Clinical relevance of tumour-associated macrophages

Nature Reviews Clinical Oncology, Journal Year: 2022, Volume and Issue: 19(6), P. 402 - 421

Published: March 30, 2022

Language: Английский

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Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2022, Volume and Issue: 19(10), P. 670 - 681

Published: June 8, 2022

Language: Английский

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The Role of Artificial Intelligence in Early Cancer Diagnosis

Cancers, Journal Year: 2022, Volume and Issue: 14(6), P. 1524 - 1524

Published: March 16, 2022

Improving the proportion of patients diagnosed with early-stage cancer is a key priority World Health Organisation. In many tumour groups, screening programmes have led to improvements in survival, but patient selection and risk stratification are challenges. addition, there concerns about limited diagnostic workforces, particularly light COVID-19 pandemic, placing strain on pathology radiology services. this review, we discuss how artificial intelligence algorithms could assist clinicians (1) asymptomatic at cancer, (2) investigating triaging symptomatic patients, (3) more effectively diagnosing recurrence. We provide an overview main approaches, including historical models such as logistic regression, well deep learning neural networks, highlight their early diagnosis applications. Many data types suitable for computational analysis, electronic healthcare records, images, slides peripheral blood, examples these can be utilised diagnose cancer. also potential clinical implications algorithms, currently used practice. Finally, limitations pitfalls, ethical concerns, resource demands, security reporting standards.

Language: Английский

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Cancer evolution: Darwin and beyond

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(18)

