The use of real-world data in cancer drug development.

Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making.

Diabetes, malignancy and age as predictors of Candida glabrata bloodstream infection: A re-evaluation of the risk factors.

OBJECTIVE: Echinocandins and azoles are widely used in the treatment of candidaemia. Guidelines of the Infectious Diseases Society of America recommend commencing treatment with an echinocandin in candidaemic patients with risk factors for Candida glabrata i.e. patients who are elderly, or who have diabetes or malignancy, or those with recent prescription of azoles. We attempted to validate whether age, diabetes and malignancy are associated with C. glabrata candidaemia. PATIENTS, MATERIALS AND METHODS: Information in relation to demographics, patient associated risk factors, and laboratory parameters were collected from the casenotes and the laboratory information system. We then analysed the distribution of the risk factors (age, diabetes, and malignancy) in candidaemic patients with C. glabrata and patients with species other than C. glabrata (excluding Candida krusei). RESULTS: Over a 42-month period (April 2011-September 2017), 124 patients had candidaemia. We analysed data for 119 patients of whom 33 (27.7%) had C. glabrata and the remaining 86 (72.2%) were infected with other species. Sixty-five patients were elderly (age≥65), 40 had some form of malignancy, 34 had diabetes, and 4 patients were prescribed azoles in the 30 days prior to candidaemia (many patients had multiple risk factors). Comparing patients with C. glabrata to patients infected with other species, we found no association with diabetes (39.3% vs. 24.4%, P=0.1), malignancy (36.3 vs. 32.5%, P=0.69), and age (54.5% vs. 54.6%, P=0.99). CONCLUSIONS: Diabetes, malignancy and age are not reliable predictors of candidaemia due to C. glabrata.

Excellent translational research in oncology: A journey towards novel and more effective anti-cancer therapies.

Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess "excellence" of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will aspire to this status.

Elevated levels of endothelial-derived microparticles, and serum CXCL9 and SCGF-ß are associated with unstable asymptomatic carotid plaques.

Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques, and may correlate with serum markers of plaque instability and inflammation. Circulating EMPs, platelet MPs (PMPs) and inflammatory markers were measured in healthy controls and patients undergoing carotid endarterectomy. EMP/PMPs were quantified using flow cytometry. Bioplex assays profiled systemic inflammatory and bone-related proteins. Immunohistological analysis detailed the contribution of differentially-regulated systemic markers to plaque pathology. Alizarin red staining showed calcification. EMPs and PMPs were significantly higher in patients with carotid stenosis (≥ 70%) compared to controls, with no differences between asymptomatic vs symptomatic patients. Asymptomatic patients with unstable plaques exhibited higher levels of EMPs, CXCL9 and SCGF-ß compared to those with stable plaques. CXCL9, and SCGF-ß were detected within all plaques, suggesting a contribution to both localised and systemic inflammation. Osteopontin and osteoprotegerin were significantly elevated in the symptomatic vs asymptomatic group, while osteocalcin was higher in asymptomatic patients with stable plaque. All plaques exhibited calcification, which was significantly greater in asymptomatic patients. This may impact on plaque stability. These data could be important in identifying patients at most benefit from intervention.

Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air.

AIM: The starting fraction of inspired oxygen for preterm resuscitation is a matter of debate, and the use of room air in full-term asphyxiated infants reduces oxidative stress. This study compared oxidative stress in preterm infants randomised for resuscitation with either 100% oxygen or room air titrated to internationally recommended levels of preductal oxygen saturations. METHODS: Blood was collected at birth, two and 12 hours of age from 119 infants <32 weeks of gestation randomised to resuscitation with either 100% oxygen (n = 60) or room air (n = 59). Oxidative stress markers, including advanced oxidative protein products (AOPP) and isoprostanes (IsoP), were measured with high-performance liquid chromatography and mass spectrometry. RESULTS: Significantly higher levels of AOPP were found at 12 hours in the 100% oxygen group (p < 0.05). Increases between two- and 12-hour AOPP (p = 0.004) and IsoP (p = 0.032) concentrations were significantly higher in the 100% oxygen group. CONCLUSION: Initial resuscitation with room air versus 100% oxygen was associated with lower protein oxidation at 12 hour and a lower magnitude of increase in AOPP and IsoP levels between two and 12 hours of life. Correlations with clinical outcomes will be vital to optimise the use of oxygen in preterm resuscitation.

