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Characterising the proteomic landscape of ultra-rare soft tissue sarcomas
No full textUltra-rare soft tissue sarcomas (STS) are a group of 56 understudied, molecularly distinct STS histotypes that account for 20% of all STS cases. The current standard of care is largely a ‘one size fits all’ approach, with few targeted therapy options approved for specific ultra-rare STS histotypes. Due to the rarity of these cases, the biology of many of these histotypes are poorly understood and these patients are commonly under-represented in STS clinical trials. This has led to delays in the development of effective targeted therapies for these patients, leading to no improvement in prognosis in recent decades. To address this unmet need, I collated the largest known cohort of ultra-rare STS cases, consisting of 288 formalin-fixed paraffin embedded patient samples representing 14 ultra-rare STS histotypes. To better characterise the disease biology of ultra-rare STS, I performed comprehensive proteomic profiling by mass spectrometry to understand the similarities and differences between histotypes at protein level and pathway gene set level. New molecular subtypes of ultra-rare STS were identified based on proteomics and biological pathway data, giving insight to patients with similar disease biology. This may help identify patients that could benefit from basket trials, and the type of pathways that may be targetable for new treatments. Associations between protein and gene expression with other clinicopathological variables, such as anatomical site and patient age were also evaluated. This led to the identification of enriched pathways that were characteristic in patients with specific features, such as in adolescents and young adults, including markers that may be indicative of patient progression and outcomes. Heterogeneity within epithelioid sarcoma, an STS histotype that I have a larger number of cases for, will also be evaluated. Epithelioid sarcomas are known to have two distinct subtypes, distal and proximal, but little is known about their differences at a molecular level. Additionally, a heterogeneous response to targeted treatments has been observed across epithelioid sarcoma patients in the clinic, thus understanding intra-subtype molecular differences within this histotype will be essential to identify patients more likely to respond to standard of care and targeted therapies
Clinical trials for patients with salivary gland cancers: A systematic review of worldwide registers and an evaluation of current challenges.
No full textBACKGROUND: Clinical trials (CT) are crucial for generating scientific evidence and improving clinical outcomes, but they can be challenging in the context of rare cancers. Salivary gland cancers (SGC) are rare and heterogeneous tumors, without standard-of-care approved systemic therapies. We analyzed completed and ongoing CTs to assess the current state of clinical research activity in the field. METHODS: ClinicalTrials.gov, WHO-ICTRP, HealthCanadaCT were searched for antineoplastic pharmacological and interventional CT involving patients with SGC from the trials database creation until August 6th, 2024. CT characteristics and status were collected. RESULTS: 134 clinical trials met inclusion criteria. Of these, 78 % were sponsored by non-industry entities. 49 % were conducted at only one site, and 61 % at up to five centers. Only 25 trials (19 %) were multinational, being 15 industry-sponsored, a significantly higher proportion compared to non-industry-sponsored trials(p < 0.01). 16 % CTs were umbrella or basket, and 6 % were randomized, again predominantly industry-sponsored(p < 0.01). Regarding SGC-specific trials, 32 % were open to all patients with SGC, regardless of specific histology. Patients with adenoid cystic, salivary duct, and mucoepidermoid carcinoma had access to 92 %, 66 % and 62 % of trials, respectively. 88 % CT targeted palliative setting, and 38 % incorporated predictive biomarkers. Tyrosine kinase inhibitors were the most studied therapy(26 %), followed by immunotherapy(15 %), chemotherapy and antibody-drug conjugate(12 % each) and androgen-blockade(8 %), among others. CONCLUSION: Clinical research for patients with SGC relies mainly in non-industry organisations, most of them limited to run trials in one to five sites, in a single country. Further collaboration between investigators is needed, as well as reconsidering inclusion criteria and trial designs
An open-source repository-based tool for quality control of imaging protocol compliance: demonstration in a multicentre MRI study.
