Anaemia is not an inconsequential side effect of cancer and its treatment should not be ignored. Current practice for anaemia management varies and its role in influencing outcome in cancer patients is under recognized. As a common complication of cancer, anaemia is prevalent in virtually all tumour types to varying degrees. Predictive factors for anaemia include baseline haemoglobin concentration, decrease in haemoglobin concentration within the first month of treatment, tumour type, duration of treatment and prior blood transfusions. Interest in the prognostic significance of anaemia in cancer patients has generated extensive clinical research. Data is now published in a wide range of tumour types confirming that anaemia is a negative prognostic indicator of outcome (e.g. survival, disease-free recurrence and local relapse), with the strongest association in patients receiving radiotherapy. The association has also been documented in patients undergoing chemotherapy and chemoradiation. A retrospective meta-analysis has shown an overall 65% increased risk of death associated with anaemia in cancer patients. The impact of anaemia as an independent prognostic factor for outcome may be mediated by several factors, however the emerging consensus is on the central role of tumour hypoxia. It has been nearly 50 years since R. Thomlinson and L. Gray (British Journal of Cancer 1955, 9: 539) first documented the existence of hypoxia in tumours and it is now well accepted that tumour hypoxia protects tumour cells from therapeutic damage directly by reducing the availability of oxygen-free radicals which are necessary for optimal impact of radiotherapy, certain chemotherapeutic agents and photodynamic therapy. The indirect effects include the impact of hypoxia on gene expression, which affects genetic stability, proliferation kinetics and cellular metabolism. There has been an emergence of preclinical and circumstantial data over recent years that are suggestive of the ability to correct the negative effect of anaemia on outcome by the use of repeated blood transfusions or recombinant human erythropoietin. This has led to some attempts to measure the impact on survival in cancer patients of treating anaemia, but early attempts have served to underline the complexity of the relationship and have produced unexpected results.

Abstract. Targeting the Ras family of monomeric GTPases has been suggested as a therapeutic strategy in proliferative renal diseases. This article reports the effects of Ras antagonist farnesylthiosalicylic acid (FTS) in rat thy-1 nephritis, a model in which cytokine-driven glomerular cell proliferation and invasion is likely to involve Ras signaling pathways. FTS in vitro specifically inhibits the binding of Ras to discrete membrane sites, thereby downregulating several Ras-dependent signaling functions and accelerating Ras degradation. Forty-four Lewis rats were given nephritis by day zero injection of a monoclonal thy-1 antibody ER4 (2.5mg/kg body wt). Twentytwo rats were then treated with daily intraperitoneal injection of FTS (5 mg/kg body wt) until sacrifice, and the remaining control rats were given vehicle alone (C). Six rats from each group were sacrificed at day 1 to establish equal injury; other sacrifice points were day 7 and day 10. Bromo-deoxyuridine (BrdU) was injected 1 h before sacrifice, after which sections were used for immunohistochemistry, which included detection of Ras expression, BrdUϩ cells and macrophages/monocytes (ED1ϩ). Thy-1 nephritis was associated with an increase in glomerular expression of Ki-Ras and N-Ras isoforms, which was almost fully prevented by FTS. FTS treatment was associated with: (a) a 54% reduction in the mean number of BrdUϩ cells per glomerulus (P Ͻ 0.01), (b) a 50% reduction in macrophages/monocytes (ED1ϩ) per glomerulus (P Ͻ 0.01), and (c) a reduction in 24-h proteinuria at day 10 (P Ͻ 0.05). These results show that Ras inhibition can reduce both glomerular cell proliferation and glomerular macrophage cell number in the thy-1 model and justify further study of FTS as a potential therapeutic in proliferative nephritis.

276 Background: Cisplatin-based neoadjuvant chemotherapy has shown survival advantage in patients (pts) with muscle-invasive bladder cancer. This benefit is strongly associated with downstaging of tumor to pT0. It was hypothesized that the addition of antiangiogenic therapy bevacizumab (Avastin [A]) to cisplatin (C) and gemcitabine (G) chemotherapy may offer improved outcomes in these pts. Methods: Patients with clinically localized, muscle-invasive, chemotherapy-naive TCC of bladder (T2-T4a), ECOG PS 0-1 received cisplatin 70 mg/m2 IV day 1, gemcitabine 1000 mg/m2 IV day 1 and 8, bevacizumab 15 mg/kg IV day 1 on a 21- day cycle for up to 4 cycles. After completion of neoadjuvant therapy all pts underwent RC. Those pts not achieving pT0 status received paclitaxel 175 mg/m2 IV day 1 and bevacizumab 15 mg/m2 IV day 1 on a 21-day cycle for up to 3 cycles. The primary objective of the trial was to achieve pT0 status. Results: By October 2010, 15 pts were enrolled, and 13 are evaluable for response. Median age was 64 (range 47-71), 9 (70%) males, 4 (30%) females. 2/13 (15%) developed PD after neo-adjuvant therapy and were taken off protocol.11/13 (85%) underwent RC. 4/13 (31%) pts were downstaged, 3/11 (27%) achieved pTis status and none achieved pT0 status. 2/11 (18%) pts received adjuvant paclitaxel chemotherapy with bevacizumab. Dose reduction or delays were noted in 12/15 (80%) pts. Grade 3 or 4 hematologic toxicity was observed in 5/15 (33%) pts. Grade 3 or 4 nonhematologic toxicity was observed in 3/15 (20%) pts: (renal dysfunction 2 pts, pulmonary embolism 1 pt). Postoperative complications were seen in 5/12 (42%) pts: enterovesicular fistula (1), delayed wound healing (1), prolonged ileus (2), and pelvic abscess (1). With a median follow-up time of 12 months (range 3-45), 8/11 (72%) pts have remained disease free. Conclusions: Neoadjuvant CGA is feasible in pts with clinically localized, muscle-invasive TCC of the bladder. The surgical complications rate appears rather high and close monitoring is needed. Accrual to the trial continuous and updated results will be presented. No significant financial relationships to disclose.

