Publications by authors named "Caroline Kelly"

24 Publications

  • Page 1 of 1

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

Radiat Oncol 2021 Aug 26;16(1):163. Epub 2021 Aug 26.

Institute of Cancer Sciences, Glasgow Royal Infirmary, University of Glasgow, Room 2.57, Level 2, New Lister Building, Glasgow, G31 2ER, UK.

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.

Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m oxaliplatin, 350 mg folinic acid and 400 mg/m bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.

Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).
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http://dx.doi.org/10.1186/s13014-021-01888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393812PMC
August 2021

A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial.

Gynecol Oncol 2021 Oct 16;163(1):72-78. Epub 2021 Aug 16.

Prince of Wales Clinical School UNSW and Royal Hospital for Women, Sydney, NSW 2031, Australia.

Background: Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs.

Methods: 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity.

Results: The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5-13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5-13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%-24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade.

Conclusions: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.024DOI Listing
October 2021

Non-operatively managed blunt and penetrating renal trauma: Does early follow up CT scan change management? A systematic review.

Injury 2021 Jul 30. Epub 2021 Jul 30.

Blizard Institute, Queen Mary University of London, United Kingdom.

Background: Renal injury accounts for 1-5% of all traumatic injuries. Non-operative management (NOM) of renal trauma has demonstrated higher renal salvage rates and reduced morbidity.

Aims: The aim of this review is to clarify the indications of early follow up CT scan for adult patients, with NOM, renal trauma, with a view to avoiding unnecessary CT scanning and radiation exposure in this cohort of patients.

Methods: A systematic search was conducted using PubMed (MEDLINE), Web of Science, Embase, and Cochrane library, with references from relevant articles also evaluated. Inclusion criteria were defined as studies reporting outcomes of patients ≥12 years of age, with NOM, renal trauma and early CT re-imaging. The outcomes of interest were renal complications requiring intervention, specifically collecting system and vascular complications.

Results: Five studies met the inclusion criteria. In total, 542 patients were included in this analysis; study sizes ranged from 48 to 207 patients. Early re-imaging was performed for 510 patients, including 489 CTs and 31 Ultrasounds (US). Mean time to re-imaging ranged from 1 - 35.9 days. Twenty three patients required intervention following re-imaging, all of which were for injuries grade ≥ 3 and presented with clinical deterioration prior to re-imaging, had a collecting system injury identified on initial CT scan or both. The number needed to re-image, in order to change the management of one patient, was 22.

Conclusions: Although the findings of this review are based on retrospective data, they suggest routine early re-imaging can be safely omitted for all NOM, renal injuries which remain asymptomatic, with no collecting system injury diagnosed on initial CT, provided appropriate delayed phase imaging is available. Future prospective studies are required to further clarify the indications of early re-imaging, specifically for NOM penetrating injuries, and the appropriate modality and timing of early re-imaging for all NOM renal trauma.
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http://dx.doi.org/10.1016/j.injury.2021.07.029DOI Listing
July 2021

The Pull-through Anastomosis of Ureter to Enteric Conduit (PAUTEC): A Novel Technique for Urinary Diversion.

Urology 2021 Jul 18. Epub 2021 Jul 18.

Royal College of Surgeons, Dublin, Ireland.

Objective: To describe and illustrate a novel technique of uretero-ileal anastomosis for use in urinary diversion - the Pull-through Anastomosis of Ureter To Enteric Conduit (PAUTEC). A second objective was to evaluate the surgical outcomes of the PAUTEC anastomosis.

Materials And Methods: Our novel anastomotic technique was described step-by-step and visually depicted with illustrations and the accompanying narrated video. Additionally, to evaluate safety and efficacy, a retrospective review of a prospectively maintained database was performed. Patients who underwent radical cystectomy alone or during pelvic exenteration, with ileal conduit diversion incorporating PAUTEC, 2016-2020 with ≥6 months follow-up were included. Surgical outcomes and renal function were analysed.

