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Since the Von Hippel-Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (RCC). Drugs such as sorafenib, sunitinib and pazopanib act on the VEGF receptor pathway, but they can also inhibit other kinases, resulting in off-target toxicities. Tivozanib was developed due to its potency and selectivity against VEGF receptors 1--3. It has a favorable pharmacokinetic profile after oral administration and a long plasma half-life. In the Phase III TIVO-1 trial, it demonstrated a higher response rate and longer progression-free survival than sorafenib with a better side-effect profile. It is currently awaiting approval to be used in the first-line treatment of metastatic RCC. An early-phase trial has also shown its tolerability at full dose when given with the mTOR inhibitor temsirolimus, suggesting its potential in combination treatment. This article examines tivozanib from its laboratory to clinical development, as well as its relevance and future role in the treatment of RCC in the era of the tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Background: Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. Methods: Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. Findings: The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7–34·4, IQR 2·5–18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7–52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. Interpretation: Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug''s safety profile requires close monitoring. Funding: Bayer HealthCare Pharmaceuticals. [Copyright &y& Elsevier]

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC—sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC. [ABSTRACT FROM PUBLISHER]

• Six targeted agents - sorafenib, sunitinib, pazopanib, bevacizumab, temsirolimus and everolimus - have been approved for the treatment of advanced renal cell carcinoma (RCC) based on evidence from large randomized controlled trials (RCTs). However, no head-to-head trials have been conducted to evaluate the relative efficacy of these agents in this setting. • Patient populations included in clinical trials do not accurately reflect the wider population of patients with RCC, as certain subgroups, such as the elderly or those with co-morbidities, are typically under-represented. • The optimum choice of therapy should be based on patient characteristics, nature of disease, and history and aims of therapy; however, there is currently no clear guidance for physicians in this decision-making process. • A patient-focussed schema has been developed that acknowledges nine different patient-, disease-, and treatment-related factors relevant to clinical decision-making, and provides a visual indication of the strength of evidence with which a particular agent can be recommended for use in specific subgroups. • To demonstrate the applicability of this tool, a review of all available evidence (published articles, congress presentations and personal communications) for sorafenib in RCC was conducted by a panel of experts, findings from which showed that sorafenib can be recommended for use in various subgroups of differing age, prognosis, performance status, tumour burden and distribution, treatment history and co-morbidity. • This patient-focussed approach has broad application and can be used to assess other agents and tumour types. Randomized controlled trials (RCTs) show that six targeted agents - sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib - improve outcome in advanced renal cell carcinoma (RCC). The populations enrolled in the pivotal phase III studies differed, and, to date, no head-to-head comparisons allow us to judge relative efficacy and tolerability. Populations recruited to RCTs under-represent certain patient subtypes, notably the elderly and those with comorbidities. Choosing the agent most appropriate in a specific case requires that we take into account the characteristics of the patient, the nature of their disease, and the history and aims of therapy. Data from expanded access programmes and clinical experience may be as relevant as the results of RCTs when making this difficult decision. To show how different sources of data can be integrated, we propose a schema that acknowledges nine patient-, disease-, and treatment-related factors relevant to clinical decision-making and provides an easily understood visual indication of the strength with which a particular agent can be recommended for use in specific subgroups of patients. As an example, we show how this tool shows the suitability of sorafenib in RCC subpopulations of differing age, prognosis, performance status, tumour burden and distribution, treatment history, and comorbidity. This patient-focused approach has broad application to other agents and tumour types. [ABSTRACT FROM AUTHOR]

Patients with renal cell carcinoma (RCC) exhibit a spectrum of clinical outcomes, with some patients following an indolent clinical course and others displaying rapidly advancing disease. As evidence points to RCC being largely refractory to traditional chemotherapy and radiotherapy strategies, immunotherapeutic approaches played a dominant role in the management of metastatic RCC for a quarter of a century. Management of this challenging tumor has been revolutionized by the incorporation of molecularly targeted therapies such as inhibitors of pathways involving tyrosine kinase signaling and the mammalian target of rapamycin (mTOR). The improvements in disease stabilization and survival seen with these agents has meant that molecularly targeted therapy now forms the foundation for treating RCC and has resulted in a multitude of studies investigating similar compounds for efficacy in RCC. Despite this, the rationale for using immunomodulatory regimens remains strong and its ongoing place in this era of targeted treatments continues to pose interesting clinical questions. The challenge of maintaining durable responses from our current therapies persists and this review highlights the plethora of options now available in RCC treatment and the directions in which modern management are heading. [ABSTRACT FROM AUTHOR]

The article reports a study which shows that the von Hippel-Lindau (VHL) disease is caused by germ line mutations in the VHL tumor-suppressor gene. It states that the disease is a hereditary neoplastic disease associated with clear-cell renal-cell carcinomas (ccRCCs), central nervous system pheochromocytomas and hemangioblastomas. It mentions a data which indicates that VHL alterations have a potential role as prognostic and predictive markers in ccRCC.

