Validation study of machine-learning chest radiograph software in primary and emergency medicine.

AIM: To evaluate the performance of a machine learning based algorithm tool for chest radiographs (CXRs), applied to a consecutive cohort of historical clinical cases, in comparison to expert chest radiologists. MATERIALS AND METHODS: The study comprised 1,960 consecutive CXR from primary care referrals and the emergency department (992 and 968 cases respectively), obtained in 2015 at a UK hospital. Two chest radiologists, each with >20 years of experience independently read all studies in consensus to serve as a reference standard. A chest artificial intelligence (AI) algorithm, Lunit INSIGHT CXR, was run on the CXRs, and results were correlated with those by the expert readers. The area under the receiver operating characteristic curve (AUROC) was calculated for the normal and 10 common findings: atelectasis, fibrosis, calcification, consolidation, lung nodules, cardiomegaly, mediastinal widening, pleural effusion, pneumothorax, and pneumoperitoneum. RESULTS: The ground truth annotation identified 398 primary care and 578 emergency department datasets containing pathologies. The AI algorithm showed AUROC of 0.881-0.999 in the emergency department dataset and 0.881-0.998 in the primary care dataset. The AUROC for each of the findings between the primary care and emergency department datasets did not differ, except for pleural effusion (0.954 versus 0.988, p<0.001). CONCLUSIONS: The AI algorithm can accurately and consistently differentiate normal from major thoracic abnormalities in both acute and non-acute settings, and can serve as a triage tool.

Coronary artery calcification is associated with mortality independent of pulmonary embolism severity: a retrospective cohort study.

AIM: To assess coronary artery calcification (CAC) and vascular calcification in patients with pulmonary embolism (PE) and correlate this with mortality. MATERIALS AND METHODS: PE severity was quantified using computed tomography pulmonary angiography (CTPA) in 400 consecutive cases using the modified Miller score (1-5, mild; 6-11, moderate; 12-16, severe). Right ventricle strain was assessed using the right/left ventricle diameter (RV/LV) ratio. CAC score (CACS) was assessed using a four-point scale (CACS mild 1-3, moderate 4-8, severe 9-12) for each vessel and summed to give the total CACS. Follow-up for mortality was obtained at 3 years. RESULTS: PE severity was classified as mild in 48%, moderate in 21%, and severe in 32% of cases. The median modified Miller score was 6 (Interquartile range [IQR] 2, 14) and median total CACS was 2 (IQR 0, 7). All-cause mortality occurred in 128 (32%) patients. Patients with CAC were three times more likely to die than patients without CAC (Hazard ratio [HR] 2.96; 95% CI 1.84, 4.77; p<0.001), and patients with severe CAC were at the highest risk (HR 4.62; 95% CI 2.73, 7.83, p<0.001). Gender, modified Miller score and RV/LV ratio were not predictive of mortality. In multivariate analysis both CACS and age were independent predictors of 3-year all-cause mortality. Of the patients with CAC who died, the presence of coronary artery disease was only documented in 34 (32%). CONCLUSION: CACS is an independent predictor of all-cause mortality in patients with PE, and has important implications for subsequent patient management.

Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

CTPA protocol optimisation audit: challenges of dose reduction with maintained image quality.

AIM: To assess computed tomography (CT) pulmonary angiography (CTPA) dose and image quality in a large teaching hospital, and subsequently, to optimise the protocol in order to reduce the dose without affecting image quality. MATERIALS AND METHODS: Dose-length product (DLP), patient size, and objective quality parameters (contrast-to-noise ratio and signal-to-noise ratio on standardised levels) were recorded from 31 patients undergoing CTPA, where also a subjective image quality evaluation was carried out independently by three specialist cardiothoracic consultant radiologists. An equivalent objective and subjective quality assessment was carried out on a cohort of the same size in a different tertiary healthcare centre. Moreover, experimental tests using anthropomorphic chest phantoms were performed, using different scan parameters. In light of the above analysis, two of the scanner settings for CTPA were modified, i.e., the SureExposure pre-set was changed to "Standard" noise level, quantified with standard deviation (SD) of 19, and the minimum amperage setting lowered from 80 to 40 mA. A second cohort of patients using this new protocol was audited, following the same methodology. RESULTS: The average DLP of patients undergoing CTPA was initially found to be higher than both local and national dose reference levels (DRLs; 559 versus 300 mGy·cm and 400 mGy·cm, respectively). The new protocol led to a reduction in average DLP (359 mGy·cm) while the image quality, assessed by three cardiothoracic consultant radiologists, was preserved. CONCLUSION: The CTPA protocol was implemented in the Royal Infirmary of Edinburgh resulting in significant dose reduction, and is now compliant with national and local DRLs. The image quality was maintained.

