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1.
Front Immunol ; 12: 749204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659249

RESUMO

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status of tumors is a distinct predictive biomarker of immune checkpoint inhibitors (ICIs) for colorectal and non-colorectal cancer populations. The overall response rate (ORR) varies from approximately 40% to 60%, indicating that nearly half of MSI-H tumors do not respond to ICIs. The mechanism of response heterogeneity in MSI-H/dMMR cancers is unclear. Some patients who have been treated with ICIs have developed a novel pattern of progression called hyperprogression, which is defined as unexpected accelerated tumor growth. No case of MSI-H/dMMR immunotherapy-associated hyperprogression has been reported in the literature. Here, we present the case of a patient with dMMR gastrointestinal cancer who suffered hyperprogressive disease (HPD) after treatment with nivolumab. We explored the potential mechanisms of HPD by clinical, immune, and genomic characteristics. Extremely high levels of serum LDH, low TMB and TILs, and the disruption of TGFß signaling, may be related to hyperprogression.

2.
Adv Mater ; : e2102562, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643001

RESUMO

Optoelectronic science and 2D nanomaterial technologies are currently at the forefront of multidisciplinary research and have numerous applications in electronics and photonics. The unique energy and optically induced interfacial electron transfer in these nanomaterials, enabled by their relative band alignment characteristics, can provide important therapeutic modalities for healthcare. Given that nano-heterostructures can facilitate photoinduced electron-hole separation and enhance generation of reactive oxygen species (ROS), 2D nano-heterostructure-based photosensitizers can provide a major advancement in photodynamic therapy (PDT), to overcome the current limitations in hypoxic tumor microenvironments. Herein, a bismuthene/bismuth oxide (Bi/BiOx)-based lateral nano-heterostructure synthesized using a regioselective oxidation process is introduced, which, upon irradiation at 660 nm, effectively generates 1 O2 under normoxia but produces cytotoxic •OH and H2 under hypoxia, which synergistically enhances PDT. Furthermore, this Bi/BiOx nano-heterostructure is biocompatible and biodegradable, and, with the surface molecular engineering used here, it improves tumor tissue penetration and increases cellular uptake during in vitro and in vivo experiments, yielding excellent oxygen-independent tumor ablation with 660 nm irradiation, when compared with traditional PDT agents.

3.
Ann Palliat Med ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34498471

RESUMO

Capecitabine (CAP) is widely used to treat gastrointestinal and breast cancer, and is generally well tolerated. Hand-foot syndrome and gastrointestinal intolerance are the most common adverse effects. Capecitabine-induced hypertriglyceridemia (CIHT) is a very rare adverse effect and, from the reported literatures, is often neglected in clinical practice. Here, we report a case of CIHT with angina. A 58-year-old man with metastatic rectal cancer was admitted to the emergency room (ER) due to severe chest pain after treatment with CAP (Xeloda). The blood sample showed separation of blood and lipids, and the lipid profile revealed rapidly increased triglyceride and cholesterol levels. After fenofibrate therapy was administered, the patient's symptoms were relieved, and the repeat lipid test was normalized. Other causes of hyperlipidemia were carefully excluded, considering that the severe adverse effects of CAP had since abated. The earliest onset of the incidence as far as we know, the symptom of angina at the same time with CIHT, and distinct blood-lipid layer in blood sample all suggest the rarity of this case. We also concluded reports of CIHT and found that CIHT accidence was higher than our known. We genuinely hope that this case could awaken clinicians' awareness of the use of CAP.

4.
J Neurol Sci ; 429: 118060, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34479167

RESUMO

BACKGROUND: The Fist-Edge-Palm (FEP) test takes 0.5-3 min to complete and is highly sensitive in differentiating Alzheimer's disease and frontotemporal dementia from normal cognition, but it has not yet been studied in Parkinson's disease (PD). OBJECTIVE: To determine the sensitivity and specificity of the FEP test in screening patients with PD for cognitive impairment and dementia. METHODS: PD patients were recruited and divided into three groups based on cognitive status: normal cognition, mild cognitive impairment (MCI) and dementia according to 2015 MDS clinical diagnostic criteria for PD and clinical dementia rating scale (CDR) assessment for cognitive status. MMSE, FEP and clock drawing test (CDT) were tested in all recruited PD patients. Chi-square test was used to compare the sensitivity of FEP and CDT in detecting PDD and PD-MCI. RESULTS: A total of 108 PD patients were included: 52 normal cognition, 28 MCI, and 28 dementia. The sensitivity of FEP in differentiating PDD from PD-NC was 96.4% and the sensitivity for PD-MCI from PD-NC was 71.4%. The sensitivity of CDT in differentiating PDD from PD-NC was 71.4% and PD-MCI from PD-NC was 53.6%. The sensitivities of FEP and CDT were 83.9% and 62.5%, respectively, in identifying cognitive impairment (CDR ≥ 0.5) in PD patients. CONCLUSION: FEP is a sensitive screening tool in differentiating PDD or PD-MCI from PD-NC, and it is much faster than MMSE and more sensitive than CDT. FEP may be a practical screening tool for daily clinical practice.

