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Researchers in the Department of Oncology have secured funding to characterise an insulin-like growth factor (IGF) signature for early detection and risk reduction of cancer.
Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.
We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.
Effect of Compression Dressing After Upper Eyelid Blepharoplasty on Edema, Ecchymosis, Pain and Ocular Surface Irritation.
PURPOSE: To investigate the effect of a compression dressing (CD) on edema, ecchymosis, aesthetic outcome, pain, and ocular surface irritation after upper eyelid blepharoplasty. METHODS: We conducted a case-control study. Bilateral blepharoplasty was performed on both upper eyelids at the same time in patients with dermatochalasis. One side was randomized for CD. Edema and ecchymosis were scored at a 4-point rating scale by a blinded observer 1 day (D1), 1 week (D7), and 8 weeks (D56) after surgery; the same for scar formation regarding redness and bulging at D7 and D56. Aesthetic outcome was evaluated by the patient and blinded observer using the global aesthetic improvement score at D1, D7, and D56. Postoperative pain was scored by the patients using a visual analogue scale (0 to 10) at D1. At D1 patients had to state which side they felt more comfortable. RESULTS: Edema, scar formation and aesthetic outcome evaluated by the patient and blinded observer did not differ between the 2 sides on any of the survey days (p > 0.05). The median degree of ecchymosis was slightly higher on the lids without CD at D1 (1 [0-2] vs. 1.5 [0-2]; p = 0.495) and D7 (0 [0-2] vs. 0.5 [0-2]; p = 0.183), but not statistically significant. Postoperative pain was similar regardless to the use of CD (p = 0.925). The majority (55%) found the side without CD more comfortable. There was no case of corneal erosion and corneal staining was similar in both groups (p > 0.05). CONCLUSIONS: Using a CD after blepharoplasty shows no advantages regarding postoperative edema, ecchymosis, scar formation, or aesthetic results in the early postoperative period. As most patients preferred the noncovered side, CD can be omitted after blepharoplasty without inferiority for the postoperative results. CLINICAL TRIAL REGISTRY: NCT06111170.
Society for Immunotherapy of Cancer (SITC) recommendations on intratumoral immunotherapy clinical trials (IICT): from premalignant to metastatic disease.
BACKGROUND: Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis. METHODS: An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript. RESULTS: The panel determined unique clinical trial designs tailored to different stages of cancer development-from premalignant to unresectable/metastatic-that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments. CONCLUSIONS: The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most.
Molecular analysis of archival diagnostic prostate cancer biopsies identifies genomic similarities in cases with progression post-radiotherapy, and those with de novo metastatic disease.
BACKGROUND: It is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin-fixed paraffin-embedded (FFPE) prostate biopsies from cohorts with post-radiotherapy (RT) long-term clinical follow-up has been limited. Utilizing parallel sequencing modalities, we performed a proof-of-principle sequencing analysis of historical diagnostic FFPE prostate biopsies. We compared patients with (i) stable PCa (sPCa) postprimary or salvage RT, (ii) progressing PCa (pPCa) post-RT, and (iii) de novo metastatic PCa (mPCa). METHODS: A cohort of 19 patients with diagnostic prostate biopsies (n = 6 sPCa, n = 5 pPCa, n = 8 mPCa) and mean 4 years 10 months follow-up (diagnosed 2009-2016) underwent nucleic acid extraction from demarcated malignancy. Samples underwent 3'RNA sequencing (3'RNAseq) (n = 19), nanoString analysis (n = 12), and Illumina 850k methylation (n = 8) sequencing. Bioinformatic analysis was performed to coherently identify differentially expressed genes and methylated genomic regions (MGRs). RESULTS: Eighteen of 19 samples provided useable 3'RNAseq data. Principal component analysis (PCA) demonstrated similar expression profiles between pPCa and mPCa cases, versus sPCa. Coherently differentially methylated probes between these groups identified ~600 differentially MGRs. The top 50 genes with increased expression in pPCa patients were associated with reduced progression-free survival post-RT (p
Differential Response of Pelvic Bone Marrow Fluorodeoxyglucose Uptake in Patients Receiving Concurrent Chemoradiotherapy.
