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Influence of imaging method on fat fraction estimation for assessing bone marrow in metastatic prostate cancer.
No full textOBJECTIVE: This study aimed to assess the accuracy of fat fraction estimation with clinically available Dixon sequences in normal-appearing marrow and bone metastases in the pelvis of metastatic prostate cancer patients. METHODS: A prospective single-centre study was conducted with metastatic prostate cancer patients and healthy volunteers. Linearity and bias of fat fraction estimates from clinically available Dixon sequences were assessed against a 6-point PDw gradient echo (q-Dixon) sequence measuring the reference standard proton density fat fraction. Lesion fat fraction estimates were cross-compared using the Friedman test. Repeatability in volunteers was evaluated with Bland-Altman plots. Sensitivity of fat fraction estimates using TSE-Dixon sequences to specific absorption rate (SAR) related modifications were evaluated with correlation plots. RESULTS: Thirty-three patients were recruited for this study. Significant (p < 0.05) absolute bias (12.4%) was demonstrated in the T1-weighted (T1w) Dixon measurements against the q-Dixon. Significant differences (p < 0.05) between fat fraction estimates provided by the T1w Dixon and PDw Dixon sequences were observed in 13 active and 6 treated lesions. Repeatability coefficients for fat fraction estimates ranged from 5.9 to 9.0% in the pelvic tissues of healthy volunteers. Reduction of slice number with repetition time for SAR had the greatest effect, reaching a maximum difference in fat fraction of 14.7% from the q-Dixon for the T2w-TSE Dixon in bone marrow. CONCLUSIONS: T1w Dixon methods can detect post-treatment changes but remain confounded by relaxation time biases. While all Dixon methods showed good repeatability, careful choice of SAR-related modifications is critical to maintaining accuracy for PD- and T2-weighted TSE sequences. KEY POINTS: Question The clinical validity of signal-weighted fat fraction estimates versus proton density fat fraction for characterising metastatic bone lesions has not been fully assessed. Findings T1-weighted Dixon sequences in line with whole-body MRI international guidelines demonstrate significant fat fraction bias, particularly in lesions and muscle. Clinical relevance Fat fraction estimation using T1-weighted Dixon sequences recommended in international guidelines are highly sensitive to relaxation time biases, making underlying physiological changes potentially ambiguous
Prevalence of depressive and anxiety symptoms in patients with head and neck cancer undergoing radiotherapy: A systematic review and meta-analysis of longitudinal studies.
No full textBACKGROUND AND PURPOSE: Patients with head and neck cancer (HNC) are particularly vulnerable to mental health concerns. Radiotherapy (RT) remains a key treatment modality for these malignancies, offering high chances of cure. However, the effects on mental health are not well defined. We aim to characterize longitudinally the prevalence and risk of depressive and anxiety symptoms over the course of RT in patients with HNC. MATERIAL AND METHODS: A literature search was performed from database inception until November 1st, 2024. PROSPERO/MOOSE-compliant and pre-registered (PROSPERO:CRD42023441432) systematic review identified studies longitudinally reporting in patients with HNC undergoing curative intent RT. Pooled prevalence and odds ratio of clinically significant anxiety and depressive symptoms between different treatment timepoints were estimated using random-effects meta-analysis. RESULTS: 18 studies (total sample 1,920, mean age 59.9[SD = 3.17], 22.2 % female, 93.0 % white ethnicity) were included. Before RT, a pooled prevalence of depressive symptoms of 18.1 % (95 % confidence intervals [CI] = 13.1 %-24.4 %) was found. Short-term after completing RT (≤3 months), the prevalence of depressive symptoms peaked to 26.1 % (95 %CI = 18.9 %-35.0 %), decreasing in long-term (≥6 months) assessments to 16.4 % (95 %CI = 12.6 %-21.0 %). Anxiety symptoms continuously decreased from baseline (pooled prevalence 29.9 % [95 %CI = 27.3 %-32.7 %]) to 17.4 % (95 %CI = 12.1 %-24.5 %) in the long-term. Female and married patients showed higher prevalence of depressive symptoms. Those who underwent surgery showed a lower prevalence of anxiety symptoms. CONCLUSIONS: High prevalence of clinically significant depressive and anxiety symptoms were found in patients with HNC undergoing RT, from baseline to long-term follow-up. The weeks following completion of RT are key, as depressive symptoms increase in this period. Screening and interventions prior to, during, and especially immediately post-RT would be beneficial
High resolution profiling of cell cycle-dependent protein and phosphorylation abundance changes in non-transformed cells.
