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BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.
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Neoplasias Esofágicas , Imunoterapia , Proteínas de Membrana , Mutação , Proteínas de Neoplasias , Fator de Crescimento Transformador beta , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/imunologia , Fator de Crescimento Transformador beta/metabolismo , Imunoterapia/métodos , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Transdução de Sinais , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/patologia , Linhagem Celular Tumoral , Prognóstico , Feminino , Masculino , Camundongos , Animais , Proteínas do CitoesqueletoRESUMO
Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. The clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than the clone-extinct ones. In contrast to the clone-extinct patients, the clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in the clone-extinct patients. The number of T cell receptor-neoantigen interactions was higher in the clone-extinct patients than in the clone-persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone-extinct patients. In conclusion, we identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT.
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OBJECTIVES: The goal of this study was to investigate the patterns and risk factors for recurrence in patients with oesophageal squamous cell carcinoma with a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT). METHODS: Between January 2008 and December 2018, a total of 96 patients with pCR were enrolled in this study. Lymph nodes with a pCR [LN-ypCR response (+)] were defined as those lymph nodes without residual tumour but with the presence of treatment response to nCRT. Prognostic factors for recurrence-free survival (RFS) were analysed with Cox proportional hazards models and Fine-Gray competing risk models. Lymph node (LN) stations were counted according to the Japan Esophageal Society classification. RESULTS: The median follow-up time was 51.5 months. Recurrence occurred in 15 cases (15.6%) with a 9.9-month median time to recurrence and a 15.6-month median survival after recurrence. The majority of recurrent diseases developed within the first 2 years postoperatively. Distant recurrences were detected in 14 cases (14.6%), in which the most common recurrence sites were no.104 LN and the lung, followed by no.16 LN. The mean RFS in the whole cohort was 116.6 months. The LN-ypCR response (+) was identified as the independent prognostic factor for worse RFS in both the multivariate Cox model and the Fine-Gray competing risk model (P = 0.001 and P = 0.002, respectively). CONCLUSIONS: Relapse is not rare in oesophageal squamous cell carcinoma cases with pCR after nCRT. Distant recurrences, the predominant pattern of relapse, occur primarily within the first 2 years after oesophagectomy. Patients with pCR with an LN-ypCR response (+) have a higher risk for postoperative recurrence.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Terapia Neoadjuvante/métodos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Fatores de Risco , Idoso , Estudos Retrospectivos , Esofagectomia , Adulto , Quimiorradioterapia/métodos , Prognóstico , Linfonodos/patologia , Metástase LinfáticaRESUMO
Bamboo has tremendous carbon sequestration potential, and bamboo green is underutilized. This work devised a green-keeping technique in bamboo flattening that preserved natural bamboo green in-situ. The impacts of flattening and green-keeping on bamboo morphology, chemical composition, physical qualities, and composite applications were examined. Bamboo cells were wrinkled after flattening, while bamboo green exhibited a more homogenous surface. Bamboo cellulose crystallinity increased after flattening, hemicellulose deteriorated little, and relative lignin content increased. The hydrophobicity and mildew resistance of the surface of G-FB (green-kept flattened bamboo board) were improved. Compared to untreated bamboo, FB and G-FB had 61.1 % and 49.5 % higher tensile strength and 8.0 % and 33.2 % higher MOR. G-FB-made flooring exhibited a MOR of 134.7 MPa and upgraded surface properties. Bamboo green preservation boosted utilization of materials and improved flattened bamboo's exterior surface without affecting lamination bonding. Simple bamboo green preservation multifunctionalizes flattened bamboo composites.
