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Bladder cancer represents a significant health burden worldwide, with non-muscle-invasive tumours representing the majority of new bladder cancer diagnoses. Non-muscle-invasive bladder cancer (NMIBC) has a high prevalence and forms a large proportion of the caseload in urological practice, accounting for a significant cost in terms of urological healthcare. The last two decades have seen the development and refinement of guidelines from national and international organisations aiming to optimise management of NMIBC and bladder cancer in general. This review outlines the most recent European and United Kingdom guidelines on NMIBC, and in particular focuses on comparing and contrasting key recommendations from guidelines published by the European Association of Urology and the UK-based National Institute for Clinical Excellence. Level of evidence: Not applicable for this multicentre audit.

Purpose of Review This review aims to evaluate research surrounding the utility of urinary biomarkers to detect bladder cancer and predict recurrence. Recent Findings Recent research has focussed on the evaluation of genetic markers found in urine to provide diagnostic and prognostic information. Furthermore, the isolation and characterisation of extracellular vesicles (EVs) from the urine patients with bladder cancer provide an exciting new development in biomarker research that is set to expand in the coming years. Summary Current urinary biomarker research is a broad field that encompasses the evaluation of urinary proteins, DNA, RNA and EVs to detect signatures that can be used to predict the presence of bladder cancer and provide prognostic information. EVs in particular offer an exciting and novel perspective in the search for accurate bladder cancer biomarkers.

Background Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. Patients and Methods Patients were treated with single agent ganetespib at 200 mg/m2 once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. Results Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). Conclusion The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.

The history of surgical treatment for prostate cancer dates back to 7 April 1904, when Dr. Hugh Young, with the assistance of William Halsted, performed the world’s first radical prostatectomy at Johns Hopkins Hospital, Baltimore [1]. His technique was adapted from an operation he learnt from the iconoclastic American surgeon, George Goodfellow, who developed a surgical method of prostatic enucleation via a transperineal route for the treatment of bladder outlet obstruction.

BACKGROUND The role of DNA methylation in the transcriptional regulation of S100A4 is unknown in human prostate cancer. METHODS Critical CpG sites within intron 1 of S100A4 were sequenced in DNA obtained from prostatic adenocarcinoma, non-malignant epithelium, and prostate cancer cell lines. S100A4 protein expression was assessed by immunohistochemistry and Western blotting. RESULTS Methylation was seen in all cases of cancer, non-malignant epithelium, and in prostate cancer cell lines, but was absent in all cases of blood DNA. S100A4 immunoexpression was absent in all cases of malignant and non-malignant epithelium, while strong–moderate expression was seen in the stroma and lymphocytes. Western blotting showed absent S100A4 expression in LNCaP and Du145 cells and low levels in PC-3 cells. CONCLUSIONS S100A4 protein is not expressed in benign or malignant prostatic epithelium nor in LNCaP and Du145 cells. The mechanism underlying absent S100A4 expression in prostatic epithelium and cell lines may involve methylation. Prostate 67: 341–347, 2007. © 2007 Wiley-Liss, Inc.

BACKGROUND S100A6 and S100A2 are members of the S100 family of calcium binding proteins, which are down regulated in prostate cancer, however the molecular mechanism(s) underlying their loss of expression is unknown. METHODS The promoter and exon 1 region of the S100A6 and S100A2 genes was sequenced in bisulfite modified DNA from non-malignant, benign prostatic hyperplasia (BPH), malignant and metastatic prostate tissues and in cell lines. Immunohistochemistry was performed to correlate S100A2 expression with methylation status. RESULTS S100A6 methylation was absent or occurred at isolated sites in 14/14 cases of non-malignant epithelium and 5/5 cases of BPH tissues, whereas methylation was seen in 14/27 (52%) cases of prostatic cancer (P

