Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules-the SPUtNIk study.

INTRODUCTION: Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently. METHODS AND ANALYSIS: The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for 18FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs. ETHICS AND DISSEMINATION: Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN30784948; Pre-results.

The role of 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography in the management of patients with carcinoma of unknown primary.

PURPOSE: Carcinoma of unknown primary is one of the ten most frequent cancers worldwide. Its median survival time is less than 10 months. Detecting primary tumour locations and/or occult metastatic lesions may inform definitive treatment and improve patients' prognosis. We aimed to determine: (1) the sensitivity, specificity and accuracy of (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography; (2) its detection rate of primary tumour locations and occult metastases and (3) factors associated with improved survival times. METHODS: We retrospectively reviewed all cases in the West of Scotland for the period 1 December 2007 to 31 May 2011 that met all our selection criteria: (1) diagnosis of carcinoma of unknown primary; (2) a thorough but negative 'work-up' and (3) (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography report. Statistical methods included frequencies, Kaplan-Meier graphs and log-rank tests to compare survival times. RESULTS: (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography detected primary tumour sites in 19/51 (37.3%) and occult metastases in 28/51 (54.9%) of eligible patients. Its sensitivity, specificity and accuracy were 79.2%, 70.4% and 74.5%, respectively; 20/51 (39.2%) patients died during the study period with a median survival of 8.4 months (range 21.4, SD ± 6.2). The number of metastatic locations was strongly associated with survival (p = 0.002), but detection of a primary tumour site (p = 0.174) or histopathology (p = 0.301) was not. CONCLUSION: (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography detected occult metastatic sites in the majority and a primary cancer location in a substantial minority of patients. Our results were comparable with international literature and may indicate that (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography have an early role to improve the accuracy of cancer staging and to optimise carcinoma of unknown primary management.

Apolipoprotein E genotype and oxidative stress response to traumatic brain injury.

Traumatic Brain Injury (TBI) is known to result in oxidative stress, and as variation at the Apolipoprotein E (APOE) gene has been shown to influence outcome following TBI, but through as yet unclear mechanisms, we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI. We administered a controlled cortical impact (CCI) injury or sham injury to transgenic mice expressing either human APOE3 or APOE4 on a murine APOE-deficient background. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray analysis was performed on unpooled samples from three mice per group to determine the genomic response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI or sham injury for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect of injury compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype dependent effects on outcome following TBI.

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers.

Promoter CpG methylation of tumour suppressor genes (TSGs) is an epigenetic biomarker for TSG identification and molecular diagnosis. We screened genome wide for novel methylated genes through methylation subtraction of a genetic demethylation model of colon cancer (double knockout of DNMT1 and DNMT3B in HCT116) and identified DLEC1 (Deleted in lung and oesophageal cancer 1), a major 3p22.3 TSG, as one of the methylated targets. We further found that DLEC1 was downregulated or silenced in most colorectal and gastric cell lines due to promoter methylation, whereas broadly expressed in normal tissues including colon and stomach, and unmethylated in expressing cell lines and immortalised normal colon epithelial cells. DLEC1 expression was reactivated through pharmacologic or genetic demethylation, indicating a DNMT1/DNMT3B-mediated methylation silencing. Aberrant methylation was further detected in primary colorectal (10 out of 34, 29%) and gastric tumours (30 out of 89, 34%), but seldom in paired normal colon (0 out of 17) and gastric (1 out of 20, 5%) samples. No correlation between DLEC1 methylation and clinical parameters of gastric cancers was found. Ectopic expression of DLEC1 in silenced HCT116 and MKN45 cells strongly inhibited their clonogenicity. Thus, DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.

The role of imaging in the pre-operative staging and post-operative follow-up of rectal cancer.

