Is it time for one-step nucleic acid amplification (OSNA) in colorectal cancer? A systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis (LNM) is prognostic in colorectal cancer (CRC). However, evaluation by routine haematoxylin and eosin histology (HE) limits nodal examination and is subjective. Missed LNMs from tissue allocation bias (TAB) might under-stage disease, leading to under-treatment. One-step nucleic acid amplification (OSNA) for CK19 messenger ribonucleic acid (mRNA), a marker of LNM, analyses the whole node. The aim of the present systematic review and meta-analysis was to assess recent studies on OSNA versus HE and its implications for CRC staging and treatment. METHODS: Databases including OVID, Medline and Google Scholar were searched for OSNA, LNM and CRC. Study results were pooled using a random-effects model. Summary receiver operator curves (SROC) assessed OSNA's performance in detecting LNM when compared to routine HE histology. RESULTS: Five case-control studies analysing 4080 nodes from 622 patients were included. The summary estimates of pooled results for OSNA were sensitivity 0.90 [95% confidence interval (CI) 0.86-0.93], specificity 0.94 (95% CI 0.93-0.95) and diagnostic odds ratio 179.5 (CI 58.35-552.2, p < 0.0001). The SROC curve indicated a maximum joint sensitivity and specificity of 0.88 and area under the curve of 0.94, p < 0.0001. On average, 5.4% HE-negative nodes were upstaged by OSNA. CONCLUSIONS: OSNA is as good as routine HE. It may avoid TAB and offer a more objective and standardised assay of LNM. However, for upstaging, its usefulness as an adjunct to HE or superiority to HE requires further assessment of the benefits, if any, of adjuvant therapy in patients upstaged by OSNA.

Microarray-based Gene Expression Profiling of Abdominal Aortic Aneurysm.

OBJECTIVE/BACKGROUND: Microarray-based gene expression profiling studies may detect transcriptional signatures carrying prognostic value in abdominal aortic aneurysms (AAA). A gene expression profiling study was conducted to compare individuals with AAA with screened controls. METHODS: The peripheral blood transcriptome was compared between 12 individuals with AAA and 12 age- and sex-matched controls using microarray. Validation by Taqman real-time quantitative (qPCR) was performed in an independent group as described. Peripheral blood RNA was hybridized to Illumina microarrays, each representing 37,846 genes, allowing comparison of gene expression between cases and controls. Eleven differentially expressed genes were re-quantified by qPCR in the independent group with AAA (n = 95), controls (n = 92), pre- and postendovascular AAA repair (EVAR, n = 31); or open AAA repair (n = 13), AAA wall biopsies (n = 11), and in matched smooth muscle cultures (n = 7). RESULTS: Microarray detected 47 significantly differentially expressed genes in AAA after correction for multiple testing (p < .05). These genes conferred roles in regulation of apoptosis, proteolysis, the electron transport chain, leukocyte migration, and the humoral immune response. Gene quantification in the independent group demonstrated three genes to be downregulated in AAA compared with controls: MSN, PSMB10, and STIM1; however, their expression remained unchanged post-AAA repair. PSMB10 was the only gene conferring a consistent direction of effect in both the discovery and validation analyses (downregulated). EIF3G, SIVA, PUF60, CYC1, FIBP, and CARD8 were downregulated post-EVAR. Expression of all 11 genes of interest was detected in aortic biopsies and matched smooth muscle cultures. CONCLUSION: This study demonstrates differential expression of transcripts in peripheral blood of individuals with AAA, with functional roles in proteolysis, inflammation, and apoptotic processes. These were modulated by aneurysm exclusion from the circulation and expressed in matched aortic biopsies and smooth muscle cultures. These observations further support the key roles for these pathways in the pathogenesis of AAA.

Identification of microRNAs associated with abdominal aortic aneurysms and peripheral arterial disease.