Results: PAUTEC anastomosis was performed on 43 ureters in 23 patients. Mean age was 66 years [50-80] and 21 of 23 patients were male. One patient had a conservatively-managed small urine leak. No ureteric strictures have been identified to date. Mean serum creatinine was 1.15 mg/dL [0.69-2.08] (102umol/L, range 61-184 umol/L) preoperatively, and 1.09 mg/dL [0.61-2.59] (96.3 umol/L, range 54-229 umol/L) at follow-up, demonstrating no significant change (P= .26, paired t-test). Mean follow-up was 15 months [6-44].

Conclusion: A PAUTEC technique of uretero-ileal anastomosis is feasible and technically straightforward, with satisfactory outcomes observed to date.
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http://dx.doi.org/10.1016/j.urology.2021.07.003DOI Listing
July 2021

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

J Thorac Oncol 2021 10 9;16(10):1705-1717. Epub 2021 Jun 9.

Cancer Research UK Beatson Institute, Glasgow, United Kingdom.

Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.

Methods: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.

Results: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.

Conclusions: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.
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http://dx.doi.org/10.1016/j.jtho.2021.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514249PMC
October 2021

Three Versus Six Months of Adjuvant Doublet Chemotherapy for Patients With Colorectal Cancer: A Multi-Country Cost-Effectiveness and Budget Impact Analysis.

Clin Colorectal Cancer 2021 09 15;20(3):236-244. Epub 2021 Apr 15.

Health Economics and Health Technology Assessment, Institute of Health and Wellbeing, University of Glasgow, Glasgow, Scotland.

Background: The Short Course Oncology Treatment (SCOT) trial demonstrated non-inferiority, less toxicity, and cost-effectiveness from a UK perspective of 3 versus 6 months of oxaliplatin-based chemotherapy for patients with colorectal cancer. This study assessed the cost-effectiveness of shorter treatment and the budget impact of implementing trial findings from the perspectives of all countries recruited to SCOT: Australia, Denmark, New Zealand, Spain, Sweden, and the United Kingdom.

Patients And Methods: Individual cost-utility analyses were performed from the perspective of each country. Resource, quality of life, and survival estimates from the SCOT trial (N = 6065) were used. Probabilistic sensitivity analysis and subgroup analyses were undertaken. Using undiscounted costs from these cost-utility analyses, the impact on country-specific healthcare budgets of implementing the SCOT trial findings was calculated over a 5-year period. The currency used was US dollars (US$), and 2019 was the base year. One-way and scenario sensitivity analysis addressed uncertainty within the budget impact analysis.

Results: Three months of treatment were cost saving and cost-effective compared to 6 months from the perspective of all countries. The incremental net monetary benefit per patient ranged from US$8972 (Spain) to US$13,884 (Denmark). The healthcare budget impact over 5 years for the base-case scenario ranged from US$3.6 million (New Zealand) to US$61.4 million (UK) and totaled over US$150 million across all countries.

Conclusion: This study has widened the transferability of results from the SCOT trial, showing that shorter treatment is cost-effective from a multi-country perspective. The vast savings from implementation could fully justify the investment in conducting the SCOT trial.
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http://dx.doi.org/10.1016/j.clcc.2021.04.001DOI Listing
September 2021

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer.

Br J Cancer 2021 02 23;124(4):786-796. Epub 2020 Nov 23.

School of Medicine, University of Glasgow, Glasgow, UK.

Background: The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy.

Methods: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.

Results: GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85-5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39-3.41, p = 0.001). In TransSCOT, chemotherapy type (p = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19-4.16, p = 0.012).

Conclusions: This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.
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http://dx.doi.org/10.1038/s41416-020-01168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884404PMC
February 2021

A comparison between MRI and CT in the assessment of primary tumour volume in mesothelioma.

Lung Cancer 2020 12 1;150:12-20. Epub 2020 Oct 1.

