RESUMO
AIMS: This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC). METHODS: Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings. RESULTS: BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33 % of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma. CONCLUSION: Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.
Assuntos
DNA Tumoral Circulante , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Humanos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , DNA Tumoral Circulante/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vemurafenib/uso terapêuticoRESUMO
Metallic lithium is considered as the ultimate anode material for lithium-based batteries due to its highest energy density. However, as an anode, commercial Li metal foils are too thick, with a large amount of trouble to balance its exorbitant areal capacity with common cathodes in full cells. Here, a new chemical thinning strategy is proposed via a simple surface dissolving reaction between lithium and naphthalene, which enables scalable, continuous, and roll-to-roll preparation of ultrathin Li foil. A Li foil less than 15 µm with a clean surface can be successfully obtained within 20 min. The thinning rate and thickness of the lithium foil can be easily adjusted by changing the concentration, temperature, and operation mode. The produced Li-Naph solution after thinning can also be used as a multifunctional reagent of great value, and the Li ions in the final waste solution can be further extracted in the form of Li2CO3, showing superior lithium atom economy of our strategy.
RESUMO
BACKGROUND: Exosomal PD-L1 (exoPD-L1) could induce immunosuppression functionally, thus impairing patients' survival in melanoma, NSCLC, and gastric cancer. However, no evidence demonstrates the feasibility of circulating exoPD-L1 and soluble PD-L1 (sPD-L1) as biomarkers for prognosis and early recurrence in colorectal liver metastasis (CRLM) patients following hepatectomy or their association with T cell infiltration at liver metastases. METHODS: In cohort 1, exoPD-L1 and sPD-L1 were preoperatively tested using ELISA. CD3, CD8, granzyme B (GB) and PD1 expressed at liver metastases were evaluated using immunohistochemistry. In cohort 2, exoPD-L1 and sPD-L1 were detected at baseline, before hepatectomy, after hepatectomy, and after disease progression. RESULTS: In cohort 1, higher preoperative exoPD-L1 or sPD-L1 significantly impaired RFS (exoPD-L1, P = 0.0043; sPD-L1, P = 0.0041) and OS (exoPD-L1, P = 0.0034; sPD-L1, P = 0.0061). Furthermore, preoperative exoPD-L1 was negatively correlated with CD3 + T-lymphocytes infiltrated at tumor center (CT), and GB and PD1 were expressed at tumor invasive margin (IM). Preoperative sPD-L1 was negatively correlated with CD3 + and CD8 + T-lymphocytes' infiltration at IM and CT, GB and PD1 expression at IM. In cohort 2, exoPD-L1 and sPD-L1 levels decreased following hepatectomy but increased when tumor progressed. Moreover, higher postoperative exoPD-L1 and sPD-L1 or a small reduction in exoPD-L1 and sPD-L1 levels after hepatectomy suggested higher early recurrence rate. CONCLUSIONS: Both preoperative exoPD-L1 and sPD-L1 had promising prognostic values and were associated with T cell infiltration at liver metastases in CRLM patients following hepatectomy. Dynamically tracking exoPD-L1 and sPD-L1 levels could monitor disease status and detect early recurrence.
Assuntos
Antígeno B7-H1/sangue , Biomarcadores Tumorais , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/secundário , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Micropartículas Derivadas de Células/metabolismo , Exossomos/metabolismo , Feminino , Expressão Gênica , Hepatectomia , Humanos , Imuno-Histoquímica , Imunomodulação , Estimativa de Kaplan-Meier , Biópsia Líquida , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Recidiva , Adulto JovemRESUMO
BACKGROUND: Tumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past. METHODS: Together with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals. RESULTS: We discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient. CONCLUSIONS: Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.
