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  • Turning the tide in aggressive lymphoma: liquid biopsy for risk-adapted treatment strategies

    Wang, S.; Mouliere, Florent; Pegtel, D. M.; Chamuleau, M. E. D.; Cancer Research UK National Biomarker Centre, University of Manchester, Wilmslow Road, Manchester, UK (2024)
    Diffuse large B cell lymphoma (DLBCL) exhibits significant biological and clinical heterogeneity that presents challenges for risk stratification and disease surveillance. Existing tools for risk stratification, including the international prognostic index (IPI), tissue molecular analyses, and imaging, have limited accuracy in predicting outcomes. The therapeutic landscape for aggressive lymphoma is rapidly evolving, and there is a pressing need to identify patients at risk of refractory or relapsed (R/R) disease in the context of personalized therapy. Liquid biopsy, a minimally invasive method for cancer signal detection, has been explored to address these challenges. We review advances in liquid biopsy strategies focusing on circulating nucleic acids in DLBCL patients and highlight their clinical potential. We also provide recommendations for biomarkerguided trials to support risk-adapted treatment modalities.
  • Preoperative chemotherapy response and survival in patients with colorectal cancer peritoneal metastases

    Tinsley, Nadina; O'Dwyer, Sarah T; Nagaraju, Raghavendar; Chakrabarty, Bipasha; Braun, Michael; Mullamitha, Saifee; Kamposioras, Konstantinos; Marti-Marti, Francisca; Saunders, Mark; Clouston, Hamish; et al. (2024)
    Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy (HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial response on preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versus NR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected by peritoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM. Perioperative chemotherapy is used in the multimodal treatment of colorectal cancer peritoneal metastases (CRPM). Preoperative chemotherapy response is an independent predictor for overall survival in patients with CRPM. Grade 3-4 adverse events related to mitomycin C (35 mg/m2) and Oxaliplatin (368 mg/m2) heated intraperitoneal chemotherapy are rare (0.5%).
  • State of the art modelling of the breast cancer metastatic microenvironment: where are we?

    Nuckhir, Mia; Withey, David; Cabral, Sara; Harrison, Hannah; Clarke, Robert B; Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Oglesby Cancer Research Building, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M20 4GJ, UK. (2024)
    Metastatic spread of tumour cells to tissues and organs around the body is the most frequent cause of death from breast cancer. This has been modelled mainly using mouse models such as syngeneic mammary cancer or human in mouse xenograft models. These have limitations for modelling human disease progression and cannot easily be used for investigation of drug resistance and novel therapy screening. To complement these approaches, advances are being made in ex vivo and 3D in vitro models, which are becoming progressively better at reliably replicating the tumour microenvironment and will in the future facilitate drug development and screening. These approaches include microfluidics, organ-on-a-chip and use of advanced biomaterials. The relevant tissues to be modelled include those that are frequent and clinically important sites of metastasis such as bone, lung, brain, liver for invasive ductal carcinomas and a distinct set of common metastatic sites for lobular breast cancer. These sites all have challenges to model due to their unique cellular compositions, structure and complexity. The models, particularly in vivo, provide key information on the intricate interactions between cancer cells and the native tissue, and will guide us in producing specific therapies that are helpful in different context of metastasis.
  • ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma

    Lu, Y. T.; Travnickova, J.; Badonyi, M.; Rambow, F.; Coates, A.; Khan, Z.; Marques, J.; Murphy, L. C.; Garcia-Martinez, P.; Marais, Richard; et al. (2024)
    Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.
  • International consensus on fasting terminology

    Koppold, D. A.; Breinlinger, C.; Hanslian, E.; Kessler, C.; Cramer, H.; Khokhar, A. R.; Peterson, C. M.; Tinsley, G.; Vernieri, C.; Bloomer, R. J.; et al. (2024)
    Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: 'fasting' (voluntary abstinence from some or all foods or foods and beverages), 'modified fasting' (restriction of energy intake to max. 25% of energy needs), 'fluid-only fasting,' 'alternate-day fasting,' 'short-term fasting' (lasting 2-3 days), 'prolonged fasting' (≥4 consecutive days), and 'religious fasting.' 'Intermittent fasting' (repetitive fasting periods lasting ≤48 h), 'time-restricted eating,' and 'fasting-mimicking diet' were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.
  • Characterizing replisome disassembly in human cells