AIMS: Irradiation of pelvic bone marrow (PBM) at the level of the typical low dose bath of intensity-modulated radiotherapy delivery (10-20 Gy) is associated with an increased risk of haematological toxicity, particularly when combined with concurrent chemotherapy. Although sparing of the whole of the PBM at a 10-20 Gy dose level is unachievable, it is known that PBM is divided into haematopoietically active and inactive regions that are identifiable based on the threshold uptake of [18F]-fluorodeoxyglucose (FDG) seen on positron emission tomography-computed tomography (PET-CT). In published studies to date, the definition of active PBM widely used is that of a standardised uptake value (SUV) greater than the mean SUV of the whole PBM prior to the start of chemoradiation. These studies include those looking at developing an atlas-based approach to contouring active PBM. Using baseline and mid-treatment FDG PET scans acquired as part of a prospective clinical trial we sought to determine the suitability of the current definition of active bone marrow as representative of differential underlying cell physiology. MATERIALS AND METHODS: Active and inactive PBM were contoured on baseline PET-CT and using deformable registration mapped onto mid-treatment PET-CT. Volumes were cropped to exclude definitive bone, voxel SUV extracted and the change between scans calculated. Change was compared using Mann-Whitney U testing. RESULTS: Active and inactive PBM were shown to respond differentially to concurrent chemoradiotherapy. The median absolute response of active PBM for all patients was -0.25 g/ml, whereas the median inactive PBM response was -0.02 g/ml. Significantly, the inactive PBM median absolute response was shown to be near zero with a relatively unskewed distribution (0.12). CONCLUSIONS: These results would support the definition of active PBM as FDG uptake greater than the mean of the whole structure as being representative of underlying cell physiology. This work would support the development of atlas-based approaches published in the literature to contour active PBM based on the current definition as being suitable.
On the use of solid 133Ba sources as surrogate for liquid 131I in SPECT/CT calibration: a European multi-centre evaluation.
INTRODUCTION: Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133Ba as a surrogate for 131I imaging. MATERIALS AND METHODS: Two sets of four traceable 133Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid 131I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133Ba sources and liquid 131I. RESULTS: As anticipated, the 131I pseudo-image calibration factors (cps/MBq) were higher than those for 133Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5%. The site-specific cross-calibration method also showed agreement between 133Ba and 131I for all cylinder volumes, which highlights the potential use of 133Ba sources to calculate recovery coefficients for partial volume correction. CONCLUSION: This comparison exercise demonstrated that traceable solid 133Ba sources can be used as surrogate for liquid 131I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals.
Sequential deep learning image enhancement models improve diagnostic confidence, lesion detectability, and image reconstruction time in PET.
BACKGROUND: Investigate the potential benefits of sequential deployment of two deep learning (DL) algorithms namely DL-Enhancement (DLE) and DL-based time-of-flight (ToF) (DLT). DLE aims to enhance the rapidly reconstructed ordered-subset-expectation-maximisation algorithm (OSEM) images towards block-sequential-regularised-expectation-maximisation (BSREM) images, whereas DLT aims to improve the quality of BSREM images reconstructed without ToF. As the algorithms differ in their purpose, sequential application may allow benefits from each to be combined. 20 FDG PET-CT scans were performed on a Discovery 710 (D710) and 20 on Discovery MI (DMI; both GE HealthCare). PET data was reconstructed using five combinations of algorithms:1. ToF-BSREM, 2. ToF-OSEM + DLE, 3. OSEM + DLE + DLT, 4. ToF-OSEM + DLE + DLT, 5. ToF-BSREM + DLT. To assess image noise, 30 mm-diameter spherical VOIs were drawn in both lung and liver to measure standard deviation of voxels within the volume. In a blind clinical reading, two experienced readers rated the images on a five-point Likert scale based on lesion detectability, diagnostic confidence, and image quality. RESULTS: Applying DLE + DLT reduced noise whilst improving lesion detectability, diagnostic confidence, and image reconstruction time. ToF-OSEM + DLE + DLT reconstructions demonstrated an increase in lesion SUVmax of 28 ± 14% (average ± standard deviation) and 11 ± 5% for data acquired on the D710 and DMI, respectively. The same reconstruction scored highest in clinical readings for both lesion detectability and diagnostic confidence for D710. CONCLUSIONS: The combination of DLE and DLT increased diagnostic confidence and lesion detectability compared to ToF-BSREM images. As DLE + DLT used input OSEM images, and because DL inferencing was fast, there was a significant decrease in overall reconstruction time. This could have applications to total body PET.
Guidance on medical physics expert support for nuclear medicine.