Empyema of the nasal conchal bulla as a cause of chronic unilateral nasal discharge in the horse: 10 cases (2013-2014).

REASONS FOR PERFORMING STUDY: Empyema of the nasal conchal bullae has recently been identified in horses suffering from chronic unilateral nasal discharge. The diagnosis and management of such cases has not been reported previously. OBJECTIVES: To describe the diagnosis and treatment of cases suffering from empyema of the nasal conchal bullae and report the frequency of diagnosis from a population of horses referred for head computed tomography (CT). STUDY DESIGN: Retrospective case review. METHODS: Records from cases diagnosed with nasal conchal bulla disease using CT were reviewed. RESULTS: Abnormalities of the nasal conchal bullae were identified by CT in 10 cases (8 ventral conchal bulla, 2 dorsal conchal bulla), from 102 equine head CT examinations. Eight cases were subsequently treated at the study clinic, 7 of which had concurrent paranasal sinus disease. In 3 cases, fenestration of the ventral conchal bulla per nasum facilitated drainage and clearance of empyema. CONCLUSIONS: Disease of the conchal bullae should be considered as a potential cause of chronic unilateral nasal discharge in horses. Clearance of empyema within these bullae is unlikely to occur through lavage of the paranasal sinuses alone. Where necessary, fenestration of the bulla allows physical removal of infected material.

Variable post-zygotic isolation in Drosophila melanogaster/D. simulans hybrids.

The study of hybrid inviability reveals cryptic divergence between the genetic interactions that maintain stable phenotypes in the pure species. We characterized the effects of natural variation on the penetrance of hybrid inviability phenotypes in crosses between Drosophila melanogaster and two species of the D. simulans subcomplex, D. simulans and D. sechellia. Using a panel of wild-caught lines, we studied the levels of genetic variance present in D. simulans and D. sechellia affecting prezygotic and post-zygotic isolation in hybridizations with D. melanogaster females. We observed extensive variability in the viability of hybrid individuals, dependent on the genotype of the parents, suggesting that intraspecific natural variation manifests directly in hybrid phenotypes. Furthermore, we found that genetic background significantly affects the penetrance of a well-studied determinant of hybrid inviability: the interaction between Hmrmel-Lhrsim. Our results suggest that hybrid inviability--and reproductive isolation generally--can be modified by polymorphisms at multiple loci segregating within the parental species. Just as the penetrance of most mutant phenotypes can be modified by the genetic background within the pure species, the penetrance of hybrid inviability phenotypes is highly influenced by the parental genotypes.

Endothelial microparticles as conveyors of information in atherosclerotic disease.

Endothelial microparticles (EMPs) are complex submicron membrane-shed vesicles released into the circulation following endothelium cell activation or apoptosis. They are classified as either physiological or pathological, with anticoagulant or pro-inflammatory effects respectively. Endothelial dysfunction caused by inflammation is a key initiating event in atherosclerotic plaque formation. Athero-emboli, resulting from ruptured carotid plaques are a major cause of stroke. Current clinical techniques for arterial assessment, angiography and carotid ultrasound, give accurate information about stenosis but limited evidence on plaque composition, inflammation or vulnerability; as a result, patients with asymptomatic, or fragile carotid lesions, may not be identified and treated effectively. There is a need to discover novel biomarkers and develop more efficient diagnostic approaches in order to stratify patients at most risk of stroke, who would benefit from interventional surgery. Increasing evidence suggests that EMPs play an important role in the pathogenesis of cardiovascular disease, acting as a marker of damage, either exacerbating disease progression or triggering a repair response. In this regard, it has been suggested that EMPs have the potential to act as biomarkers of disease status. In this review, we will present the evidence to support this hypothesis and propose a novel concept for the development of a diagnostic device that could be implemented in the clinic.

Treatment of aortoiliac aneurysms with the iliac bifurcated device for preservation of internal iliac artery flow.

