5728 research outputs found
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Addition of Dendritic Cell Vaccination to Conditioning Cyclophosphamide and Chemoembolization in Patients with Hepatocellular Carcinoma: The ImmunoTACE Trial.
No full textPURPOSE: A previous study by our group using dendritic cells (DC) pulsed ex vivo with the lysate of the HepG2 cell line showed evidence of antigen-specific T-cell responses in some patients with advanced hepatocellular carcinoma. The ImmunoTACE trial evaluated the preliminary activity of this vaccine in combination with transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma. PATIENTS AND METHODS: A randomized phase II trial was conducted in three tertiary referral centers in the United Kingdom. Eligible patients were randomly assigned in a 1:1 ratio to TACE + preconditioning cyclophosphamide or to TACE + preconditioning cyclophosphamide + DC infusions. The primary endpoint was progression-free survival time using RECIST v1.1 criteria. Additional endpoints included safety and immune responses. RESULTS: Between March 2016 and October 2019, 55 patients were randomized, of whom 48 were evaluable (24 in each group). The median progression-free survival time using RECIST criteria was 18.6 months in patients treated with chemoembolization + preconditioning cyclophosphamide + DC infusions compared with 10.4 months in those treated with chemoembolization + preconditioning cyclophosphamide alone (HR = 0.43; upper value of one-sided 80% confidence interval, 0.57; P = 0.016). The addition of DC infusions did not significantly increase the incidence or severity of adverse events. An enhanced antigen (α-fetoprotein)-specific immune response was observed in patients treated with DC vaccination. CONCLUSIONS: The addition of DC infusions to TACE and preconditioning cyclophosphamide has shown promising preliminary activity and merits further investigation in a larger randomized trial
Prostate Cancer: genetics in practice now and in the future.
No full textProstate Cancer (PrCa) is one of the most common cancers worldwide and causes a significant healthcare burden. Recent predictions estimate the incidence of new cases of PrCa will double from 1.4 million in 2020 to 2.9 million by 2040.The known risk factors for PrCa are increasing age, family history, ancestry and genetics. PrCa is one of the most heritable of the more common cancers. The heritability of PrCa is due to both rare moderate to high-risk monogenic variants and more common variants known as single nucleotide polymorphisms (SNPs) which can be used to calculate a polygenic risk score (PRS) for PrCa, while there is some of the genetic risk as yet unexplained. In recent years more PrCa risk-associated SNPs have been identified, increasing over time with the inclusion of more persons of diverse ancestry in studies. The identification of germline variants known to be associated with increased PrCa risk and disease aggressiveness has led to targeted treatments for certain pathogenic variant carriers.This is a mini review of how the genetics of PrCa can impact on screening and early detection of the disease and the treatment and management of the disease when diagnosed
Capivasertib plus fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer: phase 3 CAPItello-291 study extended Chinese cohort.
No full textIn the global CAPItello-291 randomized phase 3 study (NCT04305496) in patients with hormone receptor-positive/HER2-negative advanced breast cancer and progression during/after aromatase inhibitor treatment, capivasertib-fulvestrant significantly improved progression-free survival (PFS) in the overall population and patients with PIK3CA/AKT1/PTEN-altered tumors versus placebo-fulvestrant. We assessed efficacy and safety of capivasertib-fulvestrant in a prespecified exploratory analysis of a Chinese cohort (n = 24) and extended study with the same protocol (n = 110). Clinically meaningful PFS benefit for capivasertib-fulvestrant was observed in the overall population (median PFS: 6.9 [capivasertib-fulvestrant] versus 2.8 [placebo-fulvestrant] months; hazard ratio 0.51, 95% CI 0.34-0.76), patients with PIK3CA/AKT1/PTEN-altered tumors (n = 46; 5.7 versus 1.9 months; hazard ratio 0.41, 95% CI 0.19-0.85) and PIK3CA/AKT1/PTEN-non-altered tumors (patients with confirmed next-generation sequencing results [n = 68]; 9.2 versus 2.7 months; hazard ratio 0.38; 95% CI 0.21-0.68). The most frequent adverse events (AEs) with capivasertib-fulvestrant were diarrhea (60.6% versus 11.3% with placebo-fulvestrant) and hyperglycemia (57.7% versus 17.7%). AEs leading to capivasertib-fulvestrant discontinuation were reported in 11.3% of patients versus 3.2% for placebo-fulvestrant. The benefit-risk profile of capivasertib-fulvestrant in the Chinese cohort was favorable; further exploration in patients with PIK3CA/AKT1/PTEN-non-altered tumors is warranted
Towards rapid and efficient simulation-free radiotherapy: MR guided adaptive prostate radiotherapy on the MR-Linac using diagnostic MRI reference planning.