The Ionising Radiation (Medical Exposure) Regulations require employers to appoint suitable medical physics experts (MPE) for nuclear medicine services, and they also define the areas where MPEs are required to provide advice and specify matters that they must contribute towards. Applications for employer licences under IR(ME)R require employers to specify the level of MPE support available and if this is provided by onsite MPEs or remotely. Assessment of these applications by the Administration of Radioactive Substances Advisory Committee (ARSAC) has highlighted variability in the levels of MPE support being provided for similar services across the UK. A working party including representatives from IPEM, ARSAC, BIR and BNMS was formed and has produced these recommendations on MPE support. Nuclear medicine services were divided into seven broad categories and MPE support for each category has been considered. However, some services that differ from the scenarios provided in this guidance may require different levels of MPE support. Positron emission tomography (PET)/CT and gamma camera imaging have been considered separately here, although it is recognised that both PET/CT and gamma cameras are often sited within the same department in many centres. The separation has been done for pragmatic purposes, as there are felt to be sufficient differences in the MPE role requirements. This guidance sets out recommendations for MPE support, and broader physics support, to run a safe nuclear medicine service and defines the responsibilities of these staff for a range of clinical nuclear medicine services. The recommendations on MPE support made are advice, but will assist employers in meeting regulatory requirements.
The British nuclear medicine research strategy - the framework.
The British Nuclear Medicine Society (BNMS) has developed a Research Strategy framework led by the Research Champions of the BNMS and overseen by the BNMS Research and Innovation Committee. The objectives of the Research Strategy are to improve translation of cutting-edge nuclear medicine research from bench to bedside, the implementation of state-of-the-art multimodality technologies and to enhance multicentre radionuclide research in the UK. It strives to involve patients and the public in radionuclide research and to contribute to and work with the multi-professional national and international organisations involved in research with an ultimate aim to improve nuclear medicine services, and patients' outcomes and care.
Temporal Relations Between Pain Catastrophizing and Adverse Health and Mental Health Outcomes After Whiplash Injury.
OBJECTIVES: Pain catastrophizing has been shown to be a prognostic indicator for pain severity and the co-occurrence of mental health conditions such as depression and post-traumatic stress disorder after whiplash injury. However, the pattern of available findings is limited in its implications for the possible "antecedent" or "causal" role of pain catastrophizing. The purpose of the present study was to examine the temporal relations between pain catastrophizing, pain severity, depressive symptoms, and post-traumatic stress symptoms (PTSS) in individuals receiving treatment for whiplash injury. MATERIALS AND METHODS: The sample consisted of 388 individuals enrolled in a multidisciplinary program for whiplash injury. Participants completed self-report measures of pain catastrophizing, pain severity, depressive symptoms, and PTSS at the time of admission, mid-treatment (4 week), and treatment completion (7 week). A cross-lagged panel analysis was used to examine the temporal relations between pain catastrophizing, pain severity, depressive symptoms, and PTSS across all 3 timepoints. RESULTS: Model fit was acceptable after the inclusion of modification indices. Pain catastrophizing at the time of admission predicted all other variables at 4 weeks. Pain catastrophizing at 4 weeks also predicted all other variables at 7 weeks. In addition, some bidirectional relations were present, particularly for variables assessed at week 4 and week 7. DISCUSSION: Findings support the view that pain catastrophizing might play a transdiagnostic role in the onset and maintenance of health and mental health conditions. The findings call for greater emphasis on the development of treatment techniques that target pain catastrophizing in intervention programs for whiplash injury.
A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors
Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.
From Data to Diagnosis: Skin Cancer Image Datasets for Artificial Intelligence.
Artificial Intelligence (AI) solutions for skin cancer diagnosis continue to gain momentum, edging closer towards broad clinical use. These AI models, particularly deep learning architectures, require large digital image datasets for development. This review provides an overview of the datasets used to develop AI algorithms and highlights the importance of dataset transparency for evaluation of algorithm generalisability across varying populations and settings. Current challenges for curation of clinically valuable datasets are detailed, which include dataset shifts arising from demographic variations and differences in data collection methodologies, along with inconsistencies in labelling. These shifts can lead to differential algorithm performance, compromise of clinical utility, and the propagation of discriminatory biases when developed algorithms are implemented in mismatched populations. Limited representation of rare skin cancers and minoritised groups in existing datasets are highlighted which can further skew algorithm performance. Strategies to address these challenges are presented, which include improving transparency, representation and interoperability. Federated learning and generative methods, which may improve dataset size and diversity without compromising privacy, are also examined. Lastly, we discuss model-level techniques which may address biases entrained through the use of datasets derived from routine clinical care. As the role of AI in skin cancer diagnosis becomes more prominent, ensuring the robustness of underlying datasets is increasingly important.
A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).
PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in
Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole-genome sequencing with histopathological features.
BACKGROUND: Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification. METHODS: We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants. RESULTS: In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees. CONCLUSIONS: Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.