Assuntos
Adenocarcinoma , Neoplasias Gastrointestinais , Segunda Neoplasia Primária , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Microambiente Tumoral , Adenocarcinoma/genética , Imunoterapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
PURPOSE: This phase II trial aimed to assess the safety and efficacy of paclitaxel in combination with cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by surgery for locally advanced borderline-resectable esophageal squamous cell carcinoma (BR-ESCC). METHODS: Patients with primary tumor or bulky lymph nodes that might invade nearby organs were eligible. Treatment started with 2-3 cycles of TPF induction chemotherapy, followed by surgery if the tumor was assessed resectable, or by radical concurrent chemoradiotherapy if unresectable. The primary endpoint was pathologically proven complete resection (R0) rate. RESULTS: From July 2014 to February 2019, a total of 47 patients were enrolled. After TPF chemotherapy, 27 patients (57.4%) received surgery and 11 patients (23.4%) received radical concurrent chemoradiotherapy. R0 resection was confirmed in 25 patients (53.2%, 95% confidence interval (CI) 38.9-67.5%). Pathologic complete response was confirmed in four patients (8.5%). The median overall survival (OS) and progression-free survival (PFS) for all patients were 33.3 months and 20.3 months, respectively. The median OS was significantly more favorable in surgery group than in chemoradiotherapy and chemotherapy alone group [33.3 months vs 14.1 months, hazard ratio 0.32 (95% CI 0.12-0.88), p = 0.027]. During induction chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (29.8%), leucopenia (21.3%) and stomatitis (4.3%). No serious postoperative complications were observed in patients undergoing surgery. CONCLUSIONS: The treatment strategy of induction chemotherapy followed by surgery is promising for patients with locally advanced BR-ESCC. To further improve the R0 resection rate, more effective induction chemotherapy regimens need to be explored. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02976909.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Fluoruracila/uso terapêutico , Humanos , Quimioterapia de Indução/efeitos adversos , Paclitaxel/efeitos adversos , Resultado do TratamentoRESUMO
Background Gemcitabine plus cisplatin is regarded as the standard first-line therapy for patients with advanced biliary tract cancer (BTC); however, no standard chemotherapy has yet been recommended after treatment failure. Modified FOLFIRINOX (mFOLFIRINOX) appears to be a better-tolerated regimen, which leads to improved survival in metastatic pancreatic cancer that has histological and molecular similarities with BTC. We assessed the efficacy and safety of mFOLFIRINOX as salvage therapy in advanced BTC patients who were refractory to previous chemotherapy. Methods A total of 15 consecutive patients with documented unresectable locally advanced or metastatic BCT who received the mFOLFIRINOX regimen were included in the study. Patients were intravenously administrated with oxaliplatin (65 mg/m2), leucovorin (400 mg/m2), irinotecan (150 mg/m2), and continuous infusion of fluorouracil (2400 mg/m2) over 46 h. The objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were recorded. Results At least three cycles of mFOLFIRINOX regimen were delivered to 15 patients with a median number of 6.0 cycles (IQR 5.5-11.0). The median duration of treatment was 3.8 months (IQR 2.9-8.5). Four patients (26.7%) achieved an ORR, and 12 patients (80.0%) had a DCR. The median PFS and OS were 6.7 months (95%CI 2.3-11.1) and 13.2 months (95%CI 7.3-19.1), respectively. Five patients (33.3%) had treatment-related grade 3/4 AEs. The most common grade 3/4 AE was neutropenia (n = 3, 20.0%), while there was no occurrence of febrile neutropenia. Conclusion Treatment with mFOLFIRINOX has promising efficacy and favorable tolerance as salvage therapy in patients with refractory advanced BCT.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Terapia de Salvação , Administração Intravenosa , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Estudos Retrospectivos , Terapia de Salvação/efeitos adversos , Resultado do TratamentoRESUMO