Labour pain with remifentanil patient-controlled analgesia versus epidural analgesia: a randomised equivalence trial.

OBJECTIVE: To distinguish satisfaction with pain relief using remifentanil patient-controlled analgesia (RPCA) compared with epidural analgesia (EA) in low-risk labouring women. DESIGN: Randomised controlled equivalence trial. SETTING: Eighteen midwifery practices and six hospitals in the Netherlands. POPULATION: A total of 408 pregnant women at low risk for obstetric complications initially under the care of primary-care midwives. METHODS: Women randomised before active labour to receive analgesia with RPCA or EA, if requested. MAIN OUTCOME MEASURES: Primary outcome was satisfaction with pain relief measured hourly using a visual analogue scale and summed as area under the curve (AUC). Secondary outcomes were overall satisfaction with pain relief, pain intensity scores during labour, mode of delivery, and maternal and neonatal outcomes. RESULTS: We randomised 418 women, of whom 409 could be followed for the primary endpoint. Analgesia was received by 46% (94/203) in the remifentanil group and 37% (76/206) in the epidural group. The AUC for satisfaction with pain relief was 32 in the remifentanil group and 31 in the epidural group (mean difference -0.50; 95% CI -6.8 to 5.9). Among women who actually received analgesia, these values were 23 and 35, respectively (mean difference -12; 95% CI -22 to -1.5). Secondary outcomes were comparable. CONCLUSIONS: In low-risk labouring women, we could not demonstrate equivalence between a strategy with RPCA to EA with respect to satisfaction with pain relief assessed during the total duration of labour. However, once applied satisfaction was higher in women who received epidural analgesia. TWEETABLE ABSTRACT: Satisfaction with pain relief is higher in women receiving epidural analgesia compared with Remifentanil PCA.

Positron Emission Tomography and Magnetic Resonance Imaging of Cellular Inflammation in Patients with Abdominal Aortic Aneurysms.

OBJECTIVES: Inflammation is critical in the pathogenesis of abdominal aortic aneurysm (AAA) disease. Combined (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography with computed tomography (PET-CT) and ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) are non-invasive methods of assessing tissue inflammation. The aim of this study was to compare these techniques in patients with AAA. MATERIALS AND METHODS: Fifteen patients with asymptomatic AAA with diameter 46 ± 7 mm underwent PET-CT with (18)F-FDG, and T2*-weighted MRI before and 24 hours after administration of USPIO. The PET-CT and MRI data were then co-registered. Standardised uptake values (SUVs) were calculated to measure (18)F-FDG activity, and USPIO uptake was determined using the change in R2*. Comparisons between the techniques were made using a quadrant analysis and a voxel-by-voxel evaluation. RESULTS: When all areas of the aneurysm were evaluated, there was a modest correlation between the SUV on PET-CT and the change in R2* on USPIO-enhanced MRI (n = 70,345 voxels; r = .30; p < .0001). Although regions of increased (18)F-FDG and USPIO uptake co-localised on occasion, this was infrequent (kappa statistic 0.074; 95% CI 0.026-0.122). (18)F-FDG activity was commonly focused in the shoulder region whereas USPIO uptake was more apparent in the main body of the aneurysm. Maximum SUV was lower in patients with mural USPIO uptake. CONCLUSIONS: Both (18)F-FDG PET-CT and USPIO-MRI uptake identify vascular inflammation associated with AAA. Although they demonstrate a modest correlation, there are distinct differences in the pattern and distribution of uptake, suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively.

