Thomas Santarius

Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing

Human cancers often carry many somatically acquired genomic rearrangements, some of which may be implicated in cancer development. However, conventional strategies for characterizing rearrangements are laborious and low-throughput and have low sensitivity or poor resolution. We used massively parallel sequencing to generate sequence reads from both ends of short DNA fragments derived from the genomes of two individuals with lung cancer. By investigating read pairs that did not align correctly with respect to each other on the reference human genome, we characterized 306 germline structural variants and 103 somatic rearrangements to the base-pair level of resolution. The patterns of germline and somatic rearrangement were markedly different. Many somatic rearrangements were from amplicons, although rearrangements outside these regions, notably including tandem duplications, were also observed. Some somatic rearrangements led to abnormal transcripts, including two from internal tandem duplications and two fusion transcripts created by interchromosomal rearrangements. Germline variants were predominantly mediated by retrotransposition, often involving AluY and LINE elements. The results demonstrate the feasibility of systematic, genome-wide characterization of rearrangements in complex human cancer genomes, raising the prospect of a new harvest of genes associated with cancer using this strategy.

Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial

BACKGROUND Chronic subdural haematoma causes serious morbidity and mortality. It recurs after surgical evacuation in 5-30% of patients. Drains might reduce recurrence but are not used routinely. Our aim was to investigate the effect of drains on recurrence rates and clinical outcomes. METHODS We did a randomised controlled trial at one UK centre between November, 2004, and November, 2007. 269 patients aged 18 years and older with a chronic subdural haematoma for burr-hole drainage were assessed for eligibility. 108 were randomly assigned by block randomisation to receive a drain inserted into the subdural space and 107 to no drain after evacuation. The primary endpoint was recurrence needing redrainage. The trial was stopped early because of a significant benefit in reduction of recurrence. Analyses were done on an intention-to-treat basis. This study is registered with the International Standard Randomised Controlled Trial Register (ISRCTN 97314294). FINDINGS Recurrence occurred in ten of 108 (9.3%) people with a drain, and 26 of 107 (24%) without (p=0.003; 95% CI 0.14-0.70). At 6 months mortality was nine of 105 (8.6%) and 19 of 105 (18.1%), respectively (p=0.042; 95% CI 0.1-0.99). Medical and surgical complications were much the same between the study groups. INTERPRETATION Use of a drain after burr-hole drainage of chronic subdural haematoma is safe and associated with reduced recurrence and mortality at 6 months. FUNDING Academy of Medical Sciences, Health Foundation, and NIHR Biomedical Research Centre (Neurosciences Theme).

The management of primary chronic subdural haematoma: a questionnaire survey of practice in the United Kingdom and the Republic of Ireland

A wide range of treatment modalities are employed in the treatment of chronic subdural haematoma (CSDH). A rational and evidence-based treatment strategy has the potential to optimise treatment for the individual patient and save resources. The aim of this study was to survey aspects of current practice in the UK and Ireland. A 1-page postal questionnaire addressing the treatment of primary (i.e. not recurrent) CSDH was sent to consultant SBNS members in March 2006. There were 112 responses from 215 questionnaires (52%). The preferred surgical technique was burr hole drainage (92%). Most surgeons prefer not to place a drain, with 27% never using one and 58% using drain only in one-quarter of cases or less. Only 11% of surgeons always place a drain, and only 30% place one in 75% of cases or more. The closed subdural-to-external drainage was most commonly used (91%) with closed subgaleal-to-external and subdural-to-peritoneal conduit used less often (3 and 4%, respectively). Only 5% of responders claimed to know the exact recurrence rate. The average perceived recurrence rate among the surgeons that never use drains and those who always use drains, was the same (both 11%). Most operations are performed by registrars (77%). Postoperative imaging is requested routinely by 32% of respondents and 57% of surgeons prescribe bed rest. Ninety four per cent surgeons employ conservative management in less than one-quarter of cases. Forty-two per cent of surgeons never prescribe steroids, 55% prescribe them to those managed conservatively. This survey demonstrates that there are diverse practices in the management of CSDH. This may be because of sufficiently persuasive evidence either does not exist or is not always taken into account. The current literature provides Class II and III evidence and there is a need for randomized studies to address the role of external drainage, steroids and postoperative bed rest.

