5728 research outputs found
Sort by
Tumour reoxygenation after intratumoural hydrogen peroxide (KORTUC) injection: a novel approach to enhance radiosensitivity.
No full textBACKGROUND: KORTUC (0.5% hydrogen peroxide (H2O2) in 1% sodium-hyaluronate) releases cytotoxic levels of H2O2 in tissues after intratumoural injection. High levels of tumour control after radiotherapy plus KORTUC are reported in breast cancer patients. Here, we use human xenograft models to test the hypothesis that oxygen microbubbles released post-KORTUC are effective in modifying the hypoxic tumour microenvironment. METHODS AND MATERIALS: Pimonidazole and Image-iT™ Red (live hypoxia marker) were utilised to assess dose-dependent changes in hypoxia post-H2O2 in HCT116 and LICR-LON-HN5 spheroids. Using a dual 2-nitroimidazole-marker technique and phospho-ATM we evaluated changes in hypoxia and reactive oxygen species (ROS) respectively, in HCT116 and LICR-LON-HN5 xenografts following intratumoural KORTUC. RESULTS: A significant reduction in Image-iT™ Red fluorescence was observed in spheroids 1 h post-H2O2 at ≥1.2 mM, maintained at 24 h. Ultrasound demonstrated sustained release of oxygen microbubbles within tumours, 1 h post-KORTUC. Hypoxia markers demonstrated significant tissue reoxygenation in both models post-KORTUC and significantly increased phospho-ATM foci reflecting increased ROS production. CONCLUSION: Intratumoural KORTUC represents a novel oxygen delivery method, which can be exploited to enhance radiation response. If efficacy is confirmed in the ongoing phase 2 breast trial it could improve treatment of several tumour types where hypoxia is known to affect radiotherapy outcomes
Evaluation of simultaneous multi-slice acquisition with advanced processing for free-breathing diffusion-weighted imaging in patients with liver metastasis.
No full textOBJECTIVES: Diffusion-weighted imaging (DWI) with simultaneous multi-slice (SMS) acquisition and advanced processing can accelerate acquisition time and improve MR image quality. This study evaluated the image quality and apparent diffusion coefficient (ADC) measurements of free-breathing DWI acquired from patients with liver metastases using a prototype SMS-DWI acquisition (with/without an advanced processing option) and conventional DWI. METHODS: Four DWI schemes were compared in a pilot 5-patient cohort; three DWI schemes were further assessed in a 24-patient cohort. Two readers scored image quality of all b-value images and ADC maps across the three methods. ADC measurements were performed, for all three methods, in left and right liver parenchyma, spleen, and liver metastases. The Friedman non-parametric test (post-hoc Wilcoxon test with Bonferroni correction) was used to compare image quality scoring; t-test was used for ADC comparisons. RESULTS: SMS-DWI was faster (by 24%) than conventional DWI. Both readers scored the SMS-DWI with advanced processing as having the best image quality for highest b-value images (b750) and ADC maps; Cohen's kappa inter-reader agreement was 0.6 for b750 image and 0.56 for ADC maps. The prototype SMS-DWI sequence with advanced processing allowed a better visualization of the left lobe of the liver. ADC measured in liver parenchyma, spleen, and liver metastases using the SMS-DWI with advanced processing option showed lower values than those derived from the SMS-DWI method alone (t-test, p < 0.0001; p < 0.0001; p = 0.002). CONCLUSIONS: Free-breathing SMS-DWI with advanced processing was faster and demonstrated better image quality versus a conventional DWI protocol in liver patients. CLINICAL RELEVANCE STATEMENT: Free-breathing simultaneous multi-slice- diffusion-weighted imaging (DWI) with advanced processing was faster and demonstrated better image quality versus a conventional DWI protocol in liver patients. KEY POINTS: • Diffusion-weighted imaging (DWI) with simultaneous multi-slice (SMS) can accelerate acquisition time and improve image quality. • Apparent diffusion coefficients (ADC) measured in liver parenchyma, spleen, and liver metastases using the simultaneous multi-slice DWI with advanced processing were significantly lower than those derived from the simultaneous multi-slice DWI method alone. • Simultaneous multi-slice DWI sequence with inline advanced processing was faster and demonstrated better image quality in liver patients
Anaplastic lymphoma kinase-positive pulmonary inflammatory myofibroblastic tumour: a case report.
No full textBACKGROUND: Pulmonary inflammatory myofibroblastic tumour (IMT) is a rare condition that usually presents in young individuals and is associated with anaplastic lymphoma kinase (ALK)-translocation. CASE PRESENTATION: We report a case of an 18-year-old Caucasian man with ALK-translocated pulmonary IMT treated with multimodality therapy. The patient presented with breathlessness and was found to have a collapsed left lung. Further investigations revealed an ALK-translocated pulmonary IMT. This is usually treated with an ALK-inhibitor but patient declined after discussing potential side-effects and had repeated rigid bronchoscopic interventions for local disease control. Due to persistent local recurrence, patient received radical external beam radiotherapy (EBRT) with pulse steroids, and one year later started on Ibuprofen, a non-steroidal anti-inflammatory agent (NSAID). Following multimodality treatment, he developed a complete response. He remains treatment-free for the past seven years. Eleven years on from his diagnosis, he remains in remission with a ECOG performance status of zero. CONCLUSIONS: Achieving long-term local control in pulmonary IMT can be challenging. Multimodality treatment is sometimes needed but the overall outlook remains good
Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.
No full textBACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895)
Stereotactic Body Radiotherapy (SBRT) to Localised Prostate Cancer in the Era of MRI-Guided Adaptive Radiotherapy: Doses Delivered in the HERMES Trial Comparing Two- and Five-Fraction Treatments.
