Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients

Background Tumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments. Following the recent observation that the mitochondrial inhibitor atovaquone increases tumour oxygenation in NSCLC, we sought to assess whether atovaquone affects tumour subregions differently depending on their level of hypoxia. Methods Patients with resectable NSCLC participated in the ATOM trial (NCT02628080). Cohort 1 (n = 15) received atovaquone treatment, whilst cohort 2 (n = 15) did not. Hypoxia-related metrics, including change in mean tumour-to-blood ratio, tumour hypoxic volume, and fraction of hypoxic voxels, were assessed using hypoxia PET imaging. Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. Results Atovaquone-induced reduction in tumour hypoxia mostly occurred in the inner and outer tumour subregions, and to a lesser extent in the centre subregion. Atovaquone did not seem to act in the edge subregion, which was the only tumour subregion that was non-hypoxic at baseline. Notably, the most intensely hypoxic tumour voxels, and therefore the most radiobiologically resistant areas, were subject to the most pronounced decrease in hypoxia in the different subregions. Conclusions This study provides insights into the action of atovaquone in tumour subregions that help to better understand its role as a novel tumour radiosensitiser. Trial registration: ClinicalTrials.gov, NCT0262808. Registered 11th December 2015, https://clinicaltrials.gov/ct2/show/NCT0262808

Isolated Mediastinal Lymphadenopathy - Performance of EBUS-TBNA in Clinical Practice

Background Isolated mediastinal lymphadenopathy is an increasingly common finding as a result of the increasing use of cross-sectional thoracic imaging. We investigated the performance of endobronchial ultrasound-guided transbronchial needle-aspiration (EBUS-TBNA) in establishing a pathological diagnosis in patients with isolated mediastinal lymphadenopathy. Methods We retrospectively analysed all consecutive EBUS-TBNA examinations performed over a 4-year period at a single tertiary referral centre. Final diagnoses were made using pathology reports, correlated with clinical features and the results of any other investigations. Results In total, 126 EBUS-TBNA examinations were performed to investigate isolated mediastinal lymphadenopathy. A positive pathological diagnosis was made following EBUS-TBNA in 54 cases (43%). When the results of further investigations and variable radiological follow up were included, the final sensitivity of EBUS-TBNA for making a diagnosis in isolated mediastinal lymphadenopathy was 80% (95% CI 69%–89%). Conclusions This study confirms that EBUS-TBNA has acceptable sensitivity for detecting both benign and malignant pathologies underlying isolated mediastinal lymphadenopathy

Can dynamic imaging, using 18F-FDG PET/CT and CT perfusion differentiate between benign and malignant pulmonary nodules?

BACKGROUND: The aim of the study was to derive and compare metabolic parameters relating to benign and malignant pulmonary nodules using dynamic 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) PET/CT, and nodule perfusion parameters derived through perfusion computed tomography (CT). PATIENTS AND METHODS: Twenty patients with 21 pulmonary nodules incidentally detected on CT underwent a dynamic 18F-FDG PET/CT and a perfusion CT. The maximum standardized uptake value (SUVmax) was measured on conventional 18F-FDG PET/CT images. The influx constant (Ki ) was calculated from the dynamic 18F-FDG PET/CT data using Patlak model. Arterial flow (AF) using the maximum slope model and blood volume (BV) using the Patlak plot method for each nodule were calculated from the perfusion CT data. All nodules were characterized as malignant or benign based on histopathology or 2 year follow up CT. All parameters were statistically compared between the two groups using the nonparametric Mann-Whitney test. RESULTS: Twelve malignant and 9 benign lung nodules were analysed (median size 20.1 mm, 9-29 mm) in 21 patients (male/female = 11/9; mean age ± SD: 65.3 ± 7.4; age range: 50-76 years). The average SUVmax values ± SD of the benign and malignant nodules were 2.2 ± 1.7 vs. 7.0 ± 4.5, respectively (p = 0.0148). Average Ki values in benign and malignant nodules were 0.0057 ± 0.0071 and 0.0230 ± 0.0155 min-1, respectively (p = 0.0311). Average BV for the benign and malignant nodules were 11.6857 ± 6.7347 and 28.3400 ± 15.9672 ml/100 ml, respectively (p = 0.0250). Average AF for the benign and malignant nodules were 74.4571 ± 89.0321 and 89.200 ± 49.8883 ml/100g/min, respectively (p = 0.1613). CONCLUSIONS: Dynamic 18F-FDG PET/CT and perfusion CT derived blood volume had similar capability to differentiate benign from malignant lung nodules