Chronic subdural haematoma: modern management and emerging therapies

Chronic subdural haematoma (CSDH) is one of the most common neurological disorders, and is especially prevalent among elderly individuals. Surgical evacuation is the mainstay of management for symptomatic patients or haematomas exerting significant mass effect. Although burr hole craniostomy is the most widely practised technique worldwide, approximately 10–20% of surgically treated patients experience postoperative recurrence necessitating reoperation. Given the increasing incidence of CSDH in a growing elderly population, a need exists for refined techniques that combine a minimally invasive approach with clinical efficacy and cost-effectiveness. In addition, nonsurgical treatment modalities, such as steroids, are attracting considerable interest, as they have the potential to reduce postoperative recurrence or even replace the need for surgery in selected patients. This Review provides an overview of the contemporary management of CSDH and presents considerations regarding future approaches that could further optimize patient care and outcomes.

Radiotherapy as an adjuvant in the management of intracranial meningiomas: are we practising evidence-based medicine?

Although increasingly used, the precise role of radiotherapy in the management of meningiomas is still disputed. The objective of this study, therefore, was to appraise the evidence for adjuvant radiotherapy in benign and atypical intracranial meningiomas, and to compare and contrast it with the current opinion and practice of neurosurgeons in the United Kingdom and the Republic of Ireland. The use of radiotherapy as a primary treatment strategy or its use in the treatment of recurrence was not considered. We performed a systematic review of the evidence for adjuvant radiotherapy in benign and atypical intracranial meningiomas, surveyed current opinion amongst neurosurgeons involved in such cases and ascertained local practice using data from the regional cancer registry. Overall, 10 cohorts were identified that fulfilled our eligibility criteria. Four studies showed significantly improved local control in patients receiving adjuvant radiotherapy for incompletely resected grade I meningiomas. Our survey demonstrated that the vast majority (98%) of neurosurgeons would not recommend adjuvant radiotherapy in grade I meningioma. In grade II meningioma, most (80%) would not advocate adjuvant radiotherapy if completely excised, but the majority (59%) would recommend radiotherapy in cases of subtotal resection. Significant variation in opinion between centres exists, however, particularly in cases of completely resected atypical meningiomas (p = 0.02). Data from the Eastern Cancer Registration and Information Centre appears to be in line with these findings: less than 10% of patients with grade I meningiomas, but almost 30% of patients with grade II meningiomas received adjuvant radiotherapy in the Eastern region. In conclusion, our study has highlighted significant variation in opinion and practice, reflecting a lack of class 1 evidence to support the use of adjuvant radiotherapy in the treatment of meningiomas. Efforts are underway to address this with a randomized multicentre trial comparing a policy of watchful waiting versus adjuvant irradiation.

GLO1—A novel amplified gene in human cancer

To identify a novel amplified cancer gene a systematic screen of 975 human cancer DNA samples, 750 cell lines and 225 primary tumors, using the Affymetrix 10K SNP microarray was undertaken. The screen identified 193 amplicons. A previously uncharacterized amplicon located on 6p21.2 whose 1 Mb minimal common amplified region contained eight genes (GLO1, DNAH8, GLP1R, C6orf64, KCNK5, KCNK17, KCNK16, and C6orf102) was further investigated to determine which gene(s) are the biological targets of this amplicon. Real time quantitative PCR (qPCR) analysis of all amplicon 6p21.2 genes in 618 human cancer cell lines identified GLO1, encoding glyoxalase 1, to be the most frequently amplified gene [twofold or greater amplification in 8.4% (49/536) of cancers]. Also the association between amplification and overexpression was greatest for GLO1. RNAi knockdown of GLO1 had the greatest and most consistent impact on cell accumulation and apoptosis. Cell lines with GLO1 amplification were more sensitive to inhibition of GLO1 by bromobenzylglutathione cyclopentyl diester (BBGC). Subsequent qPCR of 520 primary tumor samples identified twofold and greater amplification of GLO1 in 8/37 (22%) of breast, 12/71 (17%) of sarcomas, 6/53 (11.3%) of nonsmall cell lung, 2/23 (8.7%) of bladder, 6/93 (6.5%) of renal and 5/83 (6%) of gastric cancers. Amplification of GLO1 was rare in colon cancer (1/35) and glioma (1/94). Collectively the results indicate that GLO1 is at least one of the targets of gene amplification on 6p21.2 and may represent a useful target for therapy in cancers with GLO1 amplification.

