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Background: Lymph node (LN) count has prognostic implications in bladder cancer patients who are treated with radical cystectomy. Standard techniques 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. Materials/Methods: We assessed 14 patients for near infrared fluorescence LN imaging using ICG intravesicular injection. 0.5 to 1 ml of ICG (2.5 mg/ml) was injected at the tumor base. 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 both in-vivo during radical cystectomy and ex-vivo in lymph node dissection packets. Potential nodes that had positive fluorescence were confirmed by histologic examination.

BACKGROUND The objectives of this study were to determine the frequency of metastatic (M1) prostate cancer (PC) at presentation in different age groups, to examine the association of age with PC-specific mortality, and to calculate the relative contribution of different age groups to the pool of M1 cases and PC deaths. METHODS Records from 464,918 patients who were diagnosed with PC from 1998 to 2007 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were categorized according to age into groups ages

OBJECTIVE: The urological complications of 210 patients who underwent simultaneous pancreas-kidney (SPK) transplantation over a 7-year period were reviewed. SUMMARY BACKGROUND DATA: Worldwide, bladder drainage has become the accepted method of exocrine drainage after pancreas transplantation. With the increasing use of bladder drainage, the surgical post-transplant complications have shifted from intra-abdominal complications to urological complications. METHODS: Two hundred ten diabetic patients received SPK transplants with bladder drainage. A retrospective review was conducted to analyze the incidence, type, and management of urological complications. RESULTS: The most frequent urological complications were hematuria, leak from the duodenal segment, recurrent urinary tract infections, urethritis, and ureteral stricture and disruption. Complications related to the renal transplant included ureteral stricture and leaks, as well as lymphoceles. CONCLUSIONS: Despite the high incidence of urological complications, 5-year actuarial patient and graft survival are excellent. Only one graft and one patient were lost secondary to urological complications.

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? In a meta-analysis of randomized trials, neoadjuvant platinum-based combination chemotherapy administered before definitive local treatment improved survival of patients with muscle-invasive bladder cancer compared with definitive local treatment alone. However, it was not known whether chemotherapy was equally effective for pure urothelial carcinoma versus urothelial carcinoma with mixed histological features, such as squamous or glandular differentiation. To address this question we performed a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone for treatment of locally advanced urothelial cancer of the bladder. Our findings suggest that presence of squamous or glandular differentiation does not confer resistance to combination chemotherapy with MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy. OBJECTIVE • To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non-urothelial components in the tumour. PATIENTS AND METHODS • This is a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. • For the purpose of these analyses, tumours were classified based on the presence of non-urothelial components as either pure UC (n= 236) or mixed tumours (n= 59). Non-urothelial components included squamous and glandular differentiation. • Cox regression models were used to estimate the effect of neoadjuvant MVAC on all-cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage. RESULTS • There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25–0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67–1.21; P= 0.48). • There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09). CONCLUSION • Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.

The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder.This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (pT1,pT2,pT3), nodal status, and surgical margins. Linear probability models were used to estimate the effect of neoadjuvant GC on tumor down-staging with adjustment for clinical staging variables.A total of 160 eligible patients were identified, of whom 25 were treated with neoadjuvant GC before RC (GC + RC) and 135 without neoadjuvant chemotherapy (RC only). Stage pT0 at cystectomy was found in 20% of patients in the GC + RC group and in 5% of patients in the RC group (adjusted risk difference [aRD] = 16%, P = .03). For other down-staging end points, the estimated treatment effect was as follows (all point estimates favoring chemotherapy):pT1 aRD = 30% (P = .005);pT2 aRD = 30% (P = .004);pT3 aRD = 31% (P = .008); margins aRD = 8% (P = .41); nodes aRD = 4% (P = .74).Neoadjuvant GC was found to be capable of down-staging UC in the bladder; however, no effect on disease in nodes was seen in this study.

von Hippel-Lindau (VHL) tumor suppressor loss is associated with renal cell carcinoma (RCC) pathogenesis. Meanwhile, aberrant activation of the insulin-like growth factor-I (IGF-I) signaling has been implicated in the development of highly invasive metastatic RCC. However, the link between VHL inactivation and RCC invasiveness is still unexplored. Here, we show that the receptor for activated C kinase 1 (RACK1) is a novel pVHL-interacting protein. pVHL competes with IGF-I receptor (IGF-IR) for binding to RACK1 thus potentially modulating the downstream IGF-I signal pathway. Upon IGF-I stimulation, pVHL-deficient RCC cells exhibit increased RACK1/IGF-IR binding and increased IGF-IR tyrosine kinase activity. pVHL-deficient RCC cells also demonstrate elevated PI3K/Akt signaling and matrix metalloproteinase-2 activity that culminates in enhanced cellular invasiveness, which can be partially suppressed by RACK1 small interfering RNA. Domain mapping analysis showed that the pVHL α-domain and the RACK1 WD 6-7 domains are critical for the interaction. Additionally, the RACK1 expression level is not regulated by pVHL expression status, suggesting that pVHL modifies RACK1 functions independent of the VHL/elongin E3 ubiquitin ligase complex. Our data indicate that RACK1 serves as a direct mediator between loss of pVHL function and enhanced IGF-IR signaling pathway in RCC.

