Investigating the Potential Impact of Four-dimensional Computed Tomography (4DCT) on Toxicity, Outcomes and Dose Escalation for Radical Lung Cancer Radiotherapy

AIMS: To investigate the potential dosimetric and clinical benefits predicted by using four-dimensional computed tomography (4DCT) compared with 3DCT in the planning of radical radiotherapy for non-small cell lung cancer.

MATERIALS AND METHODS:
Twenty patients were planned using free breathing 4DCT then retrospectively delineated on three-dimensional helical scan sets (3DCT). Beam arrangement and total dose (55 Gy in 20 fractions) were matched for 3D and 4D plans. Plans were compared for differences in planning target volume (PTV) geometrics and normal tissue complication probability (NTCP) for organs at risk using dose volume histograms. Tumour control probability and NTCP were modelled using the Lyman-Kutcher-Burman (LKB) model. This was compared with a predictive clinical algorithm (Maastro), which is based on patient characteristics, including: age, performance status, smoking history, lung function, tumour staging and concomitant chemotherapy, to predict survival and toxicity outcomes. Potential therapeutic gains were investigated by applying isotoxic dose escalation to both plans using constraints for mean lung dose (18 Gy), oesophageal maximum (70 Gy) and spinal cord maximum (48 Gy).

RESULTS:
4DCT based plans had lower PTV volumes, a lower dose to organs at risk and lower predicted NTCP rates on LKB modelling (P < 0.006). The clinical algorithm showed no difference for predicted 2-year survival and dyspnoea rates between the groups, but did predict for lower oesophageal toxicity with 4DCT plans (P = 0.001). There was no correlation between LKB modelling and the clinical algorithm for lung toxicity or survival. Dose escalation was possible in 15/20 cases, with a mean increase in dose by a factor of 1.19 (10.45 Gy) using 4DCT compared with 3DCT plans.

CONCLUSIONS:
4DCT can theoretically improve therapeutic ratio and dose escalation based on dosimetric parameters and mathematical modelling. However, when individual characteristics are incorporated, this gain may be less evident in terms of survival and dyspnoea rates. 4DCT allows potential for isotoxic dose escalation, which may lead to improved local control and better overall survival.

Immune complex formation in human diabetic retina enhances toxicity of oxidized LDL towards retinal capillary pericytes

Recently it has been shown that levels of circulating oxidized LDL immune complexes (ox-LDL-IC) predict the development of diabetic retinopathy (DR). This study aimed to investigate whether ox-LDL-IC are actually present in the diabetic retina, and to define their effects on human retinal pericytes vs. ox-LDL. In retinal sections from people with type 2 diabetes, co-staining for ox-LDL and IgG was present, proportionate to DR severity, and detectable even in the absence of clinical DR. In contrast, no such staining was observed in retinas from non-diabetic subjects. In vitro, human retinal pericytes were treated with native (N-) LDL, ox-LDL, and ox-LDL-IC (0-200 mg protein/l), and measures of viability, receptor expression, apoptosis, ER and oxidative stresses, and cytokine secretion were evaluated. Ox-LDL-IC exhibited greater cytotoxicity than ox-LDL towards retinal pericytes. Acting through the scavenger (CD36) and IgG (CD64) receptors, low concentrations of ox-LDL-IC triggered apoptosis mediated by oxidative and ER stresses, and enhanced inflammatory cytokine secretion. The data suggest that IC formation in the diabetic retina enhances the injurious effects of ox-LDL. These findings offer new insights into pathogenic mechanisms of DR, and may lead to new preventive measures and treatments.