Long-term adverse effects associated with isolated below-knee deep-vein thrombosis: a 10-year follow-up study.

AIM: To assess the effect of the presence and locality of symptomatic lower-limb deep vein thrombosis (DVT) on mortality and morbidity following contrast venography (CV), the reference standard for diagnosing below-knee DVT, with a view to determining the prevalence of recurrent episodes of DVT and post-thrombotic syndrome (PTS). MATERIALS AND METHODS: Patients with clinical DVT undergoing investigation using CV were prospectively recorded. By retrospective case note examination and mortality data evaluation, 347 patients with DVT were matched with negative controls for mortality follow-up. Long-term complications were recorded. RESULTS: Fifty-one (14.7%) of the DVT patients were diagnosed with PTS and 43 (12.4%) with possible PTS in the 10 years following presentation. The relative risk for developing definite PTS was 0.544 for below- versus above-knee DVT; 9.9% with below-knee DVT had PTS, and 9% had probable PTS. Recurrent DVT occurred in 23.3% of patients with proximal DVT as opposed to 12.6% of patients with isolated below-knee DVT. CONCLUSIONS: Morbidity is greater in patients with proximal DVT; however, a significant, albeit smaller, proportion of patients with isolated below-knee DVT develop recurrent DVT and PTS. Below-knee DVT carries sufficient morbidity and mortality to warrant vigilance in diagnosis and management of this condition.

Ten years of imaging for pulmonary embolism: too many scans or the tip of an iceberg?

AIM: To examine the number and nature of investigations performed for suspected pulmonary embolism (PE) in a large teaching hospital and the change in incidence and severity of PE over a decade. MATERIALS AND METHODS: In this retrospective study, all patients investigated for suspected PE using computed tomography pulmonary angiography (CTPA) or lung scintigraphy during 10 years to March 2012 were identified and their records reviewed. In the final year, all reportedly positive CTPA cases were reviewed and PE severity calculated, for comparison with similar historical data. RESULTS: From 2002 to 2012, total annual investigations for suspected acute PE increased by 163% (805 to 2121). CTPA increased by 325% (475 to 2019). Detection of PE increased by 121% (193 to 426 per annum), with stable distribution of severity scores. The positive scan rate decreased from 24% to 20%. The mean age of patients being investigated for PE increased from 56 to 63 years. CONCLUSIONS: Increased detection of PE is not due to disproportionate increase in small PEs, but to increased detection of PE of all severities. This finding supports the hypothesis that PE is more common in the general population than previously appreciated, which may represent an iceberg phenomenon of previously undetected disease.

Imaging of cardiovascular risk in patients with Turner's syndrome.

Turner's syndrome is a disorder defined by an absent or structurally abnormal second X chromosome and affects around 1 in 2000 newborn females. The standardised mortality ratio in Turner's syndrome is around three-times higher than in the general female population, mainly as a result of cardiovascular disorders. Most striking is the early age at which Turner's syndrome patients develop the life-threatening complications of cardiovascular disorders compared to the general population. The cardiovascular risk stratification in Turner's syndrome is challenging and imaging is not systematically used. The aim of this article is to review cardiovascular risks in this group of patients and discuss a systematic imaging approach for early identification of cardiovascular disorders in these patients.

Feasibility of radiation dose reduction using AIDR-3D in dynamic pulmonary CT perfusion.

AIM: To assess the feasibility of radiation dose reduction with adaptive iterative dose reduction (AIDR-6 3D) reconstruction in dynamic pulmonary CT perfusion. MATERIALS AND METHODS: CTP examinations of 10 patients acquired at 100 kVp/50 mAs were reconstructed with filtered back projection (FBP) and AIDR-3D. Artificial noise was added to raw data (pre-reconstruction projection data) to simulate lower tube current scanning. Radiodensity (in Hounsfield units), noise, and perfusion values were compared. RESULTS: There was no significant difference in noise between the full and simulated reduced tube current with AIDR-3D reconstruction (p = 1). There was significantly lower noise in lung tissue with AIDR-3D images when compared to reconstructions without AIDR-3D (p = 0.005) and no significant change in the radiodensity (p = 1; mean difference <6 HU). Mean perfusion values increased significantly at lower tube currents (25 and 12.5 mAs), compared to 50 mAs (p = 0.005). This effect was significantly greater in larger patients compared to thin patients. CONCLUSION: AIDR-3D produced significantly lower noise images than FBP-based algorithms and maintained consistent noise levels in lung at 12.5 mAs, indicating this algorithm is suitable for reduced dose lung perfusion imaging. Iterative reconstruction allows significant radiation dose reduction of up to fourfold in smaller patients, and up to twofold in the medium/large size patients. The increase in perfusion values at 25% simulated tube currents is attributed to attenuation bias.

Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation?

AIMS: The pathophysiology of aortic stenosis shares many similarities with atherosclerosis and skeletal bone formation. Using non-invasive imaging, we compared aortic valve calcification and inflammation activity with that measured in atherosclerosis and bone. METHODS AND RESULTS: Positron emission and computed tomography was performed using 18F-sodium fluoride (18F-NaF, calcification) and 18F-fluorodeoxyglucose (18F-FDG, inflammation) in 101 patients with calcific aortic valve disease (81 aortic stenosis and 20 aortic sclerosis). Calcium scores and positron emission tomography tracer activity (tissue-to-background ratio; TBR) were measured in the aortic valve, coronary arteries, thoracic aorta, and bone. Over 90% of the cohort had coexistent calcific atheroma, yet correlations between calcium scores were weak or absent (valve vs. aorta r(2) = 0.015, P = 0.222; valve vs. coronaries r(2) = 0.039, P = 0.049) as were associations between calcium scores and bone mineral density (BMD vs. valve r(2) = 0.000, P = 0.766; vs. aorta r(2) = 0.052, P = 0.025; vs. coronaries r(2) = 0.016, P = 0.210). 18F-NaF activity in the valve was 28% higher than in the aorta (TBR: 2.66 ± 0.84 vs. 2.11 ± 0.31, respectively, P < 0.001) and correlated more strongly with the severity of aortic stenosis (r(2) = 0.419, P < 0.001) than 18F-NaF activity outwith the valve (valve vs. aorta r(2) = 0.167, P < 0.001; valve vs. coronary arteries r(2) = 0.174, P < 0.001; valve vs. bone r(2) = 0.001, P = 0.806). In contrast, 18F-FDG activity was lower in the aortic valve than the aortic atheroma (TBR: 1.56 ± 0.21 vs. 1.81 ± 0.24, respectively, P < 0.001) and more closely associated with uptake outwith the valve (valve vs. aorta r(2) = 0.327, P < 0.001). CONCLUSION: In patients with aortic stenosis, disease activity appears to be determined by local calcific processes within the valve that are distinct from atherosclerosis and skeletal bone metabolism.

Iterative reconstruction and individualized automatic tube current selection reduce radiation dose while maintaining image quality in 320-multidetector computed tomography coronary angiography.

AIM: To assess the effect of two iterative reconstruction algorithms (AIDR and AIDR3D) and individualized automatic tube current selection on radiation dose and image quality in computed tomography coronary angiography (CTCA). MATERIALS AND METHODS: In a single-centre cohort study, 942 patients underwent electrocardiogram-gated CTCA using a 320-multidetector CT system. Images from group 1 (n = 228) were reconstructed with a filtered back projection algorithm (Quantum Denoising Software, QDS+). Iterative reconstruction was used for group 2 (AIDR, n = 379) and group 3 (AIDR3D, n = 335). Tube current was selected based on body mass index (BMI) for groups 1 and 2, and selected automatically based on scout image attenuation for group 3. Subjective image quality was graded on a four-point scale (1 = excellent, 4 = non-diagnostic). RESULTS: There were no differences in age (p = 0.975), body mass index (p = 0.435), or heart rate (p = 0.746) between the groups. Image quality improved with iterative reconstruction and automatic tube current selection [1.3 (95% confidence intervals (CI): 1.2-1.4), 1.2 (1.1-1.2) and 1.1 (1-1.2) respectively; p < 0.001] and radiation dose decreased [274 (260-290), 242 (230-253) and 168 (156-180) mGy cm, respectively; p < 0.001]. CONCLUSION: The application of the latest iterative reconstruction algorithm and individualized automatic tube current selection can substantially reduce radiation dose whilst improving image quality in CTCA.

