Therapeutic Response Evaluation in Advanced Melanoma Patients Incorporating Plasma cfDNA, LDH, VEGF, PD-L1, and IFN-γ Measurements.

BACKGROUND/AIM: Current treatment strategies for advanced melanoma require serial assessment of disease status in affected patients. In this study, we sought to examine the relationship between radiographic tumour burden and blood borne biomarkers including plasma cfDNA, serum LDH, plasma VEGF, PD-L1 and IFN-γ in advanced melanoma patients receiving immunotherapy. We hypothesized that a combination of these explanatory variables in a suitable regression analysis model may predict changes in tumour burden during patient treatment. MATERIALS AND METHODS: We extracted and quantified circulating cfDNA, LDH, VEGF, PD-L1, and IFN-γ from thirty patients with stage IV melanoma at baseline and at six months. All participating patients were evaluated with paired blood sample collection and CT scan assessments during treatment. RESULTS: Changes in radiographic tumour burden correlated with changes in levels of cfDNA (p≤0.001), LDH (p≤0.001), VEGF (p≤0.001), and PD-L1 (p<0.05) during treatment. Multiple regression analysis consisting of the follow-up to baseline assessment ratios of cfDNA, LDH, VEGF and PD-L1 explained changes in tumour burden (F (4, 23)=32.05, p<0.001); with an R2 of 0.8479 (Y=ß0+ß1*B+ß2*C+ß3*D+ß4*E). CONCLUSION: A quantitative measure of cfDNA, LDH, VEGF and PD-L1 may complement current methods of assessing tumour burden in advanced melanoma patients.

Clinical audit comparing radiation dose metrics between WEB and coil embolisation in the treatment of intracranial aneurysms.

INTRODUCTION: Intrasaccular flow disruption is a new and effective endovascular treatment for intracranial aneurysms. While endovascular treatment is a minimally invasive procedure, it does carry a radiation risk. As radiation dose should be kept as low as reasonably achievable (ALARA), the main objective of this study was to analyse KAP (kerma area product), fluoroscopy and procedure time during the treatment of aneurysms treated with coiling and the Woven-EndoBridge (WEB) device. A secondary objective was to look at the reference air kerma (RAK) to determine if the patient receives a dose that could cause tissue effects. METHODS: KAP, fluoroscopy and procedure time were retrospectively analysed in patients who had an aneurysm treatment. Aneurysms with diameters of 4-11mm, over a four-year period, in the anterior and posterior circulation of the brain were analysed in this study. Patients were treated by coiling or WEB. RAK were summed together in the working projection to give an estimated entrance surface dose (ESD) in cases with the highest KAP. RESULTS: A total of 47 aneurysms treated with WEB and 104 aneurysms treated with coiling techniques met the inclusion criteria. The average KAP was 6884.1 ± 2774.4µGym2 with coiling techniques and 5658.7 ± 1602.5µGym2 with WEB (p=0.006; CI =363-2086µGym2). This demonstrates an 18% reduction with WEB. Mean fluoroscopy time for coiling was 63.5 ± 42.6minutes and 33.8 ± 28.8minutes for WEB (p=<0.001; CI=16-43minutes). Fluoroscopy time was reduced by nearly 50% with WEB. On average, there was a 27-minute reduction of procedure time when using WEB compared to coiling. The RAK determined for the working projections did not exceed the 2Gy threshold for tissue effects. CONCLUSION: Treatment of aneurysms using the WEB shows a reduction in KAP, fluoroscopy, and procedure time. This study further demonstrates the benefits of intrasaccular flow disruption for treatment of intracranial aneurysms.

The utility of plasma circulating cell-free messenger RNA as a biomarker of glioma: a pilot study.

BACKGROUND: Research into the potential utility of plasma-derived circulating cell-free nucleic acids as non-invasive adjuncts to radiological imaging have been occasioned by the invasive nature of brain tumour biopsy. The objective of this study was to determine whether significant differences exist in the plasma transcriptomic profile of glioma patients relative to differences in their tumour characteristics, and also whether any observed differences were representative of synchronously obtained glioma samples and TCGA glioma-derived RNA. METHODS: Blood samples were collected from twenty glioma patients prior to tumour resection. Plasma ccfmRNAs and glioma-derived RNA were extracted and profiled. RESULTS: BCL2L1, GZMB, HLA-A, IRF1, MYD88, TLR2, and TP53 genes were significantly over-expressed in glioma patients (p < 0.001, versus control). GZMB and HLA-A genes were significantly over-expressed in high-grade glioma patients (p < 0.001, versus low-grade glioma patients). Moreover, the fold change of the BCL2L1 gene was observed to be higher in patients with high-grade glioma (p = 0.022, versus low-grade glioma patients). There was positive correlation between the magnitude of fold change of differentially expressed genes in plasma- and glioma-derived RNA (Spearman r = 0.6344, n = 14, p = 0.017), and with the mean FPKM in TCGA glioma-derived RNA samples (Spearman r = 0.4614, n = 19, p < 0.05). There was positive correlation between glioma radiographic tumour burden and the magnitude of fold change of the CSF3 gene (r = 0.9813, n = 20, p < 0.001). CONCLUSION: We identified significant differential expression of genes involved in cancer inflammation and immunity crosstalk among patients with different glioma grades, and there was positive correlation between their transcriptomic profile in plasma and tumour samples, and with TCGA glioma-derived RNA.