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Celulose , Lignina , Lignina/química , Celulose/química , Propriedades de Superfície , Resistência à TraçãoRESUMO
Background: Freezing of gait (FOG) is one of the most disabling gait disturbances in Parkinson's disease (PD), affecting mobility and balance severely, thereby leading to an increased risk of falls. Objectives: The purpose of this systematic review and meta-analysis was to investigate the effects of transcranial magnetic stimulation on FOG in PD. Methods: Based on PRISMA guidelines, we searched the databases of MEDLINE (PubMed), Cochrane Library, PEDro, Embase, and Web of Science. Studies of the English language published up to July 2023 were searched. We retrieved for studies of randomized controlled trials (RCTs) of transcranial magnetic stimulation to treat FOG after PD and screened by inclusion and exclusion criteria. Risk of bias was assessed using the Cochrane Collaboration's tool (Revman5.30). Characteristics of RCTs were extracted. The heterogeneity of the trials was measured by I2 statistic. The effect size was expressed by a standardized mean difference (SMD) with a 95% confidence interval (CI). Results: A total of 488 articles were screened, after screening sixteen RCTs involved in 408 patients were included in the qualitative analysis, and 15 RCTs were included in meta-analysis. The outcome measures included FOG-Q, walking time, TUG, and UPDRS. Six studies used FOG-Q as outcome measure, six studies used walking time, four studies used TUG, and six studies used UPDRS. Compared with placebo treatment, transcranial magnetic stimulation has positive significant effects in improving gait status with increased walking speed (SMD = -0.41, 95% CI = -0.75 to -0.06, I2 = 7% p = 0.02), FOG-Q scores (SMD = -0.55, 95% CI = -0.89 to -0.21, I2 = 29%, p = 0.002), UPDRS scores (SMD = -1.08, 95% CI = -1.39 to -0.78, I2 = 49%, P < 0.001) and the time of TUG (SMD = -0.56, 95% CI = -0.88 to -0.23, I2 = 25%, p = 0.02) decreased. Conclusion: Transcranial magnetic stimulation could significantly improving gait conditions in PD patients with FOG. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, CRD42023434286.
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In this study, a series of enantioenriched sp3-Ge/B bimetallic modules were successfully synthesized via an enantioselective copper-catalyzed hydroboration of carbagermatrane (Ge)-containing alkenes. Orthogonal cross-coupling selectivity under different Pd-catalyzed conditions was achieved in an enantiospecific manner. Notably, the chiral secondary Ge exhibited a remarkable transmetallation ability prior to primary or secondary Bpin. The effectiveness of this Ge/B bimetallic strategy was further demonstrated through the development of new functional small molecules with Aggregation-Induced Emission (AIE) and Circularly Polarized Luminescence (CPL) performance. This represents the first successful example of synthesis of enantioenriched alkylgermanium reagents that permit enantiospecific cross-coupling reactions.
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Carnitine palmitoyltransferase 1A (CPT1A), which resides on the mitochondrial outer membrane, serves as the rate-limiting enzyme of fatty acid ß-oxidation. Identifying the compounds targeting CPT1A warrants a promising candidate for modulating lipid metabolism. In this study, we developed a CPT1A-overexpressed mitochondrial membrane chromatography (MMC) to screen the compounds with affinity for CPT1A. Cells overexpressing CPT1A were cultured, and subsequently, their mitochondrial membrane was isolated and immobilized on amino-silica gel cross-linked by glutaraldehyde. After packing the mitochondrial membrane column, retention components of MMC were performed with LC/MS, whose analytic peaks provided structural information on compounds that might interact with mitochondrial membrane proteins. With the newly developed MMC-LC/MS approach, several Chinese traditional medicine extracts, such as Scutellariae Radix and Polygoni Cuspidati Rhizoma et Radix (PCRR), were analyzed. Five noteworthy compounds, baicalin, baicalein, wogonoside, wogonin, and resveratrol, were identified as enhancers of CPT1A enzyme activity, with resveratrol being a new agonist for CPT1A. The study suggests that MMC serves as a reliable screening system for efficiently identifying modulators targeting CPT1A from complex extracts.