Glasgow Pleural Disease Unit, Queen ElIzabeth University Hospital, Glasgow, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Introduction: Primary tumour staging in Malignant Pleural Mesothelioma (MPM) using Computed Tomography (CT) imaging is confounded by perception errors reflecting low spatial resolution between tumour and adjacent structures. Augmentation using perfusion CT is constrained by radiation dosage. In this study, we evaluated an alternative tumour staging method using perfusion-tuned Magnetic Resonance Imaging (MRI).

Methods: Consecutive patients with suspected MPM were recruited to a prospective observational study. All had MRI (T1-weighted, isotropic, contrast-enhanced 3-Tesla perfusion imaging) and CT (contrast-enhanced) pre-biopsy. Patients diagnosed with MPM underwent MRI and CT volumetry, with readers blinded to clinical data. MRI volumetry was semi-automated, using signal intensity limits from perfusion studies to grow tumour regions within a pleural volume. A similar CT method was not possible, therefore all visible tumour was manually segmented. MRI and CT volumes were compared (agreement, correlation, analysis time, reproducibility) and associations with survival examined using Cox regression.

Results: 58 patients were recruited and had MRI before biopsy. 31/58 were diagnosed with MPM and these scans were used for volumetry. Mean (SD) MRI and CT volumes were 370 cm and 302 cm, respectively. MRI volumes were larger (average bias 61.9 cm (SD 116), 95 % limits (-165.5 - 289 cm), moderately correlated with CT (r = 0.56, p = 0.002) and independently associated with survival (HR 4.03 (95 % CI 1.5-11.55), p = 0.006). CT volumes were not associated with survival, took longer to compute than MRI volumes (mean (SD) 151 (19) v 14 (2) minutes, p=<0.0001) and were less reproducible (inter-observer ICC 0.72 for CT, 0.96 for MRI).

Conclusions: MRI and CT generate different tumour volumes in MPM. In this study, MRI volumes were larger and were independently associated with survival. MRI volumetry was quicker and more reproducible than CT.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.025DOI Listing
December 2020

A microfluidic-multiwell platform for rapid phase mapping of surfactant solutions.

Rev Sci Instrum 2020 Apr;91(4):045109

Department of Chemical Engineering, Imperial College London, London SW7 2AZ, United Kingdom.

Measurement of the phase behavior and (meta)stability of liquid formulations, including surfactant solutions, is required for the understanding of mixture thermodynamics, as well as their practical utilization. We report a microfluidic platform with a stepped temperature profile, imposed by a dual Peltier module, connected to an automated multiwell plate injector and optical setup, for rapid solution phase mapping. The measurement protocol is defined by the temperature step ΔT ≡ T - T (≲100 °C), volumetric flow rate Q ≡ ΔV/Δt (≲50 μl/min), which implicitly set the thermal gradient ΔT/Δt (≃0.1-50 °C/min), and measurement time (which must exceed the intrinsic timescale of the relevant phase transformation). Furthermore, U-shaped microchannels can assess the reversibility of such transformations, yielding a facile measurement of the metastable zone width of the phase diagram. By contrast with traditional approaches, the platform precisely controls the cooling and heating rates by tuning the flow rate, and the absolute temperature excursion by the hot and cold thermal profile, which remain stationary during operation, thus allowing the sequential and reproducible screening of large sample arrays. As a model system, we examined the transition from the micellar (L) to the liquid crystalline lamellar phase (L), upon cooling, of aqueous solutions of sodium linear alkylbenzene sulfonate, a biodegradable anionic surfactant extensively employed in industry. Our findings are validated with quiescent optical microscopy and small angle neutron scattering data.
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http://dx.doi.org/10.1063/1.5144770DOI Listing
April 2020

Baseline predictors of negative and incomplete pleural cytology in patients with suspected pleural malignancy - Data supporting 'Direct to LAT' in selected groups.

Lung Cancer 2019 07 16;133:123-129. Epub 2019 May 16.