5.
Cancer Lett ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34562520

RESUMO

The members of the solute carrier (SLC) superfamily are vital membrane transporters in human cells. In the present study, we determine the expression and function of SLC5 family members in colorectal cancer (CRC). Expression analysis based on The Cancer Genome Atlas database and potential clinical relation analysis based on the Oncomine database indicate that SLC5A7 is downregulated and is predicted to correlate with the staging, and prognosis response of CRC. Additional results demonstrate that SLC5A7 is downregulated and correlates with good prognosis in patients with CRC. Ectopic expression of SLC5A7 either by overexpression, or uptake of choline efficiently inhibits CRC growth. Examination of the molecular mechanism reveals that SLC5A7 promotes p53 protein expression by directly interacting with and modifying p53 and disrupting the interaction between p53 and MDM2 in wild type p53 CRC cells. Our findings establish the clear correlation between SLC5A7 and tumour growth, providing a novel potential therapeutic target for CRC.

6.
Mol Brain ; 14(1): 139, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507588

RESUMO

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABAAR agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABAAR antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.

7.
Signal Transduct Target Ther ; 6(1): 329, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087

RESUMO

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

8.
Plant J ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587334

RESUMO

Malvids is one of the largest clades of rosids and include 58 families and exhibit remarkable morphological and ecological diversity. Here, we report a high-quality chromosome-level genome assembly for Euscaphis japonica, an early-diverging species within malvids. Genome-based phylogenetic analysis suggests that the unstable phylogenetic position of E. japonica may result from ILS and hybridization event during the diversification of the ancestral population of malvids. E. japonica experienced two polyploidisation events: the ancient whole genome triplication event (WGT) shared with most eudicots (commonly known as the γ event) and a more recent whole genome duplication event (WGD), unique to E. japonica. By resequencing 101 samples from 11 populations, we speculate that the temperature has led to the differentiation of the evergreen and deciduous of E. japonica and the completely different population histories of these two groups. A total of 1,012 candidate positively selected genes (PSGs) in the evergreen were detected, some of which are involved in flower and fruit development. We found that reddening and dehiscence of the E. japonica pericarp and long fruit-hanging time promoted the reproduction of E. japonica populations, and revealed the expression patterns of genes related to fruit reddening, dehiscence, and abscission. The key genes involved in pentacyclic triterpene synthesis in E. japonica were identified, and different expression patterns of these genes may contribute to pentacyclic triterpene diversification. Our work sheds light on the evolution of E. japonica and malvids, particularly on the diversification of E. japonica and the genetic basis for their fruit dehiscence and abscission.

9.
Eur J Radiol ; 142: 109863, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34343846

RESUMO

OBJECTIVE: To investigate the capability of a radiomics model, which was designed to identify histopathologic growth pattern (HGP) of colorectal liver metastases (CRLMs) based on contrast-enhanced multidetector computed tomography (ceMDCT), to predict early response and 1-year progression free survival (PFS) in patients treated with bevacizumab-containing chemotherapy. METHODS: Patients with unresectable CRLMs who were treated with bevacizumab-containing chemotherapy were included in this multicenter retrospective study. For each target lesion, the radiomics-diagnosed HGP (RAD_HGP) of desmoplastic (D) pattern or replacement (R) pattern was determined. Logistic regression and receiver operating characteristic (ROC) curves were used to assess lesion- and patient-based responses according to morphologic response criteria. One-year PFS was calculated using Kaplan-Meier curves. Hazard ratios for 1-year PFS were obtained through Cox proportional hazard regression analysis. RESULTS: Among 119 study patients, 206 D pattern and 140 R pattern lesions were identified. In patients with multiple lesions, 52 had D pattern, 31 had R pattern, and 36 had mixed (D + R) pattern. The area under the curve value for RAD_HGP in predicting early response was 0.707 for lesion-based analysis and 0.720 for patient-based analysis. Patients with D pattern had a significantly longer PFS than patients with R pattern or mixed pattern (P < 0.001). RAD_HGP was the only independent predictor of 1-year PFS. CONCLUSIONS: HGP diagnosed using a radiomics model could be used as an effective predictor of PFS for patients with CRLMs treated with bevacizumab-containing chemotherapy.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/tratamento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Intervalo Livre de Progressão , Estudos Retrospectivos
10.
BMC Gastroenterol ; 21(1): 294, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266410