    Jones, R. M.; Ruiz, J. H.; Scaramuzza, S.; Nath, S.; Liu, C. Y.; Henklewska, M.; Natsume, T.; Bristow, Robert G; Romero, F.; Kanemaki, M. T.; et al. (2024)
    To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2 LRR1-driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for 'backup'mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes.
  • Automated liquid handling extraction and rapid quantification of underivatized amino acids and tryptophan metabolites from human serum and plasma using dual-column U(H)PLC-MRM-MS and its application to prostate cancer study

    Kipura, T.; Hotze, M.; Hofer, A.; Egger, A. S.; Timpen, L. E.; Opitz, C. A.; Townsend, Paul A; Gethings, L. A.; Thedieck, K.; Kwiatkowski, M.; et al. (2024)
    Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample extraction and processing workflows as well as rapid, sensitive absolute quantification are required to identify candidate biomarkers and to improve screening methods. We developed a validated semi-automated robotic liquid extraction and processing workflow and a rapid method for absolute quantification of 20 free, underivatized AAs and six TRP metabolites using dual-column U(H)PLC-MRM-MS. The extraction and sample preparation workflow in a 96-well plate was optimized for robust, reproducible high sample throughput allowing for transfer of samples to the U(H)PLC autosampler directly without additional cleanup steps. The U(H)PLC-MRM-MS method, using a mixed-mode reversed-phase anion exchange column with formic acid and a high-strength silica reversed-phase column with difluoro-acetic acid as mobile phase additive, provided absolute quantification with nanomolar lower limits of quantification within 7.9 min. The semi-automated extraction workflow and dual-column U(H)PLC-MRM-MS method was applied to a human prostate cancer study and was shown to discriminate between treatment regimens and to identify metabolites responsible for discriminating between healthy controls and patients on active surveillance.
  • Generating synthetic computed tomography for radiotherapy: SynthRAD2023 challenge report

    Huijben, E. M. C.; Terpstra, M. L.; Galapon, A. J.; Pai, S.; Thummerer, A.; Koopmans, P.; Afonso, M.; van Eijnatten, M.; Gurney-Champion, O.; Chen, Z.; et al. (2024)
    Radiation therapy plays a crucial role in cancer treatment, necessitating precise delivery of radiation to tumors while sparing healthy tissues over multiple days. Computed tomography (CT) is integral for treatment planning, offering electron density data crucial for accurate dose calculations. However, accurately representing patient anatomy is challenging, especially in adaptive radiotherapy, where CT is not acquired daily. Magnetic resonance imaging (MRI) provides superior soft-tissue contrast. Still, it lacks electron density information, while cone beam CT (CBCT) lacks direct electron density calibration and is mainly used for patient positioning. Adopting MRI-only or CBCT-based adaptive radiotherapy eliminates the need for CT planning but presents challenges. Synthetic CT (sCT) generation techniques aim to address these challenges by using image synthesis to bridge the gap between MRI, CBCT, and CT. The SynthRAD2023 challenge was organized to compare synthetic CT generation methods using multi-center ground truth data from 1080 patients, divided into two tasks: (1) MRI-to-CT and (2) CBCT-to-CT. The evaluation included image similarity and dose-based metrics from proton and photon plans. The challenge attracted significant participation, with 617 registrations and 22/17 valid submissions for tasks 1/2. Top-performing teams achieved high structural similarity indices (≥0.87/0.90) and gamma pass rates for photon (≥98.1%/99.0%) and proton (≥97.3%/97.0%) plans. However, no significant correlation was found between image similarity metrics and dose accuracy, emphasizing the need for dose evaluation when assessing the clinical applicability of sCT. SynthRAD2023 facilitated the investigation and benchmarking of sCT generation techniques, providing insights for developing MRI-only and CBCT-based adaptive radiotherapy. It showcased the growing capacity of deep learning to produce high-quality sCT, reducing reliance on conventional CT for treatment planning.
  • Enhancing SNV identification in whole-genome sequencing data through the incorporation of known genetic variants into the minimap2 index

