The Prognostic Role of the Non-Canonical Nuclear Factor-Kappa B Pathway in Renal Cell Carcinoma Patients.

BACKGROUND: In the United Kingdom, 8,000 cases of renal cancer are diagnosed each year, with a 5-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the non-canonical nuclear factor-kappa B (NF-κB) pathway. This pathway plays a role in multiple oncogenic processes in solid tumors. The aim of this study was to investigate the non-canonical nuclear factor pathway in renal cell carcinoma (RCC). MATERIALS AND METHODS: NIK, IKKα, and RelB were investigated via immunohistochemistry in a cohort of 192 patients with clear cell renal cancer. RESULTS: High cytoplasmic NIK was associated with poorer cancer-specific survival (p = 0.006) and 10-year survival stratified from 85% (low) to 65% (high, p = 0.005). Similarly, high cytoplasmic RelB was associated with poorer cancer-specific survival (p = 0.041) and 10-year survival stratified from 88% (low) to 73% (high, p = 0.030). When clinicopathological characteristics were assessed, cytoplasmic NIK was associated with survival (p = 0.014), whereas cytoplasmic RelB was associated with increased tumor grade (p = 0.020) and decreased inflammation (p = 0.019). Upon multivariate analysis, it was found that cytoplasmic NIK was independently associated with cancer-specific survival (p = 0.009). CONCLUSIONS: The non-canonical NF-κB pathway is associated with poorer cancer-specific survival in RCC patients, making it a viable target for therapeutic intervention. Furthermore, cytoplasmic NIK is a potential prognostic biomarker for this disease.

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 (Y(419)) and FAK (Y(861)) 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.

The prognostic use of inflammation and tissue necrosis in benign prostatic hyperplasia.

INTRODUCTION: Evidence for the role of inflammation in benign prostatic hyperplasia (BPH) is conflicting. Establishing the prognostic significance of local and systemic inflammation and tissue necrosis scoring systems in BPH may elucidate the potential of inflammatory pathways as a target of therapeutic intervention in these patients. PATIENTS AND METHODS: Consecutive patients with histological BPH diagnosed between 1996 and 2005 were identified. Systemic inflammation was assessed by the modified Glasgow prognostic score (mGPS), local inflammation by the Klintrup-Makinen criteria and tissue necrosis was evaluated by an extent-based classification. RESULTS: In 392 BPH patients, there was a trend for increased local inflammation and tissue necrosis to be associated with shorter time to failure of pre-operative medical treatment of BPH (p = 0.096 and 0.088, respectively). High modified Glasgow prognostic score was associated with older age (p = 0.002) and higher levels of deprivation (measured by the Scottish Index of Multiple Deprivation) (p = 0.021). CONCLUSIONS: The prognostic use of established scoring systems of systemic and local inflammation and tissue necrosis in BPH requires further investigation. It remains unclear as to whether targeting inflammation in BPH has therapeutic potential.

Body mass index predicts failure of surgical management in benign prostatic hyperplasia.

INTRODUCTION: Inflammation is postulated to link obesity and benign prostatic hyperplasia (BPH). The role of inflammation and the prognostic significance of body mass index (BMI) was investigated in BPH patients. SUBJECTS AND METHODS: Consecutive patients with histological BPH were identified from 1996 to 2005. Systemic inflammation was assessed by modified Glasgow Prognostic Score (mGPS) and local inflammation by Klintrup-Makinen criteria. RESULTS: In 392 patients, BMI was associated with cardiovascular disease (p = 0.033), type 2 diabetes mellitus (p = 4.45 × 10), aspirin usage (p = 0.018) and failure of surgical treatment (p = 0.001). mGPS and Klintrup-Makinen scores were not associated with clinical variables or outcome measures. On multivariate analysis BMI was an independent predictor of time to failure of surgical management of BPH, HR 1.56 (95% CI 1.11-2.19), p = 0.010. CONCLUSIONS: The mGPS and Klintrup-Makinen scores were not associated with BMI in BPH patients. High BMI is associated with failure of surgical management of BPH. Preoperative weight loss should be strongly encouraged in these patients.

