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Risk of hematological malignancies from CT radiation exposure in children, adolescents and young adults.
No full textOver one million European children undergo computed tomography (CT) scans annually. Although moderate- to high-dose ionizing radiation exposure is an established risk factor for hematological malignancies, risks at CT examination dose levels remain uncertain. Here we followed up a multinational cohort (EPI-CT) of 948,174 individuals who underwent CT examinations before age 22 years in nine European countries. Radiation doses to the active bone marrow were estimated on the basis of body part scanned, patient characteristics, time period and inferred CT technical parameters. We found an association between cumulative dose and risk of all hematological malignancies, with an excess relative risk of 1.96 (95% confidence interval 1.10 to 3.12) per 100 mGy (790 cases). Similar estimates were obtained for lymphoid and myeloid malignancies. Results suggest that for every 10,000 children examined today (mean dose 8 mGy), 1-2 persons are expected to develop a hematological malignancy attributable to radiation exposure in the subsequent 12 years. Our results strengthen the body of evidence of increased cancer risk at low radiation doses and highlight the need for continued justification of pediatric CT examinations and optimization of doses
A tailored approach to horizon scanning for cancer medicines.
No full textBACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement. METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type. RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation. CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective. POLICY SUMMARY: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities
Boosting and broadening recruitment to UK cancer trials: towards a blueprint for action.
No full textRecruitment and retention in cancer trials are long-standing issues, exacerbated by the COVID-19 pandemic. The UK National Institute of Health Research and leading clinicians have emphasised the urgency to achieve and surpass prepandemic levels of participation. Data from a recent UK trial demonstrated the impact of COVID-19 and highlighted factors that limited recruitment. In response to this worldwide problem, studies have identified strategies for remediation at the levels of funding, the research environment, study design and trial team-related aspects, yet evidence of progress is lacking. Equality, diversity and inclusivity have become central to UK health and social policy during the 2000s. The need for greater inclusivity in trials has become a particular concern for cancer researchers and funders in the UK and in the USA, in recognition of potential bias in results. In the UK trials, the lack of standardised recording of ethnicity data renders interpretation difficult and caution is required in comparisons with the USA. Recently, the focus of concern has shifted away from the impact of deprivation and low socioeconomic status on trial participation. Barriers created by these factors and their frequent intersection with ethnicity should not be overlooked. The UK has adopted an advisory approach to broadening recruitment, publishing policy documents, guidance and toolkits. In the USA, by contrast, action on inclusion is increasingly mandated. Within the UK paradigm, the cancer research community is strongly encouraged to adopt a coordinated approach towards standardised digital data collection and embed and evaluate innovative, cocreated, locally relevant strategies
Anti-EGFR Antibody-Drug Conjugate Carrying an Inhibitor Targeting CDK Restricts Triple-Negative Breast Cancer Growth.
No full textPURPOSE: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery. EXPERIMENTAL DESIGN: Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts. RESULTS: Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth. CONCLUSIONS: Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease
Exploring the immune microenvironment in small bowel adenocarcinoma using digital image analysis.
No full textBACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy of the small intestine associated with late stage diagnosis and poor survival outcome. High expression of immune cells and immune checkpoint biomarkers especially programmed cell death ligand-1 (PD-L1) have been shown to significantly impact disease progression. We have analysed the expression of a subset of immune cell and immune checkpoint biomarkers in a cohort of SBA patients and assessed their impact on progression-free survival (PFS) and overall survival (OS). METHODS: 25 patient samples in the form of formalin fixed, paraffin embedded (FFPE) tissue were obtained in tissue microarray (TMAs) format. Automated immunohistochemistry (IHC) staining was performed using validated antibodies for CD3, CD4, CD8, CD68, PD-L1, ICOS, IDO1 and LAG3. Slides were scanned digitally and assessed in QuPath, an open source image analysis software, for biomarker density and percentage positivity. Survival analyses were carried out using the Kaplan Meier method. RESULTS: Varying expressions of biomarkers were recorded. High expressions of CD3, CD4 and IDO1 were significant for PFS (p = 0.043, 0.020 and 0.018 respectively). High expression of ICOS was significant for both PFS (p = 0.040) and OS (p = 0.041), while high PD-L1 expression in tumour cells was significant for OS (p = 0.033). High correlation was observed between PD-L1 and IDO1 expressions (Pearson correlation co-efficient = 1) and subsequently high IDO1 expression in tumour cells was found to be significant for PFS (p = 0.006) and OS (p = 0.034). CONCLUSIONS: High levels of immune cells and immune checkpoint proteins have a significant impact on patient survival in SBA. These data could provide an insight into the immunotherapeutic management of patients with SBA
The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.
Get PDFAcute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax
Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.
No full textBACKGROUND: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice. METHODS: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin- cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed. RESULTS: E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin-, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth. CONCLUSIONS: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+ cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types
Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer.
No full textPURPOSE: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. EXPERIMENTAL DESIGN: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib
75P U-PRO-CRM: Designing patient-centred dose-finding trials with patient-reported outcomes
No full textGermline sequencing in men with metastatic castration-resistant prostate cancer from the BARCODE2 study reveals a wide range of pathogenic variants in DNA repair genes.
No full textBACKGROUND: The presence of germline mutations plays an increasingly important role in risk assessment and treatment of prostate cancer (PrCa). Screening for high-risk mutations in subsets of patients is becoming routine. We explore the prevalence of germline genetic mutations in men with metastatic castration-resistant prostate cancer (mCRPC) recruited to the BARCODE2 trial. METHODS: The BARCODE2 trial is a two-part study investigating the response to carboplatin chemotherapy in mCRPC patients carrying a germline variant in a DNA repair gene (DRG). We report interim data from Part 1, in which participants are recruited for germline genetic testing using a customised next-generation sequencing panel consisting of 115 genes. RESULTS: These interim results (N = 220) demonstrate a similar frequency of germline DRG variants in mCRPC patients compared with previously published data (15% detection rate). No significant clinical differences were identified between all carriers and non-carriers, though BRCA2/ATM carriers were found to have a shorter time to mCRPC diagnosis. CONCLUSIONS: Germline pathogenic/likely pathogenic (P/LP) variants in BRCA2 and ATM genes are associated with a shorter time to progression and rarer P/LP variants in other DRG genes may play a role in mCRPC. This justifies the use of routine screening of men with advanced PrCa for germline variants and supports the need for an expanded panel test