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Carnitina O-Palmitoiltransferase , Metabolismo dos Lipídeos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/química , Carnitina O-Palmitoiltransferase/metabolismo , Resveratrol , Membranas Mitocondriais , CromatografiaRESUMO
BACKGROUND: Cervical cancer is the fourth most common malignant tumor troubling women worldwide. Whether marital status affects the prognosis of cervical cancer is still unclear. Here, we investigate the prognostic value of marital status in patients with cervical cancer based on the seer database. MATERIAL/METHODS: The demographic and clinical data of patients with cervical cancer were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2017. Patients were divided into two groups (married and unmarried) according to marital status, and then the clinical characteristics of each group were compared using the chi-square test. Propensity score matching (PSM) was used to reduce differences in baseline characteristics. The overall survival (OS) and cervical cancer-specific survival (CCSS) were assessed by the Kaplan-Meier method, univariate and multivariate Cox regression models, and stratified analysis. Moreover, univariate and multivariate competing risk regression models were performed to calculate hazard ratios (HR) of death risk. RESULTS: A total of 21,148 patients were included in this study, including 10,603 married patients and 10,545 unmarried patients. Married patients had better OS(P < 0.05) and CCSS (P < 0.05) compared to unmarried patients, and marital status was an independent prognostic factor for both OS (HR: 0.830, 95% CI: 0.798-0.862) and CCSS (HR: 0.892, 95% CI: 0.850-0.937). Moreover, after eliminating the competing risk, married patients (CCSD: HR:0.723, 95% CI: 0.683-0.765, P < 0.001) had a significantly decreased risk of death compared to unmarried patients. In stratified analysis, the married patients showed better OS and CCSS than the unmarried patients diagnosed in 1975-2000 and 2001-2017. CONCLUSIONS: Being married was associated with a favorable prognosis of cervical cancer, and marital status was an independent prognostic factor for cervical cancer.
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Neoplasias do Colo do Útero , Humanos , Feminino , Estudos Retrospectivos , Estimativa de Kaplan-Meier , Estado Civil , PrognósticoRESUMO
BACKGROUND: After radical surgery, patients with esophageal cancer should undergo long-term surveillance of disease relapse. However, the optimal follow-up strategy remains to be explored. METHOD: A total of 4688 patients were recruited. Recursive partition analysis was applied to develop recurrence risk stratification for patients. The follow-up strategies of each stratification were developed based on monthly recurrence probability and validated by bootstrap validation and an external dataset. A Markov decision-analytic model was constructed to evaluate the cost-effectiveness of the follow-up strategies. RESULTS: Patients were stratified into four groups according to four pathological features. The authors applied a random survival forest to calculate the monthly recurrence probability of each group. Based on the temporal distribution of recurrences, the authors further established surveillance strategies for four groups. The strategies were validated as optimal protocols by bootstrap resampling and another dataset. Markov cost-effective analysis indicated that our recommended strategies outperformed the mainstream protocols from guidelines. Using less than 12 visits across the first 5 years on average, our follow-up strategies were more efficient than the NCCN recommended strategies (14 visits average). Our results also supported the computerized tomography from the neck to the upper abdomen as a routine examination and PETCT of distant metastasis for some groups with high risks. CONCLUSION: Our study provided data-driven evidence of personalized and economic follow-up strategies for esophageal cancer patients and shed light on follow-up optimization for other cancer types.