Glasgow Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK; Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK. Electronic address:

Objectives: Negative effusion cytology is more common in certain forms of Malignant Pleural Effusion (MPE) and results in pathway delay. Local Anaesthetic Thoracoscopy (LAT) is extremely sensitive and safe but cannot be offered to all. A stratified pathway, including 'Direct to LAT' in selected cases could enhance patient experience but requires reliable baseline predictors of unhelpful cytology, including both negative (no malignant cells) and incomplete results (malignant cells identified but predictive markers failed), since pleural biopsies will be required in the latter for optimal management. This retrospective analysis of a prospective multi-centre study, sought to identify baseline features for pathway rationalization.

Materials And Methods: 363/638 (57%) of patients recruited to the DIAPHRAGM study (ISRCTN10079972) were included. Prospective data, including final diagnoses, asbestos exposure and fluid cytology results were supplemented by retrospective Computed Tomography (CT) and predictive marker reports. Independent predictors of negative and incomplete cytology were determined by multivariable logistic regression. Contingency tables were used to assess diagnostic value of cytology in associated phenotypes.

Results: 238/363 (66%) patients were diagnosed with MPE (18 tumour types). Fluid cytology was negative in 151/238 (63%) and independently associated with asbestos-exposure (Odds Ratio (OR) 5.34) and a malignant CT (OR 2.25). When both features were recorded the sensitivity and negative predictive value of fluid cytology were 19% (95% CI 11-30%) and 9% (95% CI 4-20%)), respectively. Cytology was incomplete in 34/238 (14%), i.e. 47% of positive cytology cases) but was not associated with any baseline feature. ORs for incomplete cytology in Ovarian, Breast, Renal and Lung Cancer were 83, 22, 21 and 9, respectively.

Conclusion: Negative cytology is extremely likely in patients with asbestos exposure and a malignant CT report. A 'Direct-to-LAT' approach may be appropriate in this setting. No baseline predictors of incomplete cytology were identified.
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http://dx.doi.org/10.1016/j.lungcan.2019.05.017DOI Listing
July 2019

Assessment of Performance of the Industrial Process of Bulk Vacuum Packaging of Raw Meat with Nondestructive Optical Oxygen Sensing Systems.

Sensors (Basel) 2018 May 2;18(5). Epub 2018 May 2.

School of Biochemistry and Cell Biology, University College Cork, Cavanagh Pharmacy Building, College Road, Cork T12 K8AF, Ireland.

The commercially-available optical oxygen-sensing system Optech-O₂ Platinum was applied to nondestructively assess the in situ performance of bulk, vacuum-packaged raw beef in three ~300 kg containers. Twenty sensors were attached to the inner surface of the standard bin-contained laminate bag (10 on the front and back sides), such that after filling with meat and sealing under vacuum, the sensors were accessible for optical interrogation with the external reader device. After filling and sealing each bag, the sensors were measured repetitively and nondestructively over a 15-day storage period at 1 °C, thus tracking residual oxygen distribution in the bag and changes during storage. The sensors revealed a number of unidentified meat quality and processing issues, and helped to improve the packaging process by pouring flakes of dry ice into the bag. Sensor utility in mapping the distribution of residual O₂ in sealed bulk containers and optimising and improving the packaging process, including handling and storage of bulk vacuum-packaged meat bins, was evident.
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http://dx.doi.org/10.3390/s18051395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981195PMC
May 2018

PARADIGM-2: Two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status.

Clin Transl Radiat Oncol 2018 Jan 21;8:12-16. Epub 2017 Nov 21.

Institute of Cancer Sciences, University of Glasgow, UK.

Glioblastoma has a dismal prognosis and molecular targeted agents have failed to improve outcomes to date. PARADIGM-2 is a phase I dose escalation study evaluating olaparib plus radiotherapy ± temozolomide in newly diagnosed glioblastoma, using MGMT methylation status to stratify patients and inform treatment schedules.
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http://dx.doi.org/10.1016/j.ctro.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862667PMC
January 2018

Early Contrast Enhancement: A novel magnetic resonance imaging biomarker of pleural malignancy.