Purpose of review Women are generally less likely to develop bladder cancer compared with men; however, once they acquire this disease, they have a less favorable prognosis. In this review, we describe our current understanding of the relationship between sex and bladder cancer incidence and outcomes and discuss the most recent developments in this area of research. Recent findings Despite some evidence suggesting involvement of hormonal factors in bladder cancer carcinogenesis, the exact mechanisms responsible for increased bladder cancer incidence in men are still incompletely understood. The causes of increased mortality in women are also unclear. It has been hypothesized that women present with more advanced stages (and thus have inferior survival) than men because early signs of bladder cancer in women are often attributed to more common benign conditions. However, recent studies have shown that excess mortality in women persists after adjustment for stage and other tumor characteristics. Women also do not appear to be significantly undertreated for bladder cancer. Summary Despite considerable research efforts, both increased incidence in men and decreased survival in women remain somewhat of a mystery. The causes of these phenomena may include poorly understood biological factors or environmental influences, which may become a subject of future research.

Despite the high frequency with which radical prostatectomy is used to treat prostate cancer, uncertainty exists regarding the merits of a simultaneous pelvic lymph node dissection. Unresolved issues include identifying the optimal candidate and selecting the appropriate surgical template, among others. In this article, the authors discuss the pros and cons of performing a pelvic lymph node dissection and the staging/diagnostic and therapeutic implications of this procedure. The lack of robust randomized clinical trials in the literature necessitates a careful analysis of retrospective and case series data.

A literature review of PubMed reveals that 1 case report is found of a retained Foley catheter for 3 years. We report a case of a straight catheter lost in the urethra and forgotten for 20 years and its safe surgical removal. The calcified straight catheter was removed through a perineal urethrostomy and incision at the meatus and fossa navicularis. A Foley catheter was inserted easily into the urethra for drainage. At last follow-up, 7 weeks after surgery, the patient was voiding successfully without any difficulties.

Transitional-cell carcinoma of the bladder is believed to arise through a series of genetic changes affecting cell growth and proliferation. Two basic types of such genes have been described: protooncogenes and tumor suppressor genes. The former have not been studied extensively in bladder cancer, although there is evidence that c-erb B-2/neu is overexpressed. Loss of specific chromosomal regions, which is common in bladder tumors, may inactivate tumor suppressor genes, of which p53 has received the most attention. Work also has been done on epidermal growth factor and its receptor, yielding evidence that malignant and normal urothelium have different sensitivities to its action. Although several advances must be made before genetic changes come to the clinical forefront, the information now being gained with such speed holds considerable promise for diagnosis and treatment.

PURPOSE A study of preradiation and postradiation, serial serum prostate-specific antigen (PSA) levels was performed in patients who had clinically localized prostate cancer. The prognostic value of the PSA in pretreatment evaluation and posttreatment follow-up was assessed. PATIENTS AND METHODS Sixty-three patients who presented with clinically localized prostate cancer and who were treated with external-beam radiation therapy were followed-up for a median of 25 months. A serum PSA and physical examination were performed at 3-month intervals, and a bone scan was done yearly. An increase in PSA triggered an additional metastatic workup. Prostate rebiopsy was performed for new, palpable nodules or for a serial increase in PSA in the context of a negative metastatic workup. RESULTS Forty-one patients remained recurrence-free and 22 recurred clinically, 15 distantly and seven locally. The PSA was the strongest, independent, pretreatment prognostic indicator (P = .019) among pretreatment PSA, stage, and grade, but lost significance when the serum prostatic acid phosphatase (PAP) status was included. The initial rate of the PSA decrease after radiation (median half-life, 2.6 months) failed to predict outcome. Recurrence-free patients reached postradiation PSA levels that were equivalent to those reported in disease-free male populations; failure of the PSA to reach such normal levels was a multivariate predictor of subsequent failure (P less than .037). All clinicopathologic documentations of failure were preceded by an increase in PSA levels during follow-up. Delayed versus early PSA increase was associated with clinically localized versus metastatic first recurrence. CONCLUSIONS The serum PSA is an independent pretreatment and posttreatment predictor of outcome. Additionally, for a median follow-up of 25 months, delayed PSA failure is associated with clinically localized rather than metastatic recurrence, a relationship that may help in selection for local salvage therapy.

Tumor grade and stage are two of the strongest predictors for indolent versus aggressive clinical course in bladder cancer. To identify age-related trends in tumor aggressiveness the authors investigated the relationships of age with grade and stage. Pathologic specimens were obtained for 89% (527 of 590) of new bladder cancer cases among men older than 50 years of age reported to the state tumor registry in Wisconsin for 1988. Tumors were grouped as low grade (G1, G2) or high grade (G3), and as superficial (Ta) or invasive (≥ T1), according to the TNM system. This analysis included 485 transitional cell carcinomas (TCC) for which the authors determined stage-stratified and grade-stratified odds ratios for men 50 through 64 years of age and older than 65 years of age. Men older than 65 years of age with superficial TCC were more than three times as likely to have a high-grade malignancy than men 50 through 64 years of age (P = 0.01); the odds ratio was 3.44 (95% CI = 1.28, 9.26). A relationship was not apparent for invasive TCC. Age and stage were weakly associated for low-grade and high-grade TCC that may be due, in part, to the strong correlation of stage with grade as a prognostic indicator. These data suggest that men in older age groups are at increased risk for superficial bladder cancer of high grade, which portends an aggressive clinical course. Cancer 1992; 69:1445-1451.

