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Hypoxia is a common characteristic of solid tumors, including non-small cell lung cancer (NSCLC). Hypoxia is associated with increased resistance to cell death, thus rendering it resistant to standard cancer treatment such as radiotherapy and chemotherapy. Surgical intervention is the primary approach of treatment for NSCLC patients in whom tumor is resectable. However, whether baseline tumour hypoxia affects overall survival and disease progression of patients with NSCLC following surgical management remains unclear. The hypothesis of this retrospective study is that surgical outcomes are worse with the presence of baseline hypoxia, as measured by radiotracer fluoromisonidazole (F-MISO) uptake detected by hypoxia-positron emission tomography/computed tomography (PET-CT), in NSCLC patients who underwent surgical resection during the ATOM trial (NCT02628080) at a single institution. We only selected participants from the ATOM trial who did not receive atovaquone prior to surgical intervention. We then extracted data such as patient demographics, stage of cancer at time of surgery, presence of baseline hypoxia (defined as tumor-to-blood ratio (TBR) 1.4 greater than 1.5 mL), overall survival (OS) at 1 and 3 years, and 1-year progression free survival (PFS). Kaplan-Meier survival analysis for time from surgery to death was compared between patients with or without baseline hypoxia and the p-value was calculated with log-rank test. A total of 26 trial participants from the ATOM study were included in this analysis. The majority were male (n = 19, 73.1%), with a mean age of 69.3 years. Three, ten, four, and nine patients were in stages 1-4 NSCLC, respectively. Fourteen patients had baseline hypoxia whilst 12 patients did not. The 1- and 3-year OS for patients with baseline hypoxia were 86% and 71%, respectively. For those without baseline hypoxia, OS at 1 and 3 years were 92% and 83%, respectively. One-year PFS for patients with baseline hypoxia was 55%; those without hypoxia had 1-year PFS of 80%. Using Kaplan-Meier analysis, there was no statistically significant difference when comparing both groups (p = 0.63). Patients with baseline hypoxia tend to have worse surgical outcomes compared to those without baseline hypoxia. However, the Kaplan Meier survival analysis demonstrated that the difference in survival is not statistically significant. A larger sample size from multi-center studies in the future is warranted to investigate this further. [ABSTRACT FROM AUTHOR]

The paper covers the research on the process of solutionizing of 7075 aluminum alloy in cold tools during the stamping of a high-strength structural element (B-pillar's base). For technological reasons, in order to obtain high strength parameters of the 7075 alloy, it is necessary to carry out a solutionization process, which allows to obtain dispersion strengthening during ageing process. Properly performed heat treatment of the alloy increases the strength of the material to approx. 600 MPa. The combination of the process of solutionization with simultaneous shaping is aimed at improving and simplifying technological operations of aluminum alloy stamping, shortening the duration of the manufacturing process and reducing production costs. The manufactured lower part of the B-pillar will be used for the verification of the validity of the developed method. During the experiment, a series of stamping tests were carried out, in which the lubricants, pressure and position of the upper and lower blankholders were the variables. The obtained results allow to estimate the influence of the cooling conditions on the strength of the drawpieces obtained after the process of artificial ageing. In order to verify and analyse the results more quickly, a numerical simulation was carried out. [ABSTRACT FROM AUTHOR]