Lung Cancer 2018 04 3;118:48-56. Epub 2018 Feb 3.

Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK; Institute of Infection, Immunity & Inflammmation, University of Glasgow, UK. Electronic address:

Introduction: Pleural Malignancy (PM) is often occult on subjective radiological assessment. We sought to define a novel, semi-objective Magnetic Resonance Imaging (MRI) biomarker of PM, targeted to increased tumour microvessel density (MVD) and applicable to minimal pleural thickening.

Materials And Methods: 60 consecutive patients with suspected PM underwent contrast-enhanced 3-T MRI then pleural biopsy. In 58/60, parietal pleura signal intensity (SI) was measured in multiple regions of interest (ROI) at multiple time-points, generating ROI SI/time curves and Mean SI gradient (MSIG: SI increment/time). The diagnostic performance of Early Contrast Enhancement (ECE; which was defined as a SI peak in at least one ROI at or before 4.5 min) was compared with subjective MRI and Computed Tomography (CT) morphology results. MSIG was correlated against tumour MVD (based on Factor VIII immunostain) in 31 patients with Mesothelioma.

Results: 71% (41/58) patients had PM. Pleural thickening was <10 mm in 49/58 (84%). ECE sensitivity was 83% (95% CI 61-94%), specificity 83% (95% CI 68-91%), positive predictive value 68% (95% CI 47-84%), negative predictive value 92% (78-97%). ECE performance was similar or superior to subjective CT and MRI. MSIG correlated with MVD (r = 0.4258, p = .02).

Discussion: ECE is a semi-objective, perfusion-based biomarker of PM, measurable in minimal pleural thickening. Further studies are warranted.
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http://dx.doi.org/10.1016/j.lungcan.2018.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884311PMC
April 2018

Reply to M. Horiguchi et al.

J Clin Oncol 2017 10 11;35(29):3373-3374. Epub 2017 Aug 11.

James Paul, Caroline Kelly, and Jon Stobo, University of Glasgow, Glasgow, United Kingdom; and Thomas Powles, Queen Mary University of London, London, United Kingdom.

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http://dx.doi.org/10.1200/JCO.2017.74.4292DOI Listing
October 2017

Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer.

J Clin Oncol 2017 Jun 12;35(16):1770-1777. Epub 2017 Apr 12.

Robert J. Jones, Judith Dixon-Hughes, Laura Alexander, Anna Morris, Caroline Kelly, Jon Stobo, and James Paul, University of Glasgow, Glasgow; Syed A. Hussain, University of Liverpool, Liverpool; Andrew S. Protheroe, Churchill Hospital, Oxford; Alison Birtle, Royal Preston Hospital, Preston; Prabir Chakraborti, Royal Derby Hospital, Derby; Robert A. Huddart, Institute of Cancer Research, Sutton; Satinder Jagdev, St James's University Hospital, Leeds; Amit Bahl, Bristol Haematology and Oncology Centre, Bristol; Andrew Stockdale, University Hospital, Coventry; Santhanam Sundar, Nottingham University Hospitals National Health Service Trust, Nottingham; Simon J. Crabb, University of Southampton, Southampton; and Thomas Powles, Queen Mary University of London, London, United Kingdom.

Purpose Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel.
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http://dx.doi.org/10.1200/JCO.2016.70.7828DOI Listing
June 2017

Sleep to Lower Elevated Blood Pressure: A Randomized Controlled Trial (SLEPT).

Am J Hypertens 2017 Mar;30(3):319-327

HRB Clinical Research Facility, National University of Ireland, Galway, Galway, Ireland.

Background: Impaired sleep quality is common and associated with an increased risk of cardiovascular disease (CVD), thought to be mediated through adverse effects on established vascular risk factors, particularly hypertension. We determined if a web-delivered sleep intervention (sleep-hygiene education, stimulus control, and cognitive behavioral therapy) reduces blood pressure compared to vascular risk factor education (standard care) alone.