Epidermal growth factor (EGF) is excreted in urine in high concentrations in a biologically active form. Several lines of evidence indicate that EGF plays a role in transitional cell carcinoma (TCC) development and growth. These include:(1) EGF in the normal urine of rats promotes chemically initiated TCC; (2) EGF in normal human urine stimulates the clonal growth of human TCC cells in vitro; (3) EGF stimulates the in vitro growth of human TCC cells, but not normal human urothelial cells; (4) the density and distribution of the EGF receptor (EGF-R) on human urothelial tissues permits significant access of premalignant, dysplastic, and malignant cells to EGF; and (5) the concentration of EGF in the voided urine of patients with TCC is reduced, implying that EGF may be “extracted” from urine by the greater number of EGF-Rs in patients with urothelial malignancy. Abnormal expression of the urothelial EGF-R and/or altered excretion of EGF may well precede overt evidence of TCC and thus may serve as markers of risk or exposure. Similarly, reversion of EGF-R expression or the return of excreted EGF to normal levels may provide a marker of response for preventive and therapeutic strategies. Interference with the EGF/EGF-R interaction through dietary or pharmacological manipulations of the urine, or via targeting strategies employing intravesical administration of conjugated toxins or isotopes is already being employed in experimental and clinical studies. These approaches offer promising new tools in the detection, monitoring, prevention, and management of early stage bladder cancer. © 1992 Wiley-Liss, Inc.

OBJECTIVE To determine whether microscopic invasion of perivesical fat by urothelial carcinoma (stage pT3a) confers a different prognosis relative to deep muscle invasion (pT2b) and/or gross extravesical extension (pT3b) among patients with a given nodal status treated by cystectomy. METHODS Cancer records for patients diagnosed with stage pT2b-pT3b bladder cancer from 1998-2006 were obtained from the SEER database (n = 2388). Pathologic substage (pT3a vs pT2b vs pT3b) was the primary covariate of interest. Other covariates included age, sex, race, grade, number of nodes examined, number of positive nodes, nodal stages, and radiotherapy. Cox regression model was used to estimate the covariate-adjusted effect of tumor substages on all-cause mortality. RESULTS The risk of nodal metastases increased with increasing substage (pT2b = 20%, pT3a = 36%, pT3b = 48%, trend P

For well over a decade, the results of prospective, randomized, controlled clinical trials performed primarily outside the United States have shown that intravesical instillation of chemotherapeutic agents immediately after transurethral resection of bladder tumor (TURB) decreases the likelihood of tumor recurrence, particularly for patients with newly diagnosed bladder cancers. Despite this, guidelines by the American Urological Association do not advocate its use as standard of care for the treatment of superficial bladder cancer while the European Association of urology does. We have reviewed the world literature and feel that there is ample evidence to recommend the routine use of intravesical mitomycin C after transurethral resection of bladder tumors in the United States.

Quantitative urinary immunocytology with our monoclonal antibody (mab) 486p 3/12 proved to be valuable for diagnostic use in bladder-cancer patients' urine, especially in the followup of patients with superficial bladder carcinoma. To evaluate the use of other monoclonal antibodies in bladder cancer, we compared 15 mabs directed against bladder-tumor-associated antigens from seven research groups in a broad panel of cellular and tissue specimens (bladder tumor, prostatic adenoma, and kidney stone). Quantitative evaluation was done in cytocentrifuged preparations and tissue specimens. None of the 15 mabs was bladder-tumor-specific. All 15 stained normal urothelium to some extent and six stained granulocytes. Each of the 15 seemed to identify a different cellular antigen, as can be clearly demonstrated by the staining pattern of different regions in the normal kidney. The sensitivity of quantitative urinary immunocytology in bladder-tumor patients can be improved by using a panel, rather than one mab in bladder-tumor patients, but specificity decreases simultaneously. A main reason for the poor specificity of quantitative urinary immunocytology with all 15 mabs is that false-positive results are obtained with all mabs in kidney-stone patients. Our quantitative urinary immunocytology method is a general tool for the diagnostic use of all mabs in bladder-tumor patients. Mabs that have a high sensitivity might be useful in the followup of patients with superficial bladder carcinoma. None of the 15 mabs (because of their poor specificity) seems to be helpful in quantitative urinary immunocytology for screening a population for bladder carcinoma.

We have shown that 15 different monoclonal antibodies (mAb) directed against transitional cell carcinoma (TCC) stain to a certain degree normal urothelium and normal other cells, like granulocytes and

Androgen deprivation therapy (ADT) has been the cornerstone of treatment for advanced prostate cancer for over 65 years. Although there can be worrisome side effects, data will be presented that for men with metastatic prostate cancer, immediate ADT can reduce the likelihood of developing the rare but catastrophic sequellae of metastatic disease, although it is unlikely to prolong survival compared with waiting for symptoms before initiating ADT. Additionally, for patients with extremely high risk prostate cancer that is not distantly metastatic (e.g. have a life expectancy from prostate cancer less than 10 years with all other available treatments except immediate ADT) and, whose life expectancy from non-prostate cancer diseases is excellent during this period, early ADT both alone and in conjunction with definitive local treatment prolongs survival. Moreover, ADT seems to be most effective when the cancer volume is low. However, eventually most men receiving ADT experience disease progression. The biological mechanisms explaining how prostate cancer escapes from ADT's control include: 1) Alterations in the androgen receptor (AR) and in the AR co-factors (which modify the responsiveness of the AR to androgens) allow molecules and medications which are not normally AR agonists to act as agonists. 2) The human prostate gland, and particularly prostate cancer, may be able to synthesize androgens from both cholesterol and adrenal androgens. This may occur because prostate cancer tissue has higher concentrations of androgens than does the serum in patients receiving ADT. Thus, castrated men may not be starving their prostate cancers of androgens. 3) The AR in prostatic stroma far more strongly stimulates both malignant and benign prostatic epithelial growth than the epithelial AR does. Indeed, the epithelial AR, particularly in advanced prostate cancer, may have anti-proliferative and anti-tumor progression properties. That is, the AR in the prostatic epithelial cells, particularly malignant ones, may act as a tumor suppressor. Thus, by inhibiting the epithelial AR, its protective effects may be abrogated. The controversial nature of these concepts, as well as the clinical and experimental data which support and question them, will be presented. Additionally, strategies for addressing each of these escape mechanisms, which may be able to prolong responsiveness to ADT, will be discussed.