No full textBACKGROUND AND PURPOSE: Simulation-free radiotherapy offers improved efficiency for adaptive treatments. This planning study presents a simulation-free pre-treatment workflow for prostate cancer online adaptive radiotherapy on a MR-Linac. Previously acquired diagnostic MR images are used to create a reference treatment plan without clinician input, and adapted plans are then simulated, and compared with those from the traditional workflow. MATERIALS AND METHODS: All patients treated with 36.25 Gy in 5-fractions within the HERMES trial were retrospectively assessed for eligibility of simulation-free reference planning. If eligible, reference images were created from existing diagnostic MRI (T1w and T2w) to enable MR-only reference treatment planning. Target and OAR reference structures were autosegmented without clinician input. Online plan adaptation was simulated using existing clinical treatment images and structure sets. Adapted plans were compared with existing clinical plans, and synthetic CT accuracy assessed. RESULTS: 87.5 % of patients had suitable diagnostic scans. Reference images and treatment plans were successfully created. Online treatment plans were simulated and were clinically acceptable for target dose and conformality, meeting all mandatory clinical goals with no detriment to OAR dose or plan deliverability. Accuracy of the synthetic CT approach was high with gamma results at 2mm/2% all above 98.9 %. CONCLUSION: This study has shown that non radiotherapy-dedicated diagnostic MRI can be used for reference prostate planning on the MR-Linac, generating clinically equivalent adapted plans when compared to those originating from radiotherapy-simulation reference plans. This potentially saves multiple weeks in the pathway, improving radiotherapy efficiency and patient experience
Mechanistic studies of substrate activation by the human CDK-activating kinase and its inhibition by small-molecule ligands
No full textThe human cyclin-dependent kinase (CDK)-activating kinase (CAK), a heterotrimeric protein complex consisting of CDK7, cyclin H, and MAT1, is a dual regulator of both transcription and the cell cycle. As a subcomplex of the general transcription factor TFIIH, it regulates transcription initiation and co-transcriptional pre-mRNA processing through phosphorylation of the C-terminal domain of RNA polymerase II. As a free complex, it regulates the cell cycle by catalysing the activating phosphorylation of CDK proteins. Due to its key activities in such fundamental cellular processes, which are commonly dysregulated in tumorigenesis, several small-molecule inhibitors of CDK7 have been developed as anti-cancer drugs.Despite a wealth of existing structural and biochemical data concerning the architecture, functions, and inhibition of the human CAK, several key questions remain. For instance, we currently lack an understanding of the molecular mechanisms by which the CAK recognises its CDK substrates. Additionally, targeting of CDK7 for cancer treatment is challenged by issues of non-selective binding of inhibitors to related CDKs, as well as possible treatment resistance.The work presented in this thesis aims to address several of these outstanding questions and challenges. I present structural and mechanistic studies of CAK-substrate complexes, which reveal the basis of CDK substrate recognition by the CAK. I additionally present structures of the CAK bound to a series of small-molecule inhibitors, thereby providing insights into inhibitor selectivity relevant to the design of future drugs, while establishing workflows for high-throughput, high-resolution structure determination by cryo-EM applicable to structure-based drug design efforts of other challenging targets. Finally, I present structural and biochemical analysis of a mutant form of the CAK that is resistant to certain inhibitors. Together, this work advances our understanding of the functions of this “master regulator” and how it can be more effectively targeted in disease
Hidden costs and unmet supportive care needs among individuals with experience of breast cancer and their carers in the United Kingdom.
No full textBACKGROUND: The impact of cancer transcends physical health, affecting mental wellbeing, financial stability, and ability to perform daily tasks, influencing not only patients but also the broader community. METHODS: Online anonymous surveys (24/01/2023-03/03/2023) were disseminated via charities to individuals treated for breast cancer in the UK and their carers. Multivariable ordered logistic regression models were used to investigate demographic, cancer-related and employment factors associated with physical, wellbeing and financial Quality-of-Life (QoL). RESULTS: 470 and 136 participants reported primary (PBC) and metastatic (MBC) breast cancer, respectively. 27% PBC and 35% MBC participants reported experience of financial problems. 17% PBC and 47% MBC participants reported trouble fulfilling caring responsibilities at the time of survey completion. For PBC participants, reports of financial problems were associated with difficulties seeking help for physical or wellbeing issues, which were associated with worse physical and wellbeing QoL. Financial problems, and other challenges were more commonly reported among MBC participants. These factors may impact QoL similarly, so there was no evidence of specific explanatory factors for MBC participants. CONCLUSIONS: Better understanding of wider impact of breast cancer could lead to better policy and support. Future clinical trials should incorporate more comprehensive assessment of breast cancer's wider effects
Updated Overall Survival and Long-Term Safety With Ripretinib Versus Sunitinib in Patients With GI Stromal Tumor: Final Overall Survival Analysis From INTRIGUE.
No full textIn the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy
Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity.
No full textBRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major barriers for successful treatments. Here, by using relevant preclinical models, we find that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, enhances the effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could provide a therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed a drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a regulator of DNA repair and BRAF/MEKi response, highlighting the therapeutic potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours
Predicting radiotherapy response, toxicities and quality of life related functional outcome in soft tissue sarcoma of the extremities (PredicT)
No full textPatients with soft tissue sarcoma of the extremities (STSE) can experience long-term permanent side-effects caused by radiotherapy, such as limb swelling, scar tissue formation, joint stiffness, all of which can lead to deterioration. Planning radiotherapy based on evidence-based dose-volume constraints and normal tissue sparing may lead to the development of less side-effects. However, these are unknown for STSE.
This thesis aims at predicting radiotherapy response, toxicities and quality-of-life (QoL) related functional outcomes in STSE (PredicT), as well as developing dose-volume constraints that when applied to normal tissues may result in less side-effects. PredicT consists of two cohorts:
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PredicT A (retrospective): predictive model will be developed using radiotherapy, toxicities, co-morbidities and patient reported outcome measures from 384 patients recruited in VorteX and IMRiS clinical trials. Dose-volume constraints will be derived using receiving operator characteristics and multivariate analysis.
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PredicT B (prospective validation): The validity of the dose-volume constraints will be tested using odds ratio in 80 patients of PredicT B observational study
Uniform Reporting of Next Generation Sequencing: Indian Society of Medical and Pediatric Oncology
No full textAbstractMolecular oncology is the cornerstone for diagnosis, treatment, prognosis, and screening of individuals who present to an oncology clinic. The integration of molecular diagnostic techniques with therapeutic management of patients has resulted in unique biomarker development and improved clinical endpoints. Amongst all laboratory diagnostic techniques applied in oncology, next generation sequencing (NGS) of nucleic acids holds cardinal merit in the present day. Multi-omic biomarkers are the mainstay of selecting variation-specific targeted therapy and immunotherapy. Hence, it is essential to utilise the right diagnostic techniques and harmonize their reporting accurately against rigorous quality standards.We aimed to develop a consensus technical standard guideline on quality assurance and reporting of genetic tests that influence clinical decision making in oncology.Under the initiative of Indian Society of Medical and Pediatric Oncology (ISMPO), a working group of national and international subject matter experts including clinicians, scientists, and bioinformaticians was formulated in 2022. Published scientific literature and laboratory technical standards were studied by this panel and a document for the Indian molecular oncology sector was drawn after obtaining consensus on every recommendation from all members of the working group.Guidelines for introducing uniformity in NGS reporting have been developed by a working group comprising of country's leading molecular oncologists, geneticists, and molecular pathologists alongside international experts, under the aegis of the Indian Society of Medical and Pediatric Oncology.The proposed guidelines and recommendations are intended to be used as a framework to standardize NGS reporting across India, which in turn will enable clinicians and allied healthcare professionals to make informed decisions for unparalleled patient care.</jats:p