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Objectives To evaluate the impact of intralesional heterogeneity on the performance of multiparametric magnetic resonance imaging (mpMRI) in determining cancer extent and treatment margins for focal therapy (FT) of prostate cancer. Patients and Methods We identified men who underwent primary radical prostatectomy for organ‐ confined prostate cancer over a 3‐year period. Cancer foci on whole‐mount histology were marked out, coding low‐grade (LG; Gleason 3) and high‐grade (HG; Gleason 4–5) components separately. Measurements of entire tumours were grouped according to intralesional proportion of HG cancer: 0%, 12 mm vs 26% for ≤12 mm) and those containing HG cancer (44%, vs 20% for LG only). Size discrepancy analysis suggests an optimal tumour size of ≤12 mm and treatment margins of 5–6 mm for FT. For tumours ≤12 mm in diameter, applying 5‐ and 6‐mm treatment margins would achieve 98.6% and 100% complete tumour ablation, respectively. For tumours of all sizes, using the same margins would ablate >95% of the HG cancer components. Conclusions Multiparametric MRI performance in estimating prostate cancer size, and consequently the treatment margin for FT, is impacted by tumour size and the intralesional heterogeneity of cancer grades.

OBJECTIVE To compare the detection rates of prostate cancer between systematic biopsy and targeted biopsy using a stereotactic robot-assisted transperineal prostate platform. MATERIALS AND METHODS We identified consecutive patients with suspicious lesion(s) on multiparametric magnetic resonance imaging (mpMRI), who underwent both systematic and MRI-transrectal ultrasonography (US) fusion targeted biopsy using our proprietary transperineal robot-assisted prostate biopsy platform between January 2015 and January 2019 at our institution, for retrospective analysis. Comparative analysis was performed between systematic and targeted biopsy using McNemar's test, and the cohort was further stratified by prior biopsy status and Prostate Imaging Reporting and Data System (PI-RADS) v2.0 score. International Society of Urological Pathology (ISUP) grade group (GG) ≥2 cancers (previously known as Gleason grade ≥7) were considered to be clinically significant. RESULTS A total of 500 patients were included in our final analysis, of whom 67 (13%) were patients with low-risk cancer on active surveillance. Of the 433 patients without prior diagnosis of cancer, 288 (67%) were biopsy-naive. A total of 248 (57%) were diagnosed with prostate cancer, with 199 (46%) having clinically significant prostate cancer (ISUP GG ≥2). There were no statistically significant differences in the overall prostate cancer and clinically significant prostate cancer detection rate between systematic and targeted biopsy (51% vs 49% and 40% vs 38% respectively; P = 0.306 and P = 0.609). Of the 248 prostate cancers detected, 75% (187/248) were detected on both systematic and targeted biopsy, 14% (35/248) were detected on systematic biopsy alone and 11% (26/248) were detected on targeted biopsy alone. Of the 199 clinically significant cancers detected, 69% (138/199) were detected on both systematic and targeted biopsy, 17% (33/199) on systematic biopsy alone and 14% (28/199) on targeted biopsy alone. There were no statistically significant differences in the detection rate between systematic and targeted biopsy for both overall and clinically significant prostate cancer, even when the cohort was stratified by prior biopsy status and PI-RADS score. Targeted biopsy has greater sampling efficiency compared to systematic biopsy for both overall and clinically significant prostate cancer (23.2% vs 9.8%, P < 0.001 and 14.8% vs 5.6%, P < 0.001). CONCLUSIONS Using our robot-assisted transperineal prostate platform, combined MRI-US targeted biopsy with concurrent systematic prostate systematic biopsy probably represents the optimal method for the detection of clinically significant prostate cancer.

This IRB-approved prospective pilot study evaluates the safety and feasibility of performing stereotactic robot-assisted transperineal MRI-US fusion targeted prostate biopsy under local anaesthesia (LA) with sedation. 30 patients who underwent robotic transperineal prostate biopsy between September 2017 and June 2018 were recruited. All biopsies were performed with the iSR’obot Mona Lisa® and BK3000 ultrasound system. Intravenous paracetamol 1 g, with midazolam and fentanyl were given at positioning. After administration of 5 mL of 1%-lidocaine into the perineal skin 2 cm above and lateral to the anus, periapical prostatic block with 10 mL mixture of 1%-Lidocaine and 0.5%-Marcaine was given. The median age of patients was 66 years (range 53–80 years). Median PSA and mean prostate volume were 8.1 ng/ml (range 4.2–20.6 ng/ml) and 40.1 cc (range 18.6–70 cc). 24 (80.0%) patients had targeted prostate biopsy, with median number of targeted cores of 8 (range 5–16). All patients had saturation biopsy and median number of saturation cores was 21 (range 9–48). Mean dose of intravenous midazolam given was 1.5 mg (range 0–5 mg) and intravenous fentanyl was 75 mcg (10–150 mcg). No patient required conversion to GA. Two patients required motion compensation of 3 mm and 7.5 mm, respectively, due minor movement. Immediate post-operative pain score was 0 for all patients. 29 of 30 patients (96.7%) were discharged within 24 h of procedure. There were no immediate severe complications. Adenocarcinoma was detected in 19/30 (63.3%) cases. This pilot feasibility study showed that stereotactic robotic transperineal MRI-US fusion targeted prostate biopsy can be safely and accurately performed under LA with sedation.

Recent evidence suggests that the presence of a systemic inflammatory response plays an important role in the progression of several solid tumors. The neutrophil-to-lymphocyte ratio (NLR) has been proposed as easily assessable markers of systemic inflammation and has been shown to represent a prognostic marker in prostate cancer in previous studies. Data from 668 patients with localized prostate cancer treated with prostatectomy (open and robot assisted) in Singapore General Hospital from 1998 to 2014 were analyzed. Correlation between NLR and histopathological status was analyzed. Association between NLR and distant metastases-free survival (MFS), cancer-specific survival (CSS), overall survival (OS), and biochemical disease-free survival (BDFS) was assessed. NLR was not significantly correlated with histopathological status, including Gleason score (≤ 6 versus 7 versus ≥ 8, p = 0.159), lymph node metastasis (negative versus positive, p = 0.159), or surgical margin status (negative versus positive, p = 0.494). NLR was categorized into two groups (

Purpose An elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with adverse outcomes in various malignancies. However, its role in prognosticating testicular cancer (TC) has not been validated. We aim to study the relationship between NLR and TC. Materials and methods We retrospectively reviewed 160 patients with histological proven TC from January 2005 to June 2016. Youden's index was used to analyse NLR and a cut-off point of 3.0 was obtained, with statistical receiver operating characteristics of 0.755. Chi-square test, Kaplan-Meier (log rank test) and logistics regression models were used to predict NLR association with survival outcomes. Results Median age was 34 years old (range, 17-68 years old). There were 102 pure seminomas and 58 non-seminomatous germ cell tumours. Median follow-up period was 8 years (range, 2.5-17 years). NLR ≥3.0 was independently associated with lymph node involvement (p=0.031; odds ratio [OR], 2.91; 95% confidence interval [CI], 1.67-5.83; p=0.038; OR, 4.12; 95% CI, 1.26-6.51) and metastatic disease (p=0.041; OR, 2.48; 95% CI, 1.22-3.98; p=0.043; OR, 2.21; 95% CI, 1.17-3.65) in both seminomatous and non-seminomatous germ cell tumours, translating to a more advanced disease. Moreover, NLR ≥3.0 also predicts poorer cancer specific survival in these patients. Conclusions NLR can be an inexpensive haematological marker in predicting advanced TC staging and poorer survival outcome. NLR complements the traditional cancer staging by identifying a group of high risk patients who may benefit from multimodal treatment and closer surveillance to achieve long term survival.