This article addresses manufacturing structures made via injection molding from biodegradable materials. The mentioned structures can be successfully used as energy-absorbing liners of all kinds of sports helmets, replacing the previously used expanded polystyrene. This paper is focused on injection technological tests and tensile tests (in quasi-static and dynamic conditions) of several composites based on a PLA matrix with the addition of other biodegradable softening agents, such as PBAT and TPS (the blends were prepared via melt blending using a screw extruder with mass compositions of 50:50, 30:70, and 15:85). Tensile tests showed a positive strain rate sensitivity of the mixtures and a dependence of the increase in the ratio of the dynamic to static yield stress on the increase in the share of the plastic component in the mixture. Technological tests showed that increasing the amount of the plasticizing additive by 35% (from 50% to 85%) results in a decrease in the minimal thickness of the thin-walled element that can be successfully injection molded by about 32% in the case of PLA/PBAT blends (from 0.22 mm to 0.15 mm) and by about 26% in the case of PLA/TPS blends (from 0.23 mm to 0.17 mm). Next, the thin-walled elements (dimensions of 55 × 55 × 20 mm) were manufactured and evaluated using a spring-loaded drop hammer. The 60 J impact energy was tested in accordance with the EN 1078 standard. The dynamic crushing test included checking the influence of the materials' temperature (-20, 0, 20, and 40 °C) and the impact velocity. It was proven that the maximum deflection increases with increasing material temperature and an increase in the share of the plastic component in the mixture. The PLA15PBAT85 blend was selected as the most effective material in terms of its use as an energy-absorbing liner for sport helmets. Johnson-Cook and Cowper-Symonds material plasticizing models were constructed. Their use during dynamic FE simulation provided results that were in good agreement with those of the conducted experiment.

Background: Stage IIIA-N2 non-small cell lung cancer (NSCLC) poses a significant clinical challenge, with low survival rates despite advances in therapy. The lack of a standardised treatment approach complicates patient management. This study utilises real-world data from Guy's Thoracic Cancer Database to analyse patient outcomes, identify key predictors of overall survival (OS) and disease-free survival (DFS), and address the limitations of randomised controlled trials., Methods: This observational, single-centre, non-randomised study analysed 142 patients diagnosed with clinical and pathological T1/2 N2 NSCLC who received curative treatment from 2015 to 2021. Patients were categorised into three groups: Group A (30 patients) underwent surgery for clinical N2 disease, Group B (54 patients) had unsuspected N2 disease discovered during surgery, and Group C (58 patients) received radical chemoradiation or radiotherapy alone (CRT/RT) for clinical N2 disease. Data on demographics, treatment types, recurrence, and survival rates were analysed., Results: The median OS for the cohort was 31 months, with 2-year and 5-year OS rates of 60% and 30%, respectively. Group A had a median OS of 32 months, Group B 36 months, and Group C 25 months. The median DFS was 18 months overall, with Group A at 16 months, Group B at 22 months, and Group C at 17 months. Significant predictors of OS included ECOG performance status, lymphovascular invasion, and histology. No significant differences in OS were found between treatment groups ( p = 0.99)., Conclusions: This study highlights the complexity and diversity of Stage IIIA-N2 NSCLC, with no single superior treatment strategy identified. The findings underscore the necessity for personalised treatment approaches and multidisciplinary decision-making. Future research should focus on integrating newer therapeutic modalities and conducting multi-centre trials to refine treatment strategies. Collaboration and ongoing data collection are crucial for improving personalised treatment plans and survival outcomes for Stage IIIA-N2 NSCLC patients.

Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is of interest to help develop novel hypoxia modifiers and guide radiation treatment planning. Yet, the optimal post-injection (p.i.) timing of hypoxic imaging remains questionable. Therefore, we investigated the correlation between hypoxia-related quantitative values in FMISO-PET acquired at 2 and 4 h p.i. in patients with non-small cell lung cancer (NSCLC). Patients with resectable NSCLC participated in the ATOM clinical trial (NCT02628080) which investigated the hypoxia modifying effects of atovaquone. Two-hour and four-hour FMISO PET/CT images acquired at baseline and pre-surgery visits (n = 58) were compared. Cohort 1 (n = 14) received atovaquone treatment, while cohort 2 (n = 15) did not. Spearman's rank correlation coefficients (ρ) assessed the relationship between hypoxia-related metrics, including standardised uptake value (SUV), tumour-to-blood ratio (TBR), and tumour hypoxic volume (HV) defined by voxels with TBR ≥ 1.4. As the primary imaging-related trial endpoint used to evaluate the action of atovaquone on tumour hypoxia in patients with NSCLC was change in tumour HV from baseline, this was also assessed in patients (n = 20) with sufficient baseline 2- and 4-h scan HV to reliably measure change (predefined as ≥ 1.5 mL). Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. In tumours overall, strong correlation (P < 0.001) was observed for SUV max ρ = 0.87, SUV mean ρ = 0.91, TBR max ρ = 0.83 and TBR mean ρ = 0.81 between 2- and 4-h scans. Tumour HV was moderately correlated (P < 0.001) with ρ = 0.69 between 2- and 4-h scans. Yet, in tumour subregions, the correlation of HV decreased from the centre ρ = 0.71 to the edge ρ = 0.45 (P < 0.001). SUV, TBR, and HV values were consistently higher on 4-h scans than on 2-h scans, indicating better tracer-to-background contrast. For instance, for TBR max , the mean, median, and interquartile range were 1.9, 1.7, and 1.6-2.0 2-h p.i., and 2.6, 2.4, and 2.0-3.0 4-h p.i., respectively. Our results support that FMISO-PET scans should be performed at 4 h p.i. to evaluate tumour hypoxia in NSCLC.Trial registration: ClinicalTrials.gov, NCT02628080. Registered 11/12/2015, https://clinicaltrials.gov/ct2/show/NCT02628080 ., (© 2022. The Author(s).)

