Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

A Zoologist with a Taste for the Past: The Earl of Cranbrook’s Contribution to Zooarchaeological Research in Southeast Asia

The Earl of Cranbrook (V) (then Lord Medway) was fi rst introduced to archaeological research in 1958 when he participated in excavations at the Niah Caves, Sarawak Borneo. In that same year he published a paper entitled ‘Food bone in Niah Cave excavations (-1958)’ in the Sarawak Museum Journal. Unbeknownst to him at the time, his individual and intuitive research was on a par with, if not methodologically ahead of, burgeoning studies in the fi eld of zooarchaeology that were taking place at leading academic institutions in Europe and the United States. This paper recounts and lauds the signifi cant contributions the Earl of Cranbrook has made to the establishment and furtherance of a discipline over more than 50 years. 

The 'human revolution' in lowland tropical Southeast Asia:the antiquity and behavior of anatomically modern humans at Niah Cave (Sarawak, Borneo)

Recent research in Europe, Africa, and Southeast Asia suggests that we can no longer assume a direct and exclusive link between anatomically modern humans and behavioral modernity (the 'human revolution'), and assume that the presence of either one implies the presence of the other: discussions of the emergence of cultural complexity have to proceed with greater scrutiny of the evidence on a site-by-site basis to establish secure associations between the archaeology present there and the hominins who created it. This paper presents one such case study: Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 in the West Mouth of the Great Cave of a modern human skull, the 'Deep Skull,' controversially associated with radiocarbon dates of ca. 40,000 years before the present. A new chronostratigraphy has been developed through a re-investigation of the lithostratigraphy left by the earlier excavations, AMS-dating using three different comparative pre-treatments including ABOX of charcoal, and U-series using the Diffusion-Absorption model applied to fragments of bones from the Deep Skull itself. Stratigraphic reasons for earlier uncertainties about the antiquity of the skull are examined, and it is shown not to be an `intrusive' artifact. It was probably excavated from fluvial-pond-desiccation deposits that accumulated episodically in a shallow basin immediately behind the cave entrance lip, in a climate that ranged from times of comparative aridity with complete desiccation, to episodes of greater surface wetness, changes attributed to regional climatic fluctuations. Vegetation outside the cave varied significantly over time, including wet lowland forest, montane forest, savannah, and grassland. The new dates and the lithostratigraphy relate the Deep Skull to evidence of episodes of human activity that range in date from ca. 46,000 to ca. 34,000 years ago. Initial investigations of sediment scorching, pollen, palynomorphs, phytoliths, plant macrofossils, and starch grains recovered from existing exposures, and of vertebrates from the current and the earlier excavations, suggest that human foraging during these times was marked by habitat-tailored hunting technologies, the collection and processing of toxic plants for consumption, and, perhaps, the use of fire at some forest-edges. The Niah evidence demonstrates the sophisticated nature of the subsistence behavior developed by modern humans to exploit the tropical environments that they encountered in Southeast Asia, including rainforest. (c) 2006 Elsevier Ltd. All rights reserved.

Prehistoric foragers and farmers in south-east Asia:Renewed investigations at Niah Cave, Sarawak

The paper describes the initial results from renewed investigations at Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 of the c. 40,000-year old 'Deep Skull'. The archaeological sequences from the West Mouth and the other entrances of the cave complex investigated by Tom and Barbara Harrisson and other researchers have potential implications for three major debates regarding the prehistory of south-east Asia: the timing of initial settlement by anatomically modern humans; the means by which they subsisted in the late Pleistocene and early Holocene; and the timing, nature, and causation of the transition from foraging to farming. The new project is informing on all three debates. The critical importance of the Niah stratigraphies was commonly identified - including by Tom Harrisson himself - as because the site provided a continuous sequence of occupation over the past 40,000 years. The present project indicates that Niah was first used at least 45,000 years ago, and probably earlier; that the subsequent Pleistocene and Holocene occupations were highly variable in intensity and character; and that in some periods, perhaps of significant duration, the caves may have been more or less abandoned. The cultural sequence that is emerging from the new investigations may be more typical of cave use in tropical rainforests in south-east Asia than the Harrisson model.

'Regina v John Terry': The Discursive Construction of an Alleged Racist Event

This article explores the conformation in discourse of a verbal exchange and its subsequent mediatised and legal ramifications. The event concerns an allegedly racist insult directed by high profile English professional footballer John Terry towards another player, Anton Ferdinand, during a televised match in October 2011. The substance of Terry’s utterance, which included the noun phrase ‘fucking black cunt’, was found by a Chief Magistrate not to be a racist insult, although the fact that these actual words were framed within the utterance was not in dispute. The upshot of this ruling was that Terry was acquitted of a racially aggravated public order offence. A subsequent investigation by the regulatory commission of the English Football Association (FA) ruled, almost a year after the event, that Terry was guilty of racially abusing Ferdinand. Terry was banned for four matches and fined £220,000.