No full textOBJECTIVES: Clinical translation of advanced MRI techniques can be hindered by the challenges of performing standardized multicentre imaging trials. This work aims to develop and demonstrate an automated tool for monitoring imaging protocol deviations, enabling corrective action to be taken. METHODS: A Python-based tool, integrated into the imaging repository XNAT, was developed to compare DICOM series with an agreed imaging protocol, highlighting missing series and parameter deviations. This was demonstrated through retrospective analysis of a prospectively acquired dataset from a ten-site whole-body (WB) MRI study of patients with multiple myeloma. The acquired data were compared to the relevant radiological guidelines and to the site-specific imaging protocols agreed for the study. RESULTS: The rate of technical software failure was 0% across 174 examinations from 10 sites. The clinical guidelines were followed in 87.9% of examinations and compliance with the site-specific imaging protocol was greater than 75.0% for all parameters. Common deviations included number of averages for diffusion-weighted imaging (DWI) and repetition time for DWI and Dixon: 85.2%, 81.7%, and 75.1%, respectively. There was a statistically significant correlation between protocol compliance and overall exam radiological image quality. CONCLUSIONS: Repository-integrated software is presented for automated monitoring of imaging protocol compliance to support standardization in multicentre studies and clinical translation. ADVANCES IN KNOWLEDGE: This study presents a novel open-source repository-integrated software tool for automatically monitoring compliance with the expected imaging protocol. Standardized acquisition protocols are crucial in multicentre imaging studies and this tool has the potential to enhance research outcomes and support clinical translation
Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors.
No full textDesmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSRCT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP inhibitors (PARPi) and ataxia-telangiectasia and Rad3-related inhibitors (ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically relevant models of DSRCT, including cell lines, a patient-derived xenograft-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2-M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cyclic GMP-AMP synthase-stimulator of IFN genes innate immune pathway and cell-surface expression of PD-L1. Taken together, these findings point toward a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT. Significance: EWS-WT1, the unique oncogenic driver of desmoplastic small round cell tumors, confers sensitivity to PARP and ATR inhibitors, supporting the potential of these drugs in treating patients with this aggressive sarcoma subtype
The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models.
No full textReovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological or genetic inhibition of PARP-1 abrogates this PARylation and enhances extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Interaction between PARP-1 and RIG-I induced by treating RT3D-infected cells with talazoparib activates downstream IFN-β and TNF/TRAIL production to amplify the therapeutic effect through positive feedback. Furthermore, the effect of RT3D-talazoparib combination is phenocopied by non-viral ds-RNA therapy and RIG-I agonism. In vivo, mouse tumour model results show that RT3D/talazoparib combination regimen induces complete control of inoculated tumour as well as protection from subsequent tumour rechallenge with the, with accompanied innate and adaptive immune activation
Surgical margins in breast conserving surgery for ductal carcinoma in situ of the breast and clinical outcomes: a national audit with long term follow-up.
No full textBACKGROUND: Optimal surgical margin width in breast conserving surgery (BCS) for ductal carcinoma in situ (DCIS) is not established. The United Kingdom (UK) Association of Breast Surgery (ABS) recommended a 1 mm margin, whereas a minimum of 2 mm has been recommended in the United States of America (USA). This paper uses precise histological margin width data from UK national datasets to understand the impact of surgical margins on time to recurrence (TTR). METHODS: Patients were included if aged ≥45-years with a new diagnosis of DCIS alone, between 2003 and 2014, within the English National Health Service (NHS) Breast Screening Programme. Primary treatment included BCS and a minimum histological excision margin width recorded. Exclusion criteria included: prior history of DCIS; prior history of invasive cancer or its diagnosis within 3-months of initial surgical treatment for DCIS. Data was extracted from NHS England National Disease Registration Service (NDRS), ABS and Sloane Project audits. FINDINGS: 16,907 patients diagnosed with DCIS having definitive BCS surgery were identified between 2003 and 2014. TTR was found to be significantly shorter for patients with surgical margins <1 mm vs ≥ 1 mm (adjusted hazard ratio (aHR) = 1·32; 95% (confidence interval) CI:1·06-1·63; p = 0·012); <2 mm vs ≥ 2 mm (aHR = 1·19; 95% CI:1·05-1·35; p = 0·0062) and ≥1-<2 mm vs ≥ 2 mm (aHR = 1·18; 95% CI:1·01-1·38; p = 0·032). There was no evidence that increasing the surgical margin width beyond 2 mm significantly improved TTR (aHR = 0·96; 95% CI: 0·86-1·08; p = 0·52 for ≥5 mm vs ≥ 2-<5 mm). The rate of recurrence across 14 years following BCS + radiotherapy was 1·2% per annum, 2129 (13%) patients had a recurrence of which 78% were invasive breast cancers. INTERPRETATION: Patients with DCIS with histological margins of <2 mm, adjusted for other clinical factors, have significantly worse TTR compared to margins ≥2 mm. These findings may inform optimum treatment of patients with DCIS. FUNDING: An ABS grant covered the cost of data extraction by NHS England and medical writing assistance. The latter was provided by Edge Health, supervised by the co-authors
Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma.