Binder-less activated char briquettes from sewage sludge were prepared and used for the liquid-phase adsorption of methylene blue. The properties of sludge char briquettes prepared under the different initial sludge moisture content, compression pressure, and heating rate were systematically investigated through the tests of thermogravimetric analysis (TGA), scanning electron microscopy (SEM), surface and mechanical properties, burn-off rates, methylene blue adsorption kinetics and isotherms. All of the prepared briquettes presented hierarchical structures and microporous/mesoporous characteristics, and the increase of initial sludge moisture content from 10 to 30 wt% resulted in a great increase of surface area (SBET), total pore volume (VT), apparent density, and a slight decrease of mechanical performance. The decrease of compression pressure markedly enhanced the equilibrium adsorption capacity (qe, exp), owing to the decreased diffusion resistance and blockage of diffusion pathways inside briquettes. In consideration of the mechanical performance and adsorption capacity, the optimum preparation condition was obtained at the initial moisture content of 30 wt%, compression pressure of 25 MPa, and heating rate of 10 °C/min, in which the axial compressive strength (ACS) and qe, exp of the prepared briquettes were as high as 22.2 ± 3.1 kg/m2 and 316.9 mg/g. The results also showed that the equilibrium adsorption data fit well into the pseudo-first order model system, and the adsorption isotherms followed the Langmuir isotherm model, suggesting that the adsorption process was attributed to physical adsorption, and was inclined to happen on the adsorption sites with the same energy level. Finally, the thermal regeneration tests demonstrated that the binder-less briquette had a good regeneration performance and was worthy of reusing for industrial applications.
Assuntos
Pirólise , Esgotos , Adsorção , Cinética , Azul de MetilenoRESUMO
Long-term trend forecast of chlorophyll-a concentration (Chla) holds significant implications for eutrophication management and pollution control planning on lakes, especially under the background of climate change. However, it is a challenging task due to the mixture of trend, seasonal and residual components in time series and the nonlinear relationships between Chla and the hydro-environmental factors. Here we developed a hybrid approach for long-term trend forecast of Chla in lakes, taking the Lake Taihu as an instantiation case, by the integration of Seasonal and Trend decomposition using Loess (STL), wavelet coherence, and Convolutional Neural Network with Bidirectional Long Short-Term Memory (CNN-BiLSTM). The results showed that long-term trends of Chla and the hydro-environmental factors could be effectively separated from the seasonal and residual terms by STL method, thereby enhancing the characterization of long-term variation. The resonance pattern and time lag between Chla and the hydro-environmental factors in the time-frequency domain were accurately identified by wavelet coherence. Chla responded quickly to variations in TP, but showed a time lag response to variations in WT in Lake Taihu. The forecasting method using multivariate and CNN-BiLSTM largely outperformed the other methods for Lake Taihu with regards to R2, RMSE, IOA and peak capture capability, owning to the combination of CNN for extracting local features and the integration of bidirectional propagation mechanism for the acquisition of higher-level features. The proposed hybrid deep learning approach offers an effective solution for the long-term trend forecast of algal blooms in eutrophic lakes and is capable of addressing the complex attributes of hydro-environmental data.
RESUMO
Estrogen plays a pivotal role in the early stage of sex differentiation in teleost. However, the underlying mechanisms of estrogen-induced feminization process are still needed for further clarification. Here, the comparative analysis of whole-transcriptome RNA sequencing was conducted between 17beta-Estradiol induced feminized XY (E-XY) gonads and control gonads (C) in Takifugu rubripes. A total of 57 miRNAs, 65 lncRNAs, and 4 circRNAs were found to be expressed at lower levels in control-XY (C-XY) than that in control-XX (C-XX), and were up-regulated in XY during E2-induced feminization process. The expression levels of 24 miRNAs, and 55 lncRNAs were higher in C-XY than that in C-XX, and were down-regulated in E2-treated XY. Furthermore, a correlation analysis was performed between miRNA-seq and mRNA-seq data. In C-XX/C-XY, 114 differential expression (DE) miRNAs were predicted to target to 904 differential expression genes (DEGs), while in C-XY/E-XY, 226 DEmiRNAs were predicted to target to 2,048 DEGs. In C-XX/C-XY, and C-XY/E-XY, KEGG pathway enrichment analysis showed that those targeted genes were mainly enriched in MAPK signaling, calcium signaling, steroid hormone biosynthesis and ovarian steroidogenesis pathway. Additionally, the competitive endogenous RNA (ceRNA) regulatory network was constructed by 24 miRNAs, 21 lncRNAs, 4 circRNAs and 5 key sex-related genes. These findings suggested that the expression of critical genes in sex differentiation were altered in E2-treated XY T. rubripes may via the lncRNA-miRNA-mRNA regulation network to facilitate the differentiation and maintenance of ovaries. Our results provide a new insight into the comprehensive understanding of the effects of estrogen signaling pathways on sex differentiation in teleost gonads.
