New treatments for advanced cancer: an approach to prioritization

The allocation of funding for new anticancer treatments within the UK has not kept pace with demand. Clinicians find themselves restricted in the use of licensed drugs which they feel are in the best interests of individual patients. Against this, health authorities have a duty to ensure that scarce resources are used equitably to meet the needs of the local population as a whole. Differential levels of funding for new treatments across the country have led to concerns about rationing by postcode. This paper outlines an approach to the prioritization of new treatment for advanced cancer developed jointly by clinicians and health authorities in South London. The approach involves evidence reviews and consensus meetings. Existing and new treatments are rated on a four-point ‘relative effectiveness scale’, which takes account of the impact of the treatment on quality of life and on survival. The strength of evidence supporting each effectiveness rating is also classified. Health Authorities have used these ratings to determine overall funding levels, while leaving decisions on individual patients to the relevant Trusts. © 2000 Cancer Research Campaig

Iododoxorubicin in advanced breast cancer: a phase II evaluation of clinical activity, pharmacology and quality of life.

Iododoxorubicin 80 mg m-2 i.v. was given 3 weekly for a maximum of six cycles as first-line chemotherapy to 14 evaluable women with metastatic breast cancer. The response rate was 14% (95% confidence intervals 4-40%); median time to progression was 3.5 months (range 0.7 to > 9.3) and median survival was 10.2 months (range 2.3 to > 20.4). Neutropenia was the main toxicity but was not associated with severe sepsis. Two patients had a significant (> 10%) but asymptomatic fall in cardiac ejection fraction; other toxicities were mild. Plasma pharmacokinetics was studied during the first cycle of treatment. Iododoxorubicin was extensively metabolised to iododoxorubicinol. Neutropenia and thrombocytopenia were both significantly correlated with the area under the concentration-time curve (AUC) for iododoxorubicin and the total AUC for iododoxorubicin and iododoxorubicinol. Quality of life (QOL), evaluated by self-report questionnaire and interview, showed little evidence of benefit in terms of physical symptom relief, level of activity, psychological symptoms or global evaluation of QOL during treatment. Iododoxorubicin is subjectively less toxic than standard anthracyclines, but at the dose and schedule used has limited activity in metastatic breast cancer, possibly because iododoxorubicinol is not clinically active

Costs and consequences of different chemotherapy regimens in metastatic colorectal cancer

An economic sub-study was run alongside a large multi-centre randomised trial (MRC-CR06) comparing three chemotherapy regimens; de Gramont, Lokich and raltitrexed in patients with metastatic colorectal cancer. Patients in six of 45 centres in the main trial were approached to take part in the sub-study. Chemotherapy delivery costs were assessed in each sub-study centre with external validity verified by questionnaire to all other centres. Patient representativeness was assessed. Stochastic resource use data, including patient borne costs and non-hospital health service resource use were monitored prospectively. Mean total societal costs were de Gramont=£5051 (s.d. £1910), raltitrexed=£2616 (s.d. £991) and Lokich=£2576 (s.d. £1711). In pairwise comparisons, statistically significant mean total cost differences were shown for de Gramont vs Lokich (mean difference=£2475, 95%CI £914–£4037, P<0.01) and for de Gramont vs raltitrexed (mean difference=£2435, 95%CI £922–£2948, P<0.01). Sensitivity analyses showed little effect on overall costs. The main trial showed de Gramont and Lokich to be equally effective in terms of survival, quality of life and response rates but Lokich had higher toxicity and hand-foot syndrome. Raltitrexed showed similar response rates and overall survival but increased toxicity and inferior quality of life making it a clinically inferior regimen despite its ease of administration and costs. For a comparable clinical outcome, Lokich can be administered for approximately half the cost of de Gramont

Fossils, fish and tropical forests: prehistoric human adaptations on the island frontiers of Oceania

Oceania is a key region for studying human dispersals, adaptations and interactions with other hominin populations. Although archaeological evidence now reveals occupation of the region by approximately 65–45 000 years ago, its human fossil record, which has the best potential to provide direct insights into ecological adaptations and population relationships, has remained much more elusive. Here, we apply radiocarbon dating and stable isotope approaches to the earliest human remains so far excavated on the islands of Near and Remote Oceania to explore the chronology and diets of the first preserved human individuals to step across these Pacific frontiers. We demonstrate that the oldest human (or indeed hominin) fossil outside of the mainland New Guinea-Aru area dates to approximately 11 800 years ago. Furthermore, although these early sea-faring populations have been associated with a specialized coastal adaptation, we show that Late Pleistocene–Holocene humans living on islands in the Bismarck Archipelago and in Vanuatu display a persistent reliance on interior tropical forest resources. We argue that local tropical habitats, rather than purely coasts or, later, arriving domesticates, should be emphasized in discussions of human diets and cultural practices from the onset of our species' arrival in this part of the world.1. Introduction 2. Background (a) Human colonization of near and remote Oceania (b) Stable isotope analysis and past human adaptations in the tropics 3. Methods (a) Radiocarbon dating (b) Stable isotope analysis (c) Phytolith analysis of dental calculus 4. Results (a) Radiocarbon dating and Bayesian modelling (b) Stable isotope analysis (c) Phytolith analysis of dental calculus 5. Discussion and conclusio