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

An investigation into the effect of atovaquone on clinical parameters of tumour hypoxia: a window of opportunity study in patients with non-small cell lung carcinoma

In no other tumour type is the need to improve tumour radiation response more evident than in non-small cell lung cancer (NSCLC), where exceptionally poor radiotherapy outcomes are part of everyday clinical practice. As tumour hypoxia confers profound resistance to radiation, there is significant interest in developing novel hypoxia modifiers as radiosensitisers. Previous attempts to address tumour hypoxia have largely focused on improving tumour oxygen supply. However, despite decades of clinical trials combining promising agents with radiotherapy, no hypoxia modifiers are in widespread clinical use. The reasons for this include an absence of clinical studies confirming hypoxia modulation and a lack of validated methods to evaluate tumour hypoxia in order to select patients for treatment. An entirely new strategy to tackle hypoxia is to reduce tumour oxygen consumption through inhibition of oxidative phosphorylation. Recently, the commonly prescribed antimalarial drug atovaquone has been discovered as the most promising agent for this purpose. The translational research presented in this thesis represents a carefully measured approach in developing atovaquone as a clinical radiosensitiser. The first aim of this work was to design and conduct a clinical trial to confirm that atovaquone reduces tumour hypoxia in patients. The Atovaquone as a Tumour hypOxia Modifier (ATOM) trial was a ‘window of opportunity’ study in patients with resectable NSCLC and used a multitude of methods to investigate the effect of atovaquone on tumour hypoxia. These included hypoxia PET imaging with FMISO and FAZA PET-CT, perfusion CT and measurement of the endogenous plasma hypoxia markers VEGF, CAIX, OPN and miR-210. Following tumour resection, extensive tumour immunohistochemical analysis was also conducted for CAIX and for exogenous pimonidazole. In recognition of the importance of developing clinical hypoxia biomarkers, the second aim of this work was to assess the validity of the techniques used by performing correlative analysis of the numerous endpoints of this study. An exciting finding from this work was that atovaquone treatment rapidly reduced tumour hypoxia in the vast majority of patients, as measured by hypoxia PET imaging. This represents the first clinical confirmation of proof of principle not only for atovaquone as a hypoxia modifier, but also for this new approach in tackling tumour hypoxia by reducing oxygen consumption. Regarding the evaluation of hypoxia biomarkers, a lack of agreement was generally observed between endogenous hypoxia markers, as well as between such markers and hypoxia PET imaging. This highlights the well-recognised challenge of evaluating tumour hypoxia using surrogate measures. However, correlation between plasma miR-210 expression and hypoxia PET imaging was observed, thus providing provisional support that this recently discovered circulating marker may hold more promise as a clinical hypoxia biomarker in NSCLC. Given the convincing reduction in tumour hypoxia observed following atovaquone treatment in this study, a new clinical trial has been developed which will combine this agent with chemoradiotherapy in patients with NSCLC.</p

Analysis of forging tool wear with the application of a measuring arm integrated with a laser scanner

