the effect of age on CSM.
The 5-year cumulative CSM rates were respectively 14.8, 19.6, and 23.6% for patients ≤59 years of age, 60 to 79 years of age, and ≥80 years of age (Gray, p < 0.01). After accounting for other-cause mortality, the 5-year OCM rates for the same age groups were respectively 14.7, 28,4, and 47.5% (Gray, p ≤ 0.001). Advanced age reached independent predictor status of CSM in competing-risks regression analyses (p ≤ 0.045).
Advanced age was found to be an independent predictor of CSM after NU, even after controlling for the potentially confounding effect of other-cause mortality. In consequence, the deleterious effect of advanced age that may be related to postponed surgery should be considered in clinical decision-making.
Data from tertiary care centers suggest that the perioperative mortality (POM) after radical cystectomy (RC) is not different in septuagenarian or octogenarian patients, compared to younger individuals. Conversely, population-based data state otherwise. We revisited this topic in a large contemporary population-based cohort.
Between 1988 and 2006, 12722 radical cystectomies were performed for urothelial carcinoma of the urinary bladder (UCUB) in 17 Surveillance, Epidemiology and End Results (SEER) registries. Of those 4480 were aged 70–79 and 1439 were 80 years and older. Univariable and multivariable logistic regression models tested 90-day mortality (90dM) after radical cystectomy. Covariates consisted of gender, race, year of surgery, SEER registry, histological grade and stage.
Of all 12722 patients, 4480 (35.2%) were septuagenarian and 1439 (11.3%) were octogenarian. The overall 90dM rate was 4% for the entire population, 2% for patients aged 69 years or younger, 5.4% for septuagenarian patients and 9.2% for octogenarian patients. In multivariable logistic regression analyses, septuagenarian (OR= 2.80; <0.001) and octogenarian (OR= 5.02; <0.001) age increased the risk of 90dM after RC.
In this population-based analysis, POM was between 3 and 5-fold higher in respectively septuagenarian and octogenarian patients which is higher in tertiary care centers. This information needs to be included in informed consent considerations, specifically if RC will not be performed at a tertiary care center.
Surgical waiting times have been shown to affect quality of life and clinical outcomes of patients with urological cancer. Prolonged wait times can raise anxiety and lower daily functioning in patients diagnosed with cancer. There is data to suggest that delay in cystectomy after diagnosis of invasive cancer is associated with worse prognosis. It is intuitive that delay in diagnosis of invasive bladder cancer must similarly affect prognosis. Elucidating the factors that affect surgical waiting times may potentially have an impact on patient quality of life, morbidity, and mortality. We sought to examine the factors that influence surgical waiting times for transurethral resection of bladder tumor (TURBT), and compare them with other published literature.
We performed a retrospective review of the last 272 consecutive TURBTs in our institution. Specifically, we examined dates of referral, initial urological consultation, decision for surgery, and TURBT, as well as patient age, gender, establishment to practice, ASA score, and specific surgeon. The study was approved by our institutional review board.
The median times for new patients from primary care referral to initial urological consultation, from initial urologic consultation to TURBT, from decision for surgery to TURBT, and from primary care referral to TURBT were 15, 28, 19 and 43 days, respectively. For all patients, the median time from decision for surgery to TURBT was 22 days. The statistically significant risk factors for increased wait times were age <50, later year of surgery, and specific surgeon. ASA score ≥3 approached significance (p = 0.06). Gender and established patient versus new patient were not associated with longer wait times.
Factors that adversely affected waiting times in our institution were younger age, earlier year of surgery, and specific surgeon. Waiting times for TURBT in our institution were shorter than those in other published literature. To our knowledge, this is the first data from the United States health care system which examines waiting times associated with the initial diagnosis and treatment of bladder cancer.
There is evidence that receiving neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) results in improved survival over surgery alone in patients with stage >T2 bladder cancer (BC). NAC may be underutilized, however, due to reported concerns of increased perioperative adverse events (ADEs). Little data exist on whether NAC affects post-operative hospitalization cost, length of stay (LOS), or readmission rates.