Methods: Phase II randomized, blinded, controlled trial of 134 participants without CVD with mild sleep impairment and blood pressure 130-160/<110 mm Hg. The primary outcome was the difference in the mean change in 24-hour ambulatory systolic blood pressure (SBP) over 8 weeks between intervention and control groups. Secondary outcomes included measures of sleep quality and psychosocial health, namely Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI).

Results: Participants in the sleep intervention group showed significantly greater improvements in sleep quality, including ISI [difference in mean improvement 2.8; 95% confidence interval (CI), 1.3-4.4], PSQI (1.1; 95% CI, 0.1-2.2), sleep condition indicator (0.8; 95% CI, 0.2-1.4), and psychosocial health, including BDI (2.0; 95% CI, 0.3-3.7) and BAI (1.4; 95% CI, 0.02-2.8). The mean improvement in 24-hour ambulatory SBP did not differ between the sleep intervention (0.9 mm Hg) and control (0.8 mm Hg) arms, (difference in mean improvement 0.1; 95% CI, -3.4 to 3.2).

Conclusion: A simple, low-cost, web-delivered sleep intervention is feasible and significantly improves sleep quality and measures of psychosocial health in individuals with mild sleep impairment but does not result in short-term improvements in blood pressure.
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http://dx.doi.org/10.1093/ajh/hpw132DOI Listing
March 2017

The diagnostic performance of routinely acquired and reported computed tomography imaging in patients presenting with suspected pleural malignancy.

Lung Cancer 2017 01 18;103:38-43. Epub 2016 Nov 18.

Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK; Institute of Infection, Immunity and Inflammation, University of Glasgow, UK. Electronic address:

Objectives: Contrast-enhanced computed tomography (CT) provides essential cross-sectional imaging data in patients with suspected pleural malignancy (PM). The performance of CT in routine practice may be lower than in previously reported research. We assessed this relative to 'real-life' factors including use of early arterial-phase contrast enhancement (by CT pulmonary angiography (CTPA)) and non-specialist radiology reporting.

Materials And Methods: Routinely acquired and reported CT scans in patients recruited to the DIAPHRAGM study (a prospective, multi-centre observational study of mesothelioma biomarkers) between January 2014 and April 2016 were retrospectively reviewed. CT reports were classified as malignant if they included specific terms e.g. "suspicious of malignancy", "stage M1a" and benign if others were used e.g. "indeterminate", "no cause identified". All patients followed a standard diagnostic algorithm. The diagnostic performance of CT (overall and based on the above factors) was assessed using 2×2 Contingency Tables.

Results: 30/345 (9%) eligible patients were excluded (non-contrast (n=13) or non-contiguous CT (n=4), incomplete follow-up (n=13)). 195/315 (62%) patients studied had PM; 90% were cyto-histologically confirmed. 172/315 (55%) presented as an acute admission, of whom 31/172 (18%) had CTPA. Overall, CT sensitivity was 58% (95% CI 51-65%); specificity was 80% (95% CI 72-87%). Sensitivity of CTPA (performed in 31/315 (10%)) was lower (27% (95% CI 9-53%)) than venous-phase CT (61% (95% CI 53-68%) p=0.0056). Sensitivity of specialist thoracic radiologist reporting was higher (68% (95% CI 55-79%)) than non-specialist reporting (53% (95% CI 44-62%) p=0.0488). Specificity was not significantly different.

Conclusion: The diagnostic performance of CT in routine clinical practice is insufficient to exclude or confirm PM. A benign CT report should not dissuade pleural sampling where the presence of primary or secondary pleural malignancy would alter management. Sensitivity is lower with non-thoracic radiology reporting and particularly low using CTPA.
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http://dx.doi.org/10.1016/j.lungcan.2016.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226066PMC
January 2017

Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study.

BMJ Open 2016 11 24;6(11):e013324. Epub 2016 Nov 24.

Department of Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, UK.

Introduction: Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information.

Methods And Analysis: Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13-20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created.

