Louise Marquart

A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.

Background Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection. Methods and Findings A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether–lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120–4786 and 7–40 respectively; p<0.01). Conclusions This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials. Trial Registration: ClinicalTrials.gov NCT01055002

Metastatic progression of breast cancer: insights from 50 years of autopsies

There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c‐Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analysed by array‐based comparative genomic hybridization for six cases##. 945 metastatic deposits were identified, with a median of four/patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%) and non‐axillary lymph nodes (55%). Major findings included: (a) patients with CNS metastases were more likely to have bone metastases (p < 0.013); (b) younger age was associated with metastasis to the liver (≤ 49 years; p < 0.001) and to gynaecological organs (≤ 49 years; p = 0.001); (c) surgical excision of the primary tumour was associated with metastasis to the liver (p = 0.002); and (d) ER and PgR showed down‐regulation during progression in a non‐random manner, particularly in lung/pleura (ER; p < 0.001), liver and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2–q12.1 and 10q22.2–q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies.

Prevention and treatment of acute radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials

BackgroundRadiation-induced skin reaction (RISR) is a common side effect that affects the majority of cancer patients receiving radiation treatment. RISR is often characterised by swelling, redness, pigmentation, fibrosis, and ulceration, pain, warmth, burning, and itching of the skin. The aim of this systematic review was to assess the effects of interventions which aim to prevent or manage RISR in people with cancer.MethodsWe searched the following databases up to November 2012: Cochrane Skin Group Specialised Register, CENTRAL (2012, Issue 11), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), CINAHL (from 1981) and LILACS (from 1982). Randomized controlled trials evaluating interventions for preventing or managing RISR in cancer patients were included. The primary outcomes were development of RISR, and levels of RISR and symptom severity. Secondary outcomes were time taken to develop erythema or dry desquamation; quality of life; time taken to heal, a number of skin reaction and symptom severity measures; cost, participant satisfaction; ease of use and adverse effects. Where appropriate, we pooled results of randomized controlled trials using mean differences (MD) or odd ratios (OR) with 95% confidence intervals (CI).ResultsForty-seven studies were included in this review. These evaluated six types of interventions (oral systemic medications; skin care practices; steroidal topical therapies; non-steroidal topical therapies; dressings and other). Findings from two meta-analyses demonstrated significant benefits of oral Wobe-Mugos E for preventing RISR (OR 0.13 (95% CI 0.05 to 0.38)) and limiting the maximal level of RISR (MD -0.92 (95% CI -1.36 to -0.48)). Another meta-analysis reported that wearing deodorant does not influence the development of RISR (OR 0.80 (95% CI 0.47 to 1.37)).ConclusionsDespite the high number of trials in this area, there is limited good, comparative research that provides definitive results suggesting the effectiveness of any single intervention for reducing RISR. More research is required to demonstrate the usefulness of a wide range of products that are being used for reducing RISR. Future efforts for reducing RISR severity should focus on promising interventions, such as Wobe-Mugos E and oral zinc.

Incidence, risk factors and estimates of a woman's risk of developing secondary lower limb lymphedema and lymphedema-specific supportive care needs in women treated for endometrial cancer