Retrospective billing record and medical chart review of 150 consecutive patients who underwent RC from 1/2006 to 12/2008 was conducted to assess association between receipt of NAC and initial post-surgical LOS, American Society of Anesthesiologists (ASA) score, clinical stage, intraoperative parameters and patient demographics. Administrative data (ICD-9 codes) were used to assess the number of perioperative ADEs as well as calculate Risk of Mortality (ROM) and Severity of Illness (SOI) scores using the 3M APR™-DRG Classification Software. To adjust for outliers, adjusted LOS was calculated as the mean of LOS values excluding the top 10%. Association between the above variables and NAC use was examined using Student t-test. Pearson’s chi-squared test was used to explore the association between NAC receipt and 90-day readmission status. Fisher’s exact test was used to analyze the clinical stage difference between recipents and non-recipents of NAC.
A statistically significant difference was seen in mean operative time, number of ADEs but not age, mean ASA, clinical stage, ROM or SOI scores, estimated blood loss (EBL), median or adjusted LOS, or total post-surgical hospitalization cost between recipents and non-recipents of NAC. No significant difference in readmission rate (30.23% vs. 25.00%, p = 0.63) was seen between these groups (Table 1) (Table 2).
In this series, neoadjuvant chemotherapy predicts increased operative time and number of post-operative complications but has no significant impact on the readmission rate, duration or cost of initial hospitalization in patients undergoing RC.
P86. Comparison of demographic and perioperative variables between recipients and non-recipients of NAC
Variable |
No NAC |
NAC |
P-value | ||||
---|---|---|---|---|---|---|---|
N | Mean | SD | N | Mean | SD | ||
Age | 129 | 70.26 | 9.09 | 20 | 66.65 | 13.39 | 0.13 |
ASA | 102 | 2.59 | 0.64 | 17 | 2.57 | 0.71 | 0.11 |
EBL (mL) | 123 | 1381.7 | 2027.05 | 19 | 2071.05 | 3574.26 | 0.21 |
Op Time (min) | 111 | 460.24 | 104.58 | 17 | 512.53 | 93.89 | 0.02* |
Median LOS | 127 | 8 | – | 20 | 11 | – | – |
Adj LOS | 115 | 9 | 3.91 | 18 | 10.9 | 4.49 | 0.05 |
Mean # ADEs | 129 | 2.57 | 3.86 | 20 | 4.45 | 3.65 | 0.02* |
ROM | 129 | 2.09 | 0.87 | 20 | 1.95 | 0.89 | 0.27 |
SOI | 129 | 2.9 | 0.56 | 20 | 2.9 | 0.55 | 0.41 |
Total Cost ($) | 129 | $48,469.00 | 36,198.00 | 20 | 48,850.00 | 17,146.00 | 0.94 |
P86. Comparison of clinical stage between recipients and non-recipients of NAC
Clinical Stage |
No NAC |
NAC |
P-value | ||
---|---|---|---|---|---|
N | % | N | % | ||
% Stage ≤cT2 | 103 | 79.8 | 15 | 75.0 | 0.15 |
% Stage ≥cT3 | 7 | 5.4 | 3 | 15.0 |
Recent literature indicates that continent urinary diversion (CD) is offered to a minority of patients after radical cystectomy (RC). An elevated rate of peri-operative complications may represent an explanation for this observation. We examined the rates of immediate inpatient complications for CD vs. incontinent urinary diversion (ID).
Between 2003 and 2008, 2719 RC were performed in the state of Florida. The type of diversion and complications were recorded within the Florida Inpatient Database. Statistical analyses assessed the overall and specific complication rates in patients with CD and ID after RC. Covariates consisted of age, gender, race, hospital volume (HV) and surgical volume (SV), as well as Charlson Comorbidity Index.