Assuntos
Estrogênios , Gônadas , MicroRNAs , Takifugu , Animais , Takifugu/genética , Feminino , Masculino , Estrogênios/toxicidade , Gônadas/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , Estradiol , Feminização/induzido quimicamente , Feminização/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA não Traduzido/genética , Diferenciação Sexual/efeitos dos fármacos , Diferenciação Sexual/genética , Transcriptoma/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacosRESUMO
Computing in the analog regime using nonlinear ferroelectric resistive memory arrays can potentially alleviate the energy constraints and complexity/footprint challenges imposed by digital von Neumann systems. Yet the current ferroelectric resistive memories suffer from either low ON/OFF ratios/imprint or limited compatibility with mainstream semiconductors. Here, for the first time, ferroelectric and analog resistive switching in an epitaxial nitride heterojunction comprising ultrathin (≈5 nm) nitride ferroelectrics, i.e., ScAlN, with potentiality to bridge the gap between performance and compatibility is demonstrated. High ON/OFF ratios (up to 105 ), high uniformity, good retention, (<20% variation after > 105 s) and cycling endurance (>104 ) are simultaneously demonstrated in a metal/oxide/nitride ferroelectric junction. It is further demonstrated that the memristor can provide programmability to enable multistate operation and linear analogue computing as well as image processing with high accuracy. Neural network simulations based on the weight update characteristics of the nitride memory yielded an image recognition accuracy of 92.9% (baseline 96.2%) on the images from Modified National Institute of Standards and Technology. The non-volatile multi-level programmability and analog computing capability provide first-hand and landmark evidence for constructing advanced memory/computing architectures based on emerging nitride ferroelectrics, and promote homo and hybrid integrated functional edge devices beyond silicon.
RESUMO
Achieving ferroelectricity in III-nitride (III-N) semiconductors by alloying with rare-earth elements, e.g., scandium, has presented a pivotal step toward next-generation electronic, acoustic, photonic, and quantum devices and systems. To date, however, the conventional growth of single-crystalline nitride semiconductors often requires the use of sapphire, Si, or SiC substrate, which has prevented their integration with the workhorse complementary metal oxide semiconductor (CMOS) technology. Herein, we demonstrate single-crystalline ferroelectric nitride semiconductors grown on CMOS compatible metal-molybdenum. Significantly, we find that a unique epitaxial relationship between wurtzite and body-centered cubic crystal structure can be well maintained, enabling the realization of single-crystalline wurtzite ferroelectric nitride semiconductors on polycrystalline molybdenum that was not previously possible. Robust and wake-up-free ferroelectricity has been measured, for the first time, in the epitaxially grown ScAlN directly on metal. We further propose and demonstrate a ferroelectric GaN/ScAlN heterostructure for synaptic memristor, which shows the capability of emulating the spike-time-dependent plasticity in a biological synapse. This work provides a viable path for the integration of III-N architectures with the mature CMOS technology and sheds light on the promising applications of ferroelectric nitride memristors in neuromorphic computing.
