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Magnetic Resonance Imaging (MRI) guided radiotherapy for the treatment of locally advanced non-small cell lung cancer
No full textThe use of Magnetic Resonance Imaging (MRI) in radiotherapy (RT) offers significant advantages over Computed Tomography (CT), including superior soft tissue contrast and the opportunity of daily treatment adaptation. For the radical RT or chemoradiotherapy (CRT) treatment of locally advanced non-small cell lung cancer (NSCLC), MR-guided RT (MRgRT) has the potential to enhance the accuracy of RT delivery, reduce treatment-related toxicity and enable treatment intensification. However, the MRgRT workflow in locally advanced NSCLC on MR-guided systems, such as the Unity MR-Linac, is still not fully implemented. MR-guided RT in the thoracic region presents unique challenges including limited clinician experience with target delineation on MRI, suboptimal MR image quality in the thorax, and complexities in dosimetric calculations due to the inherent physiological characteristics of the thorax.
This thesis explores key stages of the MRgRT online workflow for locally advanced NSCLC using the Unity MR-Linac.
In the first section I focus on clinician training on Gross Tumour Volume (GTV) delineation on thoracic MRI. I present the first contouring study to assess interobserver variability (IOV) in GTV delineation, which led to the development of the first international consensus guideline document for GTV contouring in locally advanced NSCLC on MRI. The impact of this guideline document was evaluated through a second contouring study after its circulation.
In the second section I investigate the selection of an optimal thoracic MRI sequence, acquired on the MR Linac, for integration into the MRgRT workflow. I then compare this MRI sequence to Cone Beam CT (CBCT), the imaging standard for Image Guided Radiotherapy (IGRT) on the CT-Linac, in terms of image quality and image registration to the CT planning scan.
Finally, I assess the dosimetric accuracy of using the method of bulk electron density (ED) assignment to generate synthetic CT scans for creating clinically acceptable RT plans for locally advanced NSCLC, on the Unity MR-Linac.
This research work provides critical insights towards implementing the clinical workflow for MRgRT for locally advanced NSCLC, addressing key challenges and paving the way for improved RT treatment strategies
Response adaptive randomisation in clinical trials: Current practice, gaps and future directions.
No full textIntroduction: Adaptive designs (ADs) offer clinical trials flexibility to modify design aspects based on accumulating interim data. Response adaptive randomisation (RAR) adjusts treatment allocation according to interim results, favouring promising treatments. Despite scientific appeal, RAR adoption lags behind other ADs. Understanding methods and applications could provide insights and resources and reveal future research needs. This study examines RAR application, trial results and achieved benefits, reporting gaps, statistical tools and concerns, while highlighting examples of effective practices. Methods: RAR trials with comparative efficacy, effectiveness or safety objectives, classified at least phase I/II, were identified via statistical literature, trial registries, statistical resources and researcher-knowledge. Search spanned until October 2023, including results until February 2024. Analysis was descriptive and narrative. Results: From 652 articles/trials screened, 65 planned RAR trials (11 platform trials) were identified, beginning in 1985 and gradually increasing through to 2023. Most trials were in oncology (25%) and drug-treatments (80%), with 63% led by US teams. Predominantly Phase II (62%) and multi-arm (63%), 85% used Bayesian methods, testing superiority hypotheses (86%). Binary outcomes appeared in 55%, with a median observation of 56 days. Bayesian RAR algorithms were applied in 83%. However, 71% of all trials lacked clear details on statistical implementation. Subgroup-level RAR was seen in 23% of trials. Allocation was restricted in 51%, and 88% was included a burn-in period. Most trials (85%) planned RAR alongside other adaptations. Of trials with results, 92% used RAR, but over 50% inadequately reported allocation changes. A mean 22% reduction in sample size was seen, with none over-allocating to ineffective arms. Conclusion: RAR has shown benefits in conditions like sepsis, COVID-19 and cancer, enhancing effective treatment allocation and saving resources. However, complexity, costs and simulation need limit wider adoption. This review highlights RAR's benefits and suggests enhancing statistical tools to encourage wider adoption in clinical research
Integrated Population Pharmacokinetic, Pharmacodynamic, and Safety Analyses to Inform Dosage Selection in the Clinical Development of the ATR Inhibitor Tuvusertib.