Developments in rectal cancer imaging have revolutionised the management of this condition. It has become increasingly important for oncologists and surgeons to have a working insight into radiological assessment in order to make informed clinical decisions. In this context, we discuss the role that imaging plays in the pre-operative staging, post-operative follow-up and therapy of this disease including some novel advances in the field. Rectal cancer outcomes have improved due to modern surgical techniques, namely total mesorectal excision. Meticulous pre-operative assessment remains key. Conventional TNM staging now appears less crucial compared to assessing tumour distance from the potential plane of surgical resection (particularly the circumferential margin bounded by the mesorectal fascia), and this is reliant on high-quality imaging. Those with margin threatening disease can be offered downstaging chemoradiotherapy to facilitate successful resection. Endorectal ultrasound is useful for T staging and CT for detecting metastases. Malignant lymph node identification remains a problem and the use of size and morphological criteria may lead to misdiagnosis. In the post-operative setting, intensive follow-up is associated with improved outcomes but there are many variations in protocols. Most modalities struggle to differentiate tumour from reactive or fibrotic tissue and functional imaging is being investigated as the solution. PET scanning, particularly PET/CT, has been a major recent development. It has superior utility in detecting recurrent disease, including when conventional imaging is negative, detects occult metastases and may significantly enhance our ability to deliver accurate radiotherapy. Imaging has also opened up avenues for guided therapies aimed at ablating liver metastases. Radiofrequency ablation, in particular, is being used successfully and can improve survival of stage four patients.

Colorectal stenting for colonic obstruction: the indications, complications, effectiveness and outcome--5 year review.

INTRODUCTION: Currently self-expanding metallic stents are being used for palliation and acute decompression of colonic obstruction. The aim of this study is to review our experience of using these metallic stents over a 5-year period. MATERIALS AND METHODS: Case records of 102 patients who had colorectal stenting between 1998 and 2004 were reviewed retrospectively. The indications for colorectal stenting, efficacy of the procedure in relieving the obstruction, complications and clinical outcome were analysed. RESULTS: Ninety-nine patients had malignant disease and in three patients a benign cause of obstruction was demonstrated. All procedures were performed during normal working hours. Stenting was technically successful in 87 patients (85%). A single stent was placed in 80 patients. Seven patients required two stents. Of the successful cases, 67 had stents placed by fluoroscopy alone and 20 by a combined fluoroscopy/endoscopy procedure. Four percent had early complications (within 30 days) which included four perforations. There were late complications (over 30 days) in 9% which included five stent migrations, two blocked stents and one colovesical fistula. Ninety percent (n=76) of the successful patients needed no further radiological or surgical intervention later. Survival ranged from 14 days to 2 years. CONCLUSION: Colorectal stenting when technically successful is an effective procedure for both preoperative and palliative decompression of colonic obstruction.

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products.

AIMS/HYPOTHESIS: The aim of this study was to investigate the effects of a secondary renal insult, due to chronic infusion of AGEs on renal function, and on early pathological markers in rats with a developmental nephron deficit. METHODS: Female Wistar-Kyoto rats were fed a low-protein diet (LPD; 8.7% casein) or a normal-protein diet (NPD; 20% casein) during pregnancy and lactation. Nephron number was estimated in 4-week-old female offspring. Male offspring were allowed to grow to 20 weeks of age, when AGEs derived from BSA (AGE-BSA) or BSA was infused subcutaneously (20 mg kg(-1) day(-1)) for 4 weeks. At 24 weeks, blood pressure, renal function and circulating and renal AGEs were assessed. Real-time PCR was used to investigate early molecular markers of renal pathology. RESULTS: As expected, maternal protein restriction led to reduced nephron endowment in LPD offspring. This alone did not affect blood pressure or lead to hyperfiltration in adulthood. However, when coupled with the secondary renal insult, the expression of the genes encoding transforming growth factor-beta(1) and procollagen III was significantly upregulated in the kidneys. In addition, there was renal accumulation of AGEs in LPD offspring, and this was exacerbated by AGE infusion. CONCLUSIONS/INTERPRETATION: Our results demonstrate that the adult kidney with a reduced nephron endowment is more vulnerable to secondary renal insult from AGE-BSA. Since AGE formation is markedly elevated with hyperglycaemia, our findings suggest that a developmental or acquired deficit may render the kidney susceptible to diabetic renal disease.

Colobronchial fistula: a late complication of childhood radiotherapy.

