Iron and Erythropoietin to Heal and Recover after Intensive Care (ITHRIVE):A pilot RCT

AbstractObjectiveTo determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit.DesignAn investigator-initiated, parallel group, placebo-controlled, randomised, feasibility trial.SettingA tertiary intensive care unit (ICU) in Perth, Western Australia. ParticipantsAdults with anaemia (haemoglobin <100g/L), requiring ICU-level care for more than 48 hours and likely to be ready for ICU discharge within 24 hours.InterventionsA single dose of IV ferric carboxymaltose and Epoetin alfa (active group), or an equal volume of 0.9% saline (placebo group).Main outcome measuresStudy feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥ 90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to Day 90 (DAH90).ResultsThe 40-participant planned sample size included twenty in each group and were enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8-5.1) in ICU prior to enrolment and had a mean baseline haemoglobin of 83.7g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8-9.0], DAH90 follow up was 100% (95% CI 91.2%-100%), and 39 (97.5%, 95% CI 86.8%-99.9%) participants received the allocated study intervention. No serious adverse events were reported. ConclusionThe ITHRIVE pilot demonstrated feasibility based on predefined participant recruitment, study drug administration and follow up thresholds

Prospective Study of Cetuximab, Carboplatin, and Radiation Therapy for Patients With Locally Advanced Head and Neck Squamous Cell Cancer Unfit for Cisplatin

Purpose: To report on the outcomes of a novel treatment regimen for patients with locally advanced head and neck squamous cell carcinoma who were fit for curative treatment but not fit for cisplatin

Optimising radiation therapy delivery for cancer patients using daily image guidance to maximise cure and reduce normal tissue side effects

Cancer patients treated with radiotherapy are generally treated with a large number of small daily doses of radiation to the tumour region. The displacement of the tumour relative to its expected position each day prior to treatment can be modelled mathematically to determine the required width of the safety margin required such that tumours receive high enough radiation dose to kill the tumour, without overdosing surrounding healthy tissue. In this PhD a new, more sophisticated method of calculating radiotherapy margins is developed, which considers more realistic displacement patterns than has been the case previously

Optimising Area Under the ROC Curve Using Gradient Descent

This paper introduces RankOpt, a linear binary classifier which optimises the area under the ROC curve (the AUC). Unlike standard binary classifiers, RankOpt adopts the AUC statistic as its objective function, and optimises it directly using gradient descent. The problems with using the AUC statistic as an objective function are that it is non-differentiable, and of complexity O n in the number of data observations. RankOpt uses a differentiable approximation to the AUC which is accurate, and computationally efficient, being of complexity O n . This enables the gradient descent to be performed in reasonable time

Radiotherapy margin design with particular consideration of high curvature CTVs

In applying 3D conformal radiation therapy to a tumor clinical target volume (CTV), a margin is added around the CTV to account for any sources of error in the application of treatment which may result in misalignment between the CTV and the dose distribution actually delivered. The volume enclosed within the CTV plus the margin is known as the PTV, or planning target volume. The larger the errors are anticipated to be, the wider the margin will need to be to accommodate those errors. Based on the approach of van Herk et al. ["The probability of correct target dosage: Dose-population histograms for deriving treatment margins in radiotherapy," Int. J. Radiat. Oncol. Biol., Phys. 47(4), 1121-1135 (2000)] this paper develops the mathematical theory behind the calculation of the margin width required to ensure that the entire CTV receives sufficiently high dose with sufficiently high probability. The margin recipe developed not only considers the magnitude of the errors but also includes a term to adjust for curved CTV surfaces. In doing so, the accuracy of the margin recipe is enhanced yet remains mathematically concise enough to be readily implemented in the clinical setting. The results are particularly relevant for clinical situations in which the uncertainties in treatment are large relative to the size of the CTV

18F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma

Background Immune checkpoint blockade such as ipilimumab and anti-PD1 monoclonal antibodies have significantly improved survival in advanced melanoma. Biomarkers are urgently needed as a majority of patients do not respond, despite treatment-related toxicities. We analysed pre-treatment 18F-fluorodeoxyglucose positron emission tomography/computerised tomography (FDG PET/CT) parameters to assess its correlation with patient outcome. Methods This retrospective study evaluated pre-treatment FDG PET/CT scans in a discovery cohort of patients with advanced melanoma treated with ipilimumab or anti-PD1. Pre-treatment scans were assessed for maximum tumoral standardised uptake value (SUVmax), metabolic tumour volume (MTV) and spleen to liver ratio (SLR). Progression-free survival (PFS) and overall survival (OS) were characterised and modelled using univariable and multivariable analyses. Correlation of SLR and OS was validated in an independent cohort. Blood parameters and stored sera of patients from the discovery cohort was analysed to investigate biological correlates with SLR. Results Of the 90 evaluable patients in the discovery cohort: 50 received ipilimumab monotherapy, 20 received anti-PD1 monotherapy, and 20 patients received ipilimumab followed by anti-PD1 upon disease progression. High SLR > 1.1 was associated with poor PFS (median 1 vs 3 months; HR 3.14, p = 0.008) for patients treated with ipilimumab. High SLR was associated with poor OS after ipilimumab (median 1 vs 21 months; HR 5.83, p = 0.0001); as well as poor OS after first line immunotherapy of either ipilimumab or anti-PD1 (median 1 vs 14 months; HR 3.92, p = 0.003). The association of high SLR and poor OS after ipilimumab was validated in an independent cohort of 110 patients (median 2.3 months versus 11.9 months, HR 3.74). SLR was associated with poor OS in a multi-variable model independent of stage, LDH, absolute lymphocyte count and MTV. Conclusions Pre-treatment Spleen to liver ratio (SLR) > 1.1 was associated with poor outcome after ipilimumab in advanced melanoma. This parameter warrants prospective evaluation