Androgen receptor phosphorylation at serine 308 and serine 791 predicts enhanced survival in castrate resistant prostate cancer patients.

We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR94), 308 (pAR308), 650(pAR650) and 791 (pAR791). No correlations with clinical parameters were observed for pAR94 or pAR650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR308 is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR791 expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer.

The prognostic value of histological tumor necrosis in solid organ malignant disease: a systematic review.

BACKGROUND: Tumor necrosis has been proposed as a marker of poor prognosis in a variety of solid organ malignant tumor types. Despite this, its assessment has yet to be adopted into routine clinical practice and the mechanisms underpinning the relationships with cancer outcome are undetermined. AIMS: To examine the prognostic value of tumor necrosis in solid organ malignant disease and to summarize the known clinical, pathological and inflammatory associations. METHODS: A systematic review of data published from 1966-2011 was undertaken by two reviewers according to a predefined protocol. A total of 57 independent studies relating to renal (n = 23), breast (n = 13), lung (n = 7), colorectal (n = 5) and other solid tumors (n = 9) were included in the final review. CONCLUSION: There is now a substantial body of evidence confirming the prognostic value of tumor necrosis in solid organ malignant disease. There are consistent associations between necrosis and the presence of other high-risk tumor characteristics but the survival impact appears to be independent of pathological stage. We propose that relationships with the host inflammatory response, both local and systemic, may explain the influence of tumor necrosis on cancer outcome.

Systemic inflammatory response and survival in patients with localised prostate cancer: 10-year follow-up.

AIM: To examine the prognostic value of circulating C-reactive protein concentrations at diagnosis in patients with organ-confined prostate cancer. PATIENTS AND METHODS: Ninety-eight patients with histologically proven clinically localised prostate cancer were studied. Clinical stage, tumour grade, circulating PSA and C-reactive protein concentrations at diagnosis were recorded. RESULTS: The majority of patients was under the age of 70 years and had low-grade tumours. Approximately half the patients received radical local treatment. During the follow-up period (median 10 years) 38 patients died, of whom 18 died of prostate cancer, 6 of other cancers and 14 of non-cancer causes. On univariate survival analysis, age (p < 0.001), Gleason score (p < 0.05), C-reactive protein (p < 0.05) and treatment (p < 0.05) were significant predictors of overall survival. On univariate survival analysis, age (p < 0.001), Gleason score (p < 0.05) and C-reactive protein (p < 0.05) were significant predictors of prostate cancer-specific survival. On multivariate analysis of these significant variables age (HR 4.88, 95% CI 1.79-13.29, p < 0.01), Gleason score (HR 2.16, 95% CI 1.23-3.78, p < 0.01) and C-reactive protein (HR 1.88, 95% CI 1.01-3.52, p < 0.05) remained significant independent predictors of prostate cancer-specific survival. CONCLUSION: The results of the present study show that the presence of a systemic inflammatory response, at diagnosis, independently predicts poor long-term cancer outcome in patients with localised prostate cancer.

UScale: a digital device for automatic urine volume measurement and frequency volume charting.

BACKGROUND: Health issues relating to the lower urinary tract are an increasing burden on the health economy. Measurement of urination frequency/volume using diaries to evaluate symptoms and assess severity is established in the management of these health problems. In current practice, these frequency volume diaries are completed by voiding into a measuring jug and the completion of paper or digital charts. Despite being shown useful to diagnosis, this can be a cumbersome method of data collection, leading to issues with patient compliance. In this paper we describe the established benefits of providing clinicians accurate micturition data followed by an analysis of the problems with the current data collection method. METHODS: We introduce our prototype electronic device and accompanying method, which is designed to improve data accuracy and patient compliance, while reducing patient training requirements and clinician workload. RESULTS: The device hardware calibration and testing procedure is described, and two sets of initial data from assumed healthy volunteers are presented, allowing us to demonstrate the advantages of digital data in the fast calculation of diary summary statistics and their potential use to clinicians. CONCLUSIONS: We discuss the design improvements to the UScale device, collection bag, and electronic medical records integration undertaken while validating our described method.

