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Climate change impacts and sustainability integration among breast international group members.
No full textBACKGROUND: Integration of sustainability measures into clinical research would translate into less healthcare related climate impacts. METHODS: We assessed climate change impacts, existing sustainability engagement, and challenges and facilitators to climate change mitigation strategies among Breast International Group (BIG) members. A 30 item web based survey assessing climate impacts, sustainability engagement, challenges to and facilitators of engagement, and sustainability integration in funding applications was developed, and circulated electronically between November 2023 and March 2024. RESULTS: Thirty four members (research groups and data centres) and participating sites across 5 continents, and BIG headquarters responded. Twenty six responses were received from 21 organisations, 20 from 17 participating sites. No responses were obtained from 28 groups. Trial conduct at a third of member groups had been impacted by climate change impacts such as destroyed infrastructure. 78 % of groups agreed that sustainability should feature in future funding applications. Most respondents engaged in sustainability initiatives at a host institute and organisational level. However, 39 % of coordinating centres and 65 % of representative sites had none within clinical trials conducted by their organisation. The majority of respondents foresaw challenges to sustainability engagement including competing time pressure, staff attitudes and resource constraints. Of nine potential facilitators to engagement, funding, an evidence base for sustainable research practice and training were the leading themes. CONCLUSION: In the first global survey of its kind, a third of respondents reported that climate change had impacted trial conduct. Integration of sustainability measures was absent in a significant minority. Funding and dedicated resourcing would facilitate increased engagement in cancer clinical trials
Extending the duration of endocrine treatment for early breast cancer: patient-level meta-analysis of 12 randomised trials of aromatase inhibitors in 22 031 postmenopausal women already treated with at least 5 years of endocrine therapy
No full textAn Fc-Engineered Glycomodified Antibody Supports Proinflammatory Activation of Immune Effector Cells and Restricts Progression of Breast Cancer.
No full textUNLABELLED: Fc engineering to enhance antibody effector functions harbors the potential to improve therapeutic effects. Understanding FcγR expression and distribution in the tumor microenvironment prior to and following treatment may help guide immune-engaging antibody design and patient stratification. In this study, we investigated FcR-expressing immune effector cells in HER2+ and triple-negative breast cancers (TNBC), including neoadjuvant chemotherapy-resistant disease. FcγRIIIa expression, FcγRIIIa+ NK cells, and classically activated (M1-like) macrophages correlated with improved anti-HER2 antibody efficacy. FcγRIIIa protein and FcγRIIIa+ NK cells and macrophages were present in primary TNBC and retained in treatment-resistant tumors. FcγRIIIa was spatially associated with folate receptor alpha-positive (FRα+) tumor areas at baseline and in residual tumors following neoadjuvant chemotherapy. Wild-type and Fc-engineered antibodies recognizing two breast cancer-associated antigens, HER2 and the emerging TNBC target FRα, were designed and generated to have increased FcγRIIIa-expressing effector cell engagement. The combination of glycoengineering, including fucose removal from the N-linked Fc glycan, and Fc point mutations greatly increased antibody affinity for and retention on FcγRIIIa. The Fc-engineered antibodies enhanced immune effector activity against HER2+ breast cancer and TNBC, altering proinflammatory cytokine production by NK cells and tumor-conditioned macrophages and skewing macrophages toward proinflammatory states. Furthermore, the Fc-engineered antibodies restricted orthotopic HER2+ and FRα+ breast cancer xenograft growth at doses suboptimal for equivalent wild-type antibodies and recruited FcγRIIIa-expressing cells into tumors. Antibody design through combined glycoengineering and Fc point mutations to enhance FcγRIIIa engagement of tumor-infiltrating effector cells may be a promising strategy for developing therapies for patients with aggressive and treatment-resistant breast cancers. SIGNIFICANCE: Assessment of Fc receptors and immune cells in breast cancer enables development of tailored engineering strategies for tumor-targeting monoclonal antibodies with enhanced immune-stimulating and anticancer attributes by combining glycoengineering and Fc mutations
RIPK1 is required for ZBP1-driven necroptosis in human cells
No full textNecroptosis initiated by the host sensor Z-NA binding protein 1 (ZBP1) is essential for host defense against a growing number of viruses, including herpes simplex virus 1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated necroptosis, is unclear. Here, we show that ZBP1-induced necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The receptor-interacting protein (RIP) homology interaction motif (RHIM) in RIPK3 is responsible for this difference between the 2 species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in necroptosis, with important implications for treating human diseases.</jats:p
Advances in understanding and targeting eIF4E activity
No full textEukaryotic translation initiation factor 4E (eIF4E) has long been recognised as a pivotal regulator of cap-dependent protein synthesis initiation. More recently, eIF4E has emerged as a multifunctional factor proposed to influence various aspects of RNA metabolism, including nuclear export of mRNA to the cytoplasm. Its versatile roles are largely attributed to its ability to bind the methyl-7-guanosine cap (m7G-cap) of mRNAs and participate in critical protein–protein interactions. Deregulated eIF4E expression or activity has been implicated in several diseases, but it is most prominently studied as an oncogene where its activity can drive cancer onset, progression and drug resistance. Consequently, eIF4E is a highly attractive target for the development of novel anti-tumour therapeutics. Recent advancements have provided new insights into the mechanism of action of eIF4E, leveraging fragment-based compound screening and genetically modified cell models to identify and characterise binding sites on this challenging-to-drug protein target. In this review, we summarise the multiple roles of eIF4E and features that underpin its activity in both the cytoplasm and nucleus, and the key findings related to the modulation of its activity and therapeutic potential.</jats:p
International Consensus Guideline on Delineation of the Clinical Target Volumes at Different Dose Levels for Nasopharyngeal Carcinoma (2024 Version).