Targeting androgens/androgen receptor (AR) functions via androgen deprivation therapy (ADT) remains the standard treatment for prostate cancer. However, most tumors eventually recur despite ADT. Here we demonstrate that the prostate AR may function as both a suppressor and a proliferator to suppress or promote prostate cancer metastasis. Results from orthotopically recombining stromal WPMY1 cells with epithelial PC3 prostate cancer cells in mice demonstrated that restoring AR in epithelial PC3 cells or knockdown of AR in stromal WPMY1 cells suppressed prostate cancer metastasis. Knockdown of the AR in epithelial CWR22rv1 prostate cancer cells also resulted in increased cell invasion in vitro and in vivo . Restoring AR in PC3 cells (PC3-AR9) results in decreased invasion in bone lesion assays and in vivo mouse models. Mice lacking the prostate epithelial AR have increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells. The consequences of these two contrasting results led to the expansion of CK5/CK8-positive intermediate cells, and mice developed larger and more invasive metastatic tumors in lymph nodes and died earlier than wild-type littermates. Mechanistic dissection suggested that androgens/AR might directly or indirectly modulate metastasis-related genes and suppression of TGFβ1 signals results in the partial inhibition of AR-mediated metastasis. Collectively, our understanding of these opposing roles of prostatic AR may revolutionize the way we combat prostate cancer, and allow the development of new and better therapies by targeting only the proliferative role of AR.

BackgroundSteroid hormones influence mitogenic signaling pathways, apoptosis, and cell cycle checkpoints, and it has long been known that incidence of bladder cancer (BC) in men is several times greater than in women, a difference that cannot be attributed to environmental or lifestyle factors alone. Castration reduces incidence of chemically-induced BC in rodents. It is unclear if this effect is due to hormonal influences on activation/deactivation of carcinogens or a direct effect on urothelial cell proliferation or other malignant processes. We examined the effect of castration on BC growth in UPII-SV40T transgenic mice, which express SV40 T antigen specifically in urothelium and reliably develop BC. Furthermore, because BC growth in UPII-SV40T mice is exophytic, we speculated BC growth was dependent on angiogenesis and angiogenesis was, in turn, androgen responsive.MethodsFlat panel detector-based cone beam computed tomography (FPDCT) was used to longitudinally measure exophytic BC growth in UPII-SV40T male mice sham-operated, castrated, or castrated and supplemented with dihydrotestosterone (DHT). Human normal bladder and BC biopsies and mouse bladder were examined quantitatively for thrombospondin-1 (TSP1) protein expression.ResultsMice castrated at 24 weeks of age had decreased BC volumes at 32 weeks compared to intact mice (p = 0.0071) and castrated mice administered DHT (p = 0.0233; one-way ANOVA, JMP 6.0.3, SAS Institute, Inc.). Bladder cancer cell lines responded to DHT treatment with increased proliferation, regardless of androgen receptor expression levels. TSP1, an anti-angiogenic factor whose expression is inhibited by androgens, had decreased expression in bladders of UPII-SV40T mice compared to wild-type. Castration increased TSP1 levels in UPII-SV40T mice compared to intact mice. TSP1 protein expression was higher in 8 of 10 human bladder biopsies of normal versus malignant tissue from the same patients.ConclusionFPDCT allows longitudinal monitoring of exophytic tumor growth in the UPII-SV40T model of BC that bypasses need for chemical carcinogens, which confound analysis of androgen effects. Androgens increase tumor cell growthin vitroandin vivoand decrease TSP1 expression, possibly explaining the therapeutic effect of castration. This effect may, in part, explain gender differences in BC incidence and implies anti-androgenic therapies may be effective in preventing and treating BC.

A total of 18 patients with locally advanced transitional cell carcinoma of the bladder underwent 2 preoperative cycles of chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin followed by radical cystectomy and 2 postoperative cycles of chemotherapy. Radical cystectomy was performed in 17 of 18 patients (94%) with a pathological partial response in 3 (17%) and a pathological complete response in 2 (11%), for an over-all response rate of 28% (95% confidence limits 10 to 53%). At 23-month median followup 9 patients (50%) remained without evidence of recurrent disease, while 9 (50%) died of metastatic bladder cancer. Average relative dose intensity of all therapy given was 78%. Hematological toxicity was moderate, with no septic deaths or bleeding complications. However, 4 thromboembolic events occurred. While downstaging of the primary bladder tumor can occur with this perioperative schedule our results were not as impressive as some previously reported findings. The incidence of thromboembolic events is worrisome.