No full textPURPOSE: Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. METHODS: Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. RESULTS: Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. CONCLUSION: In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making
Therapy de-escalation for testicular cancer (THERATEST): A multi-centre observational cohort feasibility study of de-escalation therapies for good prognosis stage II germ cell tumours.
No full textBACKGROUND: Standard of care (SOC) treatments for International Germ Cell Cancer Collaborative Group (IGCCCG) good prognosis stage II germ cell tumours (GCT) involve primary orchidectomy followed by combination chemotherapy for both seminoma and non-seminomatous germ cell tumours (NSGCT). Alternatively, external beam radiotherapy may be used for seminoma and retroperitoneal lymph node dissection (RPLND) for NSGCT. While these treatments achieve high cure rates, they are associated with significant toxicities. De-escalation strategies including three cycles of Carboplatin AUC10 or robotic RPLND with or without adjuvant chemotherapy have demonstrated potential to reduce treatment-related toxicity in stage II seminoma while preserving oncological efficacy. However, these approaches are not widely adopted due to limited prospective comparative trials. STUDY DESIGN: The THERATEST trial is a prospective multicentre observational feasibility study evaluating participants receiving SOC treatments for good prognosis stage II seminoma and NSGCT or de-escalated treatments for stage II seminoma. ENDPOINTS: The primary endpoints are to assess feasibility of recruitment and retention. Secondary endpoints include assessing health-related quality of life (HRQOL), sexual function and satisfaction, progression-free survival (PFS), overall survival (OS) and safety and treatment-related complications. PATIENTS AND METHODS: Thirty participants with good prognosis stage II seminoma or NSGCTs will be recruited over 18 months into two cohorts: de-escalation arm and SOC arm. The de-escalation cohort will receive either Carboplatin AUC10 or robotic RPLND with or without adjuvant therapy depending on institutional SOC. Participants who decline or are ineligible for de-escalation will receive SOC treatment: combination chemotherapy or radiotherapy for seminoma and combination chemotherapy for NSGCT. All participants will be followed for two years post-treatment or until withdrawal. Data collection includes recruitment and retention rates, disease status, surgical outcomes, adverse events and patient-reported outcomes using validated questionnaire: EORTC QLQ-TC26, EORTC QLQ-C30, Brief Male Sexual Function Inventory (BMSFI) and additional enquiries on anejaculation. COORDINATING CENTRE: THERATEST Trial Coordinator, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, Old Anatomy Building, Charterhouse Square, London, EC1M 6BQ|T: 0207882 8497|E: [email protected]. TRIAL REGISTRATION NUMBER: ISRCTN61007118
The importance of standardization and challenges of dosimetry in conventional preclinical radiation biology research.
No full textTo fully exploit the prospects presented by the increasing focus on biological approaches for enhancing radiotherapy outcomes, improvements in repeatability and translatability of radiobiological and preclinical studies are required. This requires the development and adoption of appropriate dosimetric standards and reproducible approaches to increase confidence in the studies, enabling inter-laboratory validation and facilitating clinical translation. An Institute of Physics and Engineering in Medicine (IPEM) working party reviewed the current status and challenges associated with dosimetry of medium-energy X-rays and make recommendations with the aim to optimize the potential clinical significance of radiobiological preclinical investigations. The paper discusses the currently available resources with technical recommendations for performing dosimetry in medium-energy X-rays, along with the consequences of lack of standardization and implications of dose inhomogeneity. It is clear that there is still a gap in understanding the needs for standardization of dosimetric aspects of preclinical and radiobiological studies. It is recommended that these radiobiology studies should be conducted in partnership with medical/radiation physicists. This collaboration ensures the correct utilization of suitable dosimetry systems, thus guaranteeing accuracy and consistency of dose delivery. Appropriate calibration and traceability to national/international standards laboratory, along with regular quality assurance of radiation devices, are paramount to reproducibility. Additionally, it is critical that experimental details and associated dosimetry are sufficiently reported to ensure accurate replication that enables reanalysis including evaluation of dose distributions. Increasing awareness among the researchers and the funding bodies was identified as a crucial step to improve translatability and appropriate resources are budgeted to increase the value for money of research proposals. The proposed recommendations will serve as a vital resource for researchers, encouraging uniformity in experimental design and improving the translatability of preclinical research to clinical settings