Background NLR is known to have prognostic value for metastatic prostate cancer (PCa). However for early PCa due to lack of systemic response; the role of NLR is not conclusive. In this study we aim to evaluate the predictive value of NLR for early clinical PCa in patients who underwent robotic transperineal prostate biopsy (RTPB). Methods Patients who underwent RTPB under general anesthesia (GA), at the Department of Urology, Singapore General Hospital between Sep 2006 and Feb 2016 were retrospectively reviewed. Exclusion criteria includes: 1. Patients with missing value of PSA NLR 2. Patients who underwent biopsy for non-diagnostic purposes. 3. Patients with chronic inflammation or high grade prostatic intraepithelial neoplasia. Patients who had more than one biopsies and only the last histology results were included in this study. NLR was calculated for all patients using Complete blood count that was done as pre-admission test before GA within 4 weeks before operation. NLR values were compared between PCa; clinical significant PCa and benign group. Patients were divided further into different groups according to PSA level for subgroup analysis. Results A total 652 patients who underwent RTPB for diagnostic purpose with valid pre-procedure PSA level were included in this study. There were total 409 (62.7%) benign histology and 243 (37.3%) PCa cases. Median NLR in the benign histology group and PCa group were 2.00 and 1.99. There was no statistically significant (P=0.29). In the subgroups analysis, there were also no significant difference of median NLR value in clinical significant cancer group (defined as Gleason 3 + 4 and above) when compared to benign group (NLR 2.00 vs. 2.01, P=0.41) as well as in prostate cancer group and benign group according to different pre-biopsy PSA levels (PSA < 4, 4-10, 10-20 and > 20 ug/L), respectively. (P>0.05). NLR is not a significant predictor for Gleason grade group and D’Amico risk stratification group. (P>0.05) Conclusion There were no statistical significant difference of NLR between benign and prostate cancer group as a whole or in the subgroup analyses for patients who underwent RTPB. NLR may have a limited role in predicting early prostate cancer.

Prostate cancer largely affects older men. This study aims to investigate prostate cancer in younger men (

ObjectiveTo evaluate the incidence and management of local and systemic complications afflicting patients with de novo metastatic prostate cancer (mPCa) in Singapore.DesignRetrospective analysis of a large prospective Uro-oncology registry of mPCa.SettingThis study is carried out in a tertiary hospital in Singapore.ParticipantsWe reviewed our institution’s prospectively maintained database of 685 patients with mPCa over a 20-year period (1995–2014). Patients with non-mPCa or those progressed to metastatic disease after previous curative local treatments were excluded.Primary and secondary outcome measuresThe primary outcome was to evaluate the systemic and local morbidity rates associated with mPCa. Local complication was defined as the need for palliative procedures to relieve urinary obstruction, worsening renal function or refractory haematuria, while systemic complication was related to radiographic evidence of skeletal-related pathological fractures. Secondary outcomes analysed were the management and overall survival patterns over 20 years.Results237 (34.6%) patients required local palliative treatments. 88 (12.8%) patients presented with acute urinary retention, 23 patients (9.7%) required repetitive local palliative treatments. On multivariate analyses, prostate-specific antigen >100 (p=0.02) and prostate volume >50 g (p=0.03) were independent prognostic factors for significant obstruction requiring palliative procedures. 118 (17.2%) patients developed skeletal fractures, with poor Eastern Cooperative Oncology Group Performance (ECOG) status (p=0.01) and high volume bone metastasis (pConclusionMorbidities and complications arising from mPCa are more common and debilitating than we thought, often requiring immediate palliative treatments, while many necessitate repeated interventions with progression.

Primary ADT (pADT) monotherapy is used significantly for patients with clinically localised disease in Asia and is acceptable even by guidelines, especially in intermediate- and high-risk disease. This occurs despite controversy in the West and data suggesting association with adverse effects, notably cardiovascular events. We therefore sought to assess the impact of pADT on all-cause mortality and prostate cancer-specific mortality (PCSM) in Asian men with high-risk and unfavourable intermediate-risk PCa. With cancer registry data, men from a single centre in Singapore with clinically localised high-risk/unfavourable intermediate-risk PCa diagnosed between 2004 and 2014 and either treated conservatively with no therapy or started on pADT within 1 year of diagnosis were followed up through January 2017. Patients with non-localised PCa (clinical stage T4, regional/distant lymph node involvement, metastases), or receipt of local therapy (radical prostatectomy/radiotherapy) were excluded. The primary outcomes of all-cause mortality and PCSM were analysed with Cox proportional hazards regression models. Three hundred and forty Asian men were analysed, and 177 (52.1%) were started on pADT, with mean age of 77 (49–98) years. There were 119 deaths in the cohort, and 68 (38.4%) occurred in patients treated with pADT (median follow-up, 4.4 years). After adjusting for comorbidities and clinical characteristics, pADT did not provide benefit to all-cause mortality, PCSM or cardiovascular mortality. For clinically localised unfavourable intermediate-risk and high-risk PCa, starting pADT within 12 months of diagnosis is not associated with improved 5-year all-cause mortality or PCSM compared to patients treated conservatively with no therapy and should be discouraged due to lack of mortality benefit.

