Lloyd J Ridley

Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study

BACKGROUND TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. METHODS In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 109, 7 × 109, and 9 × 109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. FINDINGS Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 109 TargomiRs once weekly. We established that 5 × 109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. INTERPRETATION The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. FUNDING Asbestos Diseases Research Foundation.

Lumen Loss in the First Year in Saphenous Vein Grafts Is Predominantly a Result of Negative Remodeling of the Whole Vessel Rather Than a Result of Changes in Wall Thickness

Background— The use of saphenous vein grafts (SVG) in coronary artery bypass surgery is established but little is known of SVG remodeling during the first year in vivo. Methods and Results— The feasibility of measuring total vessel diameter (lumen plus wall), lumen diameter, and wall thickness by a novel computed tomography (CT) method was established in phantom model tubes (r=0.98 for lumen diameter and r=0.98 for wall thickness) and in an initial clinical study of 14 patients correlating CT and intravascular ultrasound measurements of SVG (r=0.88 for total vessel diameter, r=0.85 for lumen diameter and r=0.89 for wall thickness). In a separate group of 42 patients (aged 66±10 years; 36 male, 6 female) undergoing coronary artery bypass grafting, SVG total vessel diameter, lumen diameter, and wall thickness were determined prospectively with multi-slice CT angiography at 1 and 12 months postoperatively. Mean total vessel diameter decreased from 5.95±0.83 mm to 5.39±0.87 mm, P<0.001 (range, −39% to +8% change). Twenty-six patients (62%) had a decrease of SVG vessel diameter (negative remodeling) >5%. Mean lumen diameter decreased from 3.69±0.66 mm to 3.36±0.68 mm, P<0.001, (range, −40 to +11% change). Surprisingly, mean wall thickness decreased from 1.14±0.27 mm to 1.01±0.21 mm (P<0.001; range, −48 to +33% change). Conclusions— Lumen loss in SVG between postoperative months 1 and 12 is predominantly caused by negative remodeling of the whole vessel rather than to changes in wall thickness. Therapies targeting negative remodeling may be required for optimal maintenance of SVG lumen in the first postoperative year.

Left Atrial Compression and the Mechanism of Exercise Impairment in Patients With a Large Hiatal Hernia

OBJECTIVES The purpose of this study was to determine the association between cardiac compression and exercise impairment in patients with a large hiatal hernia (HH). BACKGROUND Dyspnea and exercise impairment are common symptoms of a large HH with unknown pathophysiology. Studies evaluating the contribution of cardiac compression to the pathogenesis of these symptoms have not been performed. METHODS We collected clinical data from a consecutive series of 30 patients prospectively evaluated with resting and stress echocardiography, cardiac computed tomography, and respiratory function testing before and after laparoscopic HH repair. Left atrial (LA), inferior pulmonary vein, and coronary sinus compression was analyzed in relation to exercise capacity (metabolic equivalents [METs] achieved on Bruce treadmill protocol). RESULTS Exertional dyspnea was present in 25 of 30 patients (83%) despite normal mean baseline respiratory function. Moderate to severe LA compression was qualitatively present in 23 of 30 patients (77%) on computed tomography. Right and left inferior pulmonary vein and coronary sinus compression was present in 11 of 30 (37%), 12 of 30 (40%), and 26 of 30 (87%) patients, respectively. Post-operatively, New York Heart Association functional class and exercise capacity improved significantly (number of patients in New York Heart Association functional classes I, II, III, and IV: 6, 11, 11, and 2 vs. 26, 4, 0, and 0, respectively, p < 0.001; METs [percentage predicted]: 75 ± 24% vs. 112 ± 23%, p < 0.001) and resolution of cardiac compression was observed. Absolute change in LA diameter on the echocardiogram was the only independent cardiorespiratory predictor of exercise capacity improvement post-operatively (p = 0.006). CONCLUSIONS We demonstrate, for the first time, marked exercise impairment and cardiac compression in patients with a large HH and normal respiratory function. After HH repair, exercise capacity improves significantly and correlates with resolution of LA compression.