No full textWe present model-informed selection of the recommended dose for expansion (RDE) of investigational oral ATR inhibitor tuvusertib, by integrating clinical pharmacokinetics (PK), pharmacodynamics (PD), and safety data from DDRiver Solid Tumors 301 trial Part A1 (NCT04170153). A population PK (POPPK) model was developed to characterize PK and hemoglobin (HGB) reduction after multicycle treatment was simulated using a semi-mechanistic, multivariate POPPK/PD model of reticulocyte (RET), red blood cell (RBC), and HGB dynamics. A semi-mechanistic PK-efficacy model characterized concentration-dependent tumor growth inhibition (TGI) in ARID1A mutant xenograft models. The clinical exposure-PD relationship was described for phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) as a biomarker of ATR inhibition. POPPK simulations predict the average steady-state concentrations to exceed phosphorylated checkpoint kinase 1 (pCHK1) IC90 at 100-180 mg once daily (QD) and 180 mg QD 2 weeks (w) on/1w off. Exposure-related PD suggested target engagement of ≥80% at ≥130 mg QD. POPPK/PD modeling showed partial HGB recovery and lower rates of Grade ≥3 anemia after multicycle treatment with 180 mg QD 2w on/1w off vs. 130 mg and 180 mg QD. Lesser HGB reduction was predicted for 100 mg QD vs. higher QD doses. Translational modeling indicated no effect of the one-week dosing break on TGI at 180 mg QD. The analysis supports tuvusertib 180 mg QD 2w on/1w off as the RDE and 100 mg QD as the no-regret dose for clinical evaluation. This example underscores the value of integrated quantitative pharmacology analyses to inform dose selection using a totality of evidence approach
Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics.
No full textMolecular glue degraders (MGDs) are small molecules that co-opt the ubiquitin-proteasome system to induce degradation of target proteins, including those considered undruggable. Their discovery remains challenging due to the lack of rational design strategies and limited throughput of unbiased proteome-wide screening approaches. To address this gap, we develop a high-throughput proteomics platform based on label-free, data-independent acquisition mass spectrometry (DIA-MS), enabling integrated proteomics and ubiquitinomics profiling. Screening a diverse set of 100 cereblon (CRBN)-recruiting ligands on this platform leads to identification of a broad array of novel degraders and neosubstrates. Subsequent hit validation and structure-degradation relationship analyses guided by global proteomics reveal highly selective and potent phenyl glutarimide-based degraders targeting previously uncharacterized neosubstrates such as KDM4B, G3BP2 and VCL; none of which contain the classical CRBN β-hairpin degron. These findings underscore the power of unbiased high-throughput proteomics in MGD drug discovery and reveal a substantially expanded CRBN neosubstrate landscape beyond that defined by classical immunomodulatory imid drugs (IMiDs)
Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants.
