29 research outputs found
Class solutions for SABR-VMAT for high-risk prostate cancer with and without elective nodal irradiation
BACKGROUND: The purpose of this study is to find the optimal planning settings for prostate SABR-VMAT for high-risk prostate cancer patients irradiated to prostate only (PO) or prostate and pelvic lymph nodes (PPLN). METHODS: For 10 patients, plans using 6MV flattened, flattening-filter-free (FFF) 6MV (6 F) and FFF 10MV (10 F) photon beams with full and partial arc arrangements were generated and compared. The prescribed dose was 40Gy to the prostate with 25Gy to the PLN in 5 fractions. Plans were then evaluated for PTV coverage, dose fall-off, and OAR doses. The number of monitor units and the treatment delivery times were also compared. Statistical differences were evaluated using a paired sample Wilcoxon signed rank test with a significance level of 0.05%. RESULTS: A total of 150 plans were generated for this study. Acceptable PO plans were obtained using single arcs, while two arcs were necessary for PPLN. All plans were highly conformal (CI ≥1.3 and CN ≥0.90) with no significant differences in the PTV dose coverage. 6MV plans required significantly longer treatment time and had higher dose spillage compared to FFF plans. Superior plans were obtained using 10 F 300° partial arcs for PO with the lowest rectal dose, dose spillage and the shortest treatment times. For PPLN, 6 F and 10 F plans were equivalent. CONCLUSIONS: SABR-VMAT with FFF photon beams offers a clear benefit with respect to shorter treatment delivery times and reduced dose spillage. Class solutions using a single 10 F 300° arc for PO and two 10 F or 6 F partial 300° arcs for PPLN are proposed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-016-0730-7) contains supplementary material, which is available to authorized users
Prostate cancer treated with brachytherapy; an exploratory study of dose-dependent biomarkers and quality of life
BACKGROUND: Low-dose-rate permanent prostate brachytherapy (PPB) is an attractive treatment option for patients with localised prostate cancer with excellent outcomes. As standard CT-based post-implant dosimetry often correlates poorly with late treatment-related toxicity, this exploratory (proof of concept) study was conducted to investigate correlations between radiation − induced DNA damage biomarker levels, and acute and late bowel, urinary, and sexual toxicity. METHODS: Twelve patients treated with (125)I PPB monotherapy (145Gy) for prostate cancer were included in this prospective study. Post-implant CT based dosimetry assessed the minimum dose encompassing 90% (D(90%)) of the whole prostate volume (global), sub-regions of the prostate (12 sectors) and the near maximum doses (D(0.1cc), D(2cc)) for the rectum and bladder. Six blood samples were collected from each patient; pre-treatment, 1 h (h), 4 h, 24 h post-implant, at 4 weeks (w) and at 3 months (m). DNA double strand breaks were investigated by staining the blood samples with immunofluorescence antibodies to γH2AX and 53BP1 proteins (γH2AX/53BP1). Patient self-scored quality of life from the Expanded Prostate Cancer Index Composite (EPIC) were obtained at baseline, 1 m, 3 m, 6 m, 9 m, 1 year (y), 2y and 3y post-treatment. Spearman’s correlation coefficients were used to evaluate correlations between temporal changes in γH2AX/53BP1, dose and toxicity. RESULTS: The minimum follow up was 2 years. Population mean prostate D(90%) was 144.6 ± 12.1 Gy and rectal near maximum dose D(0.1cc) = 153.0 ± 30.8 Gy and D(2cc) = 62.7 ± 12.1 Gy and for the bladder D(0.1cc) = 123.1 ± 27.0 Gy and D(2cc) = 70.9 ± 11.9 Gy. Changes in EPIC scores from baseline showed high positive correlation between acute toxicity and late toxicity for both urinary and bowel symptoms. Increased production of γH2AX/53BP1 at 24 h relative to baseline positively correlated with late bowel symptoms. Overall, no correlations were observed between dose metrics (prostate global or sector doses) and γH2AX/53BP1 foci counts. CONCLUSIONS: Our results show that a prompt increase in γH2AX/53BP1foci at 24 h post-implant relative to baseline may be a useful measure to assess elevated risk of late RT − related toxicities for PPB patients. A subsequent investigation recruiting a larger cohort of patients is warranted to verify our findings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-017-0792-1) contains supplementary material, which is available to authorized users
Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant
Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity
Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups
IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p<0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID.ConclusionIn conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted
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Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2
Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating
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Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission
Funder: Addenbrooke's Charitable Trust, Cambridge University Hospitals; FundRef: http://dx.doi.org/10.13039/501100002927Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real-time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 12/30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19)>7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff
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Single-cell multi-omics analysis of the immune response in COVID-19
Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255Funder: University College London, Birkbeck MRC Doctoral Training ProgrammeFunder: The Jikei University School of MedicineFunder: Action Medical Research (GN2779)Funder: NIHR Clinical Lectureship (CL-2017-01-004)Funder: NIHR (ACF-2018-01-004) and the BMA FoundationFunder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194)Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944)Funder: Barbour FoundationFunder: ERC Consolidator and EU MRG-Grammar awardsFunder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002)Funder: European Molecular Biology Laboratory (EMBL)Abstract: Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion
Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era
Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial
Background
Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.
Methods
RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and
ClinicalTrials.gov
,
NCT00541047
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Findings
Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.
Interpretation
Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.
Funding
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society