Published: Aug. 30, 2021

Review30 August 2021Open Access Cancer evolution: Darwin and beyond Roberto Vendramin orcid.org/0000-0001-7191-4887 Research UK Lung Centre of Excellence, University College London Institute, London, Search for more papers by this author Kevin Litchfield Corresponding Author [email protected] Charles Swanton Evolution Genome Instability Laboratory, The Francis Crick Information Vendramin1, *,1 *,1,2 1Cancer 2Cancer *Corresponding author. Tel: +44 207679 6500; E-mail: 203796 2047; EMBO Journal (2021)40:e108389https://doi.org/10.15252/embj.2021108389 This article is part the Reviews 2021 series. PDFDownload PDF text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Clinical laboratory studies over recent decades have established branched evolution as a feature cancer. However, while grounded in somatic selection, several lines evidence suggest Darwinian model alone insufficient fully explain cancer evolution. First, role macroevolutionary events tumour initiation progression contradicts Darwin's central thesis gradualism. Whole-genome doubling, chromosomal chromoplexy chromothripsis represent examples single catastrophic which can drive Second, neutral play some tumours, indicating that selection not always driving Third, increasing appreciation ageing soma has led generalised theories age-dependent carcinogenesis. Here, we review these concepts others, collectively argue extends Darwin. We also highlight clinical opportunities be grasped through targeting vulnerabilities arising from non-Darwinian patterns Introduction In his revolutionary work (Darwin, 1859), provided an evolutionary framework enabled understanding diversification extinction application three key concepts: variation, heredity selection. More than 100 years later, observation heterogeneity advanced malignancies Peter Nowell hypothesise tumorigenesis process, whereby same principles could applied elucidate mechanisms responsible formation development (Nowell, 1976). Owing Nowell's seminal work, been historically adopted develop models therapy resistance (Michor et al, 2004; Gatenby Vincent, 2008; Pepper 2009; Greaves Maley, 2012) (see Box 1). While gene-centric shown trajectories multiple instances (Gerlinger Swanton, 2010; Purushotham Sullivan, Gillies 2012), suggested additional are required reconcile full spectrum behaviours Specifically, now supports jumps (Stephens 2011; Baca 2013; Sottoriva 2015), likely interspaced phases microevolutionary Furthermore, discordant inheritance between cells (Decarvalho 2018), (Ling 2015; Williams 2016; Wu 2016), cell plasticity (Pogrebniak Curtis, 2018; Mills 2019; Boumahdi de Sauvage, 2020) microenvironment (Coussens Werb, 2002; Lin Karin, 2007; Laconi demand consideration broader set models. Understanding how influences disease such processes shaped environmental factors treatment remains critical. With review, discuss our process but light data, must incorporate into larger conceptual inclusive alternative approaches understand, predict better respond improve patient outcome. basis subclonal diversity viewed perspective (Greaves 2012). Indeed, tumours frequently typified large population genetically diverse giving rise distinct subpopulations. Subclones will compete with one another limited nutrients metabolites face ever-shifting selective pressures driven both endogenous (i.e. microenvironmental geographical barriers) exogenous therapy) (Merlo 2006). outcome competition survival clones adapted grow under very specific conditions, highly contextual blind future. Many were dominant at point time may reach dead ends disappear, only minority able persist. Quoting "One general law, leading advancement all organic beings, namely, multiply, vary, let strongest live weakest die" 1859). two decades, direct support reported, principally using next-generation sequencing (NGS) perform detailed characterisation genetic 2). One earliest was Shah al (2009), where matched primary metastatic tissue lobular breast sequenced revealing extensive mutational ∼80% non-synonymous mutations metastasis absent site (Shah 2009). finding pervasive additionally reported Kornelia Polyak, demonstrated composed variety types morphologies behaviours, source clonal (Campbell 2007). Early abundant, subpopulations revealed single-cell 2) Nick Navin others (Navin 2011). Regarding haematological malignancies, Anderson al. among first show branching acute lymphoblastic leukaemia (Anderson Our own Gerlinger (2012) profiled 30 samples four renal carcinoma patients 63 69% detectable across every region These observations extent relevance parallel suppressor genes (SETD2, PTEN, KDM5C), suggesting inactivation gene times within tumour. report followed Nik-Zainal (2012b), who studied life history 21 identifying variation individual (Nik-Zainal 2012b). study showed further each containing lineage, representing 50% cells. Extending detail on Gundem (2015) utilised autopsy sampling 10 prostate identify seeding common event (Gundem 2015). emphasised diversification, complexity routes sites. early small sample sizes. range meant nature patterns, generalisable or histology specific, remained undetermined. Despite limitations, NGS gave hence supporting growth (Fig demonstration solid spurred change thinking community recognise importance Branched applicable relatively homogeneous and/or metastases, particularly aggressive subclones achieve sweep present clinically profile (Reiter 2018) Clear described pancreatic cancer, virtually major driver alterations (KRAS, CDKN2A, TP53, SMAD4) most ancestor observed metastases (Makohon-Moore 2017). Similar carcinomas, ∼10–20% exhibit mutations, poor (Turajlic 2018). It proposed reflect differences inherent biology given impact upon dissemination (Iacobuzio-Donahue 2020). Figure 1. Models linear (A), (B), macroevolution (C) (D) Muller plots dynamic changes size (left), lineages phylogenetic trees (centre) number (right). Colours indicate different clones. Download figure PowerPoint accumulating subject pressure sufficient histories, points existence important features Macroevolution punctuated Neo-Darwinian generally assume acquired sequentially gradual fashion time. cases, genomic aberrations occur short bursts 2013), consequence instability (CIN) (Bakhoum Landau, 2017), breakage-fusion-bridge (BFB) cycles (Gisselsson 2000), (Baca Notta 2016) other similar According model, alternate long relative equilibrium periods intense evolution, acquire strong (Cross Such saltatory that, least certain circumstances make jumps, contrary what predicted. reminiscent "hopeful monsters" theorised Richard Goldschmidt, i.e. organisms profound mutant genotype compared their parents hold potential establish novel lineage (Goldschmidt, 1941). Hence, change, potentially obtain greater fitness would possible accumulation alterations, owing simultaneous acquisition (Korbel Campbell, 2013). phenotypic hereditary if any all, often deleterious rare it result increase cellular generation viable 1941; 2014b). 