As α-melanocyte-stimulating hormone (α-MSH) is released by immunocompetent cells and has potent immunosuppressive properties, it was determined whether human dendritic cells (DCs) express the receptor for this hormone. Reverse transcription–polymerase chain reaction detected messenger RNA specific for all of the known melanocortin receptors in DCs. Mixed lymphocyte reactions also revealed that treatment with [Nle4, DPhe7]-α-MSH (NDP-MSH), a potent α-MSH analogue, significantly reduced the ability of DCs to stimulate allogeneic T cells. The expression of various cell surface adhesion, maturation and costimulatory molecules on DCs was also investigated. Although treatment with NDP-MSH did not alter the expression of CD83 and major histocompatibility complex class Ι and ΙΙ, the surface expression of CD86 (B7.2), intercellular adhesion molecule (ICAM-1/CD54) and CD1a was reduced. In summary, our data indicate that NDP-MSH inhibits the functional activity of DCs, possibly by down-regulating antigen-presenting and adhesion molecules and that these events may be mediated via the extracellular signal-regulated kinase 1 and 2 pathway. [ABSTRACT FROM AUTHOR]

Summary: Five targeted agents have shown efficacy in advanced renal cell carcinoma. These agents were evaluated in pivotal phase III clinical trials using different treatment settings and different patient populations. As patients encountered in ‘real life’ clinical practice are frequently under-represented in phase III trials, making treatment decisions based on phase III data alone may have limitations. In order to support treatment decisions for patients who do not fit within the inclusion criteria of many phase III trials, physicians must consider additional data sources such as expanded access programmes, sub- and retrospective analyses, and also clinical experience. The suitability of a specific targeted agent for a given patient group, e.g. elderly, will depend on a number of factors, including disease-, patient- and treatment-related characteristics. Here, we identify the need for an individualised patient-focused approach to the management of advanced renal cell carcinoma in clinical practice. In order to optimise therapy for individual patients, we present a schema providing guidance on the wide range of parameters that should be considered when making treatment decisions. We recommend the integration of this approach into everyday clinical practice. [Copyright &y& Elsevier]

The article presents a study which examines the effectivity of the lenalidomide in the treatment of patients with refractory metastatic malignant melanoma. It states that patients who are 18 years old and above with stage IV refractory metastatic malignant melanoma were eligible in the study. It shows that no significant differences was observed in overall survival (OS) between lenalidomide and placebo and that combination therapy is important for malignant melanoma treatment.

FDA approval of the multitargeted, antiangiogenic tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib, and the serine and threonine mammalian target of rapamycin inhibitor, temsirolimus, has revolutionized the management of metastatic clear-cell renal-cell carcinoma (CC-RCC). The inability of these targeted therapies to provide durable complete responses, however, is a serious limiting factor to their clinical usefulness. Although immunotherapeutic approaches in advanced disease are increasingly regarded as a historical treatment paradigm, we propose that a fundamental understanding of immunobiology in CC-RCC can improve the selection of patients for high-dose intravenous interleukin 2 and facilitate the development of novel immunotherapeutic strategies. In our opinion, immunotherapeutic strategies have an important place in the management of advanced CC-RCC in the era of biological targeted therapy. [ABSTRACT FROM AUTHOR]

The incidence of renal cell cancer (RCC) in the elderly is increasing, yet few older patients have been enrolled in prospective clinical trials to evaluate new anti-RCC therapies. The multi-targeted tyrosine kinase inhibitor (TKI), sorafenib, is now established as a second-line treatment in advanced RCC after immunotherapy failure, and its toxicity profile is manageable. This review discusses the data on the use of anti-RCC agents in the older patient with special emphasis on sorafenib. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m2 to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. Patients and methods: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. Results: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n =13) or limited-stage disease (n =7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1–2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. Conclusion: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m2) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC. [Copyright &y& Elsevier]