Objectives To study the role of the neutrophil-to-lymphocyte ratio in predicting survival outcomes for patients with advanced bladder cancer. Methods We retrospectively reviewed 150 patients diagnosed with advanced or metastatic bladder cancer between January 2004 and June 2014. The neutrophil-to-lymphocyte ratio was computed on diagnosis and after the first cycle of chemotherapy. A neutrophil-to-lymphocyte ratio cut-off of 3.0 was determined, with a concordance index of 0.89. Kaplan–Meier curves, log–rank tests, Cox proportional hazards and logistic regression models were used to predict the association of the neutrophil-to-lymphocyte ratio with survival outcomes. Results Just five patients were alive at the end of the study; the rest died from metastatic bladder cancer. On multivariate analysis, higher Eastern Cooperative Oncology Group status, lymphadenopathy, visceral metastases and neutrophil-to-lymphocyte ratio ≥3.0 were associated with poorer overall survival (hazard ratio 1.67, P = 0.03; hazard ratio 1.97, P =

Purpose To report the safety profile and 2-year functional outcomes of in-bore magnetic resonance (MR)-guided focused ultrasound on single cancer foci in men with prostate cancer. Materials and Methods Ethics approval was obtained from the centralized institutional review board for this prospective single-arm study, and patients provided informed consent. Patients with untreated low-volume low-grade prostate cancer (clinical stage T2a or lower; Gleason score, 3+3; index tumor ≤10 mm

The renal cell carcinoma registry (RCCR) at the Singapore General Hospital was established in the 1980s. In 2012, the registry transited to a partially automated system using Research Electronic Data Capture (REDCap) and Oracle Business Intelligence Enterprise Edition (OBIEE), which is a platform for retrieval of electronic data from the Electronic Health Intelligence System (eHIntS). A committee was formed of experts from the department of urology and the health services research center, as well as an information technology (IT) team to evaluate the efficacy of the partially automated system. In the 5 years after the new system was implemented, 1,751 cases were recorded in the RCCR. The casefinding completeness increased by 1.9%, the data accuracy rate was 97%, and the efficiency increased by 12%. Strengths of the new system after partial automation were: (1) secure access to the registry via the hospital Web, (2) direct access to REDCap via the electronic medical records system, (3) automated and timely data extraction, and (4) visual presentation of data. On the other hand, we also encountered several challenges in the process of automating the registry, including limited IT support, limited expertise in matching data variables from RCCR and eHIntS, and limited availability and accessibility of eHIntS information for import into REDCap. In summary, despite these challenges, partial automation was achieved with the REDCap/OBIEE system, enhancing efficiency, data security, and data quality.

INTRODUCTION AND OBJECTIVES:Accurate imaging is crucial in focal therapy for prostate cancer. There is limited data for the prediction of cancer size using multiparametric MRI (mp-MRI). We evaluate...

INTRODUCTION AND OBJECTIVE:The aim of this study is to validate PIRADSv2 on biopsy-naive – mpMRI in detecting all prostate cancer lesions and clinically significant prostate cancer by correlation w...

End-stage renal disease (ESRD) patients with acquired cystic kidney disease are at higher risk of developing renal cell carcinoma (RCC) than the general population. The aim of this study was to investigate the clinical and histopathological differences between ESRD patients and the general population with RCC.Data were retrospectively collected from all nephrectomies performed for localized RCC from 2000 to 2010. Age at nephrectomy, gender, race, symptoms, baseline Eastern Cooperative Oncology Group (ECOG) performance status, Charlson Comorbidity Index score and histological data were extracted. Independent-samples t test and Mann-Whitney test were used for quantitative data, while chi-squared (two-sided) and Fisher's exact tests were used for qualitative data.This study included 627 patients: 73 with and 554 without ESRD. The majority of patients were Chinese. The male to female ratio of 2:1 was identical in both groups. Baseline ECOG performance status and Charlson Comorbidity score were higher in the ESRD group. RCC in ESRD patients was more frequently asymptomatic (56.2% vs 44.9%, p = 0.071), diagnosed earlier (53.6 ± 11.8 years vs 57.9 ± 12.2 years, p = 0.004) and of lower stage (p0.001). The ESRD cohort had a higher proportion of the papillary histological subtype (21.9% vs 9.7%, p0.001). Importantly, there was a trend towards more favourable outcomes in ESRD patients in terms of cancer-specific (p = 0.203) and relapse-free survival (p = 0.096).This study suggests that RCC in ESRD patients is associated with more favourable clinical and histological features and oncological outcome compared with that in patients with normal renal function.

In this work, we propose a novel glucose binding mechanism on a highly sensitive SERS substrate, in order to overcome challenges in specific glucose detection in bio-fluids. We make use of phenylboronic acid as a receptor for saccharide capture onto the substrate and the ability of the captured glucose molecule to undergo secondary binding with an alkyne-functionalized boronic acid to form a glucose-alkyne-boronic acid complex. The formation of this complex shows high selectivity for glucose, over other saccharides. In addition, the alkyne group of the alkyne-functionalized boronic acid exhibits a distinct Raman peak at 1996 cm(-1) in a biological silent region (1800-2800 cm(-1)) where most endogenous molecules, including glucose, show no Raman scattering, thus offering a high sensitivity over other SERS glucose sensing. The substrate offers long-term stability, as well as high SERS enhancement to the glucose-alkyne boronic acid complex on substrate. In addition, the reversibility of SERS signals at various incubation stages also shows reusability capabilities, whereas positive results in clinical urine samples demonstrate clinical feasibility. All these strongly suggest that this newly developed SERS-based assay offers great potential in glucose sensing.

Conventional nanoparticle based Surface enhanced Raman scattering (SERS) technique for pH sensing often fails due to the aggregation of particles when detecting in acidic medium or biosamples having high ionic strength. Here, We develop SERS based pH sensing using a novel Raman reporter, arene chromium tricarbonyl linked aminothiophenol (Cr(CO)3–ATP), functionalized onto a nano-roughened planar substrates coated with gold. Unlike the SERS spectrum of the ATP molecule that dominates in the 400–1700 cm−1 region, which is highly interfered by bio-molecules signals, metal carbonyl-ATP (Cr(CO)3)–ATP) offers the advantage of monitoring the pH dependent strong CO stretching vibrations in the mid-IR (1800–2200 cm−1) range. Raman signal of the CO stretching vibrations at ~1820 cm−1 has strong dependency on the pH value of the environment, where its peak undergo noticeable shift as the pH of the medium is varied from 3.0 to 9.0. The sensor showed better sensitivity in the acidic range of the pH. We also demonstrate the pH sensing in a urine sample, which has high ionic strength and our data closely correlate to the value obtained from conventional sensor. In future, this study may lead to a sensitive chip based pH sensing platform in bio-fluids for the early diagnosis of diseases.