Ethics And Dissemination: The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/0240). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups.

Trial Registration Number: ISRCTN10079972, Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2016-013324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168514PMC
November 2016

Pain in Malignant Pleural Mesothelioma: A Prospective Characterization Study.

Pain Med 2016 11 26;17(11):2119-2126. Epub 2016 Apr 26.

*Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK

Introduction: Malignant pleural mesothelioma (MPM) is associated with severe pain. The underlying neurobiology of this is complex. The primary aim of this study was to characterize pain in MPM.

Methods: This study was undertaken as part of a trial examining radiotherapy for the treatment of pain in MPM (ISRCTN 10644347). Patients had MPM with associated pain for which radiotherapy was planned and a worst pain score ≥ 4/10. The following assessments were undertaken: clinical neuropathic pain assessment, Brief Pain Inventory (BPI), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Short form of the McGill Pain Questionnaire (SF-MPQ), and Quantitative Sensory Testing (QST). The relationship of these characteristics and response to radiotherapy was assessed. Unless stated, medians and interquartile range (IQR) are used.

Results: Thirty-seven patients were recruited. Average pain and worst pain was 4 (4-6) and 8 (6-8), respectively. Higher average pain and higher worst pain scores were associated with higher interference scores on the BPI, P < 0.001 and P < 0.0005. Twenty patients (54%) had a clinical diagnosis of neuropathic pain, and of these, only six patients (40%) screened positively for neuropathic pain using the LANSS. Patients with a high LANSS also had higher BPI and SF-MPQs. The presence of neuropathic pain (clinically or by LANSS) did not predict response to radiotherapy, P < 0.05. The SF-MPQ scores were higher in those with abnormal cool sensation on QST (P = 0.016).

Conclusion: Pain in mesothelioma varies among patients and may have neuropathic components. An adequate pain assessment is necessary to guide the clinician in the appropriate choice of analgesics.
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http://dx.doi.org/10.1093/pm/pnw061DOI Listing
November 2016

Elevated risk of adverse obstetric outcomes in pregnant women with depression.

Arch Womens Ment Health 2013 Dec 10;16(6):475-82. Epub 2013 Aug 10.

Department of Psychiatry and Penn Center for Women's Behavioral Wellness, Perelman School of Medicine of the University of Pennsylvania, Pennsylvania, USA,

In this study, we evaluated the association between prenatal depression symptoms adverse birth outcomes in African-American women. We conducted a retrospective cohort study of 261 pregnant African-American women who were screened with the Edinburgh Postnatal Depression Scale (EPDS) at their initial prenatal visit. Medical records were reviewed to assess pregnancy and neonatal outcomes, specifically preeclampsia, preterm birth, intrauterine growth retardation, and low birth weight. Using multivariable logistic regression models, an EPDS score ≥10 was associated with increased risk for preeclampsia, preterm birth, and low birth weight. An EPDS score ≥10 was associated with increased risk for intrauterine growth retardation, but after controlling for behavioral risk factors, this association was no longer significant. Patients who screen positive for depression symptoms during pregnancy are at increased risk for multiple adverse birth outcomes. In a positive, patient-rated depression screening at the initial obstetrics visit, depression is associated with increased risk for multiple adverse birth outcomes. Given the retrospective study design and small sample size, these findings should be confirmed in a prospective cohort study.
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http://dx.doi.org/10.1007/s00737-013-0371-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834010PMC
December 2013

Elevated risk of adverse obstetric outcomes in pregnant women with depression.

Arch Womens Ment Health 2013 Dec 10;16(6):475-82. Epub 2013 Aug 10.