Sorafenib is a potent, orally active multitargeted kinase inhibitor. In vitro, it blocks signaling through several pathways essential for renal cell and other cancers. A large body of evidence has now accrued demonstrating the activity of sorafenib, after immunotherapy failure, in advanced renal cell cancer. Although radiological responses to single-agent sorafenib by standard response evaluation criteria in solid tumors are rare, prolongation of progression-free survival has been demonstrated and is associated with stabilization of anatomically measurable disease. Compared with other available therapies such as cytotoxic chemotherapy and high-dose intravenous interleukin-2, sorafenib is well-tolerated, and studies with this exciting new agent at earlier stages in this fatal disease are awaited. [ABSTRACT FROM AUTHOR]

Background The perception that older cancer patients may be at higher risk than younger patients of toxic effects from cancer therapy but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials and the known toxic effects of cytotoxic chemotherapy. It is not known how older patients respond to targeted therapy. Methods This retrospective subgroup analysis of data from the phase 3, randomized Treatment Approach in Renal Cancer Global Evaluation Trial examined the safety and efficacy of sorafenib in older (age ⩾70 years, n = 115) and younger patients (age <70 years, n = 787) who received treatment for advanced renal cell carcinoma. Patient demographics and progression-free survival were recorded. Best tumor response, clinical benefit rate (defined as complete response plus partial response plus stable disease), time to self-reported health status deterioration, and toxic effects were assessed by descriptive statistics. Health-related quality of life was assessed with a Cox proportional hazards model. Kaplan-Meier analyses were used to summarize time-to-event data. Results Median progression-free survival was similar in sorafenib-treated younger patients (23.9 weeks; hazard ratio [HR] for progression compared with placebo = 0.55, 95% confidence interval [Cl] = 0.47 to 0.66) and older patients (26.3 weeks; HR = 0.43, 95% Cl = 0.26 to 0.69). Clinical benefit rates among younger and older sorafenib-treated patients were also similar (83.5% and 84.3%, respectively) and were superior to those of younger and older placebo-treated patients (53.8% and 62.2%, respectively). Adverse events were predictable and manageable regardless of age. Sorafenib treatment delayed the time to self-reported health status deterioration among both older patients (121 days with sorafenib vs 85 days with placebo; HR = 0.66, 95% Cl = 0.43 to 1.03) and younger patients (90 days with sorafenib vs 52 days with placebo; HR = 0.69, 95% Cl = 0.59 to 0.81) and improved quality of life over that time. Conclusions Among patients with advanced renal cell carcinoma receiving sorafenib treatment, outcomes of older (⩾70 years) and younger (<70 years) patients were similar. [ABSTRACT FROM AUTHOR]

The last decade has seen a considerable improvement in the understanding of the biology of melanoma. Advances have come in the understanding of the importance of critical oncogenes and tumour suppressor genes, epigenetic phenomena, signalling pathways, drug resistance mechanisms, the pivotal role of the local immune system, and the importance of cell–cell and cell–matrix interactions. Many of these pathways and interactions include potentially ‘drugable’ targets. These developments have allowed the identification and/or design of a range of new, targeted therapies. Evaluation of these new drugs has brought a whole new series of challenges. These include indentification of appropriate pre-clinical models, overcoming the redundancy inbuilt in complex biological systems, identification of appropriate molecular and clinical endpoints to show that the drug is hitting the target, how to combine treatments, and new toxicities. For the first time, there is the possibility of personalised treatment for melanoma patients, based on individual host and tumour characteristics. This paper discusses the range of new drugs and targets have been identified, the outcome of clinical trials, and the directions for future advances. [ABSTRACT FROM AUTHOR]

The article presents medical research into prognostic factors in clinical trials for renal cell carcinoma (RCC). Pathological factors include tumor size, spread into the inferior vena cava, and lymphadenopathy. Nonpathological factors include neutrophil count, thrombocytosis, and performance status. Algorithms have been developed that combine clinical, laboratory, and pathological factors.

Abstract: This review summarises available data and describes planned clinical trials designed to evaluate the potential of targeted agents as adjuvant therapy for renal cell carcinoma (RCC). Advanced RCC is refractory to standard cytotoxic chemotherapy, and clinical trials of adjuvant cytokine therapy in this therapeutic setting have not yet demonstrated clear evidence of clinical benefit. However, molecularly targeted therapies may offer a new approach for adjuvant therapy of this disease. Sorafenib (Nexavar®; Bayer Healthcare, West Haven, CT, USA) and sunitinib (Sutent®; Pfizer Inc, New York, NY, USA) are candidates for adjuvant therapy, because they are efficacious in the treatment of metastatic RCC and have side-effect profiles that can usually be well managed during long-term administration. The clinical benefit and tolerability of these agents as adjuvant therapies are being investigated in three ongoing phase 3 trials: ASSURE (adjuvant sorafenib or sunitinib in unfavourable renal cell carcinoma; Eastern Cooperative Oncology Group 2805), STAR (sunitinib trial in adjuvant renal cancer) and SORCE (a phase 3, randomised, double-blind, controlled study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse). The results of these studies will address important clinical and translational questions, the answers to which may help define future treatment strategies and guide treatments towards the most appropriate patients. [Copyright &y& Elsevier]