Purpose The Leibovich model was updated to prognosticate oncological outcomes in postnephrectomy nonmetastatic renal cell carcinoma (RCC) for each major histological subtype including clear cell (ccRCC), papillary (papRCC), and chromophobe RCC. We evaluated its performance in an independent population of predominantly Asian patients from Singapore. Materials and Methods Nine hundred and forty two binephric patients with nonmetastatic unilateral RCC treated with radical/partial nephrectomy from 1990 to 2015 from Singapore were retrospectively reviewed. Based on the Leibovich model, ccRCC patients were scored from 0 to 25 and papRCC patients divided into 3 risk groups. Primary outcomes of progression-free survival (PFS) and cancer-specific survival (CSS) were assessed with the Kaplan–Meier method. Receiver operating characteristic curves and calibration plots were obtained to determine discrimination and calibration respectively. Results Eight hundred and twenty nine patients (88%) had ccRCC where 16.2% experienced disease progression while 11.9% died of RCC over a median follow-up of 76 (42–117) months. There was good discrimination (c-index 0.81 for PFS, 0.83 for CSS) and calibration (PFS calibration-in-the-large 0.002 and calibration slope 0.99, CSS calibration-in-the-large 0.005 and calibration slope 0.96). One hundred and thirteen patients (12%) had papRCC, where 18.6% progressed while 14.2% died from RCC over a median follow-up of 69.5 (36.0–112.0) months. Discrimination was slightly weaker (c-index 0.72 for PFS, 0.74 for CSS), and the model was only calibrated for CSS (calibration-in-the-large 0.002, calibration slope 0.98), not for PFS (calibration-in-the-large 0.09, calibration slope 1.93). Conclusions The updated Leibovich score is applicable for prognostication of progression and death in both ccRCC and papRCC, even when applied to an independent population of Asian patients. Further validation is required to ensure accuracy in prognosticating PFS for papRCC.

Supplemental Digital Content is available in the text, Background: Enzalutamide is an androgen receptor (AR) inhibitor that acts on different steps in the AR signaling pathway. In PREVAIL, an international, phase III, double-blind, placebo-controlled trial, enzalutamide significantly reduced the risk of radiographic progression by 81% (hazard ratio [HR], 0.19; P

Background: Most of the epidemiology studies on the effects of sun exposure and prostate cancer were conducted among the temperate countries of North America and Europe. Little is known about the influence on Asian populations. The purpose of current study was to evaluate any association of sun exposure with risk of prostate cancer in Chinese, Malays and Indians who reside in the tropics. Methods: The Singapore Prostate Cancer Study is a hospital-based case-control study of 240 prostate cancer incident cases and 268 controls conducted in Singapore between April 2007 and May 2009. Detailed information on outdoor activities in the sun, skin colour, sun sensitivity and other possible risk factors were collected in personal interviews. Cases were further classified by Gleason scores and TNM staging. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression analysis, adjusted for age, ethnicity, education, family history of any cancers, BMI and skin colour. Results: We found that prostate cancer risk was increased in subjects with black/dark-brown eyes (OR 5.88, 95%CI 3.17-10.9), darker skin colour e.g. tan/dark brown/black (OR 7.62, 95%CI 3.41-17.0), frequent sunburn in lifetime (OR 4.30, 95%CI 1.7-11.2) and increased general sun exposure in adulthood per week (OR 2.03, 95%CI 1.09-3.81). The increased risk was consistent for high grade tumours and advanced stage prostate cancers. Conclusion: The findings from this study suggest that excessive sun exposure is a risk factor for prostate cancer in Asians.

Background: Active surveillance (AS) as a treatment option for low risk prostate cancer is gaining recognition. We evaluate the validity of the AS protocol in our patient population, by defining the risk of undergrading and understaging in their pathology. We also aim to determine more accurate inclusion criteria, in order to improve the prediction of early low risk prostate cancer. Materials and Methods: Data was taken from our institutional prostate cancer registry for all men who underwent radical prostatectomy (RP) between Jan 2000 and June 2009. We determined if any of the patients would have met the University of Toronto's (UoT) AS inclusion criteria and examined their post-operative pathology. The primary end-point was pathological upgrading and upstaging. The individual inclusion factors i.e. preoperative PSA, were tested for statistical significance and better cutoffs. Univariate, multivariate and ROC curves were used in the statistical analysis. Results: 216 RPs were performed between January 2000 and June 2009. We identified 79 men who fulfilled the UoT AS criteria. 35% of patients had a Gleason score upgrade from biopsy to surgery, and 21.5% of patients had an upstage to T3 disease. Overall, 34 (43%) patients had an unfavourable change in the grade and/or stage of their prostate cancer. Conclusions: There is a significant risk of undergrading and understaging with the current criteria used for AS. There is a need to identify more discriminative AS criteria before it can be offered as an option to patients with clinically early prostate cancer.

Sorafenib, a multikinase inhibitor, is currently used as monotherapy for advanced renal cell carcinoma (RCC). However, adverse effects associated with its use have been experienced by some patients. In this study, we examined the antitumor and antiangiogenic activities of low-dose sorafenib in combination with the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244 induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation of VEGFR-2, PDGFR-β and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244 also caused upregulation of p27, Bad and Bim but downregulation of survivin and cyclin B1. These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth. This study provides sound evidence for the clinical investigation of low-dose sorafenib in combination with AZD6244 in patients with advanced RCC.

The prognostic features of T1N0M0 renal cell carcinoma (RCC) in Asian patients have not been well explored in large sample studies. In this study, we retrospectively analyzed the records of 713 patients undergoing nephrectomy for T1N0M0 RCC between 1991 and 2009 in three Asian hospitals. Univariate and multivariate analysis were performed to identify the independent predictive factors for T1N0M0 RCC prognosis among a series of Clinicopathological parameters, including age, gender, tumor size, Fuhrman grade, and histological classification. Our results showed that 388 of 713 patients had tumors 4.0 cm or smaller (stage T1a) and 325 of 713 patients had tumors 4.0–7.0 cm in size (stage T1b). Five-year cancer-specific survival (CSS) and recurrence-free survival (RFS) rates for this group of patients were 96.0% and 93.5%, respectively. The patients with T1b RCC had a significantly lower 5-year CSS and RFS rates than did those with T1a RCC (CSS, 93.1% vs. 98.6%, P = 0.026; RFS, 90.0% vs. 96.5%, P < 0.001). Patients with low grade (grades I–II) tumors had a higher 5-year CSS (97.8% vs. 91.2%, P = 0.001) and RFS (95.5% vs. 85.5%, P < 0.001) rate than did those with high grade (grades I–II) tumors. More interestingly, when stratifying patients to T1a and T1b groups, the role of grade in distinguishing prognosis could be only observed in patients with T1b disease. Cox regression showed tumor size and Fuhrman grade were significant in predicting CSS and RFS. Our study suggests that the prognosis of patients with T1N0M0 RCC is excellent, and these results are comparable to previously reported studies in Western patients. Furthermore, our data indicates that patients with T1b disease and high Fuhrman grade have high risk of tumor recurrence and death, thus requiring more frequent follow-up.