In order to identify novel candidates associated with prostate cancer metastasis, we compared the proteomic profile of the poorly metastatic human prostate cancer cell line LNCaP, with its highly metastatic variant LNCaP-LN3, by two-dimensional gel electrophoresis. A major protein spot (pI of 5.9 and molecular weight of 37 kDa) was seen in LNCaP cells, but not in LNCaP-LN3 cells and was identified as lactate dehydrogenase-B (LDHB), by tandem mass spectrometry. Furthermore, enzyme kinetic assays and zymography showed a higher LDH enzyme activity in LNCaP cells compared with LNCaP-LN3. Bisulphite-modified DNA sequencing showed promoter hypermethylation in LNCaP-LN3 cells but not in LNCaP, Du145, PC3, CWR22 or BPH45 cells. Treatment of LNCaP-LN3 cells with 5'-azacytidine caused re-expression of LDHB transcripts. In tissues, LDHB promoter hypermethylation occurred at a higher frequency in prostate cancer, 14/ 31 (45%), compared to adjacent nonmalignant or benign tissue, 2/19 (11%) (P < 0.025). Immunohistochemistry showed a higher frequency of LDHB expression in benign or non-malignant tissues, 59/ 73 (81%), compared to cancer cases, 3/53 (6%) (P < 0.001). Absent LDHB expression was also seen in 7/7 (100%) cases of metastatic cancer in bone. Our data are the first to show loss of LDHB expression in prostate cancer, the mechanism of which appears to involve promoter hypermethylation.

The human prostate is a gland of the male reproductive tract, which together with the seminal vesicles, is responsible for most seminal fluid production. It is a common site of cancer, and unlike other glands, it typically enlarges in ageing men. In flies, the male accessory glands make many major seminal fluid components. Like their human equivalents, they secrete proteins from several conserved families, including proteases, lectins and cysteine-rich secretory proteins, some of which interact with sperm and affect fertility. A key protein, sex peptide, is not conserved in vertebrates, but plays a central role in mediating long-term effects on females after mating. Although post-mitotic, one epithelial cell type in the accessory glands, the secondary cell, continues to grow in adults. It secretes microvesicles called exosomes from the late endosomal multivesicular body, which after mating, fuse with sperm. They also appear to affect female post-mating behaviour. Remarkably, the human prostate epithelium also secretes exosomes, which fuse to sperm in vitro to modulate their activity. Exosomes from prostate and other cancer cells are increasingly proposed to play fundamental roles in modulating the tumour microenvironment and in metastasis. Here we review a diverse accessory gland literature, which highlights functional analogies between the male reproductive glands of flies and humans, and a critical role for extracellular vesicles in allowing seminal fluid to promote male interests within the female. We postulate that secondary cells and prostate epithelial cells use common mechanisms to control growth, secretion and signalling, which are relevant to prostate and other cancers, and can be genetically dissected in the uniquely tractable fly model.