Are MRI White Matter Lesions Clinically Significant in the ‘Old-Old’? Evidence from the Sydney Older Persons Study

Background: The number of individuals aged over 80 years is the fastest increasing group in developed countries. White matter lesions (WML) observed on magnetic resonance imaging (MRI) have uncertain clinical significance, particularly in the old. Objectives: To determine the prevalence of periventricular and deep WML in survivors of an original cohort of randomly selected elderly community dwellers, and to examine their associations with clinical markers of vascular and extrapyramidal disorders of ageing, as well as quantitative cognitive measures. Methods: Brain MRI, lifestyle interview, cognitive testing and medical examination were administered to 122 participants from the Sydney Older Persons Study 6-year review (mean age: 85.5 years). Apolipoprotein E (ApoE) genotype was also established. Presence and severity of periventricular and deep WML were ascertained using semi-quantitative rating methods and their relations to the cognitive and clinical variables investigated. Results: Periventricular WML were present in all participants in similar severity for all three regions sampled. In contrast, a gradient of severity was observed for the deep WML: most severe in the parietal region, followed by the frontal and occipital regions, and least severe in the temporal region. Associations with gender or with the ApoE Ε4 allele were non-significant. WML were inconsistently associated with age and cognitive functioning or with the clinical markers of dementia. No frontal specificity emerged. Examination of individual lesion types did not change the general pattern of associations. Supporting evidence for a threshold effect was observed on some measures. Conclusions: WML are extremely common in elderly, non-demented individuals. Unlike in younger individuals, MRI abnormalities may not be evidence of a current pathological process and their importance may change with advancing age.

Glossopharyngeal insufflation causes lung injury in trained breath-hold divers

Background and objective:  Glossopharyngeal insufflation (GI) is a technique practised by competitive breath‐hold divers to enhance their performance. Using the oropharyngeal musculature, air is pumped into the lungs to increase the lung volume above physiological TLC. Experienced breath‐hold divers can increase their lung volumes by up to 3 L. Although the potential for lung injury is evident, there is limited information available. The aim of this study was to examine whether there is any evidence of lung injury following GI, independent of diving.

Comparing white matter lesions on T2 and FLAIR MRI in the Sydney Older Persons Study

There is suggestion that magnetic resonance imaging (MRI) fluid‐attenuated inversion recovery (FLAIR) sequence may be more accurate than T2 images in detecting white matter lesions (WML) in older people. Comparative ratings of these two image sequences have not been directly investigated in very old individuals to date. We compared the ratings of periventricular and deep WML on these two sequences in a sample of 111 community dwellers (mean age 85.5 years) using semiquantitative methods. Periventricular WML were as commonly detected on T2 as on FLAIR but were more severely rated on the latter sequence. No such bias was observed for the deep WML. With one exception, correlations between the two sets of measures were significant at the P < 0.001 level (range: 0.34–0.75). Intrarater reliability coefficients were moderate to excellent for most ratings. These results suggest that ratings performed on T2‐weighted images to detect WML in very old individuals are very comparable with those performed on FLAIR images although FLAIR may allow a finer grading of periventricular lesions. Absence of FLAIR does not preclude the identification of WML in this population. These findings have clinical and epidemiological relevance where the acquisition of supplementary MRI data may not always be possible.

Modulation of phasic left atrial function and left ventricular filling in patients with extrinsic left atrial compression by hiatal hernia

10 ml/m 2 ), LAVPreA (36 ± 10 ml/m 2 vs. 40 ± 9 ml/m 2 ), LAVMin (25 ± 9m l/m 2 vs. 27 ± 9 ml/m 2 ) and active LAEV (12 ± 3 ml/m 2 vs. 13 ±

Coronary ostial morphology after modified Bentall operation assessed with dual-source multidetector computed tomography