Objectives We report the natural history of voiding function in men with clinically localized prostate cancer after robot-assisted laparoscopic radical prostatectomy (RLRP), describing the trend of functional recovery, which is currently not well described using the robot-assisted laparoscopic approach. Materials and methods We determined the impact on voiding function by prospectively evaluating 100 consecutive men who underwent RLRP between May 2005 and December 2006 and compared their reported International Prostate Symptom Score (IPSS) and Quality of Life (QOL) scores at 3, 6, and 12 months with preoperative scores after surgery. Patients with preoperative IPSS of 0-7 and 8-35 were defined as having mild lower urinary tract symptoms (LUTS) and moderate to severe LUTS, respectively. Results Continence was achieved in 82%, 87%, and 91% of men at 3, 6, and 12 months after RLRP, respectively. There were statistically and clinically significant improvements in both IPSS and QOL preoperative scores at all studied time points for patients with moderate to severe preexisting LUTS. The mean IPSS scores for these patients preoperatively and at 3, 6, and 12 months after surgery were 14.1, 5.2, 3.0, and 2.9, respectively and the corresponding mean QOL scores were 3.4, 2.1, 1.6, and 1.6, respectively. Patients with mild preexisting LUTS showed no statistically significant improvement in IPSS at 3 and 6 months after surgery but significant improvement was found at 1 year ( P = 0.04). Conclusions Good continence recovery is expected in most patients undergoing RLRP. Patients with moderate to severe preexisting LUTS can expect early and clinically significant symptom and QOL improvements after RLRP. Patients with mild preexisting LUTS show significant symptom improvement at 1 year.

OBJECTIVE To assess the effect of ageing and body mass index (BMI) on prostate-specific antigen (PSA) among Chinese men from the results of the 2005 Prostate Awareness Week in Singapore. SUBJECTS AND METHODS In all, 2714 men participated in the programme, consisting of 2431 Chinese, 114 Malays, 117 Indians and 52 'others'. Of these, 2410 Chinese men who had a PSA level of20 ng/mL and were aged50 years but80 years were included in the analysis. Height and weight were used to calculate the BMI. The relationship between age and PSA levels was analysed using linear regression and bivariate correlation, and the associations among different groups of BMI and PSA levels were analysed using analysis of variance and covariance. RESULTS PSA levels were significantly correlated with age (correlation coefficient, r = 0.27, P0.001). Analyses showed a significant inverse association between PSA level and BMI; mean PSA levels decreased with increasing BMI for both standards (standard classification; geometric mean, GM, PSA of 1.08, 1.06, 0.96, 0.83 ng/mL for a BMI of18.5, 18.5-24.9, 25-29.9 andor =30 kg/m(2), respectively, P trend0.01; and for Asian classification, GM PSA 1.08, 1.09, 0.96, 0.91 ng/mL for a BMI of18.5, 18.5-22.9, 23-27.5 andor =27.5, respectively, P trend0.001). There were significant differences (P0.05) in the age-adjusted GM PSA levels for the groups with BMI25 (1.05 ng/mL) and BMIor =25 kg/m(2) (0.97 ng/mL). Similarly, there were significant differences (P0.05) in the age-adjusted GM PSA levels in those with a BMI of30 (1.03 ng/mL) andor =30 kg/m(2) (0.85 ng/mL). CONCLUSION These data suggest that the BMI in Chinese men in Singapore is significantly associated with PSA levels, especially among the obese men aged 70-79 years.

Prostate needle biopsy findings provide important information when considering treatment options. We examine the correlation between needle biopsy and radical prostatectomy pathology to predict patients at high risk of harbouring adverse pathological findings.We reviewed data from 100 consecutive patients who underwent radical prostatectomy between 1 January 2003 and 31 January 2005 at the Singapore General Hospital. Pre-operative clinical findings and needle biopsy pathological data were prospectively collected and compared with the final histology.The mean pre-biopsy PSA level was 9.4 +/- 5.1 microg/L. Median maximum percent of tumour in any core was 50% (range 5-100) and mean percentage of positive cores was 34.5 +/- 23%. There was under-grading of the final tumour score in 27 (27%) patients on biopsy as compared with the radical prostatectomy, while over-grading occurred in eight (8%) patients. On stratifying patients pre-operatively into low risk and high risk groups, patients in the high risk group had a significantly higher chance of having adverse radical prostatectomy histology such as extraprostatic extension, positive surgical margins or tumour volume3.0 mL (p = 0.041, OR = 3.96, 95%CI 1.13-13.86).Our results demonstrated good pathological correlation between prostate needle biopsies and their radical prostatectomies. Patients with Gleason scores of 7 or more, maximum percent of tumour in any core50%, or percent of positive cores of50% on needle biopsy had a higher risk of having adverse pathological findings at radical prostatectomy. The converse, however, is not necessarily true, as a result of sampling error during the biopsy.

We have determined the influences of polyvinylpyrrolidone (PVP) on the topical delivery of chlorin e6 (Ce6) in malignant bladder cells. The chick chorioallantoic membrane (CAM) was used to model the tumor spheroids that resemble small residual bladder tumors prior to vascularization. Macroscopic fluorescence imaging showed that Ce6-PVP-induced fluorescence had a higher sensitivity and specificity for delineating tumor from the adjacent normal CAM compared to Ce6 alone. Nonlinear regression analyses have shown that Ce6-PVP has a longer half-life in the tumor compared to Ce6. The uptake ratio of Ce6-PVP was found to have a 2-fold increase across the CAM when compared to that of Ce6, indicating that PVP was able to facilitate diffusion of Ce6 across the membrane. Confocal laser scanning microscopy further confirmed that Ce6-PVP has better penetration in the CAM as well as in the tumor cells compared to Ce6. The present work contributes to our understanding of the Ce6-PVP drug–polymer system by demonstrating for the first time that the presence of PVP facilitates the transport of Ce6 across the chorioallantoic membrane. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Angiogenesis or the development of new blood vessels from the surrounding vasculature is essential for the growth and progression of solid tumors. Vascular endothelial growth factor (VEGF), a positive regulator of angiogenesis, plays a pivotal role in tumor angiogenesis and shows a high expression in almost all known tumors, including transitional cell carcinoma (TCC) of the bladder. A novel isoform, VEGF(165)b containing a novel exon 9, was recently identified in renal cell carcinoma and was shown to be down-regulated and inhibitory in nature. We aimed to analyze quantitatively expression of this isoform, VEGF(165)b, in TCC of the bladder and compare it to the benign part of the same organ. A real-time reverse transcriptase polymerase chain reaction protocol was set up to quantitate simultaneously the messenger ribonucleic acid levels of VEGF and VEGF(165)b from 34 clinical samples representing bladder cancer and matched benign tissue. Expression of VEGF(165)b showed a >or=3.0-fold change in 27 of 34 (79%) bladder tumors than the benign samples. Increased expression of VEGF(165)b was seen in superficial tumors as compared to invasive tumors, which was statistically significant (P < 0.001). Therefore, VEGF(165)b was up-regulated in TCC of the bladder.