INTRODUCTION: The iliac bifurcated device (IBD) is an innovative endovascular device for aortoiliac aneurysm repair. The objective of this study is to provide further evidence on the efficacy and safety of the device. STUDY DESIGN: Case series study with retrospective analysis of prospectively collected nonrandomized data. METHODS: Between 2007 and 2010, all consecutive IBD placements were analyzed. The main outcomes included (1) technical failure; (2) morbidity and mortality; and (3) late outcomes. Prospective follow-up was performed by interval computed tomography scanning. RESULTS: In all, 27 consecutive patients had elective placement of 28 IBDs. Mean operating time was 251.1 ± 65.4 minutes, mean fluoroscopy time was 63.9 ± 27.2 minutes, and mean contrast volume used was 186.2 ± 106.7 mL. Periprocedural type I endoleak occurred in 2 patients. No aneurysm-related adverse events were recorded. CONCLUSION: We demonstrate that IBDs can be used in patients with aortoiliac aneurysms and are associated with satisfactory medium-term results as expressed by high patency and low reintervention rates.

Plasma matrix metalloproteinase 9 levels may predict endoleaks after endovascular aortic aneurysm repair.

A simple, noninvasive and cost-effective diagnostic test for the detection of endoleaks after endovascular aneurysm repair (EVAR) would complement (or even replace) current surveillance modalities. We reviewed the literature for studies correlating circulating levels of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs with the presence of endoleaks after EVAR. An electronic search of databases was performed to identify studies reporting circulating concentrations of MMPs in patients with and without an endoleak after EVAR. Four studies were identified. Patients with an endoleak had higher plasma MMP-9 levels compared with those without an endoleak. Two studies that also evaluated plasma MMP-3 levels after EVAR suggest that these levels may also be higher in patients with an endoleak. Preliminary evidence suggests that MMP-9 levels are increased in patients developing an endoleak after EVAR. Larger studies are required to confirm or refute our findings.

Outcomes of endovascular aneurysm repair with 2 different endograft systems with suprarenal fixation in patients with hostile infrarenal aortic anatomy.

OBJECTIVE: To evaluate 2 different aortic endograft systems with suprarenal fixation in patients with unfavorable neck morphology. METHODS: A prospective observational study assigning patients with abdominal aortic aneurysm with unfriendly neck anatomy treated with 2 different endograft systems (Endurant and Zenith) was conducted. The log-rank test was applied to investigate the differences in cumulative outcome parameters. RESULTS: Successful endograft implantation was achieved in all patients. Requirement for troubleshooting techniques was similar in the 2 groups (P = .156 and P = .081, respectively). In-hospital procedure-related morbidity occurred in 7 patients (Zenith vs Endurant, P = .690). Freedom from any type of endoleak and overall mortality did not differ significantly between the groups (log-rank test, P = .068 and P = .087). Reinterventions were more commonly required in the Zenith group (log-rank rest, P = .041), and were all nongraft/aneurysm-related. CONCLUSIONS: Similar performances of the Zenith and the Endurant endograft systems were demonstrated.

A meta-analysis of endovascular versus surgical reconstruction of femoropopliteal arterial disease.

BACKGROUND: Controversy exists as to the relative merits of surgical and endovascular treatment of femoropoliteal arterial disease. METHODS: A systematic review of the literature was undertaken to identify studies comparing open surgical and percutaneous transluminal methods for the treatment of femoropopliteal arterial disease. Outcome data were pooled and combined overall effect sizes were calculated using fixed or random effects models. RESULTS: Four randomized controlled trials and six observational studies reporting on a total of 2817 patients (1387 open, 1430 endovascular) were included. Endovascular treatment was accompanied by lower 30-day morbidity (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.34-6.41) and higher technical failure (OR, 0.10; 95% CI, 0.05-0.22) than bypass surgery, whereas no differences in 30-day mortality between the two groups were identified (OR, 0.92; 95% CI, 0.55-1.51). Higher primary patency in the surgical treatment arm was found at 1 (OR, 2.42; 95% CI, 1.37-4.28), 2 (OR, 2.03; 95% CI, 1.20-3.45), and 3 (OR, 1.48; 95% CI, 1.12-1.97) years of intervention. Progression to amputation was found to occur more commonly in the endovascular group at the end of the second (OR, 0.60; 95% CI, 0.42-0.86) and third (OR, 0.55; 95% CI, 0.39-0.77) year of intervention. Higher amputation-free and overall survival rates were found in the bypass group at 4 years (OR, 1.31; 95% CI, 1.07-1.61 and OR, 1.29; 95% CI, 1.04-1.61, respectively). CONCLUSIONS: High-level evidence demonstrating the superiority of one method over the other is lacking. An endovascular-first approach may be advisable in patients with significant comorbidity, whereas for fit patients with a longer-term perspective a bypass procedure may be offered as a first-line interventional treatment.