Is intrapartum fever associated with ST-waveform changes of the fetal electrocardiogram? A retrospective cohort study.

OBJECTIVE: To investigate the association between maternal intrapartum fever and ST-waveform changes of the fetal electrocardiogram. DESIGN: Retrospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. METHODS: We studied 142 women with fever (≥38.0°C) during labour and 141 women with normal temperature who had been included in two previous studies. In both groups, we counted the number and type of ST-events and classified them as significant (intervention needed) or not significant, based on STAN(®) clinical guidelines. MAIN OUTCOME MEASURES: Number and type of ST-events. RESULTS: Both univariable and multivariable regression analysis showed no association between the presence of maternal intrapartum fever and the number or type of ST-events. CONCLUSIONS: Maternal intrapartum fever is not associated with ST-segment changes of the fetal electrocardiogram. Interpretation of ST-changes in labouring women with fever should therefore not differ from other situations.

Should cervical favourability play a role in the decision for labour induction in gestational hypertension or mild pre-eclampsia at term? An exploratory analysis of the HYPITAT trial.

OBJECTIVE: To examine whether cervical favourability (measured by cervical length and the Bishop score) should inform obstetricians' decision regarding labour induction for women with gestational hypertension or mild pre-eclampsia at term. DESIGN: A post hoc analysis of the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: A total of 756 women diagnosed with gestational hypertension or pre-eclampsia between 36 + 0 and 41 + 0 weeks of gestation randomly allocated to induction of labour or expectant management. METHODS: Data were analysed using logistic regression modelling. MAIN OUTCOME MEASURES: The occurrence of a high-risk maternal situation defined as either maternal complications or progression to severe disease. Secondary outcomes were caesarean delivery and adverse neonatal outcomes. RESULTS: The superiority of labour induction in preventing high-risk situations in women with gestational hypertension or mild pre-eclampsia at term varied significantly according to cervical favourability. In women who were managed expectantly, the longer the cervix the higher the risk of developing maternal high-risk situations, whereas in women in whom labour was induced, cervical length was not associated with a higher probability of maternal high-risk situations (test of interaction P = 0.03). Similarly, the beneficial effect of labour induction on reducing the caesarean section rate was stronger in women with an unfavourable cervix. CONCLUSION: Against widely held opinion, our exploratory analysis showed that women with gestational hypertension or mild pre-eclampsia at term who have an unfavourable cervix benefited more from labour induction than other women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825.

New possibilities for ST analysis - A post-hoc analysis on the Dutch STAN RCT.

BACKGROUND: The diagnostic value of ST analysis of the fetal electrocardiogram (fECG) during labor is uncertain. False alarms (ST events) may be explained by physiological variation of the fetal electrical heart axis. Adjusted ST events, based on a relative rather than an absolute rise from baseline, correct for this variation and may improve the diagnostic accuracy of ST analysis. AIMS: Determine the optimal cut-off for relative ST events in fECG to detect fetal metabolic acidosis. STUDY DESIGN: Post-hoc analysis on fECG tracings from the Dutch STAN trial (STAN+CTG branch). SUBJECTS: 1328 term singleton fetuses with scalp ECG tracing during labor, including 10 cases of metabolic acidosis. OUTCOME MEASURES: Cut-off value for relative ST events at the point closest to (0,1) in the receiver operating characteristic (ROC) curve with corresponding sensitivity and specificity. RESULTS: Relative baseline ST events had an optimal cut-off at an increment of 85% from baseline. Relative ST events had a sensitivity of 90% and specificity of 80%. CONCLUSIONS: Adjusting the current definition of ST events may improve ST analysis, making it independent of CTG interpretation.

Fetal blood sampling in addition to intrapartum ST-analysis of the fetal electrocardiogram: evaluation of the recommendations in the Dutch STAN® trial.