OBJECTIVES Few studies have assessed the risk and impact of lymphedema among women treated for endometrial cancer. We aimed to quantify cumulative incidence of, and risk factors for developing lymphedema following treatment for endometrial cancer and estimate absolute risk for individuals. Further, we report unmet needs for help with lymphedema-specific issues. METHODS Women treated for endometrial cancer (n = 1243) were followed-up 3-5 years after diagnosis; a subset of 643 completed a follow-up survey that asked about lymphedema and lymphedema-related support needs. We identified a diagnosis of secondary lymphedema from medical records or self-report. Multivariable logistic regression was used to evaluate risk factors and estimates. RESULTS Overall, 13% of women developed lymphedema. Risk varied markedly with the number of lymph nodes removed and, to a lesser extent, receipt of adjuvant radiation or chemotherapy treatment, and use of nonsteroidal anti-inflammatory drugs (pre-diagnosis). The absolute risk of developing lymphedema was >50% for women with 15+ nodes removed and 2-3 additional risk factors, 30-41% for those with 15+ nodes removed plus 0-1 risk factors or 6-14 nodes removed plus 3 risk factors, but ≤ 8% for women with no nodes removed or 1-5 nodes but no additional risk factors. Over half (55%) of those who developed lymphedema reported unmet need(s), particularly with lymphedema-related costs and pain. CONCLUSION Lymphedema is common; experienced by one in eight women following endometrial cancer. Women who have undergone lymphadenectomy have very high risks of lymphedema and should be informed how to self-monitor for symptoms. Affected women need greater levels of support.

Changes in supportive care needs after first‐line treatment for ovarian cancer: identifying care priorities and risk factors for future unmet needs

The objective of this paper is to determine changes in supportive care needs after first‐line treatment for ovarian cancer and identify risk factors for future unmet needs.

Impact of weight change and weight cycling on risk of different subtypes of endometrial cancer

AIM Obesity is an established risk factor for endometrial cancer. Associations tend to be stronger for the endometrioid subtype. The role of adult weight change and weight cycling is uncertain. Our study aimed to determine whether there is an association between different adult weight trajectories, weight cycling and risk of endometrial cancer overall, and by subtype. METHODS We analysed data from the Australian National Endometrial Cancer study, a population-based case-control study that collected self-reported information on height, weight at three time points (age 20, maximum and 1 year prior to diagnosis [recent]), intentional weight loss/regain (weight cycling) from 1398 women with endometrial cancer and 1538 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. RESULTS Relative to women who maintained a stable weight during adulthood, greater weight gain after the age of 20 was associated with increased risk of endometrial cancer (OR for gain 40+kg all subtypes 5.3, 95% CI 3.9-7.3; endometrioid 6.5, 95% CI 4.7-9.0). The strongest associations were observed among women who were continually overweight from the age of 20 (all subtypes OR 3.6, 95% CI 2.6-5.0). Weight cycling was associated with increased risk, particularly among women who had ever been obese (OR 2.9 95% CI 1.8-4.7), with ~3-fold risks seen for both endometrioid and non-endometrioid tumour subtypes. Women who had intentionally lost weight and maintained that weight loss were not at increased risk. CONCLUSION These results suggest that higher adult weight gain, and perhaps weight cycling, independently increase the risk of endometrial cancer, however women who lost weight and kept that weight off were not at increased risk.

Concordance, Variance, and Outliers in 4 Contemporary Cardiac Troponin Assays: Implications for Harmonization

BACKGROUND Data to standardize and harmonize the differences between cardiac troponin assays are needed to support their universal status in diagnosis of myocardial infarction. We characterized the variation between methods, the comparability of the 99th-percentile cutoff thresholds, and the occurrence of outliers in 4 cardiac troponin assays. METHODS Cardiac troponin was measured in duplicate in 2358 patient samples on 4 platforms: Abbott Architect i2000SR, Beckman Coulter Access2, Roche Cobas e601, and Siemens ADVIA Centaur XP. RESULTS The observed total variances between the 3 cardiac troponin I (cTnI) methods and between the cTnI and cardiac troponin T (cTnT) methods were larger than expected from the analytical imprecision (3.0%-3.7%). The between-method variations of 26% between cTnI assays and 127% between cTnI and cTnT assays were the dominant contributors to total variances. The misclassification of results according to the 99th percentile was 3%-4% between cTnI assays and 15%-17% between cTnI and cTnT. The Roche cTnT assay identified 49% more samples as positive than the Abbott cTnI. Outliers between methods were detected in 1 patient (0.06%) with Abbott, 8 (0.45%) with Beckman Coulter, 10 (0.56%) with Roche, and 3 (0.17%) with Siemens. CONCLUSIONS The universal definition of myocardial infarction should not depend on the choice of analyte or analyzer, and the between- and within-method differences described here need to be considered in the application of cardiac troponin in this respect. The variation between methods that cannot be explained by analytical imprecision and the discordant classification of results according to the respective 99th percentiles should be addressed.