No full textThe cell cycle governs a precise series of molecular events, regulated by coordinated changes in protein and phosphorylation abundance, that culminates in the generation of two daughter cells. Here, we present a proteomic and phosphoproteomic analysis of the human cell cycle in hTERT-RPE-1 cells using deep quantitative mass spectrometry by isobaric labelling. By analysing non-transformed cells and improving the temporal resolution and coverage of key cell cycle regulators, we present a dataset of cell cycle-dependent protein and phosphorylation site oscillation that offers a foundational reference for investigating cell cycle regulation. These data reveal regulatory intricacies including proteins and phosphorylation sites exhibiting cell cycle-dependent oscillation, and proteins targeted for degradation during mitotic exit. Integrated with complementary resources, our data link cycle-dependent abundance dynamics to functional changes and are accessible through the Cell Cycle database (CCdb), an interactive web-based resource for the cell cycle community
Practical guidance for conducting high-quality and rapid interim analyses in adaptive clinical trials.
No full textBACKGROUND: Adaptive designs are increasingly being used in clinical trials within diverse clinical areas. They can offer advantages over traditional non-adaptive approaches, including improved efficiency and patient benefit. The level of improvement observed in practice depends to a large degree on conducting interim analyses (at which adaptations can be made to the trial based on collected data) rapidly and to a high standard. METHODS: The ROBust INterims for adaptive designs (ROBIN) project aimed to identify best practice for conducting high-quality and rapid interim analyses. This was done through evidence synthesis of published work, qualitative research with trial stakeholders working at public sector clinical trials units, engagement with patients and the public, and a meeting of trial stakeholders to discuss findings and agree recommendations. RESULTS: This paper provides recommendations for teams that conduct adaptive trials about how to ensure interim analyses are done rapidly and to a high standard. We break down recommendations by stage of the trial. We also identify a lack of methodology on how best to involve patients in adaptive trials and related decision-making. A limitation of our recommendations is that the research was mostly focused on UK academic settings, although we believe much of the recommendations are relevant in other countries and to industry-sponsored trials. CONCLUSIONS: When following the recommendations outlined in this paper, the process of planning and executing interim analyses will be smoother; in turn, this will lead to more benefits from using adaptive designs
Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma.
No full textBACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer. While DNA damaging agents such as platinum and PARP inhibitors have derived clinical benefits, acquired resistance invariably develops. Hence there is an urgent need for novel therapeutic strategies to overcome acquired resistance. METHODS: Clinically relevant resistance in PDAC patient-derived cell lines was achieved by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity, flow cytometry, immunofluorescence, and transcriptomic analysis were used to investigate the efficacy of ATR (ceralasertib) and PARP (olaparib) inhibitors in overcoming acquired resistance. RESULTS: Acquired resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, metabolic control, DNA damage response (DDR), programmed cell death, and the replication stress response. Combination treatment with ceralasertib, and olaparib was synergistic in all models of acquired resistance. Sequential use of ceralasertib prior to olaparib was highly effective at low dose for DDR proficient models, whereas DDR deficient models responded better with olaparib treatment first. CONCLUSIONS: We provide in vitro evidence of a novel therapeutic strategy to overcome acquired resistance to PARP inhibitor and platinum in PDAC, using sequential exposure to ceralasertib and olaparib. A sequential regimen should be investigated clinically to circumvent dose limiting toxicity seen in concurrent combinations
Systematic review of PSA reference intervals in the gender diverse population with prostates.
