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1.
Cancer Cell ; 40(3): 277-288.e3, 2022 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-35245446

RESUMO

Platinum-based chemotherapy is the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). In this phase 3 study (ClinicalTrial.gov: NCT03829969), 514 patients with treatment-naïve advanced ESCC were randomized (1:1) to receive toripalimab or placebo in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS is observed for the toripalimab arm over the placebo arm (hazard ratio [HR] = 0.58; 95% CI, 0.46-0.74; p < 0.0001). The prespecified interim analysis of overall survival (OS) also reveals a significant OS improvement for patients treated with toripalimab plus TP over placebo plus TP (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004). The incidences of grade ≥3 treatment-emergent adverse events are similar between the two arms. Toripalimab plus TP significantly improves PFS and OS in patients with treatment-naïve, advanced ESCC, with a manageable safety profile.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Humanos , Intervalo Livre de Progressão
2.
Nat Commun ; 13(1): 2342, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487942

RESUMO

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.


Assuntos
Neoplasias Colorretais , Exoma , Instabilidade Cromossômica , Neoplasias Colorretais/genética , Exoma/genética , Genômica , Humanos , Sequenciamento Completo do Exoma/métodos
3.
Genome Med ; 14(1): 45, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488273

RESUMO

BACKGROUND: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking. METHODS: Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets. RESULTS: Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets. CONCLUSIONS: We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.


Assuntos
Neoplasias , RNA , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Humanos , Imunoterapia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas de Ligação a RNA/genética , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
4.
Gastroenterol Rep (Oxf) ; 9(6): 560-570, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34925853

RESUMO

BACKGROUND: Due to its limited efficacy and potential toxicity, anti-PD-1 monoclonal antibody is not suitable for all advanced gastric cancer (AGC) patients and predictive biomarkers identifying patients who can benefit from it are urgently needed. This study aimed to evaluate the predictive and prognostic value of inflammatory markers in the context of the systemic inflammatory status and tumour microenvironment. METHODS: The study included 58 patients from a prospective study investigating the safety and efficacy of toripalimab in chemorefractory AGC patients. Patient characteristics, treatment outcomes, and haematological parameters were analysed. Immune-cell infiltration and gene expression in tumour tissue were examined using transcriptome sequencing. RESULTS: In this cohort, the median follow-up time was 4.5 months, the median progression-free survival was 1.9 months, and the median overall survival (OS) was 4.8 months. The objective response rate was 12.1% and th disease control rate (DCR) was 39.7%. Both the baseline blood neutrophil-to-lymphocyte ratio (bNLR) with a cut-point of 2.7 and the early elevated dynamic change of the bNLR (dNLR) with a cut-point of 1.5 were prognostic factors of survival. Patients in the high bNLR or dNLR group had remarkably poor DCR (25.8% vs 59.1%, P = 0.023; 15.8% vs 54.6%, P = 0.008). In multivariate analysis, bNLR and tumour mutational burden were independent prognostic factors of OS. Tumour RNA-seq analysis revealed enriched neutrophil infiltration and a higher tumour NLR in the bNLR-high group. Corresponding tumour gene-expression profiles were associated with neutrophil recruitment and inflammatory cytokine aggregation. CONCLUSIONS: Our study demonstrated the potential clinical utility of NLR as a biomarker for patient selection and clinical management in predicting the prognosis of AGC patients as well as response to anti-PD-1 therapy. In addition, high bNLR reflected the imbalance of tumour-tissue-infiltrating neutrophils and lymphocytes, and was associated with an immunosuppressive and pro-tumour microenvironment.

6.
Gut ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489309

RESUMO

OBJECTIVE: Circulating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown. DESIGN: We conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up. RESULTS: The RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type. CONCLUSION: This prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

7.
Front Mol Biosci ; 8: 681955, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395522

RESUMO

This study aims to evaluate the association between free triiodothyronine (FT3) and outcomes of coronary artery disease (CAD) patients, as well as to assess the predictive power of FT3 and related functional markers from the perspective of potential mechanism. A total of 5104 CAD patients with an average follow-up of three years were enrolled into our study. Multivariate Cox regression was used to evaluate the associations between FT3, FT4 (free thyroxin), FT3/FT4 and death, MACE. We developed and validated an age, biomarker, and clinical history (ABC) model based on FT3 indicators to predict the prognosis of patients with CAD. In the multivariable Cox proportional hazards model, FT3 and FT3/FT4 were independent predictors of mortality (Adjusted HR = 0.624, 95% CI = 0.486-0.801; adjusted HR = 0.011, 95% CI = 0.002-0.07, respectively). Meanwhile, emerging markers pre-brain natriuretic peptide, fibrinogen, and albumin levels are significantly associated with low FT3 (p < 0.001). The new risk death score based on biomarkers can be used to well predict the outcomes of CAD patients (C index of 0.764, 95% CI = 0.731-0.797). Overall, our findings suggest that low levels of FT3 and FT3/FT4 are independent predictors of death and MACE risk in CAD patients. Besides, the prognostic model based on FT3 provides a useful tool for the death risk stratification of CAD patients.