2. Scales Schematic illustration determinants influence interdependent mechanisms, microscopic (left) macroscopic (right) scale. death, implicates drivers progression. For example, prospective TRACERx (TRAcking (Rx)) (Jamal-Hanjani elevated copy identified being strongly associated recurrence/death risk non-small lung (NSCLC), whereas nucleotide variant non-significant. Similarly, aneuploidy detected recurrent gliomas (Barthel 2019), alongside (characterised high weighted genome integrity index (Endesfelder 2014)) emerged significant determinant clear (ccRCC) ccRCC, losses chromosomes 9p21.3 (CDKN2A) 14q31.1 (HIF1A) specifically reduced prognostic form (SCNAs), above becoming increasingly recognised pan-cancer phenomenon (Smith Sheltzer, A outstanding challenge however minimal mapping SCNA cytobands, find causative genes. And even when emerge, case CDKN2A 9p21 functional delineate precise completed. Additional occurring few cataclysmic events, termed chromoplexy, ER/PR/HER2 negative cancers found undergo remain stable later stages (Gao 2016). Tumour chromothripsis, thought complex rearrangements involving dozens breakpoints types, bone 2011), colon (Kloosterman neuroblastoma (Molenaar glioblastoma (Malhotra 2013) (Notta An extreme caused aforementioned "big bang" crises tumourigenesis numerous intermixed substantially evolve due weak (Sottoriva dynamics cancers, including 2015) hepatocellular well conceptually asexually reproducing organisms, terms cannot mitigated sexual reproduction. mechanism alleviate irreversible detrimental (e.g. LOH events) whole doubling (WGD), prevalent (Storchova Pellman, Zack Dewhurst 2014; Bielski entire genome. presence additional, doubled wild-type alleles WGD allow tolerate essential (López occurrence therefore creates tolerant permissive environment fuel rapid CIN, facilitate sub functionalisation duplicated Huminiecki Conant, 2012; 2014). Consequently, rates (Zack 2014) prognosis intrinsic drug (McGranahan Importantly, classes trigger events. instance, prone arise genomically unstable cells, those harbouring damaged telomeres hyperploidy (Mardin BFB generate amounts providing free DNA engage rearrangement compromising centromere function (Umbreit replication stress promoting structural numerical (Burrell triggering nucleotide-level mutagenesis mediated via APOBEC3B induction (Kanu turn leads incomplete (Venkatesan 2021). Relatedly, regional clusters (kataegis) 2011) lesion segregation (Aitken architectures 2012a). combination rapidly accelerates causing non-gradualism class itself would. Discordant Recent oncogene amplification extrachromosomal (ecDNA) frequent (Verhaak 2019). material outside autosomal recognised, reports oncogenic ecDNAs going back far 1980s, sequences resembling MYCN (Kohl 1983). last frequency started appreciated, thanks techniques long-read whole-genome circular library enrichment structures located variable (ranging 168 kb 5 Mb, median 1.26 Mb) (Wu contain oncogenes (Bailey provide maintain potent expression open chromatin, allows increased encoded counterparts Kim defies Mendelian genetics. replicated during S phase, but, lack centromeres, they unequal randomly inherited daughter mitosis. As such, ecDNA-based accelerate non-Mendelian expansion backgrounds random distribution fosters cell-to-cell variability transcriptional levels oncogenes, enabling ITH efficiently amplifications (Turner 2017; Verhaak Several ecDNA (albeit numbers) lung, (Fan Turner Deshpande Bailey 2020; Koche Key MYC, MYCN, EGFR, PDGFRA, MET, HER2, DHFR, CDK4 MDM2 ecDNAs, ecDNA-mediated Gu proliferation, invasion metastatisation negatively correlate overall elimination decrease affect (Shimizu 1998; Nathanson Clarke Oobatake Shimizu, enable adaptation response conditions Decarvalho 2020), though represents cancer-specific vulnerability (Nathanson Neutral based Motoo Kimura's genetics postulated vast majority molecular rather fixation selectively drift (Kimura, cancer-driving selected accumulate prior initiation, carcinogenic insults. Those development, little no contribution course Therefore, entirely (nearly) study, multi-region > 300 regions indicated there particular clone allele frequencies TCGA cohorts used conclude up one-third do indications (Williams results overestimation low resolution data suffer bias modelling, since abundance distributions enough information exclude (Tarabichi Bozic theory essentially states neutral, especially sizes purifying Most variants effect, ones predominantly deleterious, predicted mathematical modelling (Cannataro Kimura never excluded occasional positive applying changes, metastatisation, therapeutic intervention) taken consideration. treatment-naïve its progression, emergence forces, pressure, still previously (Almendro worth noting non-cell-autonomous give false impression (Marusyk Polyak's group subclone does higher fitness, instead stimulates scenario, misleading absence predominant relevant frames simultaneously fuelling Non-genetic There non-genetic—often non-heritable—determinants, (TME) (Caiado Ramón y Cajal Cell notion dynamically switch state stresses without gaining recognition (discussed reviews series Milan phenomenon, plasticity, characterised fundamental biological properties reversible epigenetic (in sharp contrast binary largely effects) (Calabrese advantages ability swiftly react finely tuned graded adaptive responses stressors inflammation (Rambow classic example epithelial–mesenchymal transition (EMT) (Nieto (extensively covered Brabletz (2021) series). genome, plethora phenotypes, promoted intervention (Kemper Gunnarsson Marine extensively escape pressure. identification drug-tolerant persisters (DTPs) emerging drug-sensitive NSCLC exposure EGFR tyrosine kinase inhibitor (Sharma 2010). phenotype transiently lost thereby demonstrating reversibly non-genetic switch. phenotypically distinct—yet interdependent—drug-tolerant populations recently emerge melanoma PDX MAPKi although resistant phenotypes non-heritable, protect eradication permanent melanoma, initially transient converted stably (Shaffer healthy tissues display genes, suggests malignant transformation (Martincorena 2015, Teixeira Yizhak Yoshida noted t