CD40 induces renal cell carcinoma-specific differential regulation of TRAF proteins, ASK1 activation and JNK/p38-mediated, ROS-dependent mitochondrial apoptosis.

A unique feature of CD40 among the TNF receptor (TNFR) superfamily is its exquisitely contextual effects, as originally demonstrated in normal and malignant B-lymphocytes. We studied renal cell carcinoma (RCC) in comparison to normal (human renal proximal tubule) cells, as a model to better understand the role of CD40 in epithelial cells. CD40 ligation by membrane-presented CD40 ligand (mCD40L), but not soluble CD40 agonist, induced extensive apoptosis in RCC cells; by contrast, normal cells were totally refractory to mCD40L. These findings underline the importance of CD40 'signal-quality' on cell fate and explain the lack of pro-apoptotic effects in RCC cells previously, while confirming the tumour specificity of CD40 in epithelial cells. mCD40L differentially regulated TRAF expression, causing sustained TRAF2/TRAF3 induction in RCC cells, yet downregulation of TRAF2 and no TRAF3 induction in normal cells, observations strikingly reminiscent of TRAF modulation in B-lymphocytes. mCD40L triggered reactive oxygen species (ROS) production, critical in apoptosis, and NADPH oxidase (Nox)-subunit p40phox phosphorylation, with Nox blockade abrogating apoptosis thus implying Nox-dependent initial ROS release. mCD40L mediated downregulation of Thioredoxin-1 (Trx-1), ASK1 phosphorylation, and JNK and p38 activation. Although both JNK/p38 were essential in apoptosis, p38 activation was JNK-dependent, which is the first report of such temporally defined JNK-p38 interplay during an apoptotic programme. CD40-killing entrained Bak/Bax induction, controlled by JNK/p38, and caspase-9-dependent mitochondrial apoptosis, accompanied by pro-inflammatory cytokine secretion, the repertoire of which also depended on CD40 signal quality. Previous reports suggested that, despite the ability of soluble CD40 agonist to reduce RCC tumour size in vivo via immunocyte activation, RCC could be targeted more effectively by combining CD40-mediated immune activation with direct tumour CD40 signalling. Since mCD40L represents a potent tumour cell-specific killing signal, our work not only offers insights into CD40's biology in normal and malignant epithelial cells, but also provides an avenue for a 'double-hit' approach for inflammatory, tumour cell-specific CD40-based therapy.

The epidemiology and risk factors for renal cancer.

BACKGROUND: Renal cancer is a frequently occurring malignancy with over 270,000 new cases diagnosed and it being responsible for 110,000 deaths annually on a global basis. Incidence rates have gradually increased whilst mortality rates are starting to plateau. OBJECTIVE: To review epidemiology and risk factors for renal cancer. METHODS: The current data is based on a thorough review of available original and review articles on epidemiology and risk factors for renal cancer with a systemic literature search utilising Medline. RESULTS: The prevalence of associated risk factors such as genetic susceptibility, smoking, hypertension and obesity are changing and could account for the changes in incidence whilst the role of diet and occupational exposure to carcinogens requires further investigation. CONCLUSION: Despite the evidence of various associated risk factors, further work is required from well designed studies to gain a greater understanding of the etiology of renal cancer.

Pathological Correlation between Number of Biopsies and Radical Surgery: Does It Make a Difference to Final Pathology?