Between 2003 and 2008, the rate of complication after RC ranged from 9.2 to 10.5%. The overall complication rate after CD was 29.5% vs. 39.2% for ID (p < 0.02). In univariable models, younger age (OR: 1.02 [95% CI=1.01–1.03]; p < 0.001); female gender (OR: 0.78 [95% CI=0.63–0.96; p = 0.02) and CD (OR: 0.65 [95% CI=0.49–0.86]; p = 0.003) were significant predictors of lower overall complication rates. In multivariable analyses, younger age (OR: 1.02 [95% CI=0.66–1.22]; p < 0.001), female gender (OR: 0.72 [95% CI=0.58–0.89]; p = 0.003); higher HV (OR: 1.93 [95% CI=1.49–2.52] p < 0.001) and higher SV (OR:1.71 [95% CI=1.25–2.31]; p < 0.001) remained independent predictors of lower complication rates. However, after adjustment for covariates, the type of diversion failed to predict any type of complications.
CD does not predispose to higher rates of complications. In consequence, CD should be encouraged whenever not medically contraindicated.
To assess the rate of metastatic bladder cancer at diagnosis in a population-based tumor registry.
Between 1988 and 2006, 29381 patients were identified within 17 Surveillance, Epidemiology and End Results (SEER) registries with diagnosis of bladder cancer of all stages. We examined the rates of metastatic bladder cancer at diagnosis throughout the entire study period. Multivariable logistic regression models examined the impact of year of surgery on metastatic bladder cancer diagnosis after adjusting for patient age, gender and race.
The overall rate of metastatic bladder cancer was 7.1% and it increased from 6.3 to 8.4% over the study period (relative increase: 1.3%, χ2 trend: p < 0.001). The increase in metastatic bladder cancer rates was more pronounced in females (relative increase: 6.5%; from 1.4 to 9.1%, χ2 trend: p = 0.4) than in males (relative increase: 1.5%; from 5.2 to 7.6%, χ2 trend: p < 0.001) and in octogenarians (relative increase: 1.2%; from 8.4 to 9.8%, χ2 trend: p = 0.7) than in younger patients (relative increase: 1.1%; from 7.9 to 8.7%, χ2 trend: p = 0.003) and in Caucasians (relative increase: 1.4%; from 6.0 to 8.3%, χ2 trend: p < 0.001) than in other race categories (relative increase: 1.0%; from 8.8 to 8.9%, 2 trend: p = 0.8). Statistically significant differences in metastatic bladder cancer rates existed in various SEER registries. For example, the increase in metastatic rates was the highest in the Los Angeles and Utah registries (relative increase: 2.1%, from 6.1 to 12.6%, χ2 trend: p < 0.001 and relative increase: 2.4%, from 3.8 to 9.1%, χ2 trend: p = 0.01). In multivariable logistic regression models age, gender and race represented independent predictors of metastatic bladder cancer diagnosis (p ≤ 0.04). Finally, more contemporary year remained the foremost predictor of higher rate of metastatic bladder cancer at initial diagnosis (p < 0.001).
The increase in metastatic bladder cancer rate is worrisome. Delay at presentation as well as a delay in referrals may be the underlying cause behind these increasing rates. Although the increase in trends is marginal, it represents a cause for concern, which indicates that primary care physicians and patients should be better sensitized to the importance of expedited referrals and self diagnosis.
Urothelial carcinoma of the bladder is a common malignancy and a major cause of morbidity and mortality. Urinary cytology is the most widely used non-invasive test for its detection and surveillance. We aimed to re-evaluate the specificity of urine cytology during a contemporary period at our institution in comparison to other urinary biomarkers.
Data from 1,114 consecutive patients corresponding to 3,251 specimens (2,979 cytologic and 272 histologic specimens) between January 2006 and July 2006 were retrieved. Subsequent cytologic and surgical specimen reports up to 2008 were examined with a minimum two year follow-up period. Collected parameters included date of collection, reason for urinary evaluation, type of specimen (voided, washing or catherized) and tumor grade. Atypical diagnosis was considered negative.