    Egor, G.; Artem, K.; Maksim, B.; Gaukhar, Z.; Ekaterina, K.; Vsevolod, Makeev; Evgeny, K.; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, Manchester, M20 4BX, UK. (2024)
    MotivationAlignment of reads to a reference genome sequence is one of the key steps in the analysis of human whole-genome sequencing data obtained through Next-generation sequencing (NGS) technologies. The quality of the subsequent steps of the analysis, such as the results of clinical interpretation of genetic variants or the results of a genome-wide association study, depends on the correct identification of the position of the read as a result of its alignment. The amount of human NGS whole-genome sequencing data is constantly growing. There are a number of human genome sequencing projects worldwide that have resulted in the creation of large-scale databases of genetic variants of sequenced human genomes. Such information about known genetic variants can be used to improve the quality of alignment at the read alignment stage when analysing sequencing data obtained for a new individual, for example, by creating a genomic graph. While existing methods for aligning reads to a linear reference genome have high alignment speed, methods for aligning reads to a genomic graph have greater accuracy in variable regions of the genome. The development of a read alignment method that takes into account known genetic variants in the linear reference sequence index allows combining the advantages of both sets of methods.ResultsIn this paper, we present the minimap2_index_modifier tool, which enables the construction of a modified index of a reference genome using known single nucleotide variants and insertions/deletions (indels) specific to a given human population. The use of the modified minimap2 index improves variant calling quality without modifying the bioinformatics pipeline and without significant additional computational overhead. Using the PrecisionFDA Truth Challenge V2 benchmark data (for HG002 short-read data aligned to the GRCh38 linear reference (GCA_000001405.15) with parameters k = 27 and w = 14) it was demonstrated that the number of false negative genetic variants decreased by more than 9500, and the number of false positives decreased by more than 7000 when modifying the index with genetic variants from the Human Pangenome Reference Consortium.
  • Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in β-phosphoglucomutase

    Cruz-Navarrete, F. A.; Baxter, N. J.; Flinders, Adam J; Buzoianu, A.; Cliff, M. J.; Baker, P. J.; Waltho, J. P.; Cancer Research UK, Manchester Institute, Patterson Building, Manchester, M20 4BX, UK (2024)
    Metabolic regulation occurs through precise control of enzyme activity. Allomorphy is a post-translational fine control mechanism where the catalytic rate is governed by a conformational switch that shifts the enzyme population between forms with different activities. beta-Phosphoglucomutase (beta PGM) uses allomorphy in the catalysis of isomerisation of beta-glucose 1-phosphate to glucose 6-phosphate via beta-glucose 1,6-bisphosphate. Herein, we describe structural and biophysical approaches to reveal its allomorphic regulatory mechanism. Binding of the full allomorphic activator beta-glucose 1,6-bisphosphate stimulates enzyme closure, progressing through NAC I and NAC III conformers. Prior to phosphoryl transfer, loops positioned on the cap and core domains are brought into close proximity, modulating the environment of a key proline residue. Hence accelerated isomerisation, likely via a twisted anti/C4-endo transition state, leads to the rapid predominance of active cis-P beta PGM. In contrast, binding of the partial allomorphic activator fructose 1,6-bisphosphate arrests beta PGM at a NAC I conformation and phosphoryl transfer to both cis-P beta PGM and trans-P beta PGM occurs slowly. Thus, allomorphy allows a rapid response to changes in food supply while not otherwise impacting substantially on levels of important metabolites. A structural study shows that the enzyme beta PGM uses an allomorphically controlled switch that accelerates proline isomerisation to alleviate the wastage of valuable metabolites while allowing the organism to react quickly to changes in food supply.
  • pyRBDome: a comprehensive computational platform for enhancing RNA-binding proteome data