AIMS: To evaluate whether the number of biopsies performed via transrectal ultrasound (TRUS) accurately predicts pathological parameters such as Gleason sum, prostatic intraepithelial neoplasia and perineural invasion of the final prostatectomy specimen. MATERIALS AND METHODS: The cohort consisted of 99 patients whom had undergone radical prostatectomy. Comparisons were made between the number of biopsies utilised and the presence of the pathological parameters from tissue at time of diagnosis and tissue from the final prostatectomy. RESULTS: A significant difference was noted between Gleason sum, prostatic intraepithelial neoplasia and perineural invasion from tissue at time of diagnosis irrespective of the number of biopsies utilised and tissue from the radical specimen (p < 0.001, p < 0.001, p < 0.001 respectively). No difference was noted in the mean Gleason sum when 11-14 biopsies were utilised at TRUS and the Gleason sum from the radical specimen. CONCLUSION: We have demonstrated that the number of biopsies utilised at time of TRUS for diagnosis predicts the accuracy of pathological parameters in the final radical prostatectomy specimen. We believe that 11-14 biopsies should be utilised at time of TRUS as this allows a higher accuracy in the Gleason sum and therefore allows optimum treatment plans to be devised.

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.

A prospective study of the role of inflammation in bladder cancer.

INTRODUCTION: To examine the role of inflammation in bladder cancer, we assessed the relationship between a systemic inflammation prognostic score (modified Glasgow Prognostic Score, mGPS), the tumor inflammatory cell infiltrate as measured by the Klintrup-Makinen score and tumor necrosis with cancer specific survival in patients with bladder cancer. MATERIALS AND METHODS: The cohort consisted of 68 bladder cancer patients, 47 with localised disease and 21 with muscle invasive disease. The mGPS response was constructed by measuring C-reactive protein and albumin concentrations and the Klintrup-Makinen score was evaluated histologically for the local inflammatory response. Pathological parameters such as grade, T stage and tumor necrosis were also assessed. RESULTS: Median follow was 47 months and 24 patients died of their disease. On univariate analysis, T stage (p < 0.001), grade (p < 0.001) and mGPS (p = 0.002) were significant predictors of cancer specific survival. On multivariate analysis, T stage (hazard ratio 5.98, 95% confidence interval 3.18-11.24, p < 0.001) and mGPS (hazard ratio 1.78, 95% confidence interval 1.09-2.9, p = 0.02) were significant independent predictors of cancer specific survival. CONCLUSION: A preoperative systemic inflammatory response is an independent predictor of poor cancer specific survival in patients with bladder cancer.

Hyperuricemia and gout in renal transplant recipients.

Hyperuricemia, unlike clinical gout, is extremely common in renal transplant patients. The high prevalence of hyperuricemia is related to prolonged exposure to cyclosporine rather than to its dose or serum concentration. Serum creatinine levels do not show significant correlation with hyperuricemia, behaving more like a surrogate marker for cyclosporine dose and trough level. The low incidence of gout in renal transplant patients, despite the hyperuricemia, may be related to the prolonged immunosuppression effect.

Post-transplant erythrocytosis: a review of 47 renal transplant recipients.

Post-transplant erythrocytosis (PTE) is a well known phenomenon occurring in 5-17% of renal transplant recipients (RTR). In this retrospective study, we studied 47 RTR which included 39 males and eight females. They were divided into two groups according to the presence or absence of PTE, which was defined as a hematocrit of more than 51%. Nine of the 47 patients (19%) developed PTE all of whom were males. The mean age of patients with PTE was 44 +/- 9 years versus 40 +/-11 years for patients without PTE. The mean follow-up period was 113 +/- 26 months and 93 +/- 58 months for the PTE and non-PTE groups respectively. The mean period after transplant when PTE developed was 9.8 +/- 9 months and it lasted for 37 +/- 3 months. Thromboembolic complications in the form of lower limb deep vein thrombosis occurred in one patient. Most patients were treated with phlebotomies, and one received an angiotensin converting enzyme inhibitor. There were no apparent predisposing factors in any but one patient, who had autosomal dominant polycystic kidney disease and developed hydronephrosis of the transplanted kidney. This might have caused excessive production of erythropoietin resulting in PTE. The serum creatinine values were higher, although statistically insignificant in patients with PTE. Chronic rejection was more commonly seen in patients with PTE (44%) than those without PTE (11%). Our findings suggest that PTE is a benign condition affecting males more than females. It may have an association with chronic rejection. Most cases can be controlled using phlebotomy.