Abstract: Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation. [Copyright &y& Elsevier]

Epidemiological data has implicated heterozygosity for xeroderma pigmentosum (XP) as a risk factor for lung cancer. XP has 8 known complementation groups, 7 of which are caused by mutations in genes encoding components of the nucleotide excision repair (NER) pathway. To formally investigate the role of XP-related NER genes in lung cancer susceptibility, we screened germline DNA from 92 familial early-onset lung cancer patients for mutations in all coding regions and intron-exon boundaries of XPA, XPC, XPD, XPF, XPB, XPG and DDB2. Forty-one exonic variants were identified. Twenty-four were nonsynonymous, of which 14 were previously documented polymorphisms. Ten missense variants had not been previously described; none of which were detected in germline DNA from 278 cancer-free controls. Two of the novel missense changes are predicted to be functionally deleterious. Our findings are compatible with XP heterozygosity being a risk factor for lung cancer susceptibility. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The base excision repair gene MYH protects against damage to DNA from reactive oxygen species, which are commonly found in cigarette smoke. Inherited mutations in MYH predispose to colorectal adenomas and carcinomas that show a characteristic pattern of somatic G:C→T:A mutations in the APC gene. A similar pattern of somatic mutations in the TP53 gene is reported in smoking-related lung cancers. We therefore tested whether germline changes in MYH may also contribute to the development of lung cancer by screening for variants in 276 patients with lung carcinoma and 106 normal controls. No patients harboured truncating mutations in MYH and only a single patient was a carrier for the G382D missense mutation. We identified three common coding region (V22M, Q324H and S501F) and intronic (157+30A>G, 462+35G>A and 1435-40G>C) variants, but none were over-represented in the patient samples, indicating that MYH variants are unlikely to predispose significantly to the risk of lung cancer. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Progression of early structural lung disease in young children with cysticfibrosis assessed" by L.S. Mott, J. Park and C.P. Murray in a previous issue of the periodical.

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib. [ABSTRACT FROM AUTHOR]

Background: The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery.Methods: We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1-4, N0-1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups.Results: We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups.Conclusions: We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could be used for tailoring postoperative surveillance and defining inclusion for prospective adjuvant clinical trials. [ABSTRACT FROM AUTHOR]

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer. Super enhancers are frequently involved in the dysregulation of gene expression in cancer. Here, in kidney cancer, a super enhancer is shown to drive the expression of KLF6, which alters the expression of lipid metabolism genes and promotes tumorigenesis. [ABSTRACT FROM AUTHOR]

The author discusses the modern myths of percutaneous renal tumour mass biopsy (PRTB). Modern myths discussed include PRTB promoting metastasis and making partial nephrectomy more difficult, it does not change patient management, and the low morbidity associated with partial nephrectomy that is comparable to PRTB.

Background The imminent publication of a randomised controlled trial from the USA that suggests CT screening reduces mortality from lung cancer by more than 20%, may potentially lead to one of the most important developments in lung cancer care. However, there remain important questions about the applicability of the results to the UK and the clinical effectiveness of this intervention, including its feasibility and costeffectiveness. Objective To describe the remaining questions that need to be answered by further research and to comment on the use of CT screening in the UK outside a clinical trial. Methods The detailed design process of the UKLS protocol and international discussions were used to identify the research questions that remain to be answered and to inform those who may choose to consider offering CT screening, before these questions are answered. Results A series of research imperatives have been identified and we advise that CT screening should be part of the ongoing clinical trial in the UK, currently in the pilot phase (UKLS). UKLS is randomising 4,000 individuals for the pilot and a total of 32,000 for the main study. Conclusion There remain unresolved issues with respect to CT screening for lung cancer. These include its feasibility, psychosocial and cost-effectiveness in the UK, harmonisation of CT acquisition techniques, management of suspicious screening findings, the choice of screening frequency and the selection of an appropriate risk group for the intervention. UKLS is aimed at resolving these issues. [ABSTRACT FROM AUTHOR]

The article comments on the decision of the British National Institute of Health and Clinical Excellence's rejection of novel treatments for renal cell cancer (RCC). These drugs, including sunitinib, sorafenib and temsorolimus, have been found effective in controlling the progression of RCC. But they are very expensive, averaging 3,000 British pounds per month.