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Neoplasias Esofágicas , Recidiva Local de Neoplasia , Humanos , Estudos de Coortes , Seguimentos , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Probabilidade , Análise Custo-BenefícioRESUMO
Background: Hydrotherapy can improve the motor and non-motor symptoms of Parkinson's disease (PD), but the long-term effects of hydrotherapy on PD are still unclear. Objective: The purpose of this systematic evaluation and meta-analysis was to explore the long-term effects of hydrotherapy on balance function in PD patients. Methods: A systematic search of five databases was conducted to identify appropriate randomized controlled trials (RCTs) according to the established inclusion and exclusion criteria. The general characteristics and outcome data (balance, exercise, mobility, quality of life, etc.) of the included studies were extracted, and the quality of the included studies was evaluated using the Cochrane risk of bias assessment tool. Finally, the outcome data were integrated for meta-analysis. Results: A total of 149 articles were screened, and 5 high-quality RCTs involving 135 PD patients were included. The results of the meta-analysis showed positive long-term effects of hydrotherapy on balance function compared to the control group (SMD = 0.69; 95% CI = 0.21, 1.17; p = 0.005; I2 = 44%), However, there were no significant long-term effects of hydrotherapy on motor function (SMD = 0.06; 95% CI = -0.33, 0.44; p = 0.77; I2 = 0%), mobility and quality of life (SMD = -0.21; 95% CI = -0.98, 0.57; p = 0.6; I2 = 71%). Interestingly, the results of the sensitivity analysis performed on mobility showed a clear continuation effect of hydrotherapy on mobility compared to the control group (SMD = -0.80; 95% CI = -1.23, -0.37; p < 0.001; I2 = 0%). Conclusion: The long-term effects of hydrotherapy on PD patients mainly focus on balance function, and the continuous effects on motor function, mobility, and quality of life are not obvious.
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The parameters for survival prediction of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiotherapy (NCRT) combined with surgery are unclear. Here, we aimed to construct a nomogram for survival prediction of ESCC patients treated with NCRT combined with surgery based on pretreatment serological hepatic and renal function tests. A total of 174 patients diagnosed as ESCC were enrolled as a training cohort from July 2007 to June 2019, and approximately 50% of the cases (n = 88) were randomly selected as an internal validation cohort. Univariate and multivariate Cox survival analyses were performed to identify independent prognostic factors to establish a nomogram. Predictive accuracy of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration curve. ALT, ALP, TBA, TP, AST, TBIL and CREA were identified as independent prognostic factors and incorporated into the construction of the hepatic and renal function test nomogram (HRFTNomogram). The C-index of the HRFTNomogram for overall survival (OS) was 0.764 (95% CI 0.701-0.827) in the training cohort, which was higher than that of the TNM staging system (0.507 (95% CI 0.429-0.585), P < 0.001). The 5-year OS calibration curve of the training cohort demonstrated that the predictive accuracy of the HRFTNomogram was satisfactory. Moreover, patients in the high-risk group stratified by the HRFTNomogram had poorer 5-year OS than those in the low-risk group in the training cohort (27.4% vs. 80.3%, P < 0.001). Similar results were observed in the internal validation cohort. A novel HRFTNomogram might help predict the survival of locally advanced ESCC patients treated with NCRT followed by esophagectomy.
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At present, there is a lack of indicators, which can accurately predict the post-percutaneous coronary intervention (post-PCI) vessel-oriented composite endpoint (VOCE). Recent studies showed that the post-PCI quantitative flow ratio (QFR) can predict post-PCI VOCE. PubMed, Embase, and Cochrane were searched from inception to March 27, 2022, and the cohort studies about that the post-PCI QFR predicts post-PCI VOCE were screened. Meta-analysis was performed, including 6 studies involving 4518 target vessels. The results of the studies included in this meta-analysis all showed that low post-PCI QFR was an independent risk factor for post-PCI VOCE after adjusting for other factors, HR (95% CI) ranging from 2.718 (1.347-5.486) to 6.53 (2.70-15.8). Our meta-analysis showed that the risk of post-PCI VOCE was significantly higher in the lower post-PCI QFR group than in the higher post-PCI QFR group (HR: 4.14, 95% CI: 3.00-5.70, P < 0.001, I2 = 27.9%). Post-PCI QFR has a good predictive value for post-PCI VOCE. Trial Registration. This trial is registered with CRD42022322001.