No full textPURPOSE: Radiation therapy planning for nasopharyngeal carcinoma is one of the most challenging tasks for radiation oncologists due to the notoriously narrow therapeutic margin. The first International Guideline (IG-2018 Version) has served as a practical guide for contouring clinical target volumes (CTVs). With increasing data on locoregional extension patterns and outcomes from studies on optimizing CTV and doses, an updated International Guideline is pressingly needed to provide a reference for enhancing precision. METHODS AND MATERIALS: A comprehensive literature review was conducted to assess existing guidelines and emerging data related to contouring. A preliminary questionnaire was distributed to 30 international experts (from 26 centers in 14 countries/regions) with extensive experience in nasopharyngeal carcinoma treatment, aiming to capture diverse practices and opinions. Following initial voting and iterations, a comprehensive survey was prepared for consensus building. RESULTS: The initial questionnaire revealed marked variations in clinical practices related to CTV contouring and prescribed doses among experts. The final Delphi survey consisted of 58 questions: 20 (34%) parameters attained consensus (≥75% agreement) and 32 (55%) attained agreement (60%-74% agreement). In the current guideline (IG-2024), 36 parameters involved changes/clarifications compared with IG-2018. The major differences focus on the use of postinduction chemotherapy gross tumor volume (except in patients with advanced extranodal extension) for CTV(p/n) to 70 Gy equivalent, stepwise refinement of elective coverage to ipsilateral anatomical structures for eccentric primary tumor, selective coverage of nodal levels, and a lower elective dose of 50 Gy equivalent. CONCLUSIONS: Amidst the challenges of diverging practices, a comprehensive consensus guideline has been devised based on updated evidence and collective agreement among international experts. This serves as a practical reference for optimal target coverage at different dose levels to maximize locoregional control while minimizing toxicities and guiding principles for generating automated contouring programs to enhance standardization
Radiation-induced extracellular matrix remodelling drives prognosis and predicts radiotherapy response in muscle-invasive bladder cancer.
No full textMuscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but have not been studied in MIBC. Here, we aimed to characterise the impact of radiation on the ECM composition of MIBC. Three MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer cells and immunofluorescence to investigate changes in the morphology and number of ECM fibres. We evaluated the RNA expression of identified ECM proteins (FN1, COL5A1, COL1A1, TNF6AIP6, FLG) in one cystectomy (TCGA-BLCA, n=397) and two radiotherapy (BC2001, n=313; BCON, n=151) cohorts. There were 613 proteins affected by radiation (padj2 or <-2), 68 of which were ECM-associated proteins. There was a general increase in proteases and protease regulators but heterogeneity across cell lines. Enrichment analysis showed ECM organisation was the primary pathway affected. Immunofluorescence confirmed radiation affected ECM structure, generally, reducing the number, length and width of fibres. Five ECM genes of interest were identified (COL1A1, COL5A2, FN1, FLG, TNFAIP6), constituting an ECM signature. High FN1, COL1A1, TNF6AIP6 mRNA levels and ECM signature scores were independent poor prognostic markers, while FLG mRNA expression independently predicted radiotherapy benefit in a meta-analysis (n=861). We found high COL1A1 expression levels predicted hypoxia-modifying treatment benefit. Prognostic significance of COL5A2, FN1 and the ECM signature was dependent on patients harbouring TP53-mutations. Radiation alters the composition and structure of the ECM produced by MIBC. As a proof-of-concept, we showed that radiation-affected ECM genes are independent prognostic and predictive markers of radiotherapy benefit in MIBC. Future studies should validate these radiation-induced ECM changes in clinical samples, and explore the role of FLG in radioresistance
Quantitative and automatic plan-of-the-day assessment to facilitate adaptive radiotherapy in cervical cancer.