Chimney technique in the endovascular management of complex aortic disease.

The objective of this study was to systematically review the literature reporting on the chimney technique and perform an analysis of the outcomes. A search of electronic databases was undertaken to identify all studies reporting on the outcome of the chimney technique. The selected articles were divided into those reporting on the treatment of aortic pathology involving the visceral and those involving the supra-aortic branches. Twenty-one articles reporting on the treatment of juxta/supra-renal aorta and aortic arch disease in 102 and 37 patients, respectively, were identified. In the visceral group, an overall technical success rate of 91% was achieved, the perioperative major morbidity and mortality rates were 17 and 5%, respectively, and an early type I endoleak developed in 13 patients (13%). During follow-up, one patient died of intestinal ischemia. In the supra-aortic group, the technical success rate was recorded in 95%, and three patients (8%) developed an early type I endoleak. Three patients (13%) required conversion to open surgery during follow-up. In conclusion, this technique may be viewed as a complementary technique in high-surgical-risk patients.

Multilayer stent in the treatment of popliteal artery aneurysms.

Endovascular repair of popliteal artery aneurysms is an emerging treatment in high risk surgical patients. The location in a functionally demanding anatomical area creates limitations in terms of endograft patency. Technological advancements have been conscripted in an effort to circumvent such constraints. The multilayer stent technology effects through haemodynamic modulation. We used the multilayer stent to treat 6 asymptomatic popliteal artery aneurysms in 3 patients. All procedures were successfully accomplished without any complications. Over a mean follow up period of 9 months, thrombosis occurred in two limbs, and blood flow was restored with thrombolysis, achieving a primary and secondary patency rate at 6 months of 67 % and 100 %, respectively. Partial or complete thrombosis of the aneurysm sac was achieved in all aneurysms. Even though the use of the multilayer stent in popliteal artery aneurysms was safe in the short term, our experience showed that close surveillance is required.

Delayed carotid surgery: what are the causes in the north west of England?

INTRODUCTION: Carotid endarterectomy (CEA) should be performed within two weeks of symptoms for patients with carotid stenosis >50%. Whether these standards are being achieved and causes of delay between symptoms and CEA were investigated. DESIGN: An analysis of prospectively collected multi-centre data. MATERIALS: Consecutive data for patients undergoing CEA between January-2006 and September-2010 were collected. Asymptomatic patients and those with no details on the timing of cerebral symptoms were excluded. METHODS: 'Delay' from symptom to CEA was defined as more than two weeks and 'prolonged-delay' more than eight weeks. Univariable and multivariable analyses were used to identify factors associated with these delays. RESULTS: Of 2147 patients with symptoms of cerebral ischaemia, 1522(70.9%) experienced 'delay' and 920(42.9%) experienced 'prolonged delay'. Patients with ischaemic heart disease were more likely to experience 'delay' (OR = 1.56; 95% CI 1.11-2.19, p = 0.011), whereas patients with stroke (OR = 0.77; 95%CI 0.63-0.94, p = 0.011) and those treated at hospitals with a stroke-prevention clinic (OR = 0.57; 95%CI 0.46-0.71, p < 0.001) were less likely to experience 'delay'. Patients treated after the publication of National Institute for Health and Clinical Excellence (NICE) guidelines were less likely to experience 'prolonged delay' (OR = 0.77; 95%CI 0.65-0.91, p = 0.003) but not 'delay'. CONCLUSION: Few patients achieved CEA within two weeks of symptoms. Introducing stroke-prevention clinics with one-stop carotid imaging appears important.