8.
Biomed Environ Sci ; 34(5): 395-399, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34059177

RESUMO

Climate change has been referred to as one of the greatest threats to human health, with reports citing likely increases in extreme meteorological events. In this study, we estimated the relationships between temperature and outpatients at a major hospital in Qingdao, China, during 2015-2017, and assessed the morbidity burden. The results showed that both low and high temperatures were associated with an increased risk of outpatient visits. High temperatures were responsible for more morbidity than low temperatures, with an attributed fraction (AF) of 16.86%. Most temperature-related burdens were attributed to moderate cold and hot temperatures, with AFs of 5.99% and 14.44%, respectively, with the young (0-17) and male showing greater susceptibility. The results suggest that governments should implement intervention measures to reduce the adverse effects of non-optimal temperatures on public health-especially in vulnerable groups.


Assuntos
Assistência Ambulatorial/estatística & dados numéricos , Doenças Cardiovasculares/etiologia , Temperatura Baixa/efeitos adversos , Doenças do Sistema Digestório/etiologia , Utilização de Instalações e Serviços/estatística & dados numéricos , Temperatura Alta/efeitos adversos , Doenças Respiratórias/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/terapia , Criança , Pré-Escolar , China/epidemiologia , Efeitos Psicossociais da Doença , Doenças do Sistema Digestório/epidemiologia , Doenças do Sistema Digestório/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Doenças Respiratórias/epidemiologia , Doenças Respiratórias/terapia , Fatores de Risco , Adulto Jovem
9.
J Transl Med ; 19(1): 150, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858440

RESUMO

BACKGROUND: Sidedness (right/left) of colorectal cancer (CRC) is essential for treatment. Whether carcinogenesis of tobacco varies by sidedness remains unclear. The present study aims to evaluate the sidedness tendency of cigarette smoking and to explore its impact on prognosis. METHODS: In the multi-center retrospective study, data on 46 166 Chinese CRC patients were extracted from a big-data platform. Logistic regression analyses were performed to evaluate qualitative and quantitative associations between smoking and tumor sidedness. Survival analyses were conducted in metastatic CRC. RESULTS: History of smoking was associated with left-sided CRC (LSCRC; Adjusted odds ratio, 1.25; 95% CI, 1.16 - 1.34; P < .001). The sidedness tendency towards LSCRC increased from non-smokers, to ex-smokers, and to current smokers (P for trend < .001). Longer duration (P for trend < .001) and larger total amount of cigarette smoking (P for trend < .001) were more associated with LSCRC, respectively. The association was confirmed in both left-sided colon cancer and rectal cancer, but was stronger for rectal cancer (P = .016). Alcoholism significantly enhanced the association by 7% (P = .027). Furthermore, prognostic advantage of metastatic LSCRC diminished among ever-smokers, with contrary survival impacts of smoking on either side of CRC. CONCLUSIONS: History of smoking was associated with LSCRC in a positive dose-response relationship, and presented opposite prognostic impacts on right- and left-sided tumors. Smoking potentially plays an instrumental role in the mechanism for sidedness heterogeneity in CRC.


Assuntos
Fumar Cigarros , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Tabaco
10.
Oncoimmunology ; 10(1): 1908010, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33868792

RESUMO

Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy.


Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Apoptose , Proteínas de Ligação ao Cálcio , Comunicação Celular , Humanos , Inibidores de Checkpoint Imunológico , Proteínas de Membrana , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , RNA , Proteínas de Ligação a RNA , Análise de Sequência de RNA
11.
J Immunother Cancer ; 9(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33795385