OBJECTIVES: To evaluate the recommendations for additional fetal blood sampling (FBS) when using ST-analysis of the fetal electrocardiogram. DESIGN: Prospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. METHODS: In labouring women allocated to the STAN® arm of a previously published randomised controlled trial who underwent one or more FBS during delivery, we assessed whether FBS was performed according to the trial protocol and how fetal acidosis, defined as an FBS pH < 7.20, was related to ST-waveform analysis. MAIN OUTCOME MEASURES: The number of FBS showing fetal acidosis, related to the different STAN® criteria where additional FBS is recommended. RESULTS: Among 2827 women monitored with STAN®, 297 underwent FBS, of whom 171 (57.6%) were performed according to the predefined criteria and 126 were performed in absence of these criteria. In the first group, rates of fetal acidosis (pH < 7.20) were two of 18, none of nine, 12 of 111 and three of 33 when FBS was taken for abnormal cardiotocogram (CTG) at the start, intermediary CTG at the start, abnormal CTG >60 minutes, and poor electrocardiogram quality, respectively. When the predefined criteria were not met and ST-analysis showed no ST-events, only two incidents of fetal acidosis were seen. CONCLUSIONS: The performance of FBS is valuable in the advised STAN® criteria. When these criteria are not met, performance of FBS does not seem helpful in the detection of fetal acidosis.

Synergistic effect of bisphosphonate and docetaxel on the growth of bone metastasis in an animal model of established metastatic bone disease.

Bisphosphonates decrease bone resorption and reduce significantly the rate of skeletal complications in patients with metastatic bone disease. Bisphosphonates have also been shown to exhibit antitumor activity in vitro but in vivo results have been equivocal. In the present study, we investigated the effects of bisphosphonate treatment alone or in combination with the cytostatic docetaxel on the growth of breast cancer cells in bone. Tumor gowth was studied in an athymic nude mice model inoculated with MDA-231-B/luc+ breast cancer cells. Two days after the inoculation, mice were treated with risedronate, zolendronate or docetaxel alone or with a combination of risedronate and docetaxel. Bone destruction and tumor growth were evaluated radiographically, histologically and by whole-body bioiluminescent reporter imaging (BLI). Five week treatment with high doses risedronate or zoledronate (37.5-150 microg/kg, 5 times/week), fully protected the bones from osteolysis, but did not affect tumour growth. Docetaxel (2, 4, and 8 mg/kg, 2 times/week) inhibited tumour growth dose-dependently and after 5 weeks treatment with the highest dose, there was no detectable tumour in bone. The combination of a dose of docetaxel (4 mg/kg) that demonstrated only a minimal effect on tumour growth, with risedronate (150 microg/kg), protected bone integrity and nearly completely inhibited the growth of the cancer cells. Risedronate and docetaxel act synergistically to protect bone and decrease tumour burden in an animal model of established bone metastases from breast cancer cells.

Hyperpolarised 3He MRI versus HRCT in COPD and normal volunteers: PHIL trial.

The aim of the present study was to apply hyperpolarised (HP) (3)He magnetic resonance imaging (MRI) to identify patients with chronic obstructive pulmonary disease (COPD) and alpha(1)-antitrypsin deficiency (alpha(1)-ATD) from healthy volunteers and compare HP (3)He MRI findings with high-resolution computed tomography (HRCT) in a multicentre study. Quantitative measurements of HP (3)He MRI (apparent diffusion coefficient (ADC)) and HRCT (mean lung density (MLD)) were correlated with pulmonary function tests. A prospective three centre study enrolled 122 subjects with COPD (either acquired or genetic) and age-matched never-smokers. All diagnostic studies were completed in 94 subjects (52 with COPD; 13 with alpha(1)-ATD; 29 healthy subjects; 63 males; and 31 females; median age 62 yrs). The consensus assessment of radiologists, blinded for other test results, estimated nonventilated lung volume (HP (3)He MRI) and percentage diseased lung (HRCT). Quantitative evaluation of all data for each centre consisted of ADC (HP (3)He MRI) and MLD measurements (HRCT), and correlation with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) indicating airway obstruction, and the diffusing capacity of the lung for carbon monoxide (D(L,CO)) indicating alveolar destruction. Using lung function tests as a reference, regional analysis of HP (3)He MRI and HRCT correctly categorised normal volunteers in 100% and 97%, COPD in 42% and 69% and alpha(1)-ATD in 69% and 85% of cases, respectively. Direct comparison of HP (3)He MRI and CT revealed 23% of subjects with moderate/severe structural abnormalities had only mild ventilation defects. In comparison with lung function tests, ADC was more effective in separating COPD patients from healthy subjects than MLD (p<0.001 versus 0.038). ADC measurements showed better correlation with D(L,CO) than MLD (r = 0.59 versus 0.29). Hyperpolarised (3)He MRI correctly categorised patients with COPD and normal volunteers. It offers additional functional information, without the use of ionising radiation whereas HRCT gives better morphological information. We showed the feasibility of a multicentre study using different magnetic resonance systems.