No full textIMPORTANCE: RET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context. OBJECTIVE: To evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of 383 914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122 640 unrelated individuals from a US health system (Geisinger MyCode cohort, recruited 2004-2020, with follow-up to October 2023) compared medullary thyroid cancer risk in these cohorts with 1078 individuals who were clinically ascertained with suspicion of MEN2 from a UK routine practice. EXPOSURES: RET germline pathogenic variants causing MEN2. MAIN OUTCOMES AND MEASURES: Frequency and the spectrum of pathogenic RET variants, risk of clinically present medullary thyroid cancer, and all-cause mortality without thyroidectomy were assessed using proportions with exact binomial 95% CIs and survival analysis adjusted for age at recruitment and sex. RESULTS: In the UK Biobank, 169 unrelated individuals (mean [SD] age at recruitment, 57.0 [8.1] years; 94 male [55.6%]) had a pathogenic RET variant (prevalence, 0.04% [95% CI, 0.04%-0.05%]). In the US health system-based cohort, 77 unrelated individuals (mean [SD] age at recruitment, 56.2 [17.8] years; 45 female [58.4%]) had a pathogenic RET variant (prevalence, 0.06% [95% CI, 0.05%-0.78%]). The variants were predominantly from the moderate-risk category per American Thyroid Association guidelines (168 individuals [99.4%] and 75 individuals [94.8%], respectively). The Kaplan-Meier estimated medullary thyroid cancer risk by age 75 years in variant carriers in the UK population was 2.2% (95% CI, 0.7%-6.9) and 19.3% (95% CI, 6.4%-30.2%) in US health system cohort. These risks were significantly lower compared with the clinically ascertained cohort with the matched variants (95.7% [95% CI, 82.1%-99.7%]). In the UK Biobank, most variant carriers (166 [98.2%]) did not undergo thyroidectomy, and their all-cause mortality by age 75 years was similar to noncarriers (6.1% [95% CI, 2.7%-13.8%] vs 5.7% [95% CI, 5.6%-5.8%]), with consistent findings in the US health system cohort. CONCLUSIONS AND RELEVANCE: In this cohort study, moderate-risk RET variants were most common in incidental cases. The variants were associated with a substantially lower medullary thyroid cancer risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making
Impact of perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel delivery on postoperative survival in locally advanced oesophagogastric adenocarcinoma.
No full textBACKGROUND: Perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) is the standard of care for locally advanced oesophagogastric adenocarcinoma (LA-OGA) in Western countries. However, completing treatment is challenging for patients, particularly in the postoperative setting. This study investigated the impact of adjuvant chemotherapy (ACT) administration and treatment completion on survival outcomes in patients receiving FLOT. METHODS: Charts of LA-OGA patients treated from 2017 to 2023 were retrospectively reviewed. Survival was analysed using Kaplan-Meier and restricted mean survival time (RMST) analyses, with propensity score matching (PSM) adjustments. Subgroup analyses were stratified by pathological nodal status and tumour regression grade (Mandard TRG). The primary endpoint was 3-year overall survival (OS). RESULTS: The study included 233 patients, among whom 62.4% completed the full perioperative FLOT regimen and 21% did not receive ACT. After PSM adjustment, 3-year OS for patients who completed and those who did not complete perioperative therapy was 69% and 57%, respectively (p = 0.09). The 3-year OS was 81% and 52% for patients who did and did not receive ACT, respectively (p = 0.01). In multivariate analysis, completion of perioperative FLOT was independently associated with improved OS (p = 0.04). Survival improvement with ACT was observed in the ypN-positive subgroup but not in the ypN-negative subgroup. CONCLUSIONS: Perioperative FLOT administration is recommended as the standard of care for LA-OGA. The survival impact of ACT might be influenced by pathological lymph node metastasis
An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.
No full textSplicing factor proline- and glutamine-rich (SFPQ) is an RNA binding protein that broadly regulates RNA metabolism. Although its nuclear roles are well studied, evidence of SFPQ's cytoplasmic functionality is emerging. Altered expression and nuclear-to-cytoplasmic redistribution of SFPQ have been recognized in amyotrophic lateral sclerosis (ALS) pathology, yet the mechanistic bases for these phenomena remain undetermined. We identified altered SFPQ splicing in ALS, increasing the expression of an alternative mRNA isoform lacking a nuclear localization sequence, which we termed "altSFPQ." We find that altSFPQ mRNA contributes to SFPQ autoregulation and is highly unstable yet exhibits context-specific translation with cytoplasm-predominant localization. Notably, reduced canonical SFPQ coincides with increased altSFPQ transcript expression in familial and sporadic ALS models, providing a mechanistic basis for SFPQ nuclear-to-cytoplasmic redistribution in patients with ALS. Last, we observe that the altSFPQ protein has reduced phase separation potential and differential protein binding compared to its canonical counterpart, providing insight into its mechanistic relevance to physiology and ALS pathogenesis
Tumor Evolution Driving Genome Instability, Immune Interactions, and Response to Radiotherapy.