RESUMO

BACKGROUND: Progression-free survival (PFS) exhibits suboptimal performance as the surrogate endpoint for overall survival (OS) in trials studying immune checkpoint inhibitors (ICIs). Here we propose a novel surrogate endpoint, modified PFS (mPFS), which omits the events of disease progression (but not deaths) within 3 months after randomization. METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for randomized trials studying ICIs in advanced solid tumors with available PFS and OS data up to May 2020. Individual patient-level data (IPD) for PFS and OS were reconstructed for eligible trials. A simulation-based algorithm was used to match the reconstructed, disconnected PFS and OS IPD, and 1000 independent simulated datasets of matched PFS-OS IPD were generated for each trial. mPFS durations and statuses were then measured for each of the matched PFS-OS IPD. Trial-level correlation between Cox HRs for PFS or mPFS and HRs for OS was assessed using Pearson correlation coefficient (rp) weighted by trial size; patient-level correlation between PFS or mPFS and OS was assessed using Spearman's rank correlation coefficient (rs). Findings were further validated using the original IPD from two randomized ICI trials. RESULTS: Fifty-seven ICI trials totaling 29,429 participants were included. PFS HR showed moderate correlation with OS HR (rp=0.60), and PFS was moderately correlated with OS at the patient level (median rs=0.66; range, 0.65-0.68 among the 1000 simulations). In contrast, mPFS HR achieved stronger correlation with OS HR (median rp=0.81; range, 0.77-0.84), and mPFS was more strongly correlated with OS at the patient level (median rs=0.79; range, 0.78-0.80). The superiority of mPFS over PFS remained consistent in subgroup analyses by cancer type, therapeutic regimen, and treatment setting. In both trials with the original IPD where experimental treatment significantly improved OS, mPFS successfully captured such clinical benefits whereas PFS did not. CONCLUSIONS: mPFS outperformed PFS as the surrogate endpoint for OS in ICI trials. mPFS is worthy of further investigation as a secondary endpoint in future ICI trials.


Assuntos
Determinação de Ponto Final , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Progressão da Doença , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Imunoterapia/mortalidade , Neoplasias/imunologia , Neoplasias/mortalidade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Fatores de Tempo
12.
Genomics ; 113(3): 867-873, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33545268

RESUMO

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.


Assuntos
Neoplasias Colorretais , Estudo de Associação Genômica Ampla , /genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Curva ROC , Fatores de Risco
13.
BMC Med ; 19(1): 26, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33526018

RESUMO

BACKGROUND: A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. METHODS: Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. RESULTS: Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor. CONCLUSIONS: EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.


Assuntos
Inibidores de Checkpoint Imunológico/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor EphA7/metabolismo , Biomarcadores Tumorais/genética , Estudos de Coortes , Variações do Número de Cópias de DNA , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Mutação
14.
IEEE Trans Cybern ; 51(11): 5397-5408, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32248143

RESUMO

Segmentation of colorectal cancerous regions from 3-D magnetic resonance (MR) images is a crucial procedure for radiotherapy. Automatic delineation from 3-D whole volumes is in urgent demand yet very challenging. Drawbacks of existing deep-learning-based methods for this task are two-fold: 1) extensive graphics processing unit (GPU) memory footprint of 3-D tensor limits the trainable volume size, shrinks effective receptive field, and therefore, degrades speed and segmentation performance and 2) in-region segmentation methods supported by region-of-interest (RoI) detection are either blind to global contexts, detail richness compromising, or too expensive for 3-D tasks. To tackle these drawbacks, we propose a novel encoder-decoder-based framework for 3-D whole volume segmentation, referred to as 3-D RoI-aware U-Net (3-D RU-Net). 3-D RU-Net fully utilizes the global contexts covering large effective receptive fields. Specifically, the proposed model consists of a global image encoder for global understanding-based RoI localization, and a local region decoder that operates on pyramid-shaped in-region global features, which is GPU memory efficient and thereby enables training and prediction with large 3-D whole volumes. To facilitate the global-to-local learning procedure and enhance contour detail richness, we designed a dice-based multitask hybrid loss function. The efficiency of the proposed framework enables an extensive model ensemble for further performance gain at acceptable extra computational costs. Over a dataset of 64 T2-weighted MR images, the experimental results of four-fold cross-validation show that our method achieved 75.5% dice similarity coefficient (DSC) in 0.61 s per volume on a GPU, which significantly outperforms competing methods in terms of accuracy and efficiency. The code is publicly available.


Assuntos
Neoplasias Colorretais , Processamento de Imagem Assistida por Computador , Neoplasias Colorretais/diagnóstico por imagem , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética
15.
Clin Transl Immunology ; 9(10): e1173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33033616