During the modified Bentall operation (aortic root replacement), a cuff of native aorta is commonly implanted together with the coronary ostium into the aortic graft. We describe the radiologic appearance on computed tomography of coronary-aortic and aorto-aortic graft anastomoses over long-term follow-up in 21 consecutive asymptomatic patients (mean age, 67 +/- 12 years) with previous Bentall operation. Multidetector (64-slice, dual-source) computed tomography was performed at a median of 76 months after surgery. One patient had asymptomatic aortic dissection that extended into the carotid artery. Seven patients had aortic dilation > or =40 mm distal to the graft. All patients had dilation at the postsurgical coronary ostia-aortic attachment: mean coronary ostial diameter was 12.8 +/- 3.6 mm, which was on average 1.7-fold greater than the adjacent proximal coronary vessel diameter. All patients had at least one ostium > or =10 mm in diameter. In 16 patients, both coronary ostia were > or =10 mm. There was no relationship between time after surgery and the ostial diameter. In patients with accessible presurgery angiograms, no relationship was observed between ostial diameters before and after surgery. Dilation of the coronary ostia anastomosis site is typical after the modified Bentall operation. Asymptomatic aortic pathology is also evident in this population.

Systematic review and meta‐analysis of the diagnostic accuracy of low‐dose computed tomography of the kidneys, ureters and bladder for urolithiasis

Renal colic is a common clinical condition which is often investigated with a CT of the kidneys, ureters and bladder (CTKUB). Recent technological improvements have allowed a reduction in dose with the emergence of low‐dose CTKUB (LD‐CTKUB) techniques. The present meta‐analysis aims to determine the diagnostic accuracy of LD‐CTKUB in the diagnosis of clinically significant uroliths. A systematic review was performed using nine electronic databases from their dates of inception to May 2016. Inclusion criteria included studies reporting comparative outcomes using LD‐CTKUB with a dose less than 3 millisieverts compared to an imaging gold standard or clinical and surgical evaluation. The primary endpoint was detection of a urolith ≥3 mm where specified and any urolith when size was unspecified. Twelve studies were identified according to selection criteria, involving 1250 patients. LD‐CTKUB demonstrated a pooled sensitivity of 93.1% (95%CI 91.5–94.4), specificity of 96.6% (95%CI 95.1–97.7%), positive likelihood ratio of 19.9 (95%CI 12.7–31.2), negative likelihood ratio of 0.05 (95%CI 0.02–0.10) and AUC of 0.9877 in the detection of clinically significant uroliths. Although 86 alternative diagnoses were noted across seven studies, none assessed the accuracy of LD‐CTKUB in their detection. The majority of newer studies report an average radiation dose from 1 to 1.5 millisieverts. This study demonstrates a high sensitivity, specificity and positive predictive value in the detection of uroliths, however, its accuracy in the detection of alternative diagnoses is unknown. Therefore, we recommend using LD‐CTKUB when the pre‐test probability of stone disease is significantly higher than the pre‐test probability of alternative diagnoses, such as follow‐up of known calculi. We suggest caution when the pre‐test probability of alternative diagnoses is high, such as the initial presentation of renal colic.

A systematic review and meta-analysis of multidetector computed tomography in the assessment of coronary artery bypass grafts

PURPOSE The present meta-analysis aimed to compare the diagnostic accuracy of more recent computed tomography coronary angiography (CTCA) with invasive coronary angiography (ICA) in the assessment of graft patency after coronary artery bypass graft surgery (CABG). MATERIAL AND METHODS A systematic review was performed using nine electronic databases from their dates of inception to July 2015. Predefined inclusion criteria included studies reporting on comparative outcomes using ≥64 slice multidetector computed tomography (MDCT) and ICA. The primary endpoints included graft occlusion and significant graft stenosis ≥50%. Secondary analyses included the comparison of arterial versus venous graft conduits, and the use of different MDCT techniques. RESULTS Thirty-one studies were identified according to selection criteria, involving 1975 patients with 5364 assessed grafts. Combined assessment of stenosis and occlusion for all grafts demonstrated a sensitivity of 96.1% [95% confidence interval (CI) 94.3-97.4%] and specificity of 96.3% (95% CI 95.1-97.3%). CTCA assessment of venous grafts demonstrated higher sensitivity compared to arterial grafts, when testing for both occlusion and stenosis (97.6% vs 89.2%, p=0.004). CONCLUSION Results of this study demonstrated that CTCA had a relatively high pooled sensitivity, specificity and negative predictive value compared to ICA. However, patient baseline characteristics varied between studies, and the results should be interpreted with caution. Nonetheless, our results indicate that CTCA should be recognized as an accurate and non-invasive investigation for graft patency in symptomatic patients after CABG.