It is our contention that this event, played out in legal rulings, social media and print and broadcast media, constitutes a complex web of linguistic structures and strategies in discourse, and as such lends itself well to analysis with a broad range of tools from pragmatics, discourse analysis and cognitive linguistics. Amongst other things, such an analysis can help explain the seemingly anomalous - even contradictory - position adopted in the legal ruling with regard to the speech act status of ‘fucking black cunt’; namely, that the racist content of the utterance was not contested but that the speaker was found not to have issued a racist insult. Over its course, the article addresses this broader issue by making reference to the systemic-functional interpersonal function of language, particularly to the concepts of modality, polarity and modalisation. It also draws on models of verbal irony from linguistic pragmatics, notably from the theory of irony as echoic mention (c.f. Sperber and Wilson, 1981; Wilson and Sperber, 1992). Furthermore, the article makes use of the cognitive-linguistic framework, Text World Theory (c.f. Gavins, 2007; Werth, 1999) to examine the discourse positions occupied by key actors and adapts, from cognitive poetics, the theory of mind-modelling (c.f. Stockwell, 2009) to explore the conceptual means through which these actors discursively negotiate the event.

It is argued that the pragmatic and cognitive strategies that frame the entire incident go a long way towards mitigating the impact of so ostensibly stark an act of racial abuse. Moreover, it is suggested here that the reconciliation of Terry’s action was a result of the confluence of strategies of discourse with relations of power as embodied by the media, the law and perceptions of nationhood embraced by contemporary football culture. It is further proposed that the outcome of this episode, where the FA was put in the spotlight, and where both the conflict and its key antagonists were ‘intranational’, was strongly impelled by the institution of English football and its governing body both to reproduce and maintain social, cultural and ethnic cohesion and to avoid any sense that the event featured a discernable ‘out-group’.

The Complete Works of John Milton: Volume III: The Shorter Poems (826pp.)

Stephen B. Dobranski, Milton Quarterly 49.3 (October, 2015), 181-4:

'By addressing classical and neo-Latin works with which Milton's poems appear to engage, Haan has pursued something unattempted yet. Her erudite and engaging commentary on the Poemata is the most extensive and impressive that I have encountered in any edition ... Haan's discussion of Milton's Poemata - including the Testimonia, the one Italian and four Latin encomia by the poet's acquaintances published in 1645 and 1673 - is remarkably detailed and well-researched. In these sections, readers learn, for example, how Milton's Epitaphium Damonis borrows from both classical writers (Theocritus, Moschus) and contemporary models (Castiglione, Zanchi) while transcending all of them through a pattern of resurrection motifs. Or, readers can discover affinities between Milton's lament on the death of the Bishop of Ely and a poem by the Italian humanist Hieronymo Aleander, Jr., or learn about the connections between Milton's Elegia Quinta and George Buchanan's Maiae Calendae ... The Shorter Poems is a scholarly achievement of the highest order.'

Noam Reisner, Review of English Studies 65 (2014), 744-5:
‘Haan shines with her Neo-Latinist expertise by offering a vivid separate introduction to the Latin poems, which sets up Milton’s poemata specifically within the Neo-Latin contexts of the seventeenth century, thereby dispelling any remaining view of these poems as juvenilia (a view which results from reading the poems chronologically). … The present volume will instantly establish itself as the definitive resource for any reader interested in Milton’s shorter poems, and it is scarcely imaginable that it will ever be eclipsed or be in need of replacing. Its contribution is important in all areas, especially in providing for the first time in a single volume truly valuable documents which can teach us a lot more about Milton’s poetic development than simply reading the poems in chronological sequence. But perhaps, this edition’s greatest achievement is the way in which it succeeds in giving Milton’s Latin poems the pride of place they have long deserved as fully integral to Milton’s complete poetic imagination. Haan’s specific achievement in this regard is less in updating the translations than in providing a different context through which to look at the Latin poems themselves. Haan’s detailed commentaries set the Latin poems in a completely fresh light which looks beyond the obvious classical references and allusions, noted by Carey and many other editors, to Milton’s complex engagement with the Neo-Latin literary culture of his time. It is this aspect of the volume, more than anything else, which vindicates its essentialness.'

John Birks: Pioneer in quantitative palaeoecology

We describe the career of John Birks as a pioneering scientist who has, over a career spanning five decades, transformed palaeoecology from a largely descriptive to a rigorous quantitative science relevant to contemporary questions in ecology and environmental change. We review his influence on students and colleagues not only at Cambridge and Bergen Universities, his places of primary employment, but also on individuals and research groups in Europe and North America. We also introduce the collection of papers that we have assembled in his honour. The papers are written by his former students and close colleagues and span many of the areas of palaeoecology to which John himself has made major contributions. These include the relationship between ecology and palaeoecology, late-glacial and Holocene palaeoecology, ecological succession, climate change and vegetation history, the role of palaeoecological techniques in reconstructing and understanding the impact of human activity on terrestrial and freshwater ecosystems and numerical analysis of multivariate palaeoecological data.

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.