RESUMO

OBJECTIVES: Although the genomic landscape of small-cell carcinoma of the oesophagus (SCCE) has been dissected, its transcriptome-level aberration and immune microenvironment status are unknown. METHODS: Using ultra-deep whole transcriptome sequencing, we analysed the expression profile of nine paired SCCE samples and compared the transcriptome with public transcriptomic data set of normal oesophageal mucosa and other cancer types. Based on the transcriptome data, the immune signatures were investigated. The genomic data of 55 SCCE samples were also applied for immune checkpoint blockade therapy (ICBT) biomarker evaluation including microsatellite instability (MSI) status, tumor mutation burden (TMB) and neoantigen burden (TNB). Also, we evaluated the CD8, CD68 and programmed death-ligand 1 (PD-L1) in 62 retrospective SCCE samples with IHC assay. RESULTS: Differential expression analysis revealed that the cell cycle, p53, and Wnt pathways are significantly deregulated in SCCE. Immune microenvironment analysis showed that high leucocyte infiltration and adaptive immune resistance did occur in certain individuals, while the majority showed a relatively suppressive immune status. Immune checkpoints such as CD276 and LAG-3 were upregulated, and higher M2 macrophage infiltration in tumor tissues. Furthermore, normal tissues adjacent to the tumors of SCCE presented a more activated inflammatory status than tumor-free healthy controls. These observations showed that ICBT might benefit SCCE patients. As the critical biomarker of ICBT, TMB of SCCE was 3.64 with the predictive objective response rate 13.2%, while the PD-L1-positive rate was 43%. CONCLUSIONS: Our study systematically characterized the immune microenvironment in small-cell carcinoma of the esophagus and provided evidence that several patients with SCCE may benefit from immune checkpoint blockade therapy.

18.
J Hematol Oncol ; 13(1): 22, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188475

RESUMO

Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (m6A) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between m6A and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between m6A and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between m6A and 5mC methylation at the multiomic level. Then, we further established m6A/5mC epigenetic module eigengenes by combining hub m6A/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.


Assuntos
5-Metilcitosina/metabolismo , Adenosina/análogos & derivados , Epigênese Genética , Neoplasias/genética , 5-Metilcitosina/imunologia , Adenosina/genética , Adenosina/imunologia , Metilação de DNA , Redes Reguladoras de Genes , Genômica , Humanos , Neoplasias/diagnóstico , Neoplasias/imunologia , Prognóstico , Microambiente Tumoral
19.
Clin Cancer Res ; 26(2): 384-390, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615934

RESUMO

PURPOSE: To examine whether submucosal saline injection (SSI) can improve traditional endoscopic ultrasound (EUS) accuracy in distinguishing between T1a and T1b stage esophageal squamous cell carcinoma (ESCC). EXPERIMENTAL DESIGN: Patients with T1N0M0 stage ESCC (n = 180) ages 18 to 85 years were enrolled between February 14, 2012 to June 4, 2018 at Sun Yat-sen University Cancer Center (Guangdong, China). They were randomly assigned (1:1) to receive either EUS examination after 3-5 mL SSI or EUS only examination. All the patients were referred to thoracic surgeons to receive endoscopic resection (ER) or esophagectomy 5 to 10 days after EUS examination. Standard EUS criteria were used to preoperatively stage the ESCC cases, and surgical pathology reports after referral were used to postoperatively stage the cases. The primary endpoint was the diagnostic accuracy of T1b staging [defined as the sum of the true positive (T1b) and true negative (T1a) cases divided by the total number of cases]. RESULTS: Among the per-protocol population, the SSI+EUS group (n = 81) was superior to the EUS-only group (n = 85) in terms of the diagnostic accuracy for T1b staging [93.8% (95% confidence interval (CI), 88.6-99.1) vs. 65.9% (95% CI, 55.8-76.0); P < 0.001]. The positive predictive value of SSI+EUS for diagnosing T1b ESCC reached 90.9% (95% CI, 81.1-100), which was significantly superior to that of EUS only [0.576 (0.450-0.702), P = 0.001]. CONCLUSIONS: SSI significantly improves the diagnostic accuracy of EUS in distinguishing between T1a and T1b ESCC, which might help avoid unnecessary esophagectomy and diagnostic ER.


Assuntos
Detecção Precoce de Câncer/métodos , Endoscopia do Sistema Digestório/métodos , Endossonografia/métodos , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Esofagoscopia/métodos , Cloreto de Sódio/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/diagnóstico por imagem , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Feminino , Humanos , Mucosa Intestinal , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Adulto Jovem
20.
J Immunother Cancer ; 7(1): 264, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623662

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking. METHODS: Clinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset. RESULTS: Among twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (p=0.003). TET1 was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (n = 519), significant differences were observed between TET1-MUT and TET1-wildtype (TET1-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, P < 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, P < 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], P = 0.008). In the validation cohort (n = 1395), significant overall survival (OS) benefit was detected in the TET1-MUT patients compared to TET1-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], P = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of TET1-MUT (P > 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions. CONCLUSIONS: TET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/genética , Oxigenases de Função Mista/genética , Neoplasias/imunologia , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Metilação de DNA/genética , Conjuntos de Dados como Assunto , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/metabolismo , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/mortalidade , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas/metabolismo , Estudos Retrospectivos , Adulto Jovem
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