Department of Psychiatry and Penn Center for Women's Behavioral Wellness, Perelman School of Medicine of the University of Pennsylvania, Pennsylvania, USA,

In this study, we evaluated the association between prenatal depression symptoms adverse birth outcomes in African-American women. We conducted a retrospective cohort study of 261 pregnant African-American women who were screened with the Edinburgh Postnatal Depression Scale (EPDS) at their initial prenatal visit. Medical records were reviewed to assess pregnancy and neonatal outcomes, specifically preeclampsia, preterm birth, intrauterine growth retardation, and low birth weight. Using multivariable logistic regression models, an EPDS score ≥10 was associated with increased risk for preeclampsia, preterm birth, and low birth weight. An EPDS score ≥10 was associated with increased risk for intrauterine growth retardation, but after controlling for behavioral risk factors, this association was no longer significant. Patients who screen positive for depression symptoms during pregnancy are at increased risk for multiple adverse birth outcomes. In a positive, patient-rated depression screening at the initial obstetrics visit, depression is associated with increased risk for multiple adverse birth outcomes. Given the retrospective study design and small sample size, these findings should be confirmed in a prospective cohort study.
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http://dx.doi.org/10.1007/s00737-013-0371-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834010PMC
December 2013

GeneSigDB: a manually curated database and resource for analysis of gene expression signatures.

Nucleic Acids Res 2012 Jan 21;40(Database issue):D1060-6. Epub 2011 Nov 21.

Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

GeneSigDB (http://www.genesigdb.org or http://compbio.dfci.harvard.edu/genesigdb/) is a database of gene signatures that have been extracted and manually curated from the published literature. It provides a standardized resource of published prognostic, diagnostic and other gene signatures of cancer and related disease to the community so they can compare the predictive power of gene signatures or use these in gene set enrichment analysis. Since GeneSigDB release 1.0, we have expanded from 575 to 3515 gene signatures, which were collected and transcribed from 1604 published articles largely focused on gene expression in cancer, stem cells, immune cells, development and lung disease. We have made substantial upgrades to the GeneSigDB website to improve accessibility and usability, including adding a tag cloud browse function, facetted navigation and a 'basket' feature to store genes or gene signatures of interest. Users can analyze GeneSigDB gene signatures, or upload their own gene list, to identify gene signatures with significant gene overlap and results can be viewed on a dynamic editable heatmap that can be downloaded as a publication quality image. All data in GeneSigDB can be downloaded in numerous formats including .gmt file format for gene set enrichment analysis or as a R/Bioconductor data file. GeneSigDB is available from http://www.genesigdb.org.
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http://dx.doi.org/10.1093/nar/gkr901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245038PMC
January 2012

Consultation room design and the clinical encounter: the space and interaction randomized trial.

HERD 2009 ;3(1):41-78

Department of Planning, Policy and Design, School of Ecology, University of California, Irvine, USA.

Objective: The design of the consultation room remains largely unaltered despite major changes in clinical practice, such as the electronic medical record and patient-centered care. The value of redesigning the consultation room to accommodate these changes and the effect of a redesign on patient-clinician interaction are unclear.

Methods: The authors randomly allocated 65 patient-physician dyads to consultations in a standard room (n = 30) or in an experimental room designed with a semicircular table around which the clinician and the patient sat, with equal access to the computer screen (n = 35). Participant responses to post-visit surveys, assessing patient experiences in these rooms, were compared in an intention-to-treat fashion.

Results: The authors found no differences between the rooms in terms of patient satisfaction with the consultation, mutual respect, or communication quality. Compared to the standard room, patients in the experimental room were better able to interact with the computer monitor (24 [75%] vs. 17 [59%], P = 0.07) and had a greater ability to look at the screen at any time (22 [73%] vs. 8 [28%], P < 0.001); and they reported that clinicians allowed them to review the medical record on the screen (22 [71%] vs. 13 [45%], P = 0.012), shared information on the computer screen (24 [80%] vs. 18 [60%], P = 0.037), and reviewed information on the Internet with the patient (13 [43%] vs. 7 [26%], P = 0.010) more than those in the standard room.

Conclusions: The design of the consultation room affects the clinical encounter. In particular, ready access to a computer screen using the electronic medical record and the Internet may enhance information sharing.
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http://dx.doi.org/10.1177/193758670900300106DOI Listing
January 2011
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