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/NCT02628080., (© 2021. The Author(s).)

Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC)., Patients and Methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed., Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 ( P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported., Conclusions: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC., (©2021 American Association for Cancer Research.)

Background: Pre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia., Methods: This was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18 F-fluoromisonidazole positron-emission tomography-computed tomography at baseline and following 1 week of buparlisib., Results: Twenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD., Conclusion: This is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Tumour hypoxia is a well-recognised barrier to anti-cancer therapy and represents one of the best validated targets in oncology. Previous attempts to tackle hypoxia have focussed primarily on increasing tumour oxygen supply; however, clinical studies using this approach have yielded only modest clinical benefit, with often significant toxicity and practical limitations. Therefore, there are currently no anti-hypoxia treatments in widespread clinical use. As an emerging alternative strategy, we discuss the relevance of inhibiting tumour oxygen metabolism to alleviate hypoxia and highlight recently initiated clinical trials using this approach.

Background: To determine the relative abilities of compartment models to describe time-courses of 18F-fluoromisonidazole (FMISO) tumor uptake in patients with advanced stage non-small cell lung cancer (NSCLC) imaged using dynamic positron emission tomography (dPET), and study correlations between values of the blood flow-related parameter K 1 obtained from fits of the models and an independent blood flow measure obtained from perfusion CT (pCT). NSCLC patients had a 45-min dynamic FMISO PET/CT scan followed by two static PET/CT acquisitions at 2 and 4-h post-injection. Perfusion CT scanning was then performed consisting of a 45-s cine CT. Reversible and irreversible two-, three- and four-tissue compartment models were fitted to 30 time-activity-curves (TACs) obtained for 15 whole tumor structures in 9 patients, each imaged twice. Descriptions of the TACs provided by the models were compared using the Akaike and Bayesian information criteria (AIC and BIC) and leave-one-out cross-validation. The precision with which fitted model parameters estimated ground-truth uptake kinetics was determined using statistical simulation techniques. Blood flow from pCT was correlated with K 1 from PET kinetic models in addition to FMISO uptake levels., Results: An irreversible three-tissue compartment model provided the best description of whole tumor FMISO uptake time-courses according to AIC, BIC, and cross-validation scores totaled across the TACs. The simulation study indicated that this model also provided more precise estimates of FMISO uptake kinetics than other two- and three-tissue models. The K 1 values obtained from fits of the irreversible three-tissue model correlated strongly with independent blood flow measurements obtained from pCT (Pearson r coefficient = 0.81). The correlation from the irreversible three-tissue model (r = 0.81) was stronger than that from than K 1 values obtained from fits of a two-tissue compartment model (r = 0.68), or FMISO uptake levels in static images taken at time-points from tracer injection through to 4 h later (maximum at 2 min, r = 0.70)., Conclusions: Time-courses of whole tumor FMISO uptake by advanced stage NSCLC are described best by an irreversible three-tissue compartment model. The K 1 values obtained from fits of the irreversible three-tissue model correlated strongly with independent blood flow measurements obtained from perfusion CT (r = 0.81).