No full textOBJECTIVES: To determine mean/median serum total prostate-specific antigen (PSA) levels in transgender women and non-binary people with prostates (TWNBPP) who have received gender-affirming hormone therapy (GAHT) or an orchidectomy. The secondary objective was to identify other quantitative information that influences PSA levels in this population. METHODS: Systematic review of existing publications from primary studies published in English, excluding case reports and guidelines. INCLUDED STUDIES: TWNBPP who have received GAHT/post-orchidectomy, without a diagnosis of prostate pathology, with recorded serum PSA levels. MEDLINE and Embase databases were searched, up to July 2024. RESULTS: Four papers met the inclusion criteria, with 290 participants. Two papers measured the mean PSA level after 4 and 12 months of GAHT (mean [range] age 30 [18-45] years). A third paper measured the mean PSA level after a median of 9 years of GAHT (mean [range] age 40.1 [19-67] years). The fourth study measured 852 PSA levels in 210 participants receiving oestradiol therapy, over a 23-year period (mean [range] age 60 [40-79] years). The mean and median PSA levels ranged from 0.020 to 0.525 ng/mL. Meta-analysis of these data was unfeasible, due to low quantity, comparability, and quality of the studies. CONCLUSIONS: Existing data for serum PSA reference intervals for TWNBPP without prostate pathology were from four studies and cannot be used to make clinical recommendations. The evidence indicates that GAHT in TWNBPP lowers PSA levels from baseline, below expected levels for age-matched cisgender controls. Not all TWNBPP over the age of 40 years should be offered PSA testing; however, those with a genetic predisposition, family history, or symptoms of prostate cancer, may request or be offered a PSA test. There are currently no clinical PSA thresholds to guide interpretation of PSA levels in TWNBPP when being evaluated for suspected prostate cancer or for those seeking PSA testing
Tumour measurements on imaging for clinical trial: A national picture of service provision.
No full textBACKGROUND: Radiological response evaluation metrics such as RECIST 1.1 inform critical endpoints in oncology trials. The UK was the 6th highest recruiter into oncology trials worldwide between 1999 and 2022, with almost 9000 oncology trials registered during the same period. However, the provision of tumour measurements for oncology trials is often ad hoc and patchy across the NHS. The aim of this work was to understand the barriers to providing an effective imaging tumour measurement service, gain insight into service delivery models and consider the successes and challenges from the perspective of both service providers and end users. METHODS: An electronic survey was distributed to those who provide tumour measurement response review for clinical trials (service providers) and those that request and use such measurements in trial activities (service users). RESULTS: Responses from 35 sites demonstrated substantial variation in service provision across the UK. Despite workforce pressures, service is largely delivered through radiologists with a minority utilising radiographer role extension. Only 20% of the service providers had dedicated training and 29% received robust financial reimbursement. DISCUSSION: Service variation is likely a consequence of limited training, education and infrastructure to support robust service, compounded by increasing radiology workload and workforce pressures
ESTRO recommendations on preoperative radiation therapy in breast cancer: current and future perspectives - Endorsed by ASTRO.
No full textBACKGROUND AND PURPOSE: Preoperative radiation therapy (RT) for breast cancer is not a novel concept, though available data are insufficient to translate current knowledge into clinical practice. Nonetheless, potential advantages of this approach are emerging in multiple scenarios, incorporating increasing treatment personalization and technological improvements in RT. This paper aims to synthesize and summarize the literature on preoperative RT in distinct breast cancer treatment settings, providing perspectives based on existing evidence and gaps in knowledge. METHODS: The ESTRO Breast subgroup proposal for elaborating perspectives on preoperative RT was approved by the ESTRO Guidelines Committee, and a panel of experts in the field was identified. Four working groups were created, focusing on the different clinical settings where preoperative RT has been investigated: patients with early-stage breast cancer at low risk of recurrence, patients with breast cancer at high risk of recurrence, and patients with an indication for mastectomy. The fourth group focused its search on cross cutting themes, such as preclinical and translational aspects, radiobiology, RT techniques and quality assurance. After a literature search including the identification of key points and gaps in the literature, the four working groups presented their findings and perspectives were formulated, discussed and approved by the panel. RESULTS: Overall, 27 phase I and phase II studies enrolling patients from the year 2000 onward were considered, collecting data such as RT dose and fractionation, clinical outcomes, and complications rates. The expert panel stated perspectives for the different clinical scenarios based on available evidence and current gaps in knowledge, to be addressed by future clinical research. CONCLUSION: Given the current lack of clinical data to support the development of formal guidelines, we present our perspectives, which can be useful for implementing new clinical trials and research projects, overcoming current limitations, and potentially generating high-quality practice-changing data, introducing preoperative RT in specific breast cancer treatment settings in the future
Identifying actionable pathways in breast cancer serosal metastasis