The use of fluorescence diagnosis as a modern cancer diagnostic modality is rapidly gaining importance in the field of urology. It is based on the detection of distinctive light emission of tissues sensitized by fluorescent dyes, commonly referred to as photosensitizers, after irradiation with a specific light source. Therefore, the search for specific fluorescent dyes with high sensitivity and specificity for bladder cancer is constantly being sought after. The aim of this study is to investigate the use of a new formulation consisting a mixture of chlorin e6 and polyvinylpyrrolidone (Ce6-PVP) for the detection of human bladder cancer cells (MGH) implanted on the chick chorioallantoic membrane (CAM) model. Uptake kinetics studies were quantitatively determined for both systemic and topical administrations of Ce6-PVP to the normal CAM as well as the MGH human bladder tumor implanted on CAM using fluorescence imaging technique. Rapid elimination of Ce6-PVP was displayed following topical application compared to systemic administration in the normal CAM system. Ce6-PVP was found to localize selectively in the xenografted bladder tumor in contrast to the CAM tissue. Neither dark toxicity nor irritancy was observed on the CAM tissue at the dose of 2 mg/kg Ce6-PVP. In conclusion, the Ce6-PVP formulation appeared to have the potential as a fluorescent marker for fluorescence diagnosis of human bladder cancer.

Evaluations of the efficiency of a new formulation of chlorin consisting of a complex of trisodium salt chlorin e6 (Ce6) and polyvinylpyrrolidone (PVP) in photodynamic therapy (PDT) and fluorescence diagnosis was performed on poorly differentiated human bladder carcinoma murine model with the following specific aims: (i) to qualitatively evaluate the fluorescence accumulation in human bladder tumor, (ii) to determine fluorescence distribution of Ce6-PVP using the tissue extraction technique and fluorescence imaging technique, (iii) to compare the fluorescence distribution of Ce6, Ce6-PVP and Photofrin in skin of nude mice, and (iv) to investigate phototoxicity caused by different parameters (drug-light interval, drug dose, irradiation fluence rate and total light fluence) in PDT. The fluorescence of the Ce6-PVP formulation was determined either by fluorescence imaging measurements or by chemical extraction from the tissues displaying similar trends of distribution. Our results demonstrated that the Ce6-PVP formulation possesses less in vivo phototoxic effect compared to Ce6 alone. The phototoxicity revealed a strong dependence on the drug and light dosimetry as well as on the drug-light interval. In PDT, the Ce6-PVP compound was most toxic at the 1h drug-light interval at 200J/cm(2), while Ce6 alone was most toxic at a light dose of more that 50J/cm(2) at the 1 and 3h drug-light interval. We also confirmed that Ce6-PVP has a faster clearance compared to Ce6 alone or Photofrin. This eliminates the need for long-term photosensitivity precautions. In conclusion, the Ce6-PVP formulation seems to be a promising photosensitizer for fluorescence imaging as well as for photodynamic treatment.

Objective Greater availability and utilization of modern radiological imaging modalities have resulted in an increase in the incidental discovery of renal cell carcinoma. Such tumours tend to be smaller than their symptomatic counterparts and may potentially be adequately treated using nephron-sparing surgery. Methods A retrospective review of all patients who were diagnosed with renal cell carcinoma of 4 cm or less between January 1990 and December 2001 was conducted to review clinical presentation, surgical management and survival. Results The cohort comprised 102 patients who underwent surgery, of 402 patients diagnosed with renal cell carcinoma over the study period. Sixty-eight patients (67%) had tumours detected incidentally. Thirty patients (29%) were managed with partial nephrectomy and 72 (71%) with radical nephrectomy. The median tumour size was 3.0 cm (range, 1.5-4.0 cm). Overall, median follow-up was 60 months (range, 1-148 months). Overall 5-year survival for patients who underwent partial nephrectomy and radical nephrectomy was 96.6% and 85.8%, respectively. Cancer-specific 5-year survival was 100%. Conclusion A significant proportion of patients had incidental diagnosis of small renal cell carcinoma. Local control may be achieved with either radical or partial nephrectomy, with excellent survival expected.

Objective To determine the patient-reported urinary continence rate after retropubic radical prostatectomy (RRP) for prostate carcinoma through a third-party interview and to grade the severity of incontinence. Methods Between 1997 and 1999, 34 patients were evaluated through an independent third party about the degree of continence as well as the quality of life after RRP. Patients were interviewed either in person or over the telephone. Urinary continence was defined as wearing no diapers, pads or tissue paper. Results Of the 34 patients, 44% achieved immediate continence. Urinary incontinence gradually improved with time after surgery and 82% ( n = 28) were fully continent at 12 months. Using the quality-of-life index, 91% of patients characterized their urinary incontinence as not or minimally bothersome. There was no significant difference between urologist- and patient-reported continence rates after RRP. Conclusion Based on our grading system, urinary continence gradually improved with time and was 82% at 1 year.

OBJECTIVE To review the initial clinical results of photodynamic diagnosis (PDD) using hypericin (a new photosensitizer for PDD that helps to label flat urothelial tumours to facilitate biopsy) for the early detection of superficial bladder carcinoma, as flat noninvasive tumours of the bladder may be missed during conventional white-light cystoscopy (WLC) if there is bladder overdistension or ongoing cystitis. PATIENT AND METHODS Between 1 January 2001 and 30 October 2004, 41 consecutive patients (mean age 66.1 years, sd 9.1, range 46–81) had transurethral resection for bladder cancer. Hypericin was introduced intravesically for 2 h before cystoscopy. Immediately after WLC, fluorescence cystoscopy (FC) was used at the same location and the same bladder site inspected using violet light. FC findings, e.g. positive or negative red fluorescence, were documented for each specific bladder site examined, and the exact location sampled for biopsy. RESULTS The mean (sd, range) bladder capacity of the patients was 431 (86, 300–650) mL. In all, 179 biopsies were taken from the 41 patients; urothelial cancers were found in 41% (74) and 80% (33) had macroscopically visible bladder tumours; 40% (71) of the biopsies were positive under FC and 86% (61) of the 71 FC-positive biopsies showed cancer on histology. Twenty-five biopsies (14%) were positive on FC but not WLC. PDD testing with hypericin had a sensitivity of 82% (61/74) and specificity of 91% (95/105), vs WLC, at 62% (46/74) and 98% (103/105), respectively. The PDD test had a positive predictive value of 86% (61/71) and a negative predictive value of 88% (95/108), vs 96% (46/48) and 79% (103/131), respectively for WLC. There were no reports of significant complications after the procedure. CONCLUSION PDD using hypericin shows promise, as it has a higher sensitivity but equivalent specificity than WLC. It can be used to detect flat lesions not seen on WLC. PDD testing is also well tolerated with minimal side-effects.