Development and implementation of an ultralow-dose CT protocol for the assessment of cerebrospinal shunts in adult hydrocephalus.

BACKGROUND: Cerebrospinal fluid shunts in the treatment of hydrocephalus, although associated with clinical benefit, have a high failure rate with repeat computed tomography (CT) imaging resulting in a substantial cumulative radiation dose. Therefore, we sought to develop a whole-body ultralow-dose (ULD) CT protocol for the investigation of shunt malfunction and compare it with the reference standard, plain radiographic shunt series (PRSS). METHODS: Following ethical approval, using an anthropomorphic phantom and a human cadaveric ventriculoperitoneal shunt model, a whole-body ULD-CT protocol incorporating two iterative reconstruction (IR) algorithms, pure IR and hybrid IR, including 60% filtered back projection and 40% IR was evaluated in 18 adult patients post new shunt implantation or where shunt malfunction was suspected. Effective dose (ED) and image quality were analysed. RESULTS: ULD-CT permitted a 36% radiation dose reduction (median ED 0.16 mSv, range 0.07-0.17, versus 0.25 mSv (0.06-1.69 mSv) for PRSS (p = 0.002). Shunt visualisation in the thoracoabdominal cavities was improved with ULD-CT with pure IR (p = 0.004 and p = 0.031, respectively) and, in contrast to PRSS, permitted visualisation of the entire shunt course (p < 0.001), the distal shunt entry point and location of the shunt tip in all cases. For shunt complications, ULD-CT had a perfect specificity. False positives (3/22, 13.6%) were observed with PRSS. CONCLUSIONS: At a significantly reduced radiation dose, whole body ULD-CT with pure IR demonstrated diagnostic superiority over PRSS in the evaluation of cerebrospinal fluid shunt malfunction.

Plasma circulating cell free messenger RNA as a potential biomarker of melanoma.

BACKGROUND: Blood borne cell free nucleic acids are increasingly emerging as significant non-invasive adjuncts to current methods of disease status evaluation in cancer patients. In this study, we sought to examine whether significant differences exist in the plasma transcriptomic profile of advanced melanoma patients with a high disease burden compared to patients with a low disease burden or therapeutic response. METHODS: Pathway focussed gene expression analysis was performed using cDNA derived from the plasma circulating cell free messenger ribonucleic acid (ccfmRNA) samples of twenty-two patients with advanced melanoma. Patients were assessed with paired blood sample collection and CT scan assessments at baseline and at 3 months follow up. RESULTS: We identified several genes which were significantly over-expressed in patients with a low disease burden or therapeutic response; BCL2L1, CXCL9, IDO1, IL13, MIF, MYD88 and TLR4 (p ≤ 0.001, versus high disease burden). There was an increase in the magnitude of fold change (2^ (-dd CT)) of BCL2L1 (p = 0.031), CCL4 (p = 0.001), CCL5 (p = 0.043), CXCL9 (p = 0.012), GZMB (p = 0.023) and TNFSF10 (p = 0.039) genes in patients with therapeutic response at 3 months follow up assessment relative to baseline assessment. Moreover, in stage IV melanoma patients with brain metastases, CCL18, CCR1, CCR4, CD274, CSF2, EGF, and PTGS2 genes were significantly over-expressed (p < 0.001, versus patients without melanoma brain metastasis). CONCLUSION: Significant differences were observed in the plasma transcriptomic profile between the various melanoma patient groups, and we postulate that these differences may be exploited to identify novel therapeutic targets or biomarkers relevant to melanoma.

Monitoring neurointerventional radiation doses using dose-tracking software: implications for the establishment of local diagnostic reference levels.