Eighty-seven men with testis cancer (TC) and 35 men with other cancers (OC) completed measures of mood (Profile of Mood States) and of personality and psychopathology (Millon Clinical Multiaxial Inventory). Effects of primary disease, phase of diagnosis and treatment, locoregional vs. cytotoxic treatment, age, and marital status on these measures were examined. TC patients appeared more distressed during treatment, particularly during cytotoxic as compared to locoregional treatment, than before or after treatment, and more distressed than OC patients. Being married appeared to buffer the stress of cancer and its treatment. Although treatment, particularly cytotoxic therapy, appeared to result in transient distress, results did not offer strong evidence that cancer and its treatment typically precipitate severe psychopathology.

Detection of bladder cancer before deep invasion occurs offers patients a favorable prognosis. Because most bladder cancers, even when noninvasive, produce hematuria, screening asymptomatic persons at risk for bladder cancer for hematuria provides a means of promoting early detection and has the potential to reduce morbidity and mortality. However, bladder cancer-induced hematuria is quite intermittent; thus, repetitive testing is necessary. In a pilot study, 11.4% of asymptomatic men over age 50 who had at least one positive dipstick result were found on urologic work-up to have bladder cancers that were caught early enough to receive purportedly curative treatment. Issues concerning the applicability of this methodology to other high-risk populations are discussed and efforts now underway to confirm and expand upon this screening program are described.

Percutaneous intervention is essential in numerous medical diagnostic and therapeutic procedures. In these procedures, accurate insertion of the surgical needle is very important. But precise interstitial intervention is quite challenging. Robot-assisted needle intervention can significantly improve accuracy and consistency of various medical procedures. To design and control any robotic system, the design and control engineers must know the forces that will be encountered by the system and the motion trajectories that the needling mechanism will have to follow. Several researchers have reported needle insertion forces encountered while steering through soft tissue and soft material phantoms, but hardly any in-vivo force measurement data is available in the literature. In this paper, we present needle insertion forces and motion trajectories measured during actual brachytherapy needle insertion while implanting radioactive seeds in the prostate glands of twenty five patients.

Placement accuracy of different types of surgical needles in soft biological tissues depends on a variety of factors. The needles used for prostate brachytherapy procedures are typically about 200 mm in length and 1.27-1.47 mm in diameter. These needles are prone to deflection and thereby depositing the seeds at a location other than the planned one. Thus tumorous tissues may not receive the planned dose whereas the critical organs may be over-dosed. A significant amount of needle deflection and target movement is related to some procedure-specific criteria and some patient-specific criteria. In this paper we have developed needle insertion force models taking both procedure-specific criteria and patient-specific criteria. These statistical models can be used to estimate the force that the needle will experience during insertion and thereby control the needle to reduce the needle deflection and enhance seed delivery accuracy.

The most common symptom of bladder cancer (BC) is hematuria and microhematuria will occur in virtually all patients with BC if one tests for it frequently enough. However, hematuria even when caused by serious disease, often is intermittent, and once above some threshold the degree of microhematuria is unrelated to the seriousness of its underlying cause. Based on these principles a BC screening study was conducted to determine if repetitive hematuria testing can detect BC early and whether this resulted in reduced BC mortality, in long-term follow-up compared with disease related outcomes of a contemporary unscreened population similar to the one taking part in screening. The study and the long-term outcomes are reviewed. At 14 years minimum follow-up, none of the 21 men diagnosed with BC by hematuria screening have died of the disease; 12 were still alive and 9 had died of diseases other than BC, with a median survival of 8.8 years. The lower overall mortality in screenees with BC was primarily because of the reduced mortality from BC in that group. Screening had effected a shift of the high grade tumors to earlier (more superficial) stages at diagnosis.

In prostate brachytherapy, radioactive seeds are permanently implanted in the prostate for delivering a tumorocidal dose to the cancerous tissues. These seeds provide a significant radiation dose to a relatively small volume, requiring that the seeds be placed accurately to ensure complete treatment. Sensitivity of the urethra and rectal mucosa to radiation are other factors that heighten the need for careful placement of the seeds. In currently practiced manual procedures, the needles are inserted into the patient through fixed holes of a physical template where the maneuverability of the needle is extremely difficult. In contrast, a robotic system can not only provide flexibility in positioning and orientating along with improved consistency and accuracy of needle insertion and seed deposition but may also assist less skillful/inexperienced clinicians to treat patients with higher quality. Thus, it is important to develop an automated (or a semiautomated) seed delivery device which can provide enhanced consistency, accuracy and efficiency.

Quantification of mechanical properties of human prostate tissue is important for developing sonoelastography for prostate cancer detection. In this study, we characterized the frequency-dependent complex Young's modulus of normal and cancerous prostate tissues in vitro by using stress relaxation testing and viscoelastic tissue modeling methods. After radical prostatectomy, small cylindrical tissue samples were acquired in the posterior region of each prostate. A total of 17 samples from eight human prostates were obtained and tested. Stress relaxation tests on prostate samples produced repeatable results that fit a viscoelastic Kelvin-Voigt fractional derivative (KVFD) model (r(2)>0.97). For normal (n = 8) and cancerous (n = 9) prostate samples, the average magnitudes of the complex Young's moduli (|E*|) were 15.9 +/- 5.9 kPa and 40.4 +/- 15.7 kPa at 150 Hz, respectively, giving an elastic contrast of 2.6:1. Nine two-sample t-tests indicated that there are significant differences between stiffness of normal and cancerous prostate tissues in the same gland (p < 0.01). This study contributes to the current limited knowledge on the viscoelastic properties of the human prostate, and the inherent elastic contrast produced by cancer.