No full textMetastasis to the peritoneal and pleural cavities, also termed the serous cavities, is a common occurrence in advanced breast cancer. The serous cavities are lined by the mesothelium, an epithelial monolayer which provides a hospitable environment for the serosal spread of intra-abdominal cancers. Despite breast cancer being the most common extra-abdominal cancer spreading to the serosal cavities and the leading cause of pleural effusion and ascites in women, patients with breast cancer serosal metastasis face limited therapeutic options. The aim of this project was to uncover the mechanisms of crosstalk between mesothelial cells and breast cancer cells and to reveal therapeutic vulnerabilities that impair serosal colonisation.Using a novel ultrasound-guided intrapleural injection model and an intraperitoneal injection model, I showed that breast cancer cells co-localise with mesothelial cells and rapidly expand along the sub-mesothelial basal lamina when inoculated in the serous cavities. Furthermore, breast cancer cells co-cultured with mesothelial cells as 3D spheroids show increased viability compared to tumour cells alone, and loss of E-cadherin in tumour cells potentiates this interaction. Transcriptomic analysis and cell-cell communication inference of the co-cultured spheroids pinpointed basement membrane components as top predicted mesothelial-derived ligands binding to tumour cell receptors. In parallel, mesothelial cells acquired a cancer-associated mesothelial cell signature upon co-culture with tumour cells, displaying increased extracellular matrix (ECM) deposition and remodelling. Validation of top communication inference candidate genes by RNA interference identified mesothelial-derived fibronectin and laminin α5 as ECM components involved in the regulation of tumour cell viability. Targeting tumour cell binding of the mesothelial basement membrane via FAK inhibition is being tested as a strategy to limit serosal spread of breast cancer in vivo. Together these results demonstrate that mesothelial cells provide a supportive niche for breast cancer serosal colonisation and that mesothelial-tumour cell interaction is an actionable target against advanced metastatic disease
Understanding Barriers to Engagement With a Prostate Cancer Research and Genetic Risk Service Among UK Men of Black African or Black Caribbean Ancestry.
No full textINTRODUCTION: Prostate cancer is the second most common cancer worldwide, and there is no national prostate cancer screening programme in the United Kingdom. Men of African ancestry are twice as likely to be diagnosed as men of European ancestry and are diagnosed at a younger age. Despite this, Black men are under-represented in seeking advice about prostate cancer symptoms, screening and genetic research. There is increasing research focused on targeted prostate cancer screening, using genetic testing to guide screening by identifying those at highest risk, but this could only be considered if people of all ethnicities would accept this approach. It is vital to diagnose prostate cancer early, when it is curable. We wanted to identify the barriers to engagement with prostate cancer genetic research to increase participation from those at highest risk. METHODS: We conducted two community discussion groups, each attended by 30-35 Black men and their families. We conducted interviews with three Black community champions who have a lived experience of prostate cancer. Thematic analysis was performed on the transcripts. We used a participatory approach to develop our themes with members of the community, two of whom are co-authors on this paper. RESULTS: Themes were grouped as barriers or facilitators to engagement with prostate cancer genetic risk services. Barriers included GP reluctance to perform prostate-specific antigen (PSA) testing, cultural inhibition around discussing prostate cancer and family history, fear of rectal examination, fear of cancer diagnosis and lack of trust in the healthcare system, no awareness about the role of genetics in prostate cancer risk assessment, negative connotations of genetic testing (e.g., genetic modification) and genetic data being used inappropriately. Facilitators were family and community support, the sharing of experiences, good communication with doctors, raised prostate cancer awareness, genetic risk assessment to guide the need for screening and facilitate early diagnosis, improving future outcomes for prostate cancer in the Black community through engaging with genetic research and assurance that there are regulations in place to protect genetic and personal data with guidance around when genetic results must be disclosed. CONCLUSIONS: Understanding barriers and facilitators can guide recommendations for health services to improve access and uptake within the Black community and improve representation in genetic research. Better representation will support improvements in cancer outcomes and understanding of the genetic risk of prostate cancer in the Black community. PATIENT OR PUBLIC CONTRIBUTION: We initially attended community prostate cancer awareness events to speak to members of the community. We established trusted and two-way relationships with Black 'community champions' who lead support groups in the Black community and often have a lived experience of prostate cancer. We were invited to attend their support groups to deliver awareness talks and address concerns about prostate cancer risk and screening. We then conducted discussion groups and collected data. Our analysis was conducted in partnership with our community champions. Our findings are described in this paper, with their co-authorship. We have also disseminated our findings in a co-produced newsletter to feed back our findings to the community members, who gave us their time. We have also shared information at a stakeholder day, attended by 65 individuals from the community, where we also planned future work. We have reimbursed participants for their time, which is in line with NIHR guidance. As described above, patient and public involvement has been the guiding principle throughout this project