No full textHERMES is a phase II trial of MRI-guided daily-adaptive radiotherapy (MRIgART) randomising men with localised prostate cancer to either 2-fractions of SBRT with a boost to the tumour or 5-fraction SBRT. In the context of this highly innovative regime the dose delivered must be carefully considered. The first ten patients recruited to HERMES were analysed in order to establish the dose received by the targets and organs at risk (OARS) in the context of intrafraction motion. A regression analysis was performed to measure how the volume of air within the rectum might further impact rectal dose secondary to the electron return effect (ERE). One hundred percent of CTV target objectives were achieved on the MRI taken prior to beam-on-time. The post-delivery MRI showed that high-dose CTV coverage was achieved in 90% of sub-fractions (each fraction is delivered in two sub-fractions) in the 2-fraction cohort and in 88% of fractions the 5-fraction cohort. Rectal D1 cm3 was the most exceeded constraint; three patients exceeded the D1 cm3 < 20.8 Gy in the 2-fraction cohort and one patient exceeded the D1 cm3 < 36 Gy in the 5-fraction cohort. The volume of rectal gas within 1 cm of the prostate was directly proportional to the increase in rectal D1 cm3, with a strong (R = 0.69) and very strong (R = 0.90) correlation in the 2-fraction and 5-fraction cohort respectively. Dose delivery specified in HERMES is feasible, although for some patients delivered doses to both target and OARs may vary from those planned
m6a methylation orchestrates IMP1 regulation of microtubules during human neuronal differentiation.
No full textNeuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate gene expression programs shaping neuronal morphology are poorly understood. To address this, we studied how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the human neuronal differentiation. We perform a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we show that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity
Structure and molecular function of the SIN3B HDAC complex in gene expression programs of cell cycle exit
No full textIn multicellular organisms, the vast majority of cells contain the same underlying DNA that is intricately packaged around histone proteins, forming organised chromatin structures. Epigenetic regulation enables gene expression control without altering the underlying DNA sequence and involves the molecular modification of DNA and histones to enable cells to adapt and fine-tune their gene expression programs to environmental cues and developmental signals. Modifications on histone tails, such as acetylation and methylation, results in the activation or repression of genes. Acetylation of lysine residues on histone tails activates transcription by weakening histone-DNA interactions. To reverse this process, acetyl groups can be removed by histone deacetylases (HDACs) which often exist in multi-subunit complexes, such as the mammalian SIN3B complex. Depletion of SIN3B inhibits the ability of proliferating cells to exit the cell cycle, leading to uncontrolled growth and division of cells, and thus, cancer. Furthermore, several lines of evidence suggest that the SIN3B complex is recruited to promoters of cell cycle genes by DREAM complex, a key regulator of cell cycle-dependent transcription. Given the significant roles that HDACs play, they are drug targets. However, structural information of holo-HDAC complexes, including the SIN3B complex, has been lacking.In this thesis, I aim to elucidate the mechanism of assembly, activation, and substrate selection of the human SIN3B complex. Furthermore, another aim is to understand how the SIN3B complex interacts with the DREAM complexes. Reported here are the first high-resolution structures of the full-length human SIN3B-HDAC complex by cryo-electron microscopy. We identify a novel mechanism of activation of class I HDACs and show that the PHD finger of the SIN3B histone recognition module recruits the histone tail and is responsible for substrate specificity. The SIN3B complex can deacetylate lysine residues on H3 tails from H3K14ac onwards, but not H3K9ac. Collectively, these findings may inform more specific and effective anti-cancer drugs and improve our understanding of the role of SIN3B in cell cycle regulation
Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma.
No full textBACKGROUND: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). METHODS: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. RESULTS: Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48-1.72) and 0.69 (0.39-1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. CONCLUSIONS: bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159
Ruxolitinib versus best available therapy for PV intolerant or resistant to Hydroxycarbamide a randomised trial
No full textMosquito control exposures and breast cancer risk: analysis of 1071 cases and 2096 controls from the Ghana Breast Health Study.
No full textEpidemiologic data on insecticide exposures and breast cancer risk are inconclusive and mostly from high-income countries. Using data from 1071 invasive pathologically confirmed breast cancer cases and 2096 controls from the Ghana Breast Health Study conducted from 2013 to 2015, we investigated associations with mosquito control products to reduce the spread of mosquito-borne diseases, such as malaria. These mosquito control products were insecticide-treated nets, mosquito coils, repellent room sprays, and skin creams for personal protection against mosquitos. Multivariable and polytomous logistic regression models were used to estimate odds ratios (ORadj) and 95% confidence intervals (CI) with breast cancer risk-adjusted for potential confounders and known risk factors. Among controls, the reported use of mosquito control products were mosquito coils (65%), followed by insecticide-treated nets (56%), repellent room sprays (53%), and repellent skin creams (15%). Compared to a referent group of participants unexposed to mosquito control products, there was no significant association between breast cancer risk and mosquito coils. There was an association in breast cancer risk with reported use of insecticide-treated nets; however, that association was weak and not statistically significant. Participants who reported using repellent sprays were at elevated risks compared to women who did not use any mosquito control products, even after adjustment for all other mosquito control products (OR = 1.42, 95% CI=1.15-1.75). We had limited power to detect an association with repellent skin creams. Although only a few participants reported using repellent room sprays weekly/daily or 0.25). Our analysis was limited when determining if an association existed with repellent skin creams; therefore, we cannot conclude an association. We found limited evidence of risk associations with widely used mosquito coils and insecticide-treated nets, which are reassuring given their importance for malaria prevention. Our findings regarding specific breast cancer risk associations, specifically those observed between repellent sprays, require further study