Historical data reveal power-law dispersal patterns of invasive aquatic species

Understanding how invasive species spread is of particular concern in the current era of globalisation and rapid environmental change. The occurrence of super-diffusive movements within the context of Lévy flights has been discussed with respect to particle physics, human movements, microzooplankton, disease spread in global epidemiology and animal foraging behaviour. Super-diffusive movements provide a theoretical explanation for the rapid spread of organisms and disease, but their applicability to empirical data on the historic spread of organisms has rarely been tested. This study focuses on the role of long-distance dispersal in the invasion dynamics of aquatic invasive species across three contrasting areas and spatial scales: open ocean (north-east Atlantic), enclosed sea (Mediterranean) and an island environment (Ireland). Study species included five freshwater plant species, Azolla filiculoides, Elodea canadensis, Lagarosiphon major, Elodea nuttallii and Lemna minuta; and ten species of marine algae, Asparagopsis armata, Antithamnionella elegans, Antithamnionella ternifolia, Codium fragile, Colpomenia peregrina, Caulerpa taxifolia, Dasysiphonia sp., Sargassum muticum, Undaria pinnatifida and Womersleyella setacea. A simulation model is constructed to show the validity of using historical data to reconstruct dispersal kernels. Lévy movement patterns similar to those previously observed in humans and wild animals are evident in the re-constructed dispersal pattern of invasive aquatic species. Such patterns may be widespread among invasive species and could be exacerbated by further development of trade networks, human travel and environmental change. These findings have implications for our ability to predict and manage future invasions, and improve our understanding of the potential for spread of organisms including infectious diseases, plant pests and genetically modified organisms.

Gold nanoparticle cellular uptake, toxicity and radiosensitisation in hypoxic conditions

Background and purpose: Gold nanoparticles (GNPs) are novel agents that have been shown to cause radiosensitisation in vitro and in vivo. Tumour hypoxia is associated with radiation resistance and reduced survival in cancer patients. The interaction of GNPs with cells in hypoxia is explored.

Materials and methods: GNP uptake, localization, toxicity and radiosensitisation were assessed in vitro under oxic and hypoxic conditions.

Results: GNP cellular uptake was significantly lower under hypoxic than oxic conditions. A significant reduction in cell proliferation in hypoxic MDA-MB-231 breast cancer cells exposed to GNPs was observed. In these cells significant radiosensitisation occurred in normoxia and moderate hypoxia. However, in near anoxia no significant sensitisation occurred.

Conclusions: GNP uptake occurred in hypoxic conditions, causing radiosensitisation in moderate, but not extreme hypoxia in a breast cancer cell line. These findings may be important for the development of GNPs for cancer therapy.

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Mechanistic and toxicity studies of the photocatalytic oxidation of microcystin-LR

Cyanobacterial toxins present in drinking water sources pose a considerable threat to human health. Conventional water treatment systems have proven unreliable for the removal of these toxins and hence new techniques have been investigated. Previous work has shown that TiO₂ photocatalysis effectively destroys microcystin-LR in aqueous solutions, however, a variety of by-products were generated. In this paper, we report a mechanistic study of the photocatalytic destruction of microcystin-LR. In particular, the toxicity by-products of the process have been studied using both brine shrimp and protein phosphatase bioassays. 

Predictors of Chest Wall Toxicity after Lung Stereotactic Ablative Radiotherapy

AIMS: To determine the incidence and predictive factors of rib fracture and chest wall pain after lung stereotactic ablative radiotherapy (SABR).

MATERIALS AND METHODS: Patients were treated with lung SABR of 48-60 Gy in four to five fractions. The treatment plan and follow-up computed tomography scans of 289 tumours in 239 patients were reviewed. Dose-volume histogram (DVH) metrics and clinical factors were evaluated as potential predictors of chest wall toxicity.

RESULTS: The median follow-up was 21.0 months (range 6.2-52.1). Seventeen per cent (50/289) developed a rib fracture, 44% (22/50) were symptomatic; the median time to fracture was 16.4 months. On univariate analysis, female gender, osteoporosis, tumours adjacent (within 5 mm) to the chest wall and all of the chest wall DVH metrics predicted for rib fracture, but only tumour location adjacent to the chest wall remained significant on the multivariate model (P < 0.01). The 2 year fracture-free probability for those adjacent to the chest wall was 65.6%. Among those tumours adjacent to the chest wall, only osteoporosis (P = 0.02) predicted for fracture, whereas none of the chest wall DVH metrics were predictive. Eight per cent (24/289) experienced chest wall pain without fracture.