Background: Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains the stability of a number of key cellular oncoproteins (client proteins). When Hsp90 is inhibited, its client proteins undergo ubiquitination and degradation. HER2 is one of the most sensitive client proteins of Hsp90 and we have previously shown that tanespimycin, a geldanamycin-based Hsp90 inhibitor, is active in trastuzumab-refractory HER2+ MBC, with a RR of 22% and clinical benefit rate of 59%. Ganetespib is a synthetic, small molecule, IV administered, non-geldanamycin Hsp90 inhibitor which has broader inhibitory effects on oncoproteins with pre-clinical antitumor activity in more breast cancer (BC) subtypes, including triple negative breast cancer (TNBC). We therefore tested ganetespib in an unselected cohort of patients with advanced BC. Methods: Pts with locally advanced or MBC were treated with single agent ganetespib at 200mg/m2 once weekly for 3 weeks, on a 28 day cycle. The primary endpoint of the trial was overall response rate using RECIST 1.1. Pts with HER2+ BC were required to have received prior therapy with trastuzumab. No more than 3 lines of chemotherapy in the metastatic setting were permitted and there was no limit on prior lines of hormone therapy. Pts were evaluated for response after 2 cycles. The trial used a Simon two-stage design requiring at least 3 responses among the first 22 pts, to allow expansion to a total of 40 pts. Results: A total of 14 pts have been treated thus far with a median age of 45.3 years (36.6 to 59.1) and the following subtypes: 8 ER+/HER2+, 3 ER-/HER2+, 1 ER+/HER2− and 2 TNBC. Pts received a median of 1.84 cycles (0.33 to 4). The most common treatment-related AEs were Grade 1/2 and included the following: diarrhea (64%), fatigue (50%), nausea (35%), vomiting (14%), insomnia (14%) and hypersensitivity reactions (35%). The diarrhea had an early onset (< 24 hrs) and lasted up to 48 hrs post-infusion and was managed with either Imodium or similar anti-diarrheal medication. Pts who developed a hypersensitivity reaction were successfully re-challenged following pre-medication using dexamethasone plus H1/H2 antagonists. Grade 3 AEs were limited to 2 pts: 1 with an asymptomatic and reversible elevation in serum amylase, and the other with abdominal pain and diarrhea requiring a dose reduction to 175mg/m2. Of the 10 pts evaluable for efficacy, there is 1 confirmed partial response (PR), 1 minor response (MR) and 2 pts with stable disease (14%). The pt with MR had TNBC and was taken off-study due to a complicated pneumonia requiring hospitalization (unrelated). The remaining 3 pts had HER2+ BC; 2 of these 3 pts (1 PR, 1 SD) are continuing on study and have completed 4 cycles thus far. Updated toxicity and efficacy data will be presented. Conclusions: These data show activity for single agent ganetespib in different subtypes of breast cancer. Ganetespib was well tolerated, with expected gastrointestinal toxicity that was mild in nature and manageable in all patients. Accrual continues and we will present updated data at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-08.

Purpose Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzuamb (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival. Methods Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of ≥ 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m2) × 4 followed by P (175 mg/m2) × 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T ×1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18. Results From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced conestive heart failure (CHF). There were no cardiac deaths. Conclusion Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.

Prostate cancer is the commonest solid-organ cancer diagnosed in males and represents an important source of morbidity and mortality worldwide. Imaging plays a crucial role in diagnosing prostate cancer and informs the ongoing management of the disease at all stages. Several novel molecular imaging technologies have been developed recently that have the potential to revolutionise disease diagnosis and the surveillance of patients living with prostate cancer. These innovations include hyperpolarised MRI, choline PET/CT and PSMA PET/CT. The major utility of choline and PSMA PET/CT currently lies in their sensitivity for detecting early recurrence after radical treatment for prostate cancer and identifying discrete lesions that may be amenable to salvage therapy. Molecular imaging is likely to play a future role in characterising genetic and biochemical signatures in individual tumours, which may be of particular significance as cancer therapies move into an era of precision medicine.

Approximately 1% of the UK population receives anticoagulation with warfarin. Head injury accounts for some 1.4 million emergency department attendances in the country. Therefore, significant numbers of patients with head injury have a therapeutic coagulopathy. This review aims to examine the existing evidence for optimal management of warfarinised head injured patients, particularly with respect to the need for early CT imaging and the use of reversal agents in cases of proved haemorrhage.

In order to identify novel candidates associated with prostate cancer metastasis, we compared the proteomic profile of the poorly metastatic human prostate cancer cell line LNCaP, with its highly metastatic variant LNCaP-LN3, by two-dimensional gel electrophoresis. A major protein spot (pI of 5.9 and molecular weight of 37 KDa) was seen in LNCaP cells, but not in LNCaP-LN3 cells and was identified as Lactate dehydrogenase-B (LDHB), by tandem mass spectrometry. Furthermore, enzyme kinetic assays and Zymography showed a higher LDH enzyme activity in LNCaP cells compared with LNCaP-LN3. Bisulfite modified DNA sequencing showed promoter hypermethylation in LNCaP-LN3 cells but not in LNCaP, Du145, PC3, CWR22 or BPH45 cells. Treatment of LNCaP-LN3 cells with 5’-azacytidine caused re-expression of LDHB transcripts. In tissues, LDHB promoter hypermethylation occurred at a higher frequency in prostate cancer 14/31 (45%), compared to adjacent non-malignant or benign tissue, 2/19 (11%), (P