Language: Английский

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Biology, vulnerabilities and clinical applications of circulating tumour cells

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(2), P. 95 - 111

Published: Dec. 9, 2022

Language: Английский

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Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(8), P. 1612 - 1618

Published: Aug. 1, 2022

Abstract Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but emergence resistance mutations restricts their efficacy. We previously showed that , BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during blockade, decline upon therapy withdrawal. hypothesized monitoring blood could rationally guide subsequent with anti-EGFR antibodies. report here results CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification / levels to tailor a chemotherapy-free rechallenge panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall safety tolerability this strategy. In patients tissue- WT tumors after previous anti-EGFR-based regimens underwent interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring excluded. met; and, 27 enrolled eight (30%) achieved partial 17 (63%) disease control, including two unconfirmed responses. These favorably compare standard third-line treatments show liquid biopsies can be effectively safely exploited timely manner mCRC. Further larger randomized trials warranted formally standard-of-care therapies patient setting.

Language: Английский

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Proteomics technologies for cancer liquid biopsies

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Feb. 15, 2022

Alterations in DNAs could not reveal what happened proteins. The accumulated alterations of would change the manifestation Therefore, as is case cancer liquid biopsies, deep proteome profiling will likely provide invaluable and clinically relevant information real-time throughout all stages progression. However, due to great complexity proteomes biopsy samples limitations proteomic technologies compared high-plex sequencing technologies, discoveries have yet lagged behind their counterpart, genomic technologies. novel protein are urgent demand fulfill goals set out for biomarker discovery biopsies.Notably, conventional innovative being rapidly developed analysis biopsies. These advances greatly facilitated early detection, diagnosis, prognosis, monitoring evolution, adapted or adopted response therapeutic interventions. In this paper, we review proteomics that capable measuring at least hundreds proteins simultaneously from samples, ranging traditional based on mass spectrometry (MS) antibody/antigen arrays aptamer, proximity extension assay (PEA), reverse phase (RPPA).