MicroRNA expression profile identifies high grade, non-muscle-invasive bladder tumors at elevated risk to progress to an invasive phenotype

Abstract: The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3–T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease

Extraordinary human energy consumption and resultant geological impacts beginning around 1950 CE initiated the proposed Anthropocene Epoch

Growth in fundamental drivers—energy use, economic productivity and population—can provide quantitative indications of the proposed boundary between the Holocene Epoch and the Anthropocene. Human energy expenditure in the Anthropocene, ~22 zetajoules (ZJ), exceeds that across the prior 11,700 years of the Holocene (~14.6 ZJ), largely through combustion of fossil fuels. The global warming effect during the Anthropocene is more than an order of magnitude greater still. Global human population, their productivity and energy consumption, and most changes impacting the global environment, are highly correlated. This extraordinary outburst of consumption and productivity demonstrates how the Earth System has departed from its Holocene state since ~1950 CE, forcing abrupt physical, chemical and biological changes to the Earth’s stratigraphic record that can be used to justify the proposal for naming a new epoch—the Anthropocene

From Clinical Trials to Real-life Clinical Practice: The Role of Immunotherapy with PD-1/PD-L1 Inhibitors in Advanced Urothelial Carcinoma

ContextA number of PD-1/PD-L1 inhibitors have recently been approved for use in patients with locally advanced or metastatic urothelial carcinoma (UC) on the basis of results from several clinical trials.ObjectiveTo review the evidence from these trials and consider what it means for the use of these drugs in first-line and post-platinum settings in real-life clinical practice.Evidence acquisitionPubMed was searched for full reports of clinical trials of single-agent PD-1/PD-L1 inhibitors in advanced UC. Twelve publications were included.Evidence synthesisResponses to PD-1/PD-L1 inhibitors appear to be durable but are only achieved in 17–26% of patients. These drugs offer different toxicity and efficacy profiles to standard chemotherapy regimens. This should be considered when choosing a treatment strategy for each patient.ConclusionsPD-1/PD-L1 inhibitors represent a major step forward in the management of advanced UC, although several questions remain regarding their optimal use in routine clinical practice. A validated predictive biomarker of response is yet to be defined, and this is perhaps the most significant unmet need for currently available drugs.Patient summaryWe reviewed the results from clinical trials that investigated how well certain types of anticancer drugs called PD-1/PD-L1 inhibitors worked in patients with bladder cancer. We found that more research is required to identify (1) the factors that might predict which patients with bladder cancer will respond to PD-1/PD-L1 inhibitors and (2) the optimum duration of treatment with these drugs.</p

Pliocene Te Aute limestones, New Zealand: Expanding concepts for cool-water shelf carbonates

Acceptance of a spectrum of warm- through cold-water shallow-marine carbonate facies has become of fundamental importance for correctly interpreting the origin and significance of all ancient platform limestones. Among other attributes, properties that have become a hallmark for characterising many Cenozoic non-tropical occurrences include: (1) the presence of common bryozoan and epifaunal bivalve skeletons; (2) a calcite-dominated mineralogy; (3) relatively thin deposits exhibiting low rates of sediment accumulation; (4) an overall destructive early diagenetic regime; and (5) that major porosity destruction and lithification occur mainly in response to chemical compaction of calcitic skeletons during moderate to deep burial. The Pliocene Te Aute limestones are non-tropical skeletal carbonates formed at paleolatitudes near 40-42°S under the influence of commonly strong tidal flows along the margins of an actively deforming and differentially uplifting forearc basin seaway, immediately inboard of the convergent Pacific-Australian plate boundary off eastern North Island, New Zealand. This dynamic depositional and tectonic setting strongly influenced both the style and subsequent diagenetic evolution of the limestones. Some of the Te Aute limestones exhibit the above kinds of "normal" non-tropical characteristics, but others do not. For example, many are barnacle and/or bivalve dominated, and several include attributes that at least superficially resemble properties of certain tropical carbonates. In this regard, a number of the limestones are infaunal bivalve rich and dominated by an aragonite over a calcite primary mineralogy, with consequently relatively high diagenetic potential. Individual limestone units are also often rather thick (e.g., up to 50-300 m), with accumulation rates from 0.2 to 0.5 m/ka, and locally as high as 1 m/ka. Moreover, there can be a remarkable array of diagenetic features in the limestones, involving grain alteration and/or cementation to widely varying extents within any, or some combination of, the marine phreatic, burial, and meteoric diagenetic environments, including locally widespread development of meteoric cement sourced from aragonite dissolution. The message is that non-tropical shelf carbonates include a more diverse array of geological settings, of skeletal and mineralogical facies, and of diagenetic features than current sedimentary models mainly advocate. While several attributes positively distinguish tropical from non-tropical limestones, continued detailed documentation of the wide spectrum of shallow-marine carbonate deposits formed outside tropical regions remains an important challenge in carbonate sedimentology