Outliers as a Cause of False Cardiac Troponin Results:Investigating the Robustness of 4 Contemporary Assays

BACKGROUND It is important that cardiac troponin be measured accurately with a robust method to limit false results with potentially adverse clinical outcomes. In this study, we characterized the robustness of 4 analytical platforms by measuring the outlier rate between duplicate results. METHODS We measured cardiac troponin concurrently in duplicate with 4 analyzers on 2391 samples. The outliers were detected from the difference between duplicate results and by calculating a z value: z = (result 1 - result 2) ÷ √(SD1(est)² + SD2(est)²), with z > 3.48 identifying outliers with a probability of 0.0005. RESULTS The outlier rates were as follows: Abbott Architect i2000SR STAT Troponin-I, 0.10% (0.01%-0.19%); Beckman Coulter Access2 Enhanced AccuTnI, 0.44% (0.25%-0.63%); Roche Cobas e601 TroponinT hs, 0.06% (0.00%-0.13%); and Siemens ADVIA Centaur XP TnI-Ultra, 0.10% (0.01%-0.19%). The occurrence of outliers was higher than statistically expected on all platforms except the Cobas e601 (χ² = 2.7; P = 0.10). A conservative approach with a constant 10% CV and z > 5.0 identified outliers with clear clinical impact and resulted in outlier rates of 0.11% (0.02%-0.20%) with the Architect i2000SR STAT Troponin-I, 0.36% (0.19%-0.53%) with the Access2 Enhanced AccuTnI, 0.02% (0.00%-0.06%) with the Cobas e601 TroponinT hs, and 0.06% (0.00%-0.13%) with the ADVIA Centaur XP TnI-Ultra. CONCLUSIONS Outliers occurred on all analytical platforms, at different rates. Clinicians should be made aware by their laboratory colleagues of the existence of outliers and the rate at which they occur.

Piperaquine Monotherapy of Drug-Susceptible Plasmodium falciparum Infection Results in Rapid Clearance of Parasitemia but Is Followed by the Appearance of Gametocytemia

Background. Piperaquine, coformulated with dihydroartemisinin, is a component of a widely used artemisinin combination therapy. There is a paucity of data on its antimalarial activity as a single agent. Such data, if available, would inform selection of new coformulations. Methods. We undertook a study in healthy subjects, using the induced blood stage malaria (IBSM) model to test the antimalarial activity of single doses of piperaquine (960, 640, and 480 mg) in 3 cohorts. In a pilot study in the third cohort, gametocyte clearance following administration of 15 mg, or 45 mg or no primaquine was investigated. Results. Parasite clearance over the 48-hour period after piperaquine administration was more rapid in the 960 mg cohort, compared with the 640 mg cohort (parasite reduction ratio, 2951 [95% confidence interval {CI}, 1520–5728] vs 586 [95% CI, 351–978]; P < .001). All 24 subjects developed gametocytemia as determined by pfs25 transcripts. Clearance of pfs25 was significantly faster in those receiving primaquine than in those not receiving primaquine (P < .001). Conclusions. Piperaquine possesses rapid parasite-clearing activity, but monotherapy is followed by the appearance of gametocytemia, which could facilitate the spread of malaria. This new information should be taken into account when developing future antimalarial coformulations. Clinical Trials Registration ACTRN12613000565741.

Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study

Summary Background DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Methods Healthy participants aged 18–55 years were enrolled in a two-part study: part 1, a single ascending dose (25–1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). Findings In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42–1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17–2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7–10·2) and 6·2 h (5·7–6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552–1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001). Interpretation The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. Funding Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.