Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PURPOSE: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information. MATERIALS AND METHODS: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997–2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade. RESULTS: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system. CONCLUSIONS: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival

Challenges of early renal cancer detection: symptom patterns and incidental diagnosis rate in a multicentre prospective UK cohort of patients presenting with suspected renal cancer.

OBJECTIVES: To describe the frequency and nature of symptoms in patients presenting with suspected renal cell carcinoma (RCC) and examine their reliability in achieving early diagnosis. DESIGN: Multicentre prospective observational cohort study. SETTING AND PARTICIPANTS: Eleven UK centres recruiting patients presenting with suspected newly diagnosed RCC. Symptoms reported by patients were recorded and reviewed. Comprehensive clinico-pathological and outcome data were also collected. OUTCOMES: Type and frequency of reported symptoms, incidental diagnosis rate, metastasis-free survival and cancer-specific survival. RESULTS: Of 706 patients recruited between 2011 and 2014, 608 patients with a confirmed RCC formed the primary study population. The majority (60%) of patients were diagnosed incidentally. 87% of patients with stage Ia and 36% with stage III or IV disease presented incidentally. Visible haematuria was reported in 23% of patients and was commonly associated with advanced disease (49% had stage III or IV disease). Symptomatic presentation was associated with poorer outcomes, likely reflecting the presence of higher stage disease. Symptom patterns among the 54 patients subsequently found to have a benign renal mass were similar to those with a confirmed RCC. CONCLUSIONS: Raising public awareness of RCC-related symptoms as a strategy to improve early detection rates is limited by the fact that related symptoms are relatively uncommon and often associated with advanced disease. Greater attention must be paid to the feasibility of screening strategies and the identification of circulating diagnostic biomarkers

Challenges of early renal cancer detection: symptom patterns and incidental diagnosis rate in a multicentre prospective UK cohort of patients presenting with suspected renal cancer

Objectives: To describe the frequency and nature of symptoms in patients presenting with suspected renal cell carcinoma (RCC) and examine their reliability in achieving early diagnosis. Design: Multicentre prospective observational cohort study. Setting and participants: Eleven UK centres recruiting patients presenting with suspected newly diagnosed RCC. Symptoms reported by patients were recorded and reviewed. Comprehensive clinico-pathological and outcome data were also collected. Outcomes: Type and frequency of reported symptoms, incidental diagnosis rate, metastasis-free survival and cancer-specific survival. Results: Of 706 patients recruited between 2011 and 2014, 608 patients with a confirmed RCC formed the primary study population. The majority (60%) of patients were diagnosed incidentally. 87% of patients with stage Ia and 36% with stage III or IV disease presented incidentally. Visible haematuria was reported in 23% of patients and was commonly associated with advanced disease (49% had stage III or IV disease). Symptomatic presentation was associated with poorer outcomes, likely reflecting the presence of higher stage disease. Symptom patterns among the 54 patients subsequently found to have a benign renal mass were similar to those with a confirmed RCC. Conclusions: Raising public awareness of RCC-related symptoms as a strategy to improve early detection rates is limited by the fact that related symptoms are relatively uncommon and often associated with advanced disease. Greater attention must be paid to the feasibility of screening strategies and the identification of circulating diagnostic biomarkers

Real world outcomes of biopsy-proven oncocytic neoplasm of the kidney managed by surveillance.

OBJECTIVES: To evaluate outcomes of patients diagnosed with oncocytic renal neoplasms on routine renal mass biopsy and to describe the natural history of these tumours when managed with surveillance as opposed to immediate intervention. To report disease-specific survival. PATIENTS AND METHODS: Patients were identified from a retrospective review of pathology databases from three tertiary referral centres that utilise renal mass biopsy in routine clinical practice. All patients with biopsy-proven oncocytic tumours were included and a retrospective review of online patient records was undertaken. RESULTS: There were 184 biopsy-proven oncocytic renal neoplasms identified in 172 patients. There were two biopsy complications (both pneumothorax, Clavien-Dindo Grade I). Of these lesions, 135 were reported as oncocytomas or oncocytic renal neoplasms that were not further classified and 37 were reported as chromophobe carcinoma (ChRCC). The median age at diagnosis was 70 (33-88). The average tumour diameter at diagnosis was 33 mm. One hundred seven tumours were initially managed with surveillance (including 13 ChRCC) with a minimum follow-up of 6 months and a median of 39 months (6-144) whereas 49 patients underwent immediate treatment. The mean growth rate across all oncocytic renal neoplasms managed by surveillance was 3 mm/year. There was no statistically significant difference in growth rates between oncocytic renal neoplasms and ChRCC. Thirteen patients with oncocytic renal neoplasms initially managed by surveillance moved on to an active management strategy during follow-up. The clinical indication given for a change from surveillance was tumour growth in 12 cases and patient choice in 1 case. Where definitive pathology was available, there was 85% concordance with the biopsy. There were no cases of development of metastatic disease or disease-related morbidity or mortality during the study. CONCLUSIONS: This multicentre retrospective cohort study supports the hypothesis that selected biopsy-proven oncocytic renal neoplasms can be safely managed with surveillance in the medium term. Routine renal mass biopsy may reduce surgery for benign or indolent renal tumours and the potential associated morbidity for these patients

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered.

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.CARMENA is sponsored by Assistance Publique-Hôpitaux de Paris (APHP). CARMENA-UK was funded by Cancer Research UK and administered by the CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow. SURTIME was sponsored by the European Organisation for Research and Treatment of Cancer (EORTC)

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21

Vitamin D and bisphosphonates : studies in prostate cancer

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The use of 3D-printing and injection moulding in the development of a low-cost, perfused renal malignancy model for training of robot-assisted laparoscopic partial nephrectomy

This chapter presents a research which aims to increase accessibility and availability of surgical training in robot-assisted laparoscopic partial nephrectomy (RALPN) by producing and evaluating a low-cost training model. A methodological and technological framework is presented with a case study which uses image segmentation and 3D-modelling software to create anatomically accurate 3D-printed moulds from an abdominal CT scan of a patient who had stage T1b renal cell carcinoma. The moulds were injected with hydrogel and fitted with an artificial renal artery to allow for simulation of blood flow. The face validity (appearance and feel) of the prototype was evaluated using a 5-point Likert-style questionnaire by surgical staff (N = 8) who held and inspected the model. Content validity (how successfully the model simulates a RALPN) was evaluated by expert and trainee urology surgeons (N = 4) who performed a RALPN on the prototype using the da Vinci Robotic Surgical System. Qualitative data regarding perceptions of the usefulness of the model was also collected. The final cost of the prototype was £1.72 for single-use materials and £4.02 in total. Within this sample population the prototype achieved face validity with both the overall appearance (M=4.13 ± 0.35) and overall feel of the model scoring (M=4.13 ± 0.64). The prototype also demonstrated content validity within this sample population, with an overall average of M= 3.92 and the highest performing measures in “needle driving” (M= 4.75 ± 0.5) and “suture holding” (M= 4.25 ± 0.96). Qualitative feedback suggested the potential significant benefits of such a training model to give junior surgeons exposure to robotic techniques in training. This research demonstrates a low-cost method of producing a physical model for RALPN training. The prototype developed was considered to be an effective training tool by both experienced and trainee surgeons. Through further development of this prototype, urology surgical training programmes could have access to a cost-effective and simple means of widening access to RALPN training and implementing it at an earlier stage of training