Language: Английский

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Tumor biomarkers for diagnosis, prognosis and targeted therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 20, 2024

Abstract Tumor biomarkers, the substances which are produced by tumors or body’s responses to during tumorigenesis and progression, have been demonstrated possess critical encouraging value in screening early diagnosis, prognosis prediction, recurrence detection, therapeutic efficacy monitoring of cancers. Over past decades, continuous progress has made exploring discovering novel, sensitive, specific, accurate tumor significantly promoted personalized medicine improved outcomes cancer patients, especially advances molecular biology technologies developed for detection biomarkers. Herein, we summarize discovery development including history conventional innovative used biomarker classification biomarkers based on tissue origins, application clinical management. In particular, highlight recent advancements biomarker-based anticancer-targeted therapies emerging as breakthroughs promising strategies. We also discuss limitations challenges that need be addressed provide insights perspectives turn into opportunities this field. Collectively, multiple emphasized review may guidance precision medicine, broaden horizons future research directions, expedite patients according their rather than organs origin.

Language: Английский

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Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(4), P. e004656 - e004656

Published: April 1, 2022

Objective This study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy. Methods Initially, 20 HCC were screened 18 enrolled this open-label, single-arm, phase II clinical trial. Patients received three cycles therapy including doses concurrent for 21 days followed by surgery. Four 8 weeks after surgery, eight adjuvant combination apatinib. Major pathological reactions (MPR), complete (pCR), objective response rate (ORR), relapse-free survival (RFS), adverse events (AE) assessed. In addition, cancer tissue plasma samples collected before treatment, genetic differences between responding non-responding lesions compared tumor immune microenvironment (TIME) analysis, circulating DNA (ctDNA) analysis proteomics analysis. Results who completed therapy, 3 (16.7%) 6 (33.3%) reached ORR based on Response Evaluation Criteria Solid Tumors (RECIST) V.1.1 modified RECIST criteria, respectively. Of 17 surgical resection, (17.6%) reported MPR 1 (5.9%) patient achieved pCR. The 1-year RFS was 53.85% (95% CI: 24.77% 75.99%). Grade 3/4 AEs patients, most common being rash (11.1%), hypertension (5.6%), drug-induced liver damage neutropenia (5.6%) preoperative phase. 289 NanoString panel RNA sequencing showed that TIME cell infiltration especially dendritic cells (DCs) better tumors than tumors. Our results ctDNA revealed a higher positive (100%) among stage IIb–IIIa disease. When comparing pCR/MPR non-MPR, we observed more mutations at baseline (6 vs 2.5 mutations, p=0.025). presented trend shorter those negative. Proteomic suggested abnormal glucose metabolism multifocal might be related different sensitivity treatment lesions. Conclusion Perioperative displays promising manageable toxicity HCC. DCs predictive marker well patients’ recurrence. compose biomarker can predict relapse. Abnormal may Trial registration number NCT04297202 .

Language: Английский

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Circulating cell-free DNA for cancer early detection

The Innovation, Journal Year: 2022, Volume and Issue: 3(4), P. 100259 - 100259

Published: May 6, 2022

Effective screening modalities are currently available for only a small subset of cancers, and they generally have suboptimal performance with complicated procedures. Therefore, there is an urgent need to develop simple, accurate, non-invasive methods early detection cancers. Genetic epigenetic alterations in plasma circulating cell-free DNA (cfDNA) shown the potential revolutionize cancers facilitate subsequent diagnosis improve survival patients. The medical interest cfDNA assays has been inspired by emerging single- multi-early studies. This review summarizes current technological clinical advances, hopes providing insights into development applications various scenarios. key phases biomarkers highlighted, future developments cfDNA-based liquid biopsies outlined. It hoped that this study can boost integration workflow.

Language: Английский

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