CONCLUSIONS: None of the chest wall DVH metrics independently predicted for SABR-induced rib fracture when tumour location is taken into account. Patients with tumours adjacent (within 5 mm) to the chest wall are at greater risk of rib fracture after lung SABR, and among these, an additional risk was observed in osteoporotic patients.

Alien aquatics in Europe: assessing the relative environmental and socio-economic impacts of invasive aquatic macroinvertebrates and other taxa

Invasive alien aquatic species, including marine and freshwater macroinvertebrates, have become increasingly important in terms of both environmental and socio-economic impacts. In order to assess their environmental and economic costs, we applied the Generic Impact Scoring System (GISS) and performed a comparison with other taxa of invaders in Europe. Impacts were scored into six environmental and six socio-economic categories, with each category containing five impact levels. Among 49 aquatic macroinvertebrates, the most impacting species were the Chinese mitten crab, Eriocheir sinensis (Milne-Edwards, 1853) and the zebra mussel, Dreissena polymorpha (Pallas, 1771). The highest impacts found per GISS impact category were, separately; on ecosystems, through predation, as competitors, and on animal production. Eleven species have an impact score > 10 (high impact) and seven reach impact level 5 in at least one impact category (EU blacklist candidates), the maximum score that can be given is 60 impact points. Comparisons were drawn between aquatic macroinvertebrates and vertebrate invaders such as fish, mammals and birds, as well as terrestrial arthropods, revealing invasive freshwater macroinvertebrates to be voracious predators of native prey and damaging to native ecosystems compared with other taxa. GISS can be used to compare these taxa and will aid policy making and targeting of invasive species for management by relevant agencies, or to assist in producing species blacklist candidates.

Aquatic invasive alien species – top issues for their management. Outcomes from the IFI/EIFAAC conference “Freshwater Invasives – Networking for Strategy”

In November 2014, a new EU Regulation to address Invasive Alien Species (IAS) and protect biodiversity was published. This entered into force across the EU in January 2015. The aim of the Regulation is to ‘prevent the introduction of, control or eradicate alien species which threaten ecosystems, habitats or species’. In an effort to provide focus to the Regulation prior to its publishing and to identify the major issues relating to Invasive Alien Species in Europe, the views of invasive species experts from around the world were sought. These were consolidated at an international conference (Freshwater Invasives - Networking for Strategy (FINS)) that was held in Ireland in April 2013. A major outcome from this meeting of experts was the production of the Top 20 IAS issues that relate primarily to freshwater habitats but are also directly relevant to marine and terrestrial ecosystems. This list will support policy makers throughout the EU as preparations are made to implement this important piece of legislation. A further outcome from the conference was the formation of an expert IAS Advisory Group to support EIFAAC in its work on invasive species

Biosensor based toxicity dissection of tannery and associated environmental samples

Kenyan tannery and associated environmental samples were selected for ecotoxicological assessment. A tool-kit of techniques was developed, including whole-cell biosensor and chemical assays. A luminescence based bacterial biosensor (Escherichia coli HB101 pUCD607) (via a multi-copy plasmid) was used for toxicity assessment. Samples were manipulated prior to biosensor interrogation to identify the nature of the toxic contaminants. Untreated samples (before any manipulations) showed a strong toxic effect at the discharge point in comparison to other sampling points. Sparging was used to identify toxicity associated with volatile organics. The toxicity of contaminants, removed by treatment with activated charcoal was identified for all the sampling points except for those upstream of effluent discharges. Filtration identified toxicity associated with suspended solids. Changes in availability of toxic contaminants due to pH adjustment of most samples from the tannery effluent treatment pits were also associated with the extreme pH values (4.0 and 8.0). The approach used has highlighted the complexicity of toxic pollutants in effluent from the tanning industry and the dissection of toxicity points to possible remediation strategies for effluents from the tanning industry.