RESUMO
Histopathological images of colorectal liver metastases (CRLM) contain rich morphometric information that may predict patients' outcomes. However, to our knowledge, no study has reported any practical deep learning framework based on the histology images of CRLM, and their direct association with prognosis remains largely unknown. In this study, we developed a deep learning-based framework for fully automated tissue classification and quantification of clinically relevant spatial organization features (SOFs) in H&E-stained images of CRLM. The SOFs based risk-scoring system demonstrated a strong and robust prognostic value that is independent of the current clinical risk score (CRS) system in independent clinical cohorts. Our framework enables fully automated tissue classification of H&E images of CRLM, which could significantly reduce assessment subjectivity and the workload of pathologists. The risk-scoring system provides a time- and cost-efficient tool to assist clinical decision-making for patients with CRLM, which could potentially be implemented in clinical practice.
RESUMO
The mechanisms of Li deposition behaviors, which overwhelmingly affect battery performances and safety, are far to be understood in solid-state batteries. Here, using in situ micro-nano electrochemical scanning electron microscopy (SEM) manipulation platform, dynamic Li plating behaviors on 10 metallic substrates have been tracked, and the underlying mechanisms for dendrite-free Li plating are elucidated. Distinct Li deposition behaviors on Cu, Ti, Ni, Bi, Cr, In, Ag, Au, Pd, and Al are revealed quantitatively in nucleation densities, growth rates, and anisotropic ratios. For Li alloyable metals, the dynamic Li alloying process before Li growth is visually captured. It is concluded that a good affinity for Li and appropriate lattice compatibility between the substrate and Li are needed to facilitate homogeneous Li plating. Our work not only uncovers the Li plating dynamics, shedding light on the design of solid-state batteries, but also provides a powerful integrated SEM platform for future in-depth investigation of solid-state batteries.
RESUMO
Background: Histopathological growth patterns (HGPs) have shown important prognostic values for patients with colorectal cancer liver metastases, but the potential molecular mechanisms remain largely unknown. Methods: We performed an exploratory analysis by conducting the RNA sequencing of primary colorectal lesions, colorectal liver metastatic lesions and normal liver tissues. Findings: We found that desmoplastic HGPs of the metastatic lesions were significantly enriched in EMT, angiogenesis, stroma, and immune signaling pathways, while replacement HGPs were enriched in metabolism, cell cycle, and DNA damage repair pathways. With the exception of immune-related genes, the differentially expressed genes of the two HGPs from colorectal liver metastases were mostly inherited from the primary tumor. Moreover, normal liver tissue in the desmoplastic HGP subgroup was markedly enriched in the fibrinous inflammation pathway. Conclusions: We surmised that HGPs are observable morphological changes resulting from the regulation of molecular expressions, which is the combined effect of the heterogeneity and remodeling of primary tumors seeds and liver soils.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/patologia , PrognósticoRESUMO
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an extensive and dense fibrous stroma, which plays an active role in tumor growth and metastasis. Despite the growing importance of the tumor microenvironment in PDAC prognosis, the immune cell infiltration landscape of PDAC has not been elucidated. In this study, we applied a credible computational algorithm to comprehensively estimate the immune cell infiltration (ICI) patterns of 876 PDAC patients. Two ICI phenotypes were identified, and a ICIscore was constructed using ssGSEA algorithm. The ICIscore could significantly predict the prognosis and chemotherapy benefit of PDAC patients in both the discovery and the five validation cohorts. Multivariate cox analysis also identified the independent predictive role of the ICIscore in PDAC prognosis. A high ICIscore subtype was characterized by immune-active signaling pathways and anti-tumor immunity while a low ICIscore subtype was associated with tumor progressive signaling pathways. Four immunotherapy cohorts further supported the use of the ICIscore as a prognostic biomarker for patients receiving immune checkpoint inhibitors in other cancer types. The ICIscore reveals a close relationship between the ICI environment and prognosis and may provide new treatment strategies for PDAC patients.
Assuntos
Carcinoma Ductal Pancreático/mortalidade , Pâncreas/patologia , Neoplasias Pancreáticas/mortalidade , Microambiente Tumoral/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Prognóstico , Medição de Risco/métodosRESUMO
Importance: The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment. Objective: To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk. Design, Setting, and Participants: This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020. Interventions: Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1). Main Outcomes and Measures: The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points. Results: A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase. Conclusions and Relevance: The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption. Trial Registration: ClinicalTrials.gov Identifier: NCT03674294.
Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Aprepitanto/administração & dosagem , Náusea/prevenção & controle , Neoplasias Gástricas/tratamento farmacológico , Vômito/prevenção & controle , Adulto , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , China , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Náusea/etiologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Vômito/etiologiaRESUMO
Rationale: Hepatectomy and adjuvant chemotherapy after resection of colorectal liver metastases (CRLM) may improve survival, however, patients which may benefit cannot currently be identified. Postoperative circulating tumor DNA (ctDNA) analysis can detect minimal residual disease (MRD) and predict the prognosis and efficacy of adjuvant chemotherapy. Our study aims to determine the impact of serial ctDNA analysis to predict the outcome among patients undergoing resection of CRLM. Methods: Between May 2018 and October 2019, 91 CRLM patients were prospectively enrolled. Whole exome sequencing was performed in 50 primary and 48 metastatic liver tissues. Targeted sequencing of 451 cancer relevant genes was performed in 50 baseline plasma to determine plasma-tissue concordance. We prospectively investigated changes in the amount and constitution of ctDNA in 271 serial plasma samples taken at different time points (baseline, pre-operation, post-operation, post-operative adjuvant chemotherapy (post-ACT) and recurrence) during the treatment of CRLM. Results: Detected molecular alterations were highly consistent among baseline ctDNA, primary and liver metastases tissue. Patients with a higher variant allele frequency (VAF) level at baseline ctDNA represent a higher tumor burden, and decreased ctDNA during pre-operative chemotherapy predicted better tumor response. Patients with detectable post-operative and post-ACT ctDNA were associated with significantly shorter recurrence-free survival (RFS). ROC analysis showed that post-ACT ctDNA status was superior to post-operative ctDNA status in predicting RFS with an AUROC of 0.79. A significant difference in overall recurrence rate was observed in patients with detectable vs undetectable levels of ctDNA after resection of CRLM (79.4% vs 41.7%) and after completion of adjuvant chemotherapy (77.3% vs 40.7%). During adjuvant chemotherapy, patients with decreased ctDNA VAF after adjuvant chemotherapy had a recurrence rate of 63.6%, compared to 92.3% in patients with increased ctDNA VAF. Conclusions: We envision that dynamic ctDNA analysis, especially in a post-ACT setting, might be used to not only reflect MRD but also to determine rational personalized adjuvant therapy after the resection of CRLM.
Assuntos
Quimioterapia Adjuvante , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/sangue , Neoplasias Hepáticas/sangue , Recidiva Local de Neoplasia/sangue , Alelos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Correlação de Dados , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Neoplasia Residual , Prognóstico , Curva ROC , Sequenciamento do ExomaRESUMO
In this paper, excavated waste was added to sewage sludge for co-pyrolysis, aiming to stablize the heavy metals in sewage sludge. The effect of co-pyrolysis with various pretreatment (e.g. cooling, drying and hydrothermal pretreatment) on heavy metals stabilization was studied using orthogonal test. The results showed that the optimal conditions are 600 °C, nitrogen flow rate of 200 mL/min, mixing excavated waste with sewage sludge (25:75, wt%) and hydrothermal pretreatment. 90% of the heavy metals in the sewage sludge and excavated waste mixtures were transformed to biochars after co-pyrolysis. Moreover, the state of heavy metals changed from bio-available fractions to stable state, thereby reducing the potential ecological risk index (RI) from 116.8 to below 50, which represented a reduction in contamination levels and ecological risks from considerate to low. Finally, the study found that the synergy between hydrothermal and pyrolysis made full use of the moisture in sewage sludge and was more conducive to the solidification of heavy metals. This paper provides a good option to dispose multiple wastes and reduce their environmental risks.