238 Background: Numerous novel therapies for castration relapsed prostate cancer (CRPC) have led to a rapidly evolving approach to its management. Rationalisation of treatment combinations and sequencing of therapy requires identification of men who are more likely to benefit from a particular treatment. An unmet clinical need exists in this domain. We present the findings of a review of patients treated with abiraterone at our centre, and describe a novel predictive algorithm in this setting employing previously undefined pre-determinants of response. Methods: Patients with CRCP treated with abiraterone post-docetaxel at Queen Elizabeth Hospital between August 2010 and February 2012 were identified. Electronic patient records were utilised to extract variables including patient demographics, tumor characteristics, treatment history and other potential predictors of response such as prostate-specific antigen (PSA), hemoglobin (Hb), and alkaline phosphatase (ALP). Outcome measures included overall survival (OS), adverse events and PSA response rate. OS was estimated using the Kaplan-Meier method, and univariate and multivariate analyses were performed on potential prognosticators. Multivariate Beta coefficients were used to generate a predictive algorithm to identify two distinct risk groups. Results: Sixty one patients met the inclusion criteria. From starting abiraterone, the median OS was 12.6m, and median duration of follow-up was 11.5m. In univariate analysis seven factors impacted OS: age, response duration to androgen deprivation therapy (ADT), Hb, time from diagnosis to starting abiraterone, and ALP. Subsequent multivariate analysis identified three independent predictors of OS: duration of response to ADT (HR: 0.95, p=0.006), performance status (HR: 0.71, p=0.013), and baseline Hb (HR: 0.47, p=<0.001). A predictive algorithm dividing the cohort into high- and low-risk groups derived a diverging Kaplan-Meier curve without overlapping 95% CI’s. The low risk group did not reach median survival. Conclusions: This retrospective review has identified a predictive scoring algorithm for response to abiraterone in CRPC. We suggest that further analysis in the form of external validation is needed in order to justify its use in individualisation of patient management and stratification of patients for prospective clinical trials.

Summary Twenty-two asymptomatic women with rising CA 125 levels after chemotherapy for ovarian cancer were entered into a trial of isotretinoin combined with calcitriol. Tumours were evaluated according to precise criteria based on serial CA 125 levels and by comparing regression slopes of CA 125 before and during therapy. There was no evidence based on CA 125 of any responses or significant change in tumour growth rate.

BackgroundThe use of abdominoperineal resection (APR) in the management of low rectal cancer has received criticism over high rates of incomplete resection due to tumour involvement at the circumferential resection margin. Extralevator abdominoperineal resection has been advocated as a means of improving complete resection. However, Extralevator abdominoperineal resection can result in increased cost, morbidity and reduced quality of life.This study aims to assess the histological features and long-term outcomes of patients undergoing standard abdominoperineal resection and discusses the potential role of Extralevator abdominoperineal resection in this cohort.MethodA retrospective review of a prospectively maintained database of rectal cancer patients at a single centre. Patients undergoing standard APR were included from 01/06/2007 to 31/05/2012 to allow a minimum 2-year follow-up. Data was collected on age, gender, co-morbidity, pre-operative stage, neo-adjuvant therapy, histology, recurrence and mortality.ResultsSeventy patients were identified (45 (64%) male, median age 67; (range 36–85)). 12 (17.1%) patients had a positive circumferential resection margin; 4 (6.1%) tumours were located anteriorly, 8 (11%) were located posteriorly or laterally and may potentially have been completely resected with extralevator abdomino-perineal resection, Number-needed to treat = 9. Positive circumferential resection margin was more common in advanced tumours (p < 0.001). Local recurrence was more common with positive circumferential resection margins (16.7% Vs 0%, p = 0.027), with no statistically significant difference in 5-year survival, although there was a tendency towards worse survival in these patients.ConclusionPositive circumferential resection margin following APR resulted in significantly increased local recurrence with a trend towards poorer survival outcomes. Extralevator abdomino-perineal resection may have benefited some of these patients with locally advanced tumours and postero-lateral recurrences. However, this has to be balanced against exposing patients to increased risk of adverse events. We would recommend selective use of Extralevator abdominoperineal resection for locally advanced and node-positive tumours although further studies to help refine selection criteria are required with long-term follow-up.

BackgroundHeterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease.Case presentationA 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient’s renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards.ConclusionsIn an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.

There was good agreement between PlGF tests and limited agreement between PlGF tests and the sFlt-1/PlGF ratio. All tests have heightened predictive accuracy for preterm pre-eclampsia. Abnormal PlGF or sFlt-1/PlGF ratio relates to abnormal uterine artery Doppler but not platelet response to aspirin.