OBJECTIVE To assess the factors that influence the onset of androgen independence (AI, which heralds a dismal outcome) in patients with metastatic prostate carcinoma. PATIENTS AND METHODS The records of 361 consecutive patients with prostate carcinoma diagnosed and treated in the authors’ institution from 1 January 1996 to 31 December 1999 were reviewed retrospectively; 92 with metastatic prostate carcinoma were assessed (median age 71.0 years, range 42–93). Patients were included if they developed metastatic disease from prostate cancer at the time of diagnosis. The nadir for prostate specific antigen (PSA) level was defined as the date of the lowest PSA level after hormonal therapy, and AI was defined as the date of the third consecutive PSA increase above the nadir value by any threshold. RESULTS The median Gleason sum was 8 and the modal Gleason score 4 + 5. The median (range) pretreatment PSA level was 274.0 (1.3–2179) ng/mL. Of the 92 men, 57 (62%) attained a nadir PSA, including 23 with a nadir of

Background: Using sextant biopsy, 16–41% of prostate cancers were diagnosed on repeat biopsy. The objective of the present study was to compare the differences in the clinical, biochemical and pathological features between patients with positive results on initial and repeat biopsies, with an aim to identify factors that can be used to improve the detection rate of transrectal ultrasound (TRUS) biopsy of the prostate. Methods: Between February 2000 and April 2001, 222 patients with a mean age of 64 years (range 38–85) underwent TRUS-guided 10-core prostate biopsy for either abnormal prostate specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination (DRE). Of this number, 165 patients underwent their first biopsy, whereas 45 and 12 patients had had one or two previous biopsies, respectively. Results: Prostate cancer detection rates for the initial biopsy group (n = 165), second biopsy group (n = 45) and third biopsy group (n = 12) were 29.7, 23.0 and 41.7%, respectively. Six patients who had a negative first 10-core biopsy underwent a second 10-core biopsy and one patient (16%) was found to have cancer. Apart from total prostate volume, there were no significant statistical differences between the patient age, mean total PSA, PSA density, PSA-transition zone density, DRE and TRUS findings between the initial and repeat biopsy groups of subjects who had cancer. Those who had cancer detected only on repeat biopsies had larger prostate glands (P = 0.041). Conclusion: Patients who had cancer detected only on repeat biopsies had bigger prostate glands, supporting the hypothesis that TRUS sextant biopsy as a technique suffers the error of under-sampling in a bigger prostate.

Tissue autofluorescence depends on endogenous fluorophores in the tissue, which undergo a change associated with malignant transformation. This change can be detected as an alteration in the spectral profile and intensity of autofluorescence. Our purpose was to determine the optimal excitation and emission wavelengths for autofluorescence diagnosis of bladder cancer. A total of 52 bladder tissue specimens were obtained from 25 patients undergoing mucosal biopsies or surgical resections of bladder tumors. Light-induced autofluorescence measurements were performed to study the spectroscopic differences between normal and malignant bladder tissue. Fluorescence excitation wavelengths varying from 220 to 500 nm were used to induce tissue autofluorescence, and emission spectra were measured in the 280-700 nm range. These spectra were then combined to construct 2-dimensional fluorescence excitation-emission matrices (EEMs). Significant changes in fluorescence intensity of EEMs were observed between normal and tumor bladder tissues, the most marked differences being at the excitation wavelengths of 280 and 330 nm. The diagnostic algorithm based on the combination of the fluorescence peak intensity ratios of I(350)/I(470) at 280 nm excitation and I(390)/I(470) at 330 nm excitation yielded a sensitivity of 100% [95% confidence interval (CI) 0.95-1.0] and specificity of 100% (95% CI 0.90-1.0). The results of the present fluorescence EEM study demonstrate that autofluorescence spectroscopy can distinguish malignant from normal bladder tissue and that excitation wavelengths of 280 and 330 nm are the most significant for differentiation between normal and malignant bladder mucosae with a high degree of diagnostic accuracy.

Objectives To evaluate if changing the biopsy regime to 10 cores might improve the positive predictive value (PPV) of elevated prostate-specific antigen (PSA, elevated range, 4-20 ng/ml, normal range, Methods From February 2000 to April 2001, 191 patients, mean age 64 years (range, 38-85 yr), underwent transrectal ultrasound (TRUS) for either elevated PSA (elevated range, 4-20 ng/ml) and/or abnormal digital rectal examination (DRE). A 10-core TRUS-guided biopsy of the prostate was performed. This included the standard sextant biopsy and two additional cores for each far lateral zone. Results Using this technique, 47 out of 191 patients (24.6%) had prostate cancer. The PPV for PSA levels of 4.1 to 10.0 ng/ml and 10.1 to 20.0 ng/ml were 19.3% and 35.4%, respectively. The lateral cores contributed 21.3% of the cancer cases, which would have been missed if only sextant biopsies were performed. Conclusions With the 10-core biopsy method, the PPV for prostate cancer for patients with a PSA in the range of 4 to 20 ng/ml was in the range of 25%. This is significantly different from previous reports. The reason for this may be due to the adoption of a better, more uniform and systematic biopsy strategy for patients with elevated PSA, or it may be a true reflection of the current population incidence. Hence, this biopsy strategy is highly recommended. ( Asian J Surg 2002;25(3):238-43)

A metal carbonyl-functionalized nanostructured substrate can be used in a rapid and simple assay for the detection of A1AT, a potential biomarker for bladder cancer, in clinical urine samples. The assay involves monitoring changes in the carbonyl stretching vibrations of the metal carbonyl via surface-enhanced Raman spectroscopy (SERS). These vibrations lie in the absorption spectral window of 1800–2200 cm−1, which is free of any spectral interference from biomolecules. ASTAR (Agency for Sci., Tech. and Research, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore)

BACKGROUND: Outcomes after surgical removal of localized renal cell carcinoma (RCC) are variable. There have been multiple prognostic nomograms and risk groups developed for estimation of survival outcomes, with different models in use for evaluating patient eligibility in ongoing trials of adjuvant therapy. The authors aimed to establish the most useful prognostic model for patients with localized RCC to guide trial design, biomarker research, and clinical counseling. METHODS: A total of 390 consecutive patients who underwent nephrectomy for sporadic localized RCC in a tertiary institution (1990-2006) with 65 months median follow-up were retrospectively evaluated. The Karakiewicz nomogram, the Kattan nomogram, the Sorbellini nomogram, and the Leibovich model were compared in predicting survival outcomes (overall survival, cancer-specific survival, and freedom from recurrence) using likelihood analysis, adequacy indices, decision curve analysis, calibration, and concordance indices. RESULTS: Overall, the Karakiewicz nomogram outperformed the Kattan nomogram, the Sorbellini nomogram, and the Leibovich model. Highly improved accuracy was seen using the Karakiewicz nomogram in survival prediction, using likelihood ratio analysis in bivariate models including the competing prognostic models. The Karakiewicz nomogram showed higher adequacy and concordance indices and improved clinical benefit relative to all other nomograms. All 4 models were reasonably calibrated. Exploratory comparisons of prespecified discretized Karakiewicz nomograms and the SORCE trial recruitment criteria (a discretized Leibovich model) of high-risk patients favored the discretized Karakiewicz nomograms. CONCLUSIONS: The Karakiewicz nomogram was shown to be superior to the other tested nomograms and risk groups in predicting survival outcomes in localized RCC. Routine integration of this model into trial design and biomarker research should be considered. Cancer 2011;. © 2011 American Cancer Society.