PET scan in clinically suspected paraneoplastic neurological syndromes: a 6-year prospective study in a regional neuroscience unit.

BACKGROUND: The role of PET in the diagnosis of paraneoplastic neurological syndromes (PNS) has previously been reported in retrospective studies, from specialized neuro-oncology units, often selecting patients with positive paraneoplastic antibodies. OBJECTIVES: To prospectively assess the usefulness of PET in detecting malignancy in patients clinically suspected of having PNS. METHODS: PET was performed in patients suspected of PNS within 4 weeks of the normal CT body scan. All patients were followed up. RESULTS: Eighty patients suspected of having PNS underwent PET. 18/80 (23%) were abnormal and suspicious of malignancy. The total number of definite and probable PNS with abnormal PET was 11/18 (61%). The total number of definite and probable PNS with a normal PET was 3/62 (5%). Only 50% of patients with biopsy-proven malignancy were positive for paraneoplastic antibodies. The prevalence of abnormal PET in patients presenting with classical PNS was 41% as opposed to 21% in patients with non-classical PNS. The sensitivity and specificity of PET in diagnosing PNS was 75% and 87% respectively. CONCLUSIONS: PET is a valuable tool in clinically suspected PNS. Its use should not be restricted to specialized neuro-oncology units or in patients with positive paraneoplastic antibodies. Positive yield is the highest amongst patients with classical PNS.

Comparative expression analysis of isolated human adipocytes and the human adipose cell lines LiSa-2 and PAZ6.

OBJECTIVE: To obtain insight in the extent to which the human cell lines LiSa-2 and PAZ6 resemble isolated primary human adipocytes. DESIGN: A combination of cDNA subtraction (representative difference analysis; RDA) and cDNA microarray analysis was used to select adipose specific genes to compare isolated (pre-)adipocytes with (un)differentiated LiSa-2 and PAZ6 cells. MEASUREMENTS: RDA was performed on adipose tissue against lung tissue. A total of 1400 isolated genes were sequenced and cDNA microarray technology was used for further adipose related gene selection. 30 genes that were found to be enriched in adipose tissue were used to compare isolated human adipocytes and LiSa-2 and PAZ6 cells in the differentiated and undifferentiated states. RESULTS: RDA and microarray analysis resulted in the identification of adipose enriched genes, but not in adipose specific genes. Of the 30 most differentially expressed genes, as expected, most were related to lipid metabolism. The second category consisted of methyltransferases, DNMT1, DNMT3a, RNMT and SHMT2, of which the expression was differentiation dependent and higher in differentiated adipocytes. Using the 30 adipose expressed genes, it was found that isolated adipocytes on one hand, and PAZ6 and LiSa-2 adipocytes on the other, differ primarily in lipid metabolism. Furthermore, LiSa-2 cells seem to be more similar to isolated adipocytes than PAZ6 cells. CONCLUSION: The LiSa-2 cell line is a good model for differentiated adipocytes, although one should keep in mind that the lipid metabolism in these cells deviates from the in vivo situation Furthermore, our results imply that methylation may have an important function in terminal adipocyte differentiation.