We present the case of a colobronchial fistula in a 41-year-old man who underwent radiotherapy for nephroblastoma as an infant. He attended for barium enema, which demonstrated a fistula between colon and bronchial tree. Following right hemicolectomy and pathological examination of the resected bowel, no active disease process was identified to explain the development of this rare fistula. Radiotherapy was deemed the most probable aetiology. We are unaware of this having been previously described.

Accuracy of thin section magnetic resonance using phased-array pelvic coil in predicting the T-staging of rectal cancer.

Magnetic resonance (MR) imaging may contribute to staging rectal cancer and inform the decision regarding administration of pre-operative radiotherapy. The accuracy of MR has been debated. The aim of the present study was to determine the accuracy of thin section T2-weighted MR images in rectal cancer patients. MR results were compared with histological assessment of resection specimens. Over a 2-year period, 42 patients were studied. Histological staging was pT2 n = 13, pT3 n = 25 and pT4 n = 4. MR diagnostic accuracy was 74%. MR sensitivity and specificity was 62% and 79% for pT2 lesions, 84% and 59% for pT3 lesions and 50% and 76% for pT4 lesions. Estimation of tumour penetration by thin section MR imaging of rectal cancers using pelvic phased-array coil has moderate diagnostic accuracy. The limitations of MR should be acknowledged when selecting rectal cancer patients for pre-operative radiotherapy.

Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial.

BACKGROUND: Evidence for disease modifying activity of low dose corticosteroid treatment in rheumatoid arthritis is contradictory. Studies showing radiological benefit suggest that continued treatment is required to sustain the effect. OBJECTIVE: To evaluate the effect of low dose oral prednisolone in early rheumatoid arthritis on disease activity over two years. DESIGN: Double blind placebo controlled trial. METHODS: Patients with rheumatoid arthritis, duration <3 years (n = 167), were started on a disease modifying antirheumatic drug (DMARD; sulphasalazine) and allocated by stratified randomisation to prednisolone 7 mg/day or placebo. Primary outcome measure was radiological damage, assessed by the modified Sharp method. Clinical benefit was a secondary outcome. A proactive approach to identifying and treating corticosteroid adverse events was adopted. Patients who discontinued sulphasalazine were offered an alternative DMARD. RESULTS: 90 of 257 patients eligible for the study refused to participate (more women than men). Of those enrolled, 84% were seropositive for rheumatoid factor, median age 56 years, median disease duration 12 months, female to male ratio 1.8:1. Prednisolone was given to 84 patients; of these 73% continued prednisolone and 70% sulphasalazine at 2 years. Of the 83 patients on placebo, 80% continued placebo and 64% sulphasalazine at 2 years. There were no significant differences in radiological score or clinical and laboratory measures at 0 and 2 years. CONCLUSIONS: Low dose prednisolone conferred no radiological or clinical benefit on patients maintained on a DMARD over two years. Low dose corticosteroids have no role in the routine management of rheumatoid arthritis treated with conventional disease modifying drugs.

The relationship of pudendal nerve terminal motor latency to squeeze pressure in patients with idiopathic fecal incontinence.

PURPOSE: With the advent of transanal ultrasonography it has been possible to identify those incontinent patients without sphincter defects. The majority of these patients are now thought to have neurogenic fecal incontinence secondary to pudendal neuropathy. They have been found to have reduced anal sphincter pressures and increased pudendal nerve terminal motor latencies. The aim of this study was to determine whether in those incontinent patients who do not have a sphincter defect, prolonged pudendal nerve terminal motor latency correlates with anal manometry, in particular maximum squeeze pressure. METHODS: Sixty-six incontinent patients were studied with transanal ultrasonography, anorectal manometry, and pudendal nerve terminal motor latency. Twenty-seven continent controls had anorectal manometry and pudendal nerve terminal motor latency measured. RESULTS: Maximum resting pressure and maximum squeeze pressure were significantly lower in the group of incontinent patients with bilateral prolonged pudendal nerve terminal motor latency (median maximum resting pressure = 26.5 mmHg; median maximum squeeze pressure = 60 mmHg) when compared with incontinent patients with normal bilateral pudendal nerve terminal motor latencies (median maximum resting pressure = 46 mmHg; median maximum squeeze pressure = 79 mmHg; maximum resting pressure P = 0.004; and maximum squeeze pressure P = 0.04). In incontinent patients with no sphincter defects no correlation between pudendal nerve terminal motor latency and maximum squeeze pressure was found (r = -0.109, P = 0.48) and maximum squeeze pressure did not correlate with bilateral or unilateral prolonged pudendal nerve terminal motor latency (r = -0.148, P = 0.56 and r = 0.355, P = 0.19 respectively). CONCLUSIONS: In patients with idiopathic fecal incontinence damage to the pelvic floor is more complex than damage to the pudendal nerve alone. Although increased pudendal nerve terminal motor latency may indicate that neuropathy is present, in patients with neuropathic fecal incontinence, pudendal nerve terminal motor latency does not correlate with maximum squeeze pressure. Normal pudendal nerve terminal motor latency does not exclude weakness of the pelvic floor.