Summary Background Bladder sparing treatment options for high risk non-muscle invasive blader cancer (NMIBC) after intravesical Bacillus Calmette-Guerin (BCG) failure are limited. Objective To evaluate photodynamic therapy (PDT) using chlorin e6-polyvinylpyrrolidone (Ce6-PVP) as a bladder sparing therapy for NMIBC refractory to intravesical BCG therapy. Materials and methods Between July 2004 and June 2009, patients with recurrent NMIBC after induction intravesical BCG therapy were treated with PDT performed with a 665 nm laser and light dosimetry of 10–24 J/cm 2 . The patients underwent cystoscopic surveillance for tumour recurrence post PDT. Post treatment lower urinary tract symptoms and bladder capacity were also monitored. Serum and urine samples were collected for spectrometric quantification of photosensitizer levels. Results Five patients underwent PDT, with a total of seven treatments performed. One patient received intravenous Ce6-PVP, while the rest received intravesical Ce6-PVP.The median age was 80 years (mean 79 years, range 72–88 years). There were three patients with primary CIS of the bladder and two with T1 high grade TCC and CIS of the bladder. At a median follow-up of 29 months (mean 25 months, range 6–36 months), two patients were disease free, two patients developed recurrence and one patient progressed to muscle invasive disease. There were no immediate adverse effects. The patient receiving intravenous Ce6-PVP developed an enterovesical fistula 16 months post PDT. Conclusions Despite being a small pilot study, intravesical Ce6-PVP mediated PDT is a feasible bladder sparing treatment option for recurrent high risk non-muscle invasive bladder carcinoma in selected individuals.

To elucidate the mechanism behind selective uptake of hypericin in bladder cancer after intravesical instillation for photodynamic diagnosis of urothelial cell carcinoma of bladder.Clinical studies were done on a series of 60 bladder cancer biopsies obtained from 28 patients who received intravesical instillations with 8 μM hypericin. Serial 5 μm cryosections were cut from 43 biopsies, and expression of the E-cadherin and associated catenins were determined using immunohistochemical and immunofluorescence staining. Hypericin was assessed using fluorescence confocal laser scanning microscopy. In addition, mRNA expression of these cell-adhesion molecules was analyzed in 17 biopsies using reverse transcription-PCR.Increased variability in the expression of E-cadherin and associated molecules was found in high-grade, advanced stage bladder carcinoma. An inverse association was found between immunoreactivity for E-cadherin, β- and γ-catenin, and both stage and grade of cancer (P0.05). A positive association was observed between the hypericin fluorescence and tumor grade. There was a significant down-regulation of E-cadherin and β-catenin mRNA in grade 2 and 3 tumors. Although a small sample size was studied, it provided sufficient proof to support the hypothesis that altered expression of cell adhesion molecules would lead to preferential hypericin uptake in urothelial cell carcinoma.Our study has unraveled one of the many factors contributing to the selective uptake of hypericin in bladder cancer. We have thus identified the effects of alteration of E-cadherin-catenin complex and transformed intercellular junction in the modified paracellular uptake of hypericin that provides the rationale for using this photosensitizer in photodynamic diagnosis of bladder carcinoma.

Photodynamic diagnosis (PDD) exploits the photoactive nature of certain compounds, namely photosensitizers, in order to enhance the visual demarcation between normal and neoplastic tissue. Hypericin is one such potent photosensitizer that preferentially accumulate in neoplastic tissue, and fluoresce in the visible spectrum when illuminated with light of an appropriate wavelength. In our study, we investigated the role of E-cadherin in the selective permeation of hypericin in bladder cancer tissues. Clinical studies were done on a series of 43 histologically graded bladder cancer biopsy specimens, obtained from 28 patients who received intravesical instillations with 8μM hypericin solution for at least 2 hours. Immunohistochemical staining was used to assess the expression of E-cadherin, in the cryosectioned tissues. Hypericin uptake was examined by fluorescence microscopy. Immunohistochemical staining showed a clear expression of E-cadherin along the urothelial lining of the normal and pre-malignant tissues. Partial expression of these cell adhesion molecules were still observed in malignant tissues, however there was a loss of expression to variable extends along the urothelium. Thus, loss of intercellular adhesion can be associated with enhanced hypericin permeation through paracellular diffusion.

Chondroitin sulfate is a structurally diverse glycosaminoglycan, which contains a variable degree of sulfation that helps to determine its biological function. It is involved in the regulation of cellular activity and has been implicated in carcinogenesis. To determine if the non-sulfated chondroitin backbone has a functional role in prostate cancer, we analyzed its expression by immunohistochemistry using the 1B5 monoclonal antibody and a set of tissue microarrays constructed with 227 prostate specimen cores from 81 cases of benign prostate tissue and 77 cases of prostate cancer, of which 69 of these cases are matched. Non-sulfated chondroitin was found in the secretory epithelial cells and stromal regions of both prostatic adenocarcinoma and benign prostatic tissues, as well as in the basal cells of benign glands. A higher percentage of cancerous cells were stained positively for non-sulfated chondroitin as compared with benign secretory cells of the same patient. Cancerous cells stained more intensely for non-sulfated chondroitin. This increase in percentage of cells stained and increase in staining intensity were associated with higher pathological T stage and extraprostatic extension. Non-sulfated chondroitin expression (either staining intensity or percentage of cells stained) in adenocarcinoma and its peritumoral stroma correlated significantly with several clinicopathological parameters of unfavorable outcome, including higher pathological T stage and Gleason score, presence of tumor in both prostatic lobes, extraprostatic extension, seminal vesicle involvement and preoperative prostate-specific antigen levels. These data suggest that non-sulfated chondroitin is a potentially useful biomarker for prostate cancer, and may be involved in regulating prostate cancer behavior.

The age-adjusted risk of prostate cancer (PC) has increased in Singapore since 1968. We investigated the relationship between polymorphisms in four genes, androgen receptor (AR), prostate-specific antigen (PSA), 5alpha-reductase type II (SRD5A2) and cytochrome P450c17alpha (CYP17) and PC and benign prostatic hyperplasia (BPH). Men with shorter CAG repeats in AR and above 69 years at diagnosis showed a trend of decreased PC risk (OR=0.28, 95% CI=0.08-1.03; p=0.05). Shorter CAG repeats and non-GG genotypes in the AR and PSA loci, respectively, showed a trend of decreased PC risk (OR=0.25, 95% CI=0.06-1.03; p=0.06) and a significantly decreased BPH risk (OR=0.38, 95% CI=0.15-0.94; p=0.04). The results indicate that allelic variation in PSA promoter activity may be androgen dependent and interaction of genes in androgen pathway may influence the risk of BPH and PC in Singapore males.