No full textThis review article explores the role of immuno-radiotherapy in the context of genome instability and tumor evolution. Genomic changes in tumors exist in a delicate balance with the immune system, offering evolutionary pathways to adapt and grow but risking provoking an immune response. Rapid developments across both immunotherapy and radiotherapy have raised questions about the potential benefits combination therapy, and how best to identify ideal treatment populations. Here we discuss foundational studies of genomic instability and tumor evolution, how these paradigms translate into immune surveillance and evasion, and subsequently go on to explore recent preclinical and clinical studies of both treatment modalities. Understanding how cancers evolve in the context of the immune system could provide a key insight in delivering better therapies that could overcome treatment resistance
INTERLINK-1: A Phase III, Randomized, Placebo-Controlled Study of Monalizumab plus Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.
No full textPURPOSE: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor treatment and platinum-based chemotherapy are limited. Preliminary data suggested that monalizumab plus cetuximab had clinical activity in R/M HNSCC. PATIENTS AND METHODS: INTERLINK-1 (NCT04590963) was a double-blind, phase III study. Participants with R/M HNSCC who had received immune checkpoint inhibitor therapy and progressed despite platinum-based chemotherapy were randomized 2:1 to monalizumab (750 mg, every 2 weeks) or placebo, plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2, weekly). The primary endpoint was overall survival (OS) in participants with non-oropharyngeal cancer or human papillomavirus (HPV)-negative oropharyngeal cancer (HPV-unrelated analysis set). Secondary endpoints included progression-free survival and objective response rate. RESULTS: At data cutoff, 216 participants were randomized in the HPV-unrelated analysis set: 145 to monalizumab plus cetuximab and 71 to placebo plus cetuximab. Median OS was 8.8 months for monalizumab plus cetuximab versus 8.6 months for placebo plus cetuximab (HR, 1.00; 95% confidence interval, 0.66-1.54); median progression-free survival was 3.6 versus 3.8 months, respectively (HR, 1.11; 95% confidence interval, 0.79-1.57); and the objective response rate was 15.2% versus 23.9%, respectively. INTERLINK-1 was terminated after a preplanned interim analysis showed that futility criteria were met (predetermined futility HR >0.874). Grade 3/4 treatment-related adverse events were reported in 18.3% and 17.2% of participants treated in the monalizumab and placebo arms, respectively. CONCLUSIONS: Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy
Detecting homologous recombination deficiency for breast cancer through integrative analysis of genomic data.
No full textHomologous recombination deficiency (HRD) leads to genomic instability, and patients with HRD can benefit from HRD-targeting therapies. Previous studies have primarily focused on identifying HRD biomarkers using data from a single technology. Here we integrated features from different genomic data types, including total copy number (CN), allele-specific copy number (ASCN) and single nucleotide variants (SNV). Using a semi-supervised method, we developed HRD classifiers from 1404 breast tumours across two datasets based on their BRCA1/2 status, demonstrating improved HRD identification when aggregating different data types. Notably, HRD-positive tumours in ER-negative disease showed improved survival post-adjuvant chemotherapy, while HRD status strongly correlated with neoadjuvant treatment response. Furthermore, our analysis of cell lines highlighted a sensitivity to PARP inhibitors, particularly rucaparib, among predicted HRD-positive lines. Exploring somatic mutations outside BRCA1/2, we confirmed variants in several genes associated with HRD. Our method for HRD classification can adapt to different data types or resolutions and can be used in various scenarios to help refine patient selection for HRD-targeting therapies that might lead to better clinical outcomes