No full textObjective.To facilitate implementation of plan-of-the-day (POTD) selection for treating locally advanced cervical cancer (LACC), we developed a POTD assessment tool for CBCT-guided radiotherapy (RT). A female pelvis segmentation model (U-Seg3) is combined with a novel quantitative standard operating procedure (qSOP) to identify optimal and acceptable plans.Approach.The planning CT[i], corresponding structure set[ii], and manually contoured CBCTs[iii] (n= 226) from 39 LACC patients treated with POTD (n= 11) or non-adaptive RT (n= 28) were used to develop U-Seg3, an algorithm incorporating deep-learning and deformable image registration techniques to segment the low-risk clinical target volume (LR-CTV), high-risk CTV (HR-CTV), bladder, rectum, and bowel bag. A single-channel input model (iii only, U-Seg1) was also developed. Contoured CBCTs from the POTD patients were (a) reserved for U-Seg3 validation/testing, (b) audited to determine optimal and acceptable plans, and (c) used to empirically derive a qSOP that maximised classification accuracy.Main results.The median (interquartile range) dice similarity coefficient (DSC) between manual and U-Seg3 contours was 0.83 [0.80], 0.78 [0.13], 0.94 [0.05], 0.86 [0.09], and 0.90 [0.05] for the LR-CTV, HR-CTV, bladder, rectum, and bowel. These were significantly higher than U-Seg1 in all structures but bladder. The qSOP classified plans as acceptable if they met target coverage thresholds (LR-CTV⩾99%, HR-CTV⩾99.8%), with lower LR-CTV coverage (⩾95%) sometimes allowed. The acceptable plan minimizing bowel irradiation was considered optimal unless substantial bladder sparing could be achieved. With U-Seg3 embedded in the qSOP, optimal and acceptable plans were identified in 46/60 and 57/60 cases.Significance.U-Seg3 outperforms U-Seg1 and all known CBCT-based segmentation models of the female pelvis both in terms of scope and accuracy (median DSC improvement ranging from 0.03-0.06). The tool combining U-Seg3 and the qSOP identifies optimal plans with equivalent accuracy as two observers. In an implementation strategy whereby this tool serves as the second observer, plan selection confidence and decision-making time could be improved whilst simultaneously reducing the required number of POTD-trained radiographers by 50%
Advancing equitable access to innovation in breast cancer.
No full textThis manuscript critically examines the challenges associated with the design and conduct of academic global breast cancer trials outside the influence of pharmaceutical companies, leveraging insights from the Breast International Group (BIG). In the past 4 decades significant declines in breast cancer mortality have occurred, partly related to industry-academic clinical and translational partnerships with long term study follow up. However, in the past decade these partnerships have largely uncoupled. The increasing complexity and non-alignment of trials, funding constraints, regulatory complexity, declining academic freedom, lack of transparency, and lack of affordability of new agents have become key barriers to equitably improving cancer outcomes. Industry research expenditure in the United States is now 5 fold greater than publically funded academic research. To address these challenges, we advocate for patient centred systemic reforms, with trials balancing commercial interests with public health imperatives. These reforms should include equitable research funding models, streamlined international clinical trial regulatory processes, and increased collaboration across diverse stakeholders. Practical solutions to enhance global trial accessibility and efficacy include leveraging digital technologies, artificial intelligence, real world data, decentralizing clinical trial infrastructure, and embedding translational research frameworks across countries
Defining benchmark values for outcomes of comprehensive resection of primary retroperitoneal liposarcoma: a retrospective multicenter study.
No full textBACKGROUND: Comprehensive resection represents the standard of care for patients affected by retroperitoneal well- or dedifferentiated liposarcoma (WDLPS/DDLPS). However, reference values to indicate the best achievable results are currently lacking. As such, the study aimed to define clinically relevant benchmark values for intra- and postoperative outcomes of patients undergoing comprehensive resection for primary retroperitoneal WDLPS/DDLPS. METHODS: The international, prospectively maintained Retroperitoneal Sarcoma Registry (RESAR; NCT03838718) was used to calculate benchmark values for 22 outcomes, including intraoperative factors, and rates of complications, recurrence and survival. Only low-risk patients undergoing comprehensive resection for WDLPS/DDLPS at high-volume centers between 1st January 2017 and 31st December 2021 were used to calculate the benchmark values. Specifically, "low risk" was defined as age <75 years, with minimal comorbidities, and undergoing a "standard" comprehensive resection including at least colon and kidney with or without other organs-excluding those associated with significant morbidity (e.g., pancreas). Benchmark values were defined based on the 25th or 75th percentiles of the center-level data. To validate the benchmark values, these were applied to two cohorts expected to have inferior outcomes, which were defined by changing one of the exclusion criteria; namely those treated in low-volume centers, and those with American Society of Anesthesiologists (ASA) score ≥3 ("ASA ≥ 3"). FINDINGS: Of the 1510 patients undergoing surgery, 147 met the inclusion criteria and were included in the benchmarking analysis. This identified benchmark values including: median duration of surgery ≤278 min, intraoperative packed red cell transfusion rate ≤30%, R0/R1 resection rate ≥89%, median length of hospital stay ≤15 days, reoperation rate ≤13%, major postoperative complication rate ≤21%, and 90-day postoperative mortality/failure-to-rescue rates of 0%. The "low-volume centers" cohort failed to meet 10 of these benchmarks, including duration of surgery (median: 293 vs. ≤278 min), R0/R1 resection rate (82% vs. ≥ 89%), major postoperative complication rate (35% vs. ≤21%), and reoperation rate (35% vs. ≤13%), whilst the "ASA ≥ 3" cohort failed to meet seven benchmarks. INTERPRETATION: These novel benchmark values can act as reference values to which sarcoma centers or individual surgeons can compare, which may help to identify performance gaps and improve the quality of care. FUNDING: "5 x mille" fund for healthcare research (Italian Ministry of Health)