Purpose Southwest Oncology Group (SWOG) trial 8794 demonstrated that adjuvant radiation reduces the risk of biochemical (prostate-specific antigen [PSA]) treatment failure by 50% over radical prostatectomy alone. In this analysis, we stratified patients as to their preradiation PSA levels and correlated it with outcomes such as PSA treatment failure, local recurrence, and distant failure, to serve as guidelines for future research. Patients and Methods Four hundred thirty-one subjects with pathologically advanced prostate cancer (extraprostatic extension, positive surgical margins, or seminal vesicle invasion) were randomly assigned to adjuvant radiotherapy or observation. Results Three hundred seventy-four eligible patients had immediate postprostatectomy and follow-up PSA data. Median follow-up was 10.2 years. For patients with a postsurgical PSA of ≤ 0.2 ng/mL, radiation was associated with reductions in the 10-year risk of biochemical treatment failure (72% to 42%), local failures (20% to 7%), and distant failures (12% to 4%). For patients with a postsurgical PSA between higher than 0.2 and ≤ 1.0 ng/mL, reductions in the 10-year risk of biochemical failure (80% to 73%), local failures (25% to 9%), and distant failures (16% to 12%) were realized. In patients with postsurgical PSA higher than 1.0, the respective findings were 94% versus 100%, 28% versus 9%, and 44% versus 18%. Conclusion The pattern of treatment failure in high-risk patients is predominantly local with a surprisingly low incidence of metastatic failure. Adjuvant radiation to the prostate bed reduces the risk of metastatic disease and biochemical failure at all postsurgical PSA levels. Further improvement in reducing local treatment failure is likely to have the greatest impact on outcome in high-risk patients after prostatectomy.

BACKGROUND. The U.S. Food and Drug Administration recently approved screening high-risk patients for bladder cancer using urine-based markers. The cost and life-years saved associated with bladder cancer screening were evaluated. METHODS. A Markov model was created to estimate cumulative cancer-related costs and efficacy of screening (vs. no screening) of a high-risk population for bladder cancer using a urine-based tumor marker over a 5-year period. Assumptions were based on literature review of survival and progression rates for patients with bladder cancer and costs associated with different bladder cancer disease states. RESULTS. Screening for bladder cancer in a population with a 4% incidence of bladder cancer resulted in a gain of 3.0 life years per 1000 subjects at a cost savings of $101,000 for the population, assuming a 50% downstaging in the screened population from muscle-invasive to nonmuscle-invasive disease. One-way sensitivity analyses found that screening is the most cost-effective strategy if cancer incidence is >1.6%, tumor marker costs 26%, marker specificity is >54%, downstaging with screening is >20%, and office cystoscopy costs

Males have a higher incidence of bladder cancer than females, but the reason remains unknown. Unlike prostate cancer, human bladder cancer is not generally considered to be dependent on hormone activity. We investigated the possible involvement of androgens and the androgen receptor (AR) in bladder cancer.We used N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) to induce bladder cancer in wild-type male and female mice, with and without castration in males, and in AR knockout (ARKO) male and female mice, with and without dihydrotestosterone (DHT) supplementation in males. We also treated human bladder cancer cell lines, including TCC-SUP and UMUC3, and mouse xenograft models established from these same lines with androgen deprivation therapy (antiandrogen treatment or castration), AR-small-interfering RNA (AR-siRNA), or the anti-AR molecule ASC-J9, which causes selective degradation of the AR.More than 92% of wild-type male and 42% of wild-type female mice treated with BBN eventually developed bladder cancer, whereas none of the male or female ARKO mice did. Treatment with BBN induced bladder cancer in 25% of ARKO mice supplemented with DHT and in 50% of castrated wild-type male mice. Androgen deprivation of AR-positive human bladder cancer cells by androgen depletion in vitro or castration in mice and/or by treatment with the antiandrogen flutamide in vitro or in vivo, as well as AR knockdown by AR-siRNA or by ASC-J9, suppressed cell proliferation in vitro and xenograft tumor growth in vivo.Our findings implicate the involvement of both androgens and the AR in bladder cancer. Targeting AR and androgens may provide novel chemopreventive and therapeutic approaches for bladder cancer.

Purpose To examine the association between extended-duration prophylaxis (EDP), low-molecular-weight heparin prophylaxis for 28 days after surgery for urologic cancer in patients at high risk of developing a venous thromboembolism (VTE), the risk of VTE, and the complications resulting from VTE prophylaxis. Materials and methods The cohort included 332 patients at high risk for VTE who were surgically treated for urologic cancer from June 2011 to June 2014. Adherence to VTE prophylaxis protocol, VTEs, and complications within 365 days from surgery were tracked. Patients were grouped as follows: (1) per protocol in-hospital prophylaxis with EDP ( n = 107), (2) per protocol in-hospital prophylaxis without EDP ( n = 42), (3) not per protocol in-hospital prophylaxis with EDP ( n = 83), and (4) not per protocol in-hospital prophylaxis without EDP ( n = 100). The risk of VTE was compared between the 4 groups using the Cox model, with adjustment for baseline risk factors. Results The rates of VTEs and median times to VTE were 7% and 58 days in group 1, 17% and 44 days in group 2, 17% and 46 days in group 3, and 21% and 15 days in group 4, respectively. Adjusted hazard ratios (HR) for VTE were HR = 0.27 (95% CI: 0.11–0.70) for groups 1 vs. 4; HR = 0.66 (95% CI: 0.25–1.60) for groups 2 vs. 4; and HR = 0.66 (95% CI: 0.29–1.26) for groups 3 vs. 4 with a trend of P = 0.002. The incidence of complications from VTE prophylaxis was not significantly different between the groups, with a rate of 8% in group 1, 17% in group 2, 6% in group 3, and 12% in group 4 ( P = 0.33). Conclusions In high-risk urologic cancer surgery patients, a clinical protocol, with perioperative and EDP, is safe and effective in reducing VTE events.