BACKGROUND: MicroRNAs are crucial in the regulation of cardiovascular disease and represent potential therapeutic targets to decrease abdominal aortic aneurysm (AAA) expansion. The aim of this study was to identify circulating microRNAs associated with AAA. METHODS: Some 754 microRNAs in whole-blood samples from 15 men with an AAA and ten control subjects were quantified using quantitative reverse transcriptase-PCR. MicroRNAs demonstrating a significant association with AAA were validated in peripheral blood and plasma samples of men in the following groups (40 in each): healthy controls, controls with peripheral arterial disease (PAD), men with a small AAA (30-54 mm), those with a large AAA (over 54 mm), and those following AAA repair. MicroRNA expression was also assessed in aortic tissue. RESULTS: Twenty-nine differentially expressed microRNAs were identified in the discovery study. Validation study revealed that let-7e (fold change (FC) -1·80; P = 0·001), miR-15a (FC -2·24; P < 0·001) and miR-196b (FC -2·26; P < 0·001) were downregulated in peripheral blood from patients with an AAA, and miR-411 was upregulated (FC 5·90; P = 0·001). miR-196b was also downregulated in plasma from the same individuals (FC -3·75; P = 0·029). The same miRNAs were similarly expressed differentially in patients with PAD compared with healthy controls. Validated and predicted microRNA targets identified through miRWalk revealed that these miRNAs were all regulators of AAA-related genes (vascular cell adhesion molecule 1, intercellular cell adhesion molecule 1, DAB2 interacting protein, α1-antitrypsin, C-reactive protein, interleukin 6, osteoprotegerin, methylenetetrahydrofolate reductase, tumour necrosis factor α). CONCLUSION: In this study, circulating levels of let-7e, miR-15a, miR-196b and miR-411 were differentially expressed in men with an AAA compared with healthy controls, but also differentially expressed in men with PAD. Modulation of these miRNAs and their target genes may represent a new therapeutic pathway to affect the progression of AAA and atherosclerosis.

A multicentre observational study of the outcomes of screening detected sub-aneurysmal aortic dilatation.

OBJECTIVES: Currently most abdominal aortic aneurysm screening programmes discharge patients with aortic diameter of less than 30 mm. However, sub-aneurysmal aortic dilatation (25 mm-29 mm) does not represent a normal aortic diameter. This observational study aimed to determine the outcomes of patients with screening detected sub aneurysmal aortic dilatation. DESIGN AND METHODS: Individual patient data was obtained from 8 screening programmes that had performed long term follow up of patients with sub aneurysmal aortic dilatation. Outcome measures recorded were the progression to true aneurysmal dilatation (aortic diameter 30 mm or greater), progression to size threshold for surgical intervention (55 mm) and aneurysm rupture. RESULTS: Aortic measurements for 1696 men and women (median age 66 years at initial scan) with sub-aneurysmal aortae were obtained, median period of follow up was 4.0 years (range 0.1-19.0 years). Following Kaplan Meier and life table analysis 67.7% of patients with 5 complete years of surveillance reached an aortic diameter of 30 mm or greater however 0.9% had an aortic diameter of 54 mm. A total of 26.2% of patients with 10 complete years of follow up had an AAA of greater that 54 mm. CONCLUSION: Patients with sub-aneurysmal aortic dilatation are likely to progress and develop an AAA, although few will rupture or require surgical intervention.

Outcomes of endovascular aneurysm repair in patients with hostile neck anatomy.

OBJECTIVES: This study aims to evaluate outcomes following EVAR in patients with hostile neck anatomy (HNA). METHODS: Data prospectively collected from 552 elective EVARs were analysed retrospectively. Data regarding neck morphology was obtained from aneurysm stent plans produced prior to EVAR. HNA was defined as any of; neck diameter >28 mm, neck angulation >60°, neck length <15 mm, neck thrombus, or neck flare. RESULTS: 552 patients underwent EVAR. Mean age 73.9 years, mean follow-up 4.1 years. 199 patients had HNA, 353 had favourable neck anatomy (FNA). There was a significant increase in late type I endoleaks (FNA 4.5%, HNA 9.5%; P = 0.02) and total reinterventions (FNA 11.0%, HNA 22.8%; P < 0.01), and a significant decrease in late type II endoleaks in patients with HNA (FNA 16.7%, HNA 10.6%; P < 0.05). There was no significant difference in technical success (FNA 0.6%, HNA 2.0%; p = 0.12), 30-day re-intervention (FNA 2.8%, HNA 5.0%; P = 0.12), 30-day mortality (FNA 1.1%, HNA 0.5%; P = 0.45), 30-day type I endoleaks (FNA 0.8%, HNA 2.5%; P = 0.12), 5-year mortality (FNA 15.1%, HNA 14.6%; P = 0.86), aneurysm-related mortality (FNA 1.7% versus HNA 2.0%; P = 0.79), stent-graft migration (FNA 2.5%, HNA 3.0%; P = 0.75), sac expansion (FNA 13.0%, HNA 9.5%; P = 0.22), or graft rupture (FNA 1.1%, HNA 3.5%; P = 0.05). Binary logistic regression of individual features of HNA revealed secondary intervention (P = 0.009), technical failure (P = 0.02), and late type I endoleaks (P = 0.002), were significantly increased with increased neck diameter. CONCLUSIONS: HNA AAAs can be successfully treated with EVAR. However, surveillance is necessary to detect and treat late type I endoleaks in HNA patients.

