An Empirical Evaluation of the ClubsNSW (Australia) Multi-Venue Self-Exclusion Program

Few empirical studies have evaluated the effectiveness of self-exclusion programs. Research is required to identify factors contributing to decisions to enter and/or breach self-exclusion orders, or to self-excluded gamblers to seek additional treatment. Clinical characteristics of self-excluders remain relatively unknown in addition to factors that differentiate gamblers who do or do not breach. Limitations of current programs are that gamblers can self-exclude from only one or a limited number of venues. The Multi-venue Self-exclusion program, developed and implemented by ClubsNSW (Australia), is a centralised web-based system designed to help problem gamblers self exclude from up to 35 venues at a time. The online system presents gamblers with the choice of registering from within the venue assisted by the club manager or a trained staff member, or to self-exclude offsite through a gambling counsellor. In a retrospective design, the population characteristics, and the motivations and behaviours of a sample of self-excluded gamblers will be described; the implications of the study findings for the management of the Multi-venue Self-exclusion program will be discussed

Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure

Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers

AbstractBackgroundCandidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated.ObjectiveTo validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising markers to guide biomarker optimisation.Design, setting, and participantsCancer-specific survival (CSS) for each of 28 identified genetic or transcriptomic biomarkers was assessed in 350 ccRCC patients. ITH was interrogated in a multiregion biopsy data set of 10 ccRCCs.Outcome measurements and statistical analysisBiomarker association with CSS was analysed by univariate and multivariate analyses.Results and limitationsA total of 17 of 28 biomarkers (TP53 mutations; amplifications of chromosomes 8q, 12, 20q11.21q13.32, and 20 and deletions of 4p, 9p, 9p21.3p24.1, and 22q; low EDNRB and TSPAN7 expression and six gene expression signatures) were validated as predictors of poor CSS in univariate analysis. Tumour stage and the ccB expression signature were the only independent predictors in multivariate analysis. ITH of the ccB signature was identified in 8 of 10 tumours. Several genetic alterations that were significant in univariate analysis were enriched, and chromosomal instability indices were increased in samples expressing the ccB signature. The study may be underpowered to validate low-prevalence biomarkers.ConclusionsThe ccB signature was the only independent prognostic biomarker. Enrichment of multiple poor prognosis genetic alterations in ccB samples indicated that several events may be required to establish this aggressive phenotype, catalysed in some tumours by chromosomal instability. Multiregion assessment may improve the precision of this biomarker.Patient summaryWe evaluated the ability of published biomarkers to predict the survival of patients with clear cell kidney cancer in an independent patient cohort. Only one molecular test adds prognostic information to routine clinical assessments. This marker showed good and poor prognosis results within most individual cancers. Future biomarkers need to consider variation within tumours to improve accuracy

Selection of metastasis competent subclones in the tumour interior

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action

Seismic geomorphology of cretaceous megaslides offshore Namibia (Orange Basin):Insights into segmentation and degradation of gravity-driven linked systems

This study applies modern seismic geomorphology techniques to deep-water collapse features in the Orange Basin (Namibian margin, Southwest Africa) in order to provide unprecedented insights into the segmentation and degradation processes of gravity-driven linked systems. The seismic analysis was carried out using a high-quality, depth-migrated 3D volume that images the Upper Cretaceous post-rift succession of the basin, where two buried collapse features with strongly contrasting seismic expression are observed. The lower Megaslide Complex is a typical margin-scale, extensional-contractional gravity-driven linked system that deformed at least 2 km of post-rift section. The complex is laterally segmented into scoop-shaped megaslides up to 20 km wide that extend downdip for distances in excess of 30 km. The megaslides comprise extensional headwall fault systems with associated 3D rollover structures and thrust imbricates at their toes. Lateral segmentation occurs along sidewall fault systems which, in the proximal part of the megaslides, exhibit oblique extensional motion and define horst structures up to 6 km wide between individual megaslides. In the toe areas, reverse slip along these same sidewall faults, creates lateral ramps with hanging wall thrust-related folds up to 2 km wide. Headwall rollover anticlines, sidewall horsts and ramp anticlines may represent novel traps for hydrocarbon exploration on the Namibian margin.The Megaslide Complex is unconformably overlain by few hundreds of metres of highly contorted strata which define an upper Slump Complex. Combined seismic attributes and detailed seismic facies analysis allowed mapping of headscarps, thrust imbrications and longitudinal shear zones within the Slump Complex that indicate a dominantly downslope movement of a number of coalesced collapse systems. Spatial and stratal relationships between these shallow failures and the underlying megaslides suggest that the Slump Complex was likely triggered by the development of topography created by the activation of the main structural elements of the lower Megaslide Complex. This study reveals that gravity-driven linked systems undergo lateral segmentation during their evolution, and that their upper section can become unstable, favouring the initiation of a number of shallow failures that produce widespread degradation of the underlying megaslide structures. Gravity-driven linked systems along other margins are likely to share similar processes of segmentation and degradation, implying that the megaslide-related, hydrocarbon trapping structures discovered in the Namibian margin may be common elsewhere, making megaslides an attractive element of deep-water exploration along other gravitationally unstable margins

Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions <it>in vivo </it>as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease.</p> <p>Methods</p> <p>This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25–50 mg, weekly by perispinal administration for six months. Two additional case studies are presented.</p> <p>Results</p> <p>Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented.</p> <p>Conclusion</p> <p>In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.</p