Exosomes are 30-100nM membrane-bound vesicles that participate in intercellular communication and facilitate tumor microenvironments. The mechanisms by which exosomes modify tumor niches are not fully understood. One possibility is that exosomes deliver biologically active molecules like mRNA, protein, miRNA and long non coding RNA (lncRNA) that alter the metabolism of recipient cells to produce pathological phenotypes. Exosomes may also activate the expression of genes involved in tumor progression in recipient cells. Overexpression of the lncRNA HOTAIR is associated with poor prognosis and affects tumor progression, in part, by recruiting PRC2 and LSD1 chromatin modifying complexes to thousands of target genes involved in tumor progression processes such as epithelial-to-mesenchyme transition (EMT). We show that HOTAIR is enriched in bladder cancer (BC) patient tumors and urinary exosomes. BC cell lines also express elevated levels of HOTAIR. Knockdown of HOTAIR in BC cell lines significantly reduces migration and invasion in trans-well and 3D culture, which correlates with EMT gene expression changes in these cells. Exosomes isolated from shHOTAIR vs shScramble cells fail to facilitate migration and invasion in 3D culture of a recipient BC cell line. Selected bands were isolated from a coomassie gel of shHOTAIR and shScramble exosomes and sent for mass spectrometry. Hundreds of putative proteins were identified including proteins involved in RNA binding, apoptosis, vesicle trafficking and integrins. These data support HOTAIR as an important player in exosome-mediated BC tumor progression possibly through affects on gene expression in exosome producer cells. For example, in shHOTAIR cells the loss of PRC2 and/or LSD1 complexes from key genes may ultimately affect the proteins available for packaging into exosomes. Exosomes have important roles in the tumor microenvironment and these data support a role for HOTAIR in the modulation of exosome-mediated tumor progression. Citation Format: Claudia Berrondo, Jonathan Flax, Edward M. Messing, Carla Beckham. The long non-coding RNA HOTAIR affects exosome-mediated bladder cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 152. doi:10.1158/1538-7445.AM2015-152

Exsosomes are nano-vesicles secreted by most types of cells, and substantially increased secretion in cancer cells. Their role in tumorigenesis/cancer progression have been extensively studied but their role in regulating therapy response have been suggested without in depth investigation. We are particularly interested in exosome's roles in cisplatin resistant, since cisplatin is one of the most widely used chemodrugs for many cancer types. To investigate the role of exosomes in cisplatin resistance in bladder cancer, we examined the cisplatin sensitivity among five bladder cancer cell lines. The expression levels of exosome associated genes that are involved in exosome biogenesis and secretion/internalization were examined by quantative PCR. Interestingly, cisplatin resistant bladder cancer cells express relative high level of exosome associated genes as compared to cisplatin sensitive cells. More importantly, cisplatin treatment induces the expression of exosome associated genes’ expression in cisplatin resistant cells, but not in sensitive cell. Among all those genes, we are particularly interested in Rab gene family, and mechanistic study of targeting those Rab proteins is undergoing. The correlative exosome genes profiles with cisplatin resistance suggested exosome production might facilitate cancer cells escaping from cisplatin-induced cell death; thereby, inhibition of exosome might sensitize cancer cells response to cisplatin. To test this, we have screened several compounds that are known to inhibit exosome biogenesis and uptake, and. found that inhibition of exosomes by dynasore + NSC23766, indeed can sensitize bladder cancer cells to cisplatin. In summary, we concluded that cancer exosome play a critical role of promoting cisplatin resistance in bladder cancer, and inhibition of exosomes sensitizes bladder cancer cell response to cisplain. The exosome related profiles potentially can serve as therapy biomarkers Citation Format: Chiahao Wu, Chris Silvers, Elizabeths Guancial, Jong-Wei Hsu, Edward Messing, Yi-Fen Lee. Cancer exosome promotes cisplatin resistance In bladder cancer and inhibition of exosome sensitizes bladder cancer cells to cisplatin chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5475. doi:10.1158/1538-7445.AM2015-5475

A methodology to study the relationship between clinical variables [e.g., prostate specific antigen (PSA) or Gleason score] and cancer spatial distribution is described. Three-dimensional (3-D) models of 216 glands are reconstructed from digital images of whole mount histopathological slices. The models are deformed into one prostate model selected as an atlas using a combination of rigid, affine, and B-spline deformable registration techniques. Spatial cancer distribution is assessed by counting the number of tumor occurrences among all glands in a given position of the 3-D registered atlas. Finally, a difference between proportions is used to compare different spatial distributions. As a proof of concept, we compare spatial distributions from patients with PSA greater and less than [Formula: see text] and from patients older and younger than 60 years. Results suggest that prostate cancer has a significant difference in the right zone of the prostate between populations with PSA greater and less than [Formula: see text]. Age does not have any impact in the spatial distribution of the disease. The proposed methodology can help to comprehend prostate cancer by understanding its spatial distribution and how it changes according to clinical parameters. Finally, this methodology can be easily adapted to other organs and pathologies.

Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC.

341 Background: Platinum (Pt) resistance is a major limitation in the treatment of muscle-invasive bladder cancer (MIBC), for which Pt-based chemotherapy remains the standard of care. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our previous studies in lung cancer demonstrate significant correlation between tissue Pt concentration and tumor response to neoadjuvant chemotherapy (NAC). Tissue Pt concentration was measured in bladder specimens exposed to Pt-based NAC and correlated to pathologic response. Methods: A cohort of 19 clinically annotated, archived frozen bladder specimens from MIBC patients treated with three to four cycles of Pt-based NAC was identified [pT0 (pathologic complete response, pCR), n=4; pTis or pT1 (pathologic partial response, pPR), n=6; >/= pT2 (minimal pathologic response/progression), n=9]. Two cystectomy specimens from MIBC patients treated with Pt-based adjuvant therapy were used as controls. Non-tumor bearing adjacent bladder tissue (“normal”) was identified in cystectomy specimens by a genitourinary pathologist. Total Pt concentration in normal tissue was measured by flameless atomic absorption spectrophotometry. Three group Kruskal-Wallis tests were used to compare the distributions of Pt concentrations by pathologic response (pCR, pPR, minimal response/progression). Mann-Whitney non-parametric two-sided tests were used for two group comparisons. Results: Total Pt concentration in normal adjacent bladder tissue differed by tumor pathologic response (p=0.011). Specimens with a pCR had the highest Pt concentrations compared to those with a pPR (p=0.0095) or no response/progression (p=0.0196). There was no significant difference in Pt levels between PR and no response/progression group (p=0.37). Conclusions: Our findings suggest that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Studies investigating factors that modulate intracellular Pt concentration, such as expression of influx/efflux Pt transporters, may serve as predictive biomarkers and promote increased use of Pt-based NAC.

Bladder cancer (BC) screening is not accepted in part owing to low overall incidence. We used the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Cancer Screening Trial (NLST) to identify optimal high-risk populations most likely to benefit from screening.Data were extracted from PLCO and NLST to stratify risk of BC by overall population, sex, race, age at inclusion, and smoking status. Incidence rates between groups were compared using chi-square test.BC was identified in 1,430/154,898 patients in PLCO and 439/53,173 patients in NLST. BCs were grade III/IV in 36.8% and 41.3%. Incidence rates were significantly higher in men than in women (PLCO: 1.4 vs. 0.31/1,000 person-years and NLST: 1.84 vs. 0.6/1,000 person-years, both P0.0001). In proportional hazards models, male sex, higher age, and duration and intensity of smoking were associated with higher risk of BC (all P0.0001). In men older than 70 years with smoking exposure of 30 pack-years (PY) and more, incidence rates were as high as 11.92 (PLCO) and 5.23 (NLST) (per 1,000 person-years). In current high-intensity smokers (≥50 PY), the sex disparity in incidence persists in both trials (0.78 vs. 2.99 per 1,000 person-years in PLCO and 1.12 vs. 2.65 per 1,000 person-years in NLST).Men older than 60 years with a smoking history of30 PY had incidence rates of more than 2/1,000 person-years, which could serve as an excellent population for screening trials. Sex differences in the incidence of BC cannot be readily explained by the differences in exposure to tobacco, as sex disparity persisted regardless of smoking intensity.

ContextDespite a stage-shift to earlier cancer stages and lower tumor volumes for prostate cancer, pathologically advanced disease is detected at radical prostatectomy in 38% to 52% of patients. However, the optimal management of these patients after radical prostatectomy is unknown.ObjectiveTo determine whether adjuvant radiotherapy improves metastasis-free survival in patients with stage pT3 N0 M0 prostate cancer.Design, Setting, and PatientsRandomized, prospective, multi-institutional, US clinical trial with enrollment between August 15, 1988, and January 1, 1997 (with database frozen for statistical analysis on September 21, 2005). Patients were 425 men with pathologically advanced prostate cancer who had undergone radical prostatectomy.InterventionMen were randomly assigned to receive 60 to 64 Gy of external beam radiotherapy delivered to the prostatic fossa (n = 214) or usual care plus observation (n = 211).Main Outcome MeasuresPrimary outcome was metastasis-free survival, defined as time to first occurrence of metastatic disease or death due to any cause. Secondary outcomes included prostate-specific antigen (PSA) relapse, recurrence-free survival, overall survival, freedom from hormonal therapy, and postoperative complications.ResultsAmong the 425 men, median follow-up was 10.6 years (interquartile range, 9.2-12.7 years). For metastasis-free survival, 76 (35.5%) of 214 men in the adjuvant radiotherapy group were diagnosed with metastatic disease or died (median metastasis-free estimate, 14.7 years), compared with 91 (43.1%) of 211 (median metastasis-free estimate, 13.2 years) of those in the observation group (hazard ratio [HR], 0.75; 95% CI, 0.55-1.02; P = .06). There were no significant between-group differences for overall survival (71 deaths, median survival of 14.7 years for radiotherapy vs 83 deaths, median survival of 13.8 years for observation; HR, 0.80; 95% CI, 0.58-1.09; P = .16). PSA relapse (median PSA relapse–free survival, 10.3 years for radiotherapy vs 3.1 years for observation; HR, 0.43; 95% CI, 0.31-0.58; P