    Chu, L. C.; Christopoulou, N.; McCaughan, H.; Winterbourne, S.; Cazzola, D.; Wang, S.; Litvin, U.; Brunon, S.; Harker, Patrick J; McNae, I.; et al. (2024)
    High-throughput proteomics approaches have revolutionised the identification of RNA-binding proteins (RBPome) and RNA-binding sequences (RBDome) across organisms. Yet, the extent of noise, including false positives, associated with these methodologies, is difficult to quantify as experimental approaches for validating the results are generally low throughput. To address this, we introduce pyRBDome, a pipeline for enhancing RNA-binding proteome data in silico. It aligns the experimental results with RNA-binding site (RBS) predictions from distinct machine-learning tools and integrates high-resolution structural data when available. Its statistical evaluation of RBDome data enables quick identification of likely genuine RNA-binders in experimental datasets. Furthermore, by leveraging the pyRBDome results, we have enhanced the sensitivity and specificity of RBS detection through training new ensemble machine-learning models. pyRBDome analysis of a human RBDome dataset, compared with known structural data, revealed that although UV-cross-linked amino acids were more likely to contain predicted RBSs, they infrequently bind RNA in high-resolution structures. This discrepancy underscores the limitations of structural data as benchmarks, positioning pyRBDome as a valuable alternative for increasing confidence in RBDome datasets.
  • No clear benefit of preventive cranial radiotherapy in childhood Philadelphia-positive acute lymphoblastic leukemia: a retrospective analysis of the EsPhALL2010 study

    Conter, V.; Valsecchi, M. G.; De Lorenzo, P.; Gandemer, V.; Heyman, M.; Saha, Vaskar; Diaz, P.; Li, C. K.; Attarbaschi, A.; Escherich, G.; et al. (2024)
    Not available.
  • IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development

    Thambyrajah, R.; Maqueda, M.; Fadlullah, Muhammad Z; Proffitt, M.; Neo, Wen H; Guillén, Y.; Casado-Pelaez, M.; Herrero-Molinero, P.; Brujas, C.; Castelluccio, N.; et al. (2024)
    Recent findings suggest that Hematopoietic Stem Cells (HSC) and progenitors arise simultaneously and independently of each other already in the embryonic aorta-gonad mesonephros region, but it is still unknown how their different features are established. Here, we uncover I kappa B alpha (Nfkbia, the inhibitor of NF-kappa B) as a critical regulator of HSC proliferation throughout development. I kappa B alpha balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of I kappa B alpha decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, I kappa B alpha deficient HSCs respond with superior activation to in vitro culture and in serial transplantation. At the molecular level, chromatin regions harboring binding motifs for retinoic acid signaling are hypo-methylated for the PRC2 dependent H3K27me3 mark in I kappa B alpha deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a I kappa B alpha-PRC2 axis, which controls retinoic acid signaling. Hematopoietic stem cells are generated during development, though how and when they become dormant long term-HSCs remains unclear. Here they show that retinoic acid receptor levels are regulated by a I kappa B alpha-PRC2 axis in HSCs, and that I kappa B alpha KO mice have HSCs that are fewer in number, but functionally and molecularly more dormant.
  • Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma

    Saner, F. A. M.; Takahashi, K.; Budden, Timothy; Pandey, A.; Ariyaratne, D.; Zwimpfer, T. A.; Meagher, N. S.; Fereday, S.; Twomey, L.; Pishas, K. I.; et al. (2024)
    PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
  • Crowd-sourced benchmarking of single-sample tumor subclonal reconstruction

    Salcedo, A.; Tarabichi, M.; Buchanan, A.; Espiritu, S. M. G.; Zhang, H.; Zhu, K.; Ou Yang, T. H.; Leshchiner, I.; Anastassiou, D.; Guan, Y.; et al. (2024)
    Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability were associated with the performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumor evolution.
  • Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology

    Kinnersley, B.; Sud, A.; Everall, A.; Cornish, A. J.; Chubb, D.; Culliford, R.; Gruber, A. J.; Lärkeryd, A.; Mitsopoulos, C.; Wedge, David; et al. (2024)
    Tumor genomic profiling is increasingly seen as a prerequisite to guide the treatment of patients with cancer. To explore the value of whole-genome sequencing (WGS) in broadening the scope of cancers potentially amenable to a precision therapy, we analysed whole-genome sequencing data on 10,478 patients spanning 35 cancer types recruited to the UK 100,000 Genomes Project. We identified 330 candidate driver genes, including 74 that are new to any cancer. We estimate that approximately 55% of patients studied harbor at least one clinically relevant mutation, predicting either sensitivity or resistance to certain treatments or clinical trial eligibility. By performing computational chemogenomic analysis of cancer mutations we identify additional targets for compounds that represent attractive candidates for future clinical trials. This study represents one of the most comprehensive efforts thus far to identify cancer driver genes in the real world setting and assess their impact on informing precision oncology. Analysis of whole-genome sequencing data from over 10,000 tumor samples spanning 35 cancer types identifies putative driver genes and highlights new therapeutic opportunities.
  • A joint ESTRO and AAPM guideline for development, clinical validation and reporting of artificial intelligence models in radiation therapy