Pethidine-augmented white cell scintigraphy in inflammatory bowel disease.

Technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) white cell scintigraphy is invaluable for assessing the presence and extent of disease activity in patients with inflammatory bowel disease. Interpretation of images can be compromised by physiological excretion of tracer into the bowel via the biliary tree. This study assesses the effect of intravenous pethidine administered with the labelled white cells in an attempt to reduce the enterohepatic circulation of the tracer. Ninety-one subjects with proven or suspected inflammatory bowel disease were included in this study, all of whom underwent 99mTc-HMPAO white cell scintigraphy. The control group of 50 subjects underwent the standard protocol for this study performed in our department. The other 41 subjects received an intravenous injection of 0.3 mg/kg of pethidine at the same time as re-injection of the labelled white cells. Images were graded using a five-point scale at both 1 and 2.5 h and categorised as positive, negative or non-diagnostic. Each scan was also assessed for the presence of a visible gall-bladder. The pethidine group had significantly fewer non-diagnostic scans than the control group (P=0.003), and significantly (P=0.001) more studies in which the gall-bladder was visualised. It is concluded that the use of pethidine appears to reduce biliary excretion of tracer during 99mTc-HMPAO white cell scintigraphy. This may allow the delayed images, and early images with low-grade tracer uptake in the bowel, to be interpreted with greater confidence and thereby reduce the number of scans classified as non-diagnostic.

Late focal pancreatic metastasis of renal cell carcinoma.

Metastatic carcinoma to the pancreas is uncommon. Pancreatic metastasis from a renal cell carcinoma is exceptional, but may occur many years after the initial diagnosis and treatment of the primary tumor. Presentation of our patient mimicked a head of the pancreas carcinoma so well that it was only after the resectional phase of a Whipple operation that the diagnosis of metastatic renal carcinoma was made 18 years after left nephrectomy. The patient is alive and well 18 months after surgery, having gained weight.

A prospective study of six methods for detection of hepatic colorectal metastases.

Many techniques are available for the identification of patients with hepatic colorectal metastases. The accuracy and clinical relevance of transabdominal ultrasound (US), computed tomography (CT), static scintigraphy, dynamic scintigraphy (HPI), intraoperative ultrasound (IOUS) and manual palpation, in the detection of intrahepatic colorectal metastases were assessed in 73 consecutive patients presenting with colorectal carcinoma; 39 were male and 34 female with a mean age of 68 years (range 43-90 years). In 33 patients either intraoperative ultrasound or palpation were omitted owing to emergency presentation (n = 14) or subsequent non-operative management (n = 19). All six investigations were completed in 40 patients. Computed tomography and hepatic perfusion scintigraphy (HPI) were the most sensitive, detecting over 90% of lesions, the others identifying approximately 80% of lesions, Specificity in all methods, apart from dynamic scintigraphy, was over 80%. Contrast-enhanced CT would appear to remain the most accurate method available. However, if the prognostic ability of HPI is confirmed on subsequent follow-up, the accuracy of HPI will rise with time, whereas that of CT will fall. Intraoperative ultrasonography took time to perform and did not alter the management of any patient within the study. We suggest that its use is limited to those patients in whom resection is contemplated, where the vascular anatomical detail provided may be invaluable.