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Intervenção Coronária Percutânea , Humanos , Fatores de RiscoRESUMO
Background: Different intratumoral microbiotaexist in different tumors and play a crucial function in carcinogenesis. However, whether they impact clinical outcomes in esophageal squamous cell carcinoma (ESCC) and their mechanism remain unclear. Methods: 16S rDNA amplicon sequencing was performed on surgically resected samples from 98 ESCC patients to analyze intratumoral microbiome abundance and composition. Multiplex fluorescent immunohistochemistry staining was used to profile the phenotypes of immune infiltrates in the tumor microenvironment (TME). Results: Patients with higher intratumoral Shannon index had significantly worse surgical outcomes. When patients were divided into short-term survivors and long-term survivors based on the median survival time, both intratumoral alpha-diversity and beta-diversity were found to be significantly inconsistent, and the relative abundance of Lactobacillus and Leptotrichia emerged as the two microorganisms that probably influenced the survival of ESCC patients. Only Lactobacillus in ESCC was validated to significantly worsen patients' prognoses and to be positively correlated with the Shannon index. Multivariate analysis revealed that the intratumoral Shannon index, the relative abundance of Lactobacillus, and the pathologic tumor-node-metastasis (pTNM) stage were independently associated with patients' overall survival. Furthermore, the relative abundance of both Lactobacillus and Shannon index was positively correlated with the proportions of PD-L1+ epithelial cells (ECs) and tumor-associated macrophages (TAMs). The Shannon index was negatively correlated with the proportions of natural killer (NK) cells in the TME. Conclusions: A high abundance of intratumoral Lactobacillus and bacterial alpha-diversity was associated with the formation of the immunosuppressive TME and predicted poor long-term survival in ESCC patients.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/patologia , Microambiente Tumoral , Células Matadoras NaturaisRESUMO
Background: Lymph node dissection (LND) is crucial procedure during radical resection of non-small cell lung cancer (NSCLC), but the prognostic value of L4 LND remains elusive. To investigate the prognostic value of L4 LND in patients with left-side NSCLC who underwent video-assisted thoracoscopic surgery (VATS). Methods: Three hundred twelve patients who underwent VATS between Jan. 2007 and Dec. 2016 were reviewed. Of those, 119 underwent L4 LND (L4D+), whereas the other 193 patients did not (L4D-). The inclusion criteria were as follows: patients diagnosed with primary left-sided NSCLC who underwent VATS lobectomy combined with LND; patients subjected to R0 resection and tumor pathological stage T1-4N0-2M0. The primary endpoint was overall survival (OS). OS was calculated from the operation date to the date of death. The chi-square test was used for categorical variables, and a t test was used for continuous variables. Results: A total of 119 patients underwent L4 LND, and the procedure was more likely to be performed on upper lobe tumors (P=0.019). Patient distributions with respect to age, gender, smoking history, clinical stage, adjuvant therapy, tumor differentiation and tumor size were well balanced between two groups. More lymph nodes (LNs) were dissected in the L4D+ group than in the L4D- group (P<0.001). The rate of metastasis to L4 lymph nodes was 9.2%, which was comparable between patients with upper and lower lobe tumors (8.9% vs. 10.0%, P=1.000). The L4D+ group exhibited a significantly better OS than the L4D- group (median OS: undefined vs. 130 months, HR 0.47; 95% CI: 0.31-0.72; P=0.002). Multivariate analysis showed that L4 LND was an independent factor for OS. However, OS did not significantly differ between the two groups of cT1aN0 and cT1bN0 patients (OS: HR 0.44; 95% CI: 0.18-1.06; P=0.12). Conclusions: L4 LND is recommended for patients with left-sided NSCLC as an essential component of radical resection. The role of L4 LND in cT1a-bN0 disease warrants further study.