OBJECTIVES: There is potential for high radiation exposure during neurointerventional procedures. Increasing regulatory requirements mandate dose monitoring of patients and staff, and justification of high levels of radiation exposure. This paper demonstrates the potential to use radiation dose-tracking software to establish local diagnostic reference levels. METHODS: Consecutive neurointerventional procedures, performed in a single institution within a one-year period, were retrospectively studied. Dose area product (DAP) data were collected using dose-tracking software and clinical data obtained from a prospectively generated patient treatment database. RESULTS: Two hundred and sixty-four procedures met the selection criteria. Median DAP was 100 Gy.cm2 for aneurysm coiling procedures, 259 Gy.cm2 for arteriovenous malformation (AVM) embolisation procedures, 87 Gy.cm2 for stroke thrombolysis/thrombectomy, and 74 Gy.cm2 for four-vessel angiography. One hundred and nine aneurysm coiling procedures were further studied. Six significant variables were assessed using stepwise regression analysis to determine effect on DAP. Aneurysm location (anterior vs posterior circulation) had the single biggest effect (p = 0.004). CONCLUSIONS: This paper confirms variable radiation exposures during neurointerventional procedures. The 75th percentile (used to define diagnostic reference levels) of DAP measurements represents a reasonable guidance metric for monitoring purposes. Results indicate that aneurysm location has the greatest impact on dose during coiling procedures and that anterior and posterior circulation coiling procedures should have separate diagnostic reference levels. KEY POINTS: • Dose-tracking software is useful for monitoring patient radiation dose during neurointerventional procedures • This paper provides a template for methodology applicable to any interventional suite • Local diagnostic reference levels were defined by using the 75th percentile of DAP as per International Commission on Radiological Protection recommendations • Aneurysm location is the biggest determinant of radiation dose during coiling procedures. • Anterior and posterior circulation coiling procedures should have separate diagnostic reference levels.

CT of the head for acute stroke: Diagnostic performance of a tablet computer prior to intravenous thrombolysis.

INTRODUCTION: The authors propose that tablet computers could benefit patients with acute stroke in the remote care setting, where time to and accuracy of CT interpretation greatly influences patient outcome. METHODS: One hundred and fifty consecutive patients who presented to the Emergency Department of a tertiary referral neurosciences centre within a time window suitable for intravenous thrombolytic therapy were included. Images were wirelessly transmitted to a tablet computer (iPad 3rd Generation, model = A1430, Apple, Cupertino, CA) and were reviewed by radiologists with three levels of experience for signs of intracranial haemorrhage, large vessel occlusion and parenchymal infarction. Reference standard interpretation was performed by two neuroradiologists using a diagnostic monochrome display. RESULTS: Consensus neuroradiologist review on the tablet display found and correctly classified all of the 23 cases of intracranial haemorrhage including 21 cases of parenchymal haematoma, two cases of petechial haemorrhage and one patient with an acute subdural haematoma. Less experienced readers missed cases of petechial and subdural haematomas. There was excellent agreement between the tablet and diagnostic monochrome display in cases with no infarct or extensive parenchymal infarction. CONCLUSIONS: Tablet computers can be used to facilitate rapid preliminary CT interpretation in patients with acute stroke in the remote setting.

Low-Dose Carotid Computed Tomography Angiography Using Pure Iterative Reconstruction.

UNLABELLED: The aim of this study was to assess if a low-dose carotid computed tomography angiography (CTA) performed with pure iterative reconstruction (IR) is comparable to a conventional dose CTA protocol. METHODS: Twenty patients were included. Radiation dose was divided into a low-dose acquisition reconstructed with pure IR and a conventional dose acquisition reconstructed with 40% hybrid IR. Dose, image noise, contrast resolution, spatial resolution, and carotid artery stenosis were measured. RESULTS: Mean effective dose was significantly lower for low-dose than conventional dose studies (1.84 versus 3.71 mSv; P < 0.001). Subjective image noise, contrast resolution, and spatial resolution were significantly higher for the low-dose studies. There was excellent agreement for stenosis grading accuracy between low- and conventional dose studies (Cohen κ = 0.806). CONCLUSIONS: A low-dose carotid CTA protocol reconstructed with pure IR is comparable to a conventional dose CTA protocol in terms of image quality and diagnostic accuracy while enabling a dose reduction of 49.6%.

Superior cerebellar aneurysm causing subarachnoid haemorrhage in a 17-year-old with alagille syndrome.

Alagille syndrome is a rare autosomal dominant condition characterised by mutation in Jagged1 gene. Intracranial aneurysms may be seen in this condition and may present as subarachnoid hemorrhage. We describe the first case of superior cerebellar aneurysm rupture causing WFNS grade 1 subarachnoid haemorrhage in a 17-year-old girl. The clinical condition and management of this rare occurrence is discussed with a review of literature.