On cytological examination, 71% of specimens were benign, 23% atypical and 6% suspicious or positive for urothelial carcinoma. The reason for collection was surveillance in 61% and new symptoms in 28%. Depending on tumor grade, sensitivity results ranged from 10% for low-grade tumors to 51% for high-grade ones. Importantly, specificity of urine cytology ranged from 83% to 88% (depending on type of urine collection and type of clinical presentation), similar to other reported results from other urinary markers (40–90%).
Our institution’s experience with regards to the sensitivity and specificity of urine cytology is lower than reported historically. Whether this is a consequence of heterogeneous study designs and parameters is open to debate. These findings need to be validated in a larger cohort of patients across several institutions to definitively evaluate whether there remains an advantage for urine cytology over the other urinary marker assays.
The prognostic significance of prostatic stromal invasion in patients with muscle invasive bladder cancer is not fully known. We tested the effect of prostatic stromal invasion on cancer specific mortality (CSM) after radical cystectomy in a large population based cohort
Our analysis relied on 7938 patients with transitional cell carcinoma (TCC) treated with radical cystectomy within 17 Surveillance, Epidemiology, and End Results (SEER) registries between 1988 till 2006. Univariable and multivariable models tested for the effect of pathologic tumor stage on CSM rates. Covariates consisted of age, gender, race and SEER region.
Overall, 3538 patients had pT2bN0M0 tumors, 3538 had pT3N0M0, 2249 had pT4aN0M0 and 307 had pT4bN0M0. In Kaplan Meier analyses the 5 year survival was 66.7%, 45.6%, 41.6% and 18% for respective pT2bN0M0, pT3N0M0, pT4aN0M0, pT4bN0M0. (overall log rank p < 0.001). In a multivariable Cox regression analysis adjusted for age, gender, race and SEER region, the hazard rate of pT3N0M0, pT4aN0M0, pT4bN0M0 patients were respectively 1.96, 2.27, 4.65 relative to pT2bN0M0 patients.
This data indicates that patients with pT4aN0M0 TCC have significantly worse prognosis than either pT2bN0M0 or pT3N0M0 patients. Conversely patients with pT4aN0M0 TCC have significantly better survival pT4bN0M0 disease. In consequence pT4a represents a specific entity.
Lymph node (LN) count has prognostic implications in bladder cancer patients who are treated with radical cystectomy. Carnoy solution and palpation may not identify all LNs, leading to additional effort and expense for report completion. Indocyanine green (ICG), a nontoxic dye with near infrared fluorescence properties, is transferred through lymphatics, allowing for identification of LNs. We investigated the ability of intravesically injected ICG to identify pelvic LNs.
We assessed 5 patients for near infrared fluorescence LN imaging using ICG intravesical injection. 0.5 to 1 mL of ICG (2.5 mg/mL) was injected at the tumor base or resection margins. LN dissection was performed within 2–4 hours. The SPY imaging system (Novadaq, Bonita Springs, FL, USA) was used to detect ICG fluorescence in pelvic LN specimens. The specimens were placed in Carnoy solution overnight and were then analyzed for additional nodes. The remaining tissue was entirely submitted. Tissue was grouped as ICG LN, Carnoy LN and residual LN.
In 5 patients we identified 114 LNs, ranging from 4–36 per patient. We identified 16 (14%) of LNs with ICG, 38 (33%) with Carnoy, and 60 (53%) with submission of residual tissue. One LN contained metastatic disease and was identified with ICG (Fig. 1).
ICG near infrared fluorescence can identify LNs. Many ICG LNs were <1 mm in size and might have been missed with other techniques. This simple, nontoxic imaging may prove advantageous for LN identification in pelvic LN dissection specimens. Additional investigation is needed to assess this method’s sensitivity, specificity and predictive values.
P91.