Praca dotyczy możliwości wykorzystania technik skanowania 3D do kontroli zmian geometrii warstwy wierzchniej narzędzi kuźniczych w oparciu o pomiar zmian geometrycznych odkuwek cyklicznie pobieranych z procesu. Do badań wytypowano proces kucia odkuwki pokrywy stosowanej jako uszczelniacz wału korbowego w samochodach ciężarowych. Szczegółowej analizie poddano zużywanie się narzędzia – wypełniacza, stosowanego w drugiej operacji kucia (w górnym zestawie narzędzi). Badania zostały podzielone na dwa etapy. Pierwszym etapem była analiza zużycia narzędzi na podstawie bezpośredniego skanowania ich powierzchni, a następnie opracowania krzywej zużycia – ubytku materiału w zależności od liczby odkuwek. W drugim etapie przeprowadzono skanowanie wybranej powierzchni cyklicznie pobieranych odkuwek i na tej podstawie dokonywano analizy postępującego przyrostu materiału, co jednocześnie stanowiło ubytek materiału na narzędziach. Następnie wyznaczono charakterystykę zmian geometrii odkuwek i porównano z krzywą zużycia dla narzędzi. Uzyskane analizy wykazały dużą zgodność, co wskazuje na możliwość wykorzystania pośredniej metody skanowania odwrotnego 3D (na podstawie pomiarów powierzchni odkuwek) do analizy zmian geometrii warstwy wierzchniej narzędzi kuźniczych, bez konieczności ich demontażu z agregatu kuźniczego. Zaproponowane przez autorów innowacyjne podejście do oceny aktualnego stanu narzędzia kuźniczego pozwala na podejmowanie decyzji o przedłużeniu bądź skróceniu czasu jego eksploatacji na podstawie rzeczywistego (bieżącego) zużycia, a nie na podstawie sztywno ustalonej trwałości (maksymalnej liczby wykonanych odkuwek). Wykazane w pracy wady i zalety opracowanej metody z wykorzystaniem skanowania 3D pozwalają na wydłużenie czasu eksploatacji oprzyrządowania kuźniczego, a tym samym na wymierne obniżenie kosztów produkcji.The study discusses the possibilities of the application of 3D scanning techniques to control the changes in the geometry of the forging tool surface layer on the basis of a measurement of the geometrical changes of the forgings periodically collected from the process. For the investigations, the process of producing a forging of a lid used as a crankshaft seal in motor trucks was selected. A detailed analysis was performed on the wear of the tool – a filler used in the second forging operation (in the upper tool set). The studies were divided into two stages. The first stage was an analysis of the tools’ wear based on direct scanning of their surface, followed by the elaboration of the wear curve – material loss depending on the number of forgings. The second stage involved scanning of the selected surface of the periodically collected forgings and, based on it, an analysis of the proceeding material growth, which simultaneously constituted a material loss on the tools. Next, the characteristics of the geometry change of the forgings were determined and compared with the wear curve for the tools. The obtained analyses were in a good agreement, which suggests the possibility of using the indirect method of 3D reverse scanning (based on the forging surface measurements) for the analysis of the geometry changes of the forging tool surface layer, without the necessity to disassemble the tools from the forging aggregate. The innovative approach to the assessment of the current state of a forging tool proposed by the authors makes it possible to make decisions about a prolongation or shortening of its operation time based on the actual (pre-sent) wear, rather than on the basis of a predetermined, hardcoded durability (maximal number of produced forgings). The pros and cons of the elaborated method with the use of 3D scanning presented in the paper make it possible to prolong the operation time of forging instrumentation, thus measurably lowering the production costs

Analiza i opracowanie efektywnego sposobu wstępnego nagrzewania narzędzi do kucia na gorąco

This article contains an overview of available preheating methods which are commonly used in hot forging processes. Then a comprehensive analysis of the temperature changes that occur on the surface and directly below the surface of the forging die was carried out during the preheating process. The temperature measurement was performed with fast thermal camera and a thermocouple inserted inside the tool. The temperature was measured in traditional preheating process, and its value after preheating was about 200ºC, which can be acceptable, however this process was improper, because of possibility of tempering surface layer of forging tool. That’s why new method of preheating tools in contact with heated billets was developed and detailed instructions for time and layout of billets were prepared. The tool temperature was measured also after application of new method presented in this manuscript, and it reached over 200ºC after two preheating cycles. After three cycles of preheating also good results obtained because temperature in surface layer was about 260ºC. In conclusion, method proposed by authors obtained good result, is quite efficient and prevents from tempering of forging tools. Finally, two pre-heating instructions were prepared, for the Massey 2500T press and the Massey 1300T press, which are attached at the end of the manuscript