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Apple polyphenols exert neuroprotective effects by improving the mitochondrial tricarboxylic acid (TCA) cycle function, but the details of their mechanisms are still not fully understood. TCA cycle metabolites regulate the level of 5-hydroxymethylcytosine (5hmC) by affecting the ten-eleven translocation (TET) enzyme activity. Therefore, we hypothesized that thinned young apple polyphenols (TYAPs) inhibit neuronal apoptosis by up-regulating the level of 5hmC in the cerebral cortex of high-fat diet-induced diabetic mice. C57BL/6J mice were randomly divided into 5 groups (n = 10 each group): the control (CON) group, the high-fat diet (HFD, negative control) group, the lovastatin (LOV, positive drug control) group, the resveratrol (RES, positive polyphenol control) group and the TYAP group during an eight-week intervention. The presented results verified that in the HFD group, the level of 5hmC and the expression of TET2 in the cerebral cortex were significantly lower, and the ratio of (succinic acid + fumaric acid)/α-ketoglutarate and the neuronal apoptosis rate were significantly higher than those in the CON group. However, TYAP intervention effectively restored the level of 5hmC through up-regulating the expression and activity of TET2, so as to improve diabetes symptoms and prevent diabetes-induced neuronal apoptosis.
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Diabetes Mellitus Experimental , Polifenóis , Camundongos , Animais , Polifenóis/farmacologia , Dieta Hiperlipídica/efeitos adversos , Diabetes Mellitus Experimental/tratamento farmacológico , Camundongos Endogâmicos C57BL , Córtex CerebralRESUMO
BACKGROUND: The role of adjuvant chemotherapy in patients with pathological lymph node-positive (pN+) resectable esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to explore whether adjuvant chemotherapy could improve the overall survival (OS) of patients with pN+ ESCC and whether oral chemotherapy could be used as an alternative to intravenous chemotherapy. METHODS: The patients were divided into two groups: a surgery plus chemotherapy group (S + CT group, 400 patients) and a surgery alone group (S group, 582 patients). Propensity score matching (PSM) was used to create patient groups that were balanced across several covariates (n = 331 in each group). The survival rates of patients receiving oral chemotherapy (69 patients with S-1 and 68 patients with tegafur tablets) and intravenous chemotherapy (263 patients) were compared using the Kaplan-Meier method. RESULTS: In the overall study cohort, the 3-year OS was significantly higher in the S + CT group than in the S group (66.3% vs. 49.9%, p < 0.001). These data were confirmed in the matched groups (3-year OS, 72.9% vs. 62.0%, p < 0.001). Multivariate Cox regression analysis in the matched samples showed that adjuvant chemotherapy was an independent prognostic factor for ESCC (HR: 0.62, 95% CI: 0.50-0.76, p < 0.001). Patients who received oral chemotherapy had a similar OS as patients who received intravenous chemotherapy. CONCLUSIONS: Adjuvant chemotherapy could significantly improve the OS of patients with pN+ ESCC, and oral chemotherapy drugs might be a better option because of their similar efficacy but fewer side effects than intravenous chemotherapy. This conclusion warrants further study in prospective, randomized controlled trials.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas/patologia , Quimioterapia Adjuvante/métodos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Linfonodos/patologia , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is recommended for locally advanced esophageal squamous cell carcinoma (ESCC) treatment. Patients who achieve a pathological complete response (pCR) have better survival. Our study aimed to discover immune-associated predictors of pCR in ESCC. Herein, we found that Th1-cell infiltration inferred from RNA sequencing was higher in the pCR group than in the non-pCR group. Multiplexed immunohistochemistry (mIHC) confirmed that Th1-, CD8+ T-, NK-, NKT-, and dendritic-cell infiltration was positively associated with pCR. The spatial relationships between Th1 cells and CD8+ T, NK, NKT, dendritic, or ESCC cells were significant pCR predictors. The active and desert subtypes were identified based on immune cell infiltration, and showed different pCR rates. In vitro experiments confirmed that Th1 cells inhibited the proliferation and improved the chemosensitivity and radiosensitivity of ESCC cells. Th1 cells upregulated interferon-gamma response signaling and antigen presentation pathways and downregulated lipid metabolism and MAPK pathways of ESCC cells. These findings highlight the important role of Th1 cells as the predictor of pCR and the regulator of chemosensitivity and radiosensitivity of ESCC, and suggest elevating Th1-infiltration as a strategy to improve NCRT response.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/terapia , Terapia Neoadjuvante , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , QuimiorradioterapiaRESUMO
BACKGROUND: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the most common approach for locally advanced resectable esophageal squamous cell carcinoma (ESCC) patients. How neoCRT impacts ESCC tumor immune microenvironment (TIME) has not been fully understood. METHODS: Single-cell RNA sequencing (scRNA-seq) was conducted to examine the neoCRT-driven cellular and molecular dynamics in 8 pre- and 7 post-neoCRT ESCC samples from 8 male patients. FINDINGS: scRNA-seq data of about 112,000 cells were obtained. Expression programs of cell cycle, epithelium development, immune response, and extracellular structure in pre-treatment tumor cells were related to neoCRT response. Spearman correlation between CD8+ T cells' cytotoxicity and expression of checkpoint molecules was prominent in pre-neoCRT intermediate activated/exhausted CD8+ T cells. NeoCRT increased CD8+ T cells' infiltration but promoted their exhaustion in both major and minor responders. NeoCRT promoted differentiation of Th but demoted that of Treg cells in major responders. Maturation of cDC1s and expression of M2 macrophage markers increased while the number of cDC2s decreased after neoCRT. Higher activities of immune-related pathways in pre-neoCRT CD8+ T cells and macrophages, as well as a pronounced decrease of them after neoCRT, correlated with better neoCRT response. Interactions between intermediate activated/exhausted CD8+ T and macrophages, cDC1s, and LAMP3+ cDCs decreased after neoCRT. INTERPRETATION: Our comprehensive picture of the neoCRT-related immune changes provides deeper insights into immunological mechanisms associated with ESCC response to neoCRT, which may aid in future development of immune-strategies for improving ESCC treatment. FUNDING: This work was supported by the National Natural Science Foundation of China (82072607).
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Masculino , Terapia Neoadjuvante , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Linfócitos T CD8-Positivos , Microambiente TumoralRESUMO
BACKGROUND: Tertiary lymphoid structures (TLSs) play key roles in tumour adaptive immunity. However, the prognostic value and molecular properties of TLSs in oesophageal squamous cell carcinoma (ESCC) patients have not been studied. METHODS: The prognostic values of the presence and maturation status of tumour-associated TLSs were determined in 394 and 256 ESCC patients from Sun Yat-sen University Cancer Center (Centre A) and the Cancer Hospital of Shantou University Medical College (Centre B), respectively. A deep-learning (DL) TLS classifier was established with haematoxylin and eosin (H&E)-stained slides using an inception-resnet-v2 neural network. Digital spatial profiling was performed to determine the cellular and molecular properties of TLSs in ESCC tissues. RESULTS: TLSs were observed in 73.1% of ESCCs from Centre A via pathological examination of H&E-stained primary tumour slides, among which 42.9% were TLS-mature and 30.2% were TLS-immature tumours. The established DL TLS classifier yielded favourable sensitivities and specificities for patient TLS identification and maturation evaluation, with which 55.1%, 39.5% and 5.5% of ESCCs from Centre B were identified as TLS-mature, TLS-immature and TLS-negative tumours. Multivariate analyses proved that the presence of mature TLSs was an independent prognostic factor in both the Centre A and Centre B cohorts (p < .05). Increased proportions of proliferative B, plasma and CD4+ T helper (Th) cells and increased B memory and Th17 signatures were observed in mature TLSs compared to immature ones. Intratumoural CD8+ T infiltration was increased in TLS-mature ESCC tissues compared to mature TLS-absent tissues. The combination of mature TLS presence and high CD8+ T infiltration was associated with the best survival in ESCC patients. CONCLUSIONS: Mature TLSs improve the prognosis of ESCC patients who underwent complete resection. The use of the DL TLS classifier would facilitate precise and efficient evaluation of TLS maturation status and offer a novel probability of ESCC treatment individualization.