Immunotherapies in Early and Advanced Renal Cell Cancer

The development of new immunomodulatory monoclonal antibodies targeting the CTLA-4 or PD-1 axis has led to a revival of research on immunotherapies in solid tumours including renal cell cancer (RCC). The initial results observed with these monoclonal antibodies in the treatment of advanced melanoma have resulted in considerable interest in this treatment strategy in all tumour types. Preliminary data of these new antibodies in advanced RCC are promising and they have good safety profiles. Response rates are low but durable tumour control has been observed in some patients. However, at the moment there is no evidence that targeting the CTLA-4 or PD-1 axis provides a substantial clinical benefit compared to established treatment with tyrosine kinase or mTOR inhibitors. There are also no reliable predictive markers. At the moment, several randomised trials have been initiated to investigate the new immunomodulatory antibodies either as single agents or in combination with anti-VEGF targeted therapy. Vaccines have continued to be investigated in advanced and adjuvant settings. No trial has so far established vaccines as a standard treatment in either situation. There are still large randomised trials ongoing investigating the potential benefit of a vaccine in combination with standard tyrosine kinase inhibitor therapy. In this chapter we will summarise selected studies on immunotherapy in advanced RCC with a focus on anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. We will also touch briefly on the adjuvant situation and tumour vaccines

Spatial dilemmas of diffusible public goods

The emergence of cooperation is a central question in evolutionary biology. Microorganisms often cooperate by producing a chemical resource (a public good) that benefits other cells. The sharing of public goods depends on their diffusion through space. Previous theory suggests that spatial structure can promote evolution of cooperation, but the diffusion of public goods introduces new phenomena that must be modeled explicitly. We develop an approach where colony geometry and public good diffusion are described by graphs. We find that the success of cooperation depends on a simple relation between the benefits and costs of the public good, the amount retained by a producer, and the average amount retained by each of the producer’s neighbors. These quantities are derived as analytic functions of the graph topology and diffusion rate. In general, cooperation is favored for small diffusion rates, low colony dimensionality, and small rates of decay of the public good. DOI: http://dx.doi.org/10.7554/eLife.01169.00

Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: Bevacizumab in combination with interferon-α2a compared with sunitinib

Background: Bevacizumab plus interferon-α2a (IFN) prolongs progression-free survival to>10 months, which is comparable with sunitinib as first-line treatment of metastatic renal cell carcinoma (RCC). The two regimens have different tolerability profiles; therefore, costs for managing adverse events may be an important factor in selecting therapy.Methods: Costs of managing adverse events affecting patients with metastatic RCC eligible for treatment with bevacizumab plus IFN or sunitinib were evaluated using a linear decision analytical model. Management costs were calculated from the published incidence of adverse events and health-care costs for treating adverse events in the United Kingdom, Germany, France and Italy.Results: Adverse event management costs were higher for sunitinib than for bevacizumab plus IFN. The average cost per patient for the management of grade 3-4 adverse events was markedly lower with bevacizumab plus IFN compared with sunitinib in the United Kingdom (\[euro]1475 vs \[euro]804), Germany (\[euro]1785 vs \[euro]1367), France (\[euro]2590 vs \[euro]1618) and Italy (\[euro]891 vs \[euro]402). The main cost drivers were lymphopaenia, neutropaenia, thrombocytopaenia, leucopaenia and fatigue/asthaenia for sunitinib; and proteinuria, fatigue/asthaenia, bleeding, anaemia and gastrointestinal perforation for bevacizumab plus IFN.Conclusion: The costs of managing adverse events are lower for bevacizumab plus IFN than for sunitinib. The potential for cost savings should be considered when selecting treatments for RCC

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Predictive response-relevant clustering of expression data provides insights into disease processes

This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of ;response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the ;meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes-including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets

RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients

Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL

On the Correspondence between Display Postulates and Deep Inference in Nested Sequent Calculi for Tense Logics

We consider two styles of proof calculi for a family of tense logics, presented in a formalism based on nested sequents. A nested sequent can be seen as a tree of traditional single-sided sequents. Our first style of calculi is what we call "shallow calculi", where inference rules are only applied at the root node in a nested sequent. Our shallow calculi are extensions of Kashima's calculus for tense logic and share an essential characteristic with display calculi, namely, the presence of structural rules called "display postulates". Shallow calculi enjoy a simple cut elimination procedure, but are unsuitable for proof search due to the presence of display postulates and other structural rules. The second style of calculi uses deep-inference, whereby inference rules can be applied at any node in a nested sequent. We show that, for a range of extensions of tense logic, the two styles of calculi are equivalent, and there is a natural proof theoretic correspondence between display postulates and deep inference. The deep inference calculi enjoy the subformula property and have no display postulates or other structural rules, making them a better framework for proof search

A key to the species of Keetia (Rubiaceae: Vanguerieae) in West Africa, with three new, threatened species from Guinea and Ivory Coast

Keetia susu Cheek and K. futa Cheek from the Republic of Guinea, and K. abouabou Cheek from Ivory Coast are described here. Each species is assessed using the IUCN standard as, respectively, Vulnerable, Endangered and Critically Endangered. Each species is illustrated and mapped. A key to the 16 species of Keetia in West Africa (Senegal to Benin) is provided. The number of species of Keetia currently accepted is now known to total 35

Industrial strategy and the UK regions: Sectorally narrow and spatially blind

The UK government's new Industrial Strategy could have a significant impact on the country's regions and localities. However, this has received little attention to date. The analysis presented here examines the existing location of the sectors targeted by the first phase of the Industrial Strategy Challenge Fund and the location of the R&D laboratories likely to be first in line for funding. In focusing on an extremely narrow range of sectors, the Fund is likely to have limited impact on the UK's persistent regional inequalities. The activities eligible for support account for relatively little of manufacturing or the rest of the economy and the basis of this targeting and its potential distributional consequences are spatially blind. As such, it runs the risk of widening regional divides in prosperity