    Hurkmans, C.; Bibault, J. E.; Brock, K. K.; van Elmpt, W.; Feng, M.; David Fuller, C.; Jereczek-Fossa, B. A.; Korreman, S.; Landry, G.; Madesta, F.; et al. (2024)
    BACKGROUND AND PURPOSE: Artificial Intelligence (AI) models in radiation therapy are being developed with increasing pace. Despite this, the radiation therapy community has not widely adopted these models in clinical practice. A cohesive guideline on how to develop, report and clinically validate AI algorithms might help bridge this gap. METHODS AND MATERIALS: A Delphi process with all co-authors was followed to determine which topics should be addressed in this comprehensive guideline. Separate sections of the guideline, including Statements, were written by subgroups of the authors and discussed with the whole group at several meetings. Statements were formulated and scored as highly recommended or recommended. RESULTS: The following topics were found most relevant: Decision making, image analysis, volume segmentation, treatment planning, patient specific quality assurance of treatment delivery, adaptive treatment, outcome prediction, training, validation and testing of AI model parameters, model availability for others to verify, model quality assurance/updates and upgrades, ethics. Key references were given together with an outlook on current hurdles and possibilities to overcome these. 19 Statements were formulated. CONCLUSION: A cohesive guideline has been written which addresses main topics regarding AI in radiation therapy. It will help to guide development, as well as transparent and consistent reporting and validation of new AI tools and facilitate adoption.
  • Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer

    Goyal, L.; Meric-Bernstam, F.; Hollebecque, A.; Valle, Juan W; Morizane, C.; Karasic, T. B.; Abrams, T. A.; Furuse, J.; Kelley, R. K.; Cassier, P. A.; et al. (2024)
    What is this summary about?This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. What were the results?Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. What do the results mean?The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2) What do the results mean?The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.
  • Integrating spatial and morphological characteristics into melanoma prognosis: a computational approach

    Bian, C.; Ashton, Garry; Grant, Megan; Rodriguez, Valeria P; Martin, Isabel P; Tsakiroglou, A. M.; Cook, M.; Fergie, M.; Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK (2024)
    In this study, the prognostic value of cellular morphology and spatial configurations in melanoma has been examined, aiming to complement traditional prognostic indicators like mitotic activity and tumor thickness. Through a computational pipeline using machine learning and deep learning methods, we quantified nuclei sizes within different spatial regions and analyzed their prognostic significance using univariate and multivariate Cox models. Nuclei sizes in the invasive band demonstrated a significant hazard ratio (HR) of 1.1 (95% CI: 1.03, 1.18). Similarly, the nuclei sizes of tumor cells and Ki67 S100 co-positive cells in the invasive band achieved HRs of 1.07 (95% CI: 1.02, 1.13) and 1.09 (95% CI: 1.04, 1.16), respectively. Our findings reveal that nuclei sizes, particularly in the invasive band, are potentially prognostic factors. Correlation analyses further demonstrated a meaningful relationship between cellular morphology and tumor progression, notably showing that nuclei size within the invasive band correlates substantially with tumor thickness. These results suggest the potential of integrating spatial and morphological analyses into melanoma prognostication.
  • Serum tumor markers and outcomes in patients with appendiceal adenocarcinoma

    Yousef, A.; Yousef, M.; Zeineddine, M. A.; More, A.; Fanaeian, M.; Chowdhury, S.; Knafl, M.; Edelkamp, P.; Ito, I.; Gu, Y.; et al. (2024)
    ImportanceSerum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma. ObjectiveTo assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma. Design, Setting, and ParticipantsThis is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023. Main Outcomes and MeasuresAssociation of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival). ResultsA total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9. Conclusions and RelevanceIn this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

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