Chronic subdural haematoma: time to rationalize treatment?

This article reviews chronic subdural haematoma in terms of evidence relating to incidence, pathogenesis and treatment. While it is one of the commonest neurosurgical conditions, unanswered questions persist, particularly in terms of treatment options, with a multitude of personal preferences. Current management strategies are summarized and the need to rationalise treatment backed up by Class I randomized studies is discussed.

Processed pseudogenes acquired somatically during cancer development

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.

Papillary tumour of the pineal region.

Papillary tumour of the pineal region (PTPR) is a relatively new and rare pathological entity, which appears to run a spectrum of clinical courses. We add another case with detailed description of the clinical course documented with serial imaging over the total of 7 years. In accordance with previous reports we recommend total surgical resection with subsequent focal radiotherapy. Clinical and radiological follow up of the entire cerebrospinal axis is mandatory.

Primary decompressive craniectomy for acute subdural haematomas: results of an international survey

Dear Sir, Approximately two-thirds of patients with traumatic brain injury (TBI) undergoing emergency cranial surgery have an acute subdural haematoma (ASDH) evacuated [2]. These haematomas are frequently associated with underlying cerebral parenchymal injury, which further exacerbates brain swelling [5]. Therefore, even though craniotomy and evacuation comprise the established primary treatment for ASDH, leaving the bone flap out (i.e. decompressive craniectomy) is an option either because the brain is swollen beyond the confines of the cranium or because the patient is thought to be at high risk for worsening brain swelling during the ensuing days. The European Brain Injury Consortium survey, which was conducted in 2001, demonstrated that a decompressive craniectomy (DC) was undertaken in approximately onequarter of operations performed for ASDH [2]. Since then, there has been a resurgence of interest in the use of DC after TBI. A randomised controlled trial of early/neuroprotective DC in patients with severe diffuse TBI (but no mass lesions) was published in 2011 (DECRA), while another randomised study assessing the role of DC as a last-tier therapy for refractory post-traumatic intracranial hypertension (RESCUEicp) has now recruited 85 % of the required sample size [3, 4]. Nevertheless, there is only class III evidence with retrospective studies investigating the role of DC as a primary procedure for ASDH [1]. With the objective of examining current practice patterns of DC after TBI, we undertook a survey of members of the European Association of Neurosurgical Societies (EANS), Neurocritical Care Society, NeuroCritical Care Network (NCCNet), full members of the Society of British Neurological Surgeons (SBNS) and members of the British Neurosurgical Trainees Association (BNTA) during October and November 2011. We used a secure online survey tool to disseminate the questionnaires. The questionnaire survey was approved by the Academic Committee of the SBNS (project no. NE0026). In this letter, we wish to discuss the results of our survey regarding the use of primary DC for ASDH. As part of the survey, we asked the following question: “When evacuating a traumatic ASDH, how often do you perform a primary DC (i.e. leave the bone flap out)”? This question was answered by 283 neurosurgeons (201 board-certified Consultants or equivalent; 82 trainees). There were 138 UK/Irish, 110 from other European countries, 13North American and 22 respondents from various other countries (see Appendix 1). We decided to group together the responses of neurosurgeons working in countries with national representation to the EANS in order to have two similar-sized groups (UK/Irish A. G. Kolias : L. M. Li : I. Timofeev : E. A. Corteen : T. Santarius : J. D. Pickard : P. J. Kirkpatrick : P. J. Hutchinson Division of Neurosurgery, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK