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Ultrasound-guided intra-tumoral administration of directly-injected therapies: a review of the technical and logistical considerations.
No full textBACKGROUND: Directly-injected therapies (DIT) include a broad range of agents within a developing research field in cancer immunotherapy, with encouraging clinical trial results in various tumour subtypes. Currently, the majority of such therapies are only available within clinical trials; however, more recently, talimogene laherparepvec (T-VEC, Imlygic) has been approved as the first oncolytic virus therapy in the USA and Europe. Our institution contributes to multiple different trials exploring the efficacy of DIT, the majority of which are performed by oncologists in clinic. However, specific, challenging cases - mainly neck tumours - require image-guided administration. MAIN BODY: This review article addresses the technical and logistical factors relevant to the incorporation of image-guided DIT into an established ultrasound service. Image-guidance (usually with ultrasound) is frequently needed for certain targets that cannot be palpated or are in high-risk locations, e.g. adjacent to blood vessels. A multi-disciplinary approach is essential to facilitate a safe and efficient service, including careful case-selection. Certain protocols and guidance need to be followed when incorporating such a service into an established ultrasound practice to enhance efficiency and optimise safety. Key learning points are drawn from the literature and from our early experience at a tertiary cancer centre following image guided DIT for an initial cohort of 22 patients (including 11 with a neck mass), addressing trial protocols, pre-procedure work-up, organisation, planning, consent, technical aspects, procedure tolerability, technical success, and post-procedure considerations. CONCLUSION: With appropriate planning and coordination, and application of the learning points discussed herein, image-guided administration of DIT can be safely and efficiently incorporated into an established procedural ultrasound list. This has relevance to cancer centres, radiology departments, individual radiologists, and other team members with a future role in meeting the emerging need for these procedures. This paper provides advice on developing such an imaging service, and offers certain insights into the evolving remit of radiologists within cancer care in the near future
BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review.
No full textIMPORTANCE: Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration-approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs. OBSERVATIONS: This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males. CONCLUSIONS AND RELEVANCE: Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer
Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.
No full textCDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer
A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours.
No full textBACKGROUND: Gartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours. METHODS: This phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients). RESULTS: Overall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation. CONCLUSION: Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued. CLINICALTRIALS: GOV: NCT02278250
Bone health and body composition in prostate cancer: Meet-URO and AIOM consensus about prevention and management strategies.
No full textBACKGROUND: Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and contradictory. This consensus, based on the Delphi method, provides further guidance on BH management in PCa. MATERIALS AND METHODS: In May 2023, a survey made up of 37 questions and 74 statements was developed by a group of oncologists and endocrinologists with expertise in PCa and BH. In June 2023, 67 selected Italian experts, belonging to the Italian scientific societies Italian Association of Medical Oncology and Italian Network for Research in Urologic-Oncology (Meet-URO), were invited by e-mail to complete it, rating their strength of agreement with each statement on a 5-point scale. An agreement ≥75% defined the statement as accepted. RESULTS: In non-metastatic hormone-sensitive PCa, the panel agreed that androgen deprivation therapy (ADT) alone implies sufficient fracture risk to warrant antifracture therapy with bone-targeting agents (BTAs) for cancer treatment-induced bone loss (CTIBL) prevention (79%). Therefore, no consensus was reached (48%) for the treatment with BTAs of patients receiving short-term ADT (<6 months). All patients receiving active treatment for metastatic hormone-sensitive PCa (75%), non-metastatic castration-resistant PCa (89%) and metastatic castration-resistant PCa (mCRPC) without bone metastases (84%) should be treated with BTAs at the doses and schedule for CTIBL prevention. All mCRPC patients with bone metastasis should be treated with BTAs to reduce skeletal-related events (94%). In all settings, the panel analyzed the type and timing of treatments and examinations to carry out for BH monitoring. The panel agreed on the higher risk of sarcopenic obesity of these patients and its correlation with bone fragility. CONCLUSIONS: This consensus highlights areas lacking major agreement, like non-metastatic hormone-sensitive prostate cancer patients undergoing short-term ADT. Evaluation of these issues in prospective clinical trials and identification of early biomarkers of bone loss are particularly urgent
Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of the Phase 2 RAIDER Randomised Controlled Trial.
No full textBACKGROUND AND OBJECTIVE: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule. METHODS: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART. KEY FINDINGS AND LIMITATIONS: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy. CONCLUSIONS AND CLINICAL IMPLICATIONS: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts
Structural investigation of the Intron-Binding Complex in RNA splicing and HIV integration
No full textPre-mRNA splicing is an essential step of gene expression required for the selection and ligation of coding exons into the mature mRNA. Splicing occurs by two chemical steps – splicing and exon ligation - on the spliceosome, a multimegadalton complex, composed of five ribonucleoprotein particles (snRNPs) and numerous non-snRNP proteins. The spliceosome is a dynamic machinery that undergoes profound remodeling as it transitions through various landmark stages, each differing in composition and conformation. This extensive dynamics is powered by RNA helicases—molecular motors that integrate within the spliceosome and remodel RNA-RNA or RNA-protein interactions using the energy from NTP hydrolysis. Aquarius is a splicing helicase that joins the spliceosomes as part of the pentameric intron-binding complex (IBC) and drives the remodeling necessary to achieve a catalytically competent state of the spliceosome. During this process, known as catalytic activation, the branch duplex, which carries a reactive adenosine, must be liberated from the grasp of the SF3B complex and relocated to the catalytic center of the spliceosome for the branching reaction. How Aquarius and, implicitly, the IBC act in and regulate splicing is unclear. My thesis is structured in three parts. The first and most important part involves the reconstitution and cryo-EM analyses of several IBC-RNA complexes in three different catalytic steps: pre-catalytic, transition state, and post-catalytic. Furthermore, I stalled and analyzed two spliceosomes (i.e., B AQR and C complexes) before and after the action of Aquarius. Collectively, these structures allow us to propose a model for how this helicase remodels the spliceosome to enable branching catalysis. We conclude Aquarius translocates with 5’-3’ polarity, pulling the intron and extracting the branch duplex, facilitating its transfer to the catalytic center. In complementation, Aquarius triggers a coordinated dissociation and recruitment of numerous spliceosome subunits. In the second part of my thesis, I examined a different role of the IBC, specifically its interaction with HIV1 integrase. Integrase is a viral protein that forms multimers at the ends of viral DNA, creating intasomes. These intasomes facilitate the integration of viral DNA into the host genome, aided by the host protein LEDGF/p75. By reconstituting recombinant intasomes, LEDGF, and IBC, I could provide evidence for the direct interaction of these purified components in vitro. This development paves the way for future cryo-EM reconstructions of intasomes in complex with IBC and LEDGF, enhancing our understanding of how IBC mediates HIV genome integration. In the third part of my thesis, I explored the connection between splicing and the DNA damage response (DDR). Building on previously reported interactions between splicing and DDR factors, we aimed to evaluate the stability of these interactions and attempt to reconstitute complexes for structural analysis. I developed molecular baits composed of ssDNA, the different types of recombinant RPA complexes, and various nuclear extracts, including those from cells subjected to X-ray-induced DNA damage. Our systematic analysis indicates that the reported interactions are not reproducible. However, this has facilitated the development of valuable and more reliable protocols for future biochemical studies of splicing and DDR
Image directed redesign of bladder cancer treatment pathways: the BladderPath RCT.
No full textBACKGROUND: Transurethral resection of bladder tumour has been the mainstay of bladder cancer staging for > 60 years. Staging inaccuracies are commonplace, leading to delayed treatment of muscle-invasive bladder cancer. Multiparametric magnetic resonance imaging offers rapid, accurate and non-invasive staging of muscle-invasive bladder cancer, potentially reducing delays to radical treatment. OBJECTIVES: To assess the feasibility and efficacy of the introducing multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour in the staging of suspected muscle-invasive bladder cancer. DESIGN: Open-label, multistage randomised controlled study in three parts: feasibility, intermediate and final clinical stages. The COVID pandemic prevented completion of the final stage. SETTING: Fifteen UK hospitals. PARTICIPANTS: Newly diagnosed bladder cancer patients of age ≥ 18 years. INTERVENTIONS: Participants were randomised to Pathway 1 or 2 following visual assessment of the suspicion of non-muscle-invasive bladder cancer or muscle-invasive bladder cancer at the time of outpatient cystoscopy, based upon a 5-point Likert scale: Likert 1-2 tumours considered probable non-muscle-invasive bladder cancer; Likert 3-5 possible muscle-invasive bladder cancer. In Pathway 1, all participants underwent transurethral resection of bladder tumour. In Pathway 2, probable non-muscle-invasive bladder cancer participants underwent transurethral resection of bladder tumour, and possible muscle-invasive bladder cancer participants underwent initial multiparametric magnetic resonance imaging. Subsequent therapy was determined by the treating team and could include transurethral resection of bladder tumour. MAIN OUTCOME MEASURES: Feasibility stage: proportion with possible muscle-invasive bladder cancer randomised to Pathway 2 which correctly followed the protocol. Intermediate stage: time to correct treatment for muscle-invasive bladder cancer. RESULTS: Between 31 May 2018 and 31 December 2021, of 638 patients approached, 143 participants were randomised; 52.1% were deemed as possible muscle-invasive bladder cancer and 47.9% probable non-muscle-invasive bladder cancer. Feasibility stage: 36/39 [92% (95% confidence interval 79 to 98%)] muscle-invasive bladder cancer participants followed the correct treatment by pathway. Intermediate stage: median time to correct treatment was 98 (95% confidence interval 72 to 125) days for Pathway 1 versus 53 (95% confidence interval 20 to 89) days for Pathway 2 [hazard ratio 2.9 (95% confidence interval 1.0 to 8.1)], p = 0.040. Median time to correct treatment for all participants was 37 days for Pathway 1 and 25 days for Pathway 2 [hazard ratio 1.4 (95% confidence interval 0.9 to 2.0)]. LIMITATIONS: For participants who underwent chemotherapy, radiotherapy or palliation for multiparametric magnetic resonance imaging-diagnosed stage T2 or higher disease, it was impossible to conclusively know whether these were correct treatments due to the absence of histopathologically confirmed muscle invasion, this being confirmed radiologically in these cases. All patients had histological confirmation of their cancers. Due to the COVID-19 pandemic, we were unable to realise the final stage. CONCLUSION: The multiparametric magnetic resonance imaging-directed pathway led to a substantial 45-day reduction in time to correct treatment for muscle-invasive bladder cancer, without detriment to non-muscle-invasive bladder cancer participants. Consideration should be given to the incorporation of multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour into the standard pathway for all patients with suspected muscle-invasive bladder cancer. The improved decision-making accelerated time to treatment, even though many patients subsequently needed transurethral resection of bladder tumour. A proportion of patients can avoid transurethral resection of bladder tumour completely, reducing costs and morbidity, given the much lower cost of magnetic resonance imaging and biopsy compared to transurethral resection of bladder tumour. FUTURE WORK: Further work to cross-correlate with the recently developed Vesical Imaging-Reporting and Data System will improve accuracy and aid dissemination. Longer follow-up to examine the effect of the pathway on outcomes is also required. Incorporation of liquid deoxyribonucleic acid-based biomarkers may further improve the quality of decision-making and should also be investigated further. STUDY REGISTRATION: This study is registered as ISRCTN 35296862. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135775) and is published in full in Health Technology Assessment; Vol. 28, No. 42. See the NIHR Funding and Awards website for further award information
Synthetic 4D CT for Adaptive MR-Guided Radiotherapy Treatment on an MR-Linac
No full textPurpose: To investigate and develop synthetic CT (synCT) methods for adaptive MR-guided radiotherapy of lung cancer on a 1.5T MR-Linac. This application is challenging due to 1) respiratory motion, 2) rapidly decaying MRI signal in lung tissue, 3) complex tissue-density structure in the thorax, and 4) the need for fast acquisition and reconstruction methods.
Objectives: Develop a synCT technique which 1) is respiratory resolved (4D), 2) employs ultrashort echo time (UTE) imaging to minimise signal loss related to lung’s fast MRI relaxation parameters, 3) uses a machine-learning based approach to generate synCT, and 4) performs image acquisition and reconstruction in a clinically feasible time frame.
Methods: A UTE-Dixon sequence was developed on an Elekta Unity MR-Linac and used to acquire data for 13 lung-cancer patient volunteers who underwent 4D-CT as part of their workup. To allow for offline reconstruction of UTE images, the gradient system transfer function (GSTF) of the MR-Linac was measured with a phantom-based approach and used to correct k-space trajectories. Self-navigation, and two iterative, compressed sensing algorithms were used to reconstruct 4D UTE-Dixon, fat, and water images. For each patient, 4D-CT images were collected and used with 4D UTE/fat/water images to train a cycle-GAN to generate synCT. One synCT image volume was evaluated by comparison of Hounsfield units and dose metrics for a 4D-CT of the same patient. To accelerate a motion-compensated 4D-MRI reconstruction technique, a convolutional neural network for fast image registration was trained using 4D abdominal data acquired on the MR-Linac and compared with a Demons registration algorithm.
Results: Acquisition, reconstruction, and generation methods for 4D synCT of the thorax were demonstrated using MR-Linac data. Measuring Hounsfield units in the cardiac blood yielded 40.3+/-33.5 vs 38.0+/-11.5 (mean+/-stdv) The machine-learning based registration model performed well and was 48× faster than a standard Demons registration algorithm. The methods developed in this work could be used to further develop the cycle-GAN approach and validate dose metrics across a range of patients
The role of maintenance therapy following autologous stem cell transplantation in newly diagnosed multiple myeloma: Considerations on behalf of the Chronic Malignancies Working Party of the EBMT.
Get PDFRecent treatment advancements in multiple myeloma have led to significant improvements in patient outcomes. Maintenance therapy following autologous haematopoietic stem cell transplantation (AHCT) is now standard of care and has been demonstrated to prolong and deepen treatment responses. Currently, lenalidomide remains the single agent that has been approved for maintenance post-AHCT in Europe and the USA which, if tolerated, is continued until disease progression. The treatment landscape is rapidly expanding however, and the optimal personalised maintenance approach for a patient is becoming more complex. Treatment outcomes for patients with high-risk disease remain poor and choice of maintenance in this population also remains unclear. This review article evaluates up-to-date literature regarding established maintenance approaches. It further analyses ongoing studies exploring maintenance regimens using combination and novel agents, approaches to maintenance in patients with cytogenetic high-risk disease and minimal residual disease response-adapted strategies that reflect the current evolving treatment paradigm