Low density lipoprotein receptor related protein 1 and abdominal aortic aneurysms.

OBJECTIVES: A recent GWAS demonstrated an association between low density lipoprotein receptor related protein 1 (LRP1) and abdominal aortic aneurysm (AAA). This review aims to identify how LRP1 may be involved in the pathogenesis of abdominal aortic aneurysm. DESIGN AND MATERIALS: A systematic review of the English language literature was undertaken in order to determine whether LRP1 and associated pathways were plausible candidates for contributing to the development and/or progression of AAA. METHODS AND RESULTS: A comprehensive literature search of MEDLINE (since 1948), Embase (since 1980) and Health and Psychological Instruments (since 1985) was conducted in January 2012 identified 50 relevant articles. These studies demonstrate that LRP1 has a diverse range of biological functions and is a plausible candidate for playing a central role in aneurysmogenesis. Importantly, LRP1 downregulates MMP (matrix metalloproteinase) activity in vascular smooth muscle cells and regulates other key pathways involved in extracellular matrix remodelling and vascular smooth muscle migration and proliferation. Crucially animal studies have shown that LRP1 depletion leads to progressive destruction of the vascular architecture and aneurysm formation. CONCLUSIONS: Published evidence suggests that LRP1 may play a key role in the development of AAA.

The epidemiology of cervical spondylotic myelopathy.

OBJECTIVES: This is an observational study looking at the epidemiology of cervical spondylotic myelopathy of patients presenting to our hospital. MATERIALS AND METHODS: The notes and MRI scans of 41 patients presenting to the Leicester General Hospital with a clinical diagnosis of cervical myelopathy between January 2004 and December 2008 were reviewed retrospectively. RESULTS: Cervical myelopathy was found to be more common in male patients to the ratio of approximately 2.7:1, with an average age at diagnosis of 63.8 years. Multi-level disease was seen in the majority of patients, with C5/6 being the most commonly affected level. CONCLUSIONS: Cervical myelopathy predominantly affects men in their 7th decade of life. It is often a multi-level disease with C5/6 being the most commonly affected. It has little in common with cervical radiculopathy and is more analogous to lumber spinal stenosis.

Survival analysis of elderly patients with a fracture of the odontoid peg.

Fractures of the odontoid peg are common spinal injuries in the elderly. This study compares the survivorship of a cohort of elderly patients with an isolated fracture of the odontoid peg versus that of patients who have sustained a fracture of the hip or wrist. A six-year retrospective analysis was performed on all patients aged > 65 years who were admitted to our spinal unit with an isolated fracture of the odontoid peg. A Kaplan-Meier table was used to analyse survivorship from the date of fracture, which was compared with the survivorship of similar age-matched cohorts of 702 consecutive patients with a fracture of the hip and 221 consecutive patients with a fracture of the wrist. A total of 32 patients with an isolated odontoid fracture were identified. The rate of mortality was 37.5% (n = 12) at one year. The period of greatest mortality was within the first 12 weeks. Time made a lesser contribution from then to one year, and there was no impact of time on the rate of mortality thereafter. The rate of mortality at one year was 41.2% for male patients (7 of 17) compared with 33.3% for females (5 of 15). The rate of mortality at one year was 32% (225 of 702) for patients with a fracture of the hip and 4% (9 of 221) for those with a fracture of the wrist. There was no statistically significant difference in the rate of mortality following a hip fracture and an odontoid peg fracture (p = 0.95). However, the survivorship of the wrist fracture group was much better than that of the odontoid peg fracture group (p < 0.001). Thus, a fracture of the odontoid peg in the elderly is not a benign injury and is associated with a high rate of mortality, especially in the first three months after the injury.