RESUMO

BACKGROUND: The prognostic potential of early tumor shrinkage (ETS) and depth of response (DpR) in pancreatic cancer (PC) is unclear. Here, we recruited 90 patients with recurrent and metastatic PC (RMPC) who had received chemotherapy as first-line therapy to assess the prognostic potential of these markers. METHODS: ETS is characterized as a ≥ 20% depletion in the sum-of-the-longest-diameters (SLD) of measurable tumor lesions at 6-12 weeks than the baseline. DpR is the maximum shrinkage (%) from the baseline to nadir. We evaluated corrections in ETS and DpR with survival. RESULTS: Of the 63 patients in which ETS assessment was possible, 21 (33.3%) achieved ETS. We found a significant association between the incidence of ETS and an improved rate of progression-free survival (PFS; 6.5 vs. 2.2 months; p < 0.001) and overall survival (OS; 12.1 vs. 6.0 months; p = 0.014). The median value of DpR was - 23.66%. DpR was also related to improved PFS (9.3 vs. 3.1 months; p < 0.001) and OS (18.2 vs. 7.3 months; p < 0.001). Patients who had distant metastasis, not local recurrence, with ETS showed markedly better outcomes. In a multivariate model, both ETS and DpR were independent predictors of OS in the whole population. CONCLUSIONS: ETS and DpR may predict favorable outcomes for RMPC patients who had received chemotherapy as first-line therapy, independent of the agents used. Further studies on the exploratory analyses of the optimum ETS cut-off value in recurrent PC patients to predict favorable clinical outcomes are required.


Assuntos
Neoplasias Colorretais , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
11.
Int J Biochem Cell Biol ; 137: 106037, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34217812

RESUMO

BACKGROUND: The tumor microenvironment plays an important role in the progression and recurrence of tumors and immunotherapy outcomes. The use of immune checkpoint blockers to improve the overall survival rate of patients with advanced hepatocellular carcinoma has yielded inconsistent outcomes. We examined the tumor microenvironment-related genes for their clinical significance and biological functions in hepatocellular carcinoma. METHODS: Bioinformatic analysis was performed to screen the differentially expressed genes and to identify the core gene of the tumor microenvironment in hepatocellular carcinoma. The expression of KIF18B in hepatocellular carcinoma cell lines and tumor samples was determined using western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The malignancy-promoting ability of KIF18B was evaluated using Cell Counting Kit-8, colony formation, cell proliferation, migration and invasion, and xenograft tumor assays. RESULTS: KIF18B was identified as one of the core genes in the hepatocellular carcinoma microenvironment and was significantly associated with infiltrating immune cell subtypes and tumor cell stemness. Upregulation of KIF18B was associated with poor clinicopathological characteristics and poor patient outcomes; its downregulation inhibited the proliferation ability of hepatocellular carcinoma cells, which was consistent with the findings of in vivo experiments. Knockdown of KIF18B inhibited epithelial-mesenchymal transition which reduced the migration and invasion abilities of tumor cells. A pulmonary metastasis model confirmed that the downregulation of KIF18B inhibited hepatocellular carcinoma cell metastasis in vivo. CONCLUSION: KIF18B could be a useful marker for determining the treatment outcomes of immune checkpoint blockers in the context of hepatocellular carcinoma.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Cinesina/metabolismo , Neoplasias Hepáticas/patologia , Microambiente Tumoral/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Humanos , Cinesina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Clin Oncol ; 39(27): 3002-3011, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34185551

RESUMO

PURPOSE: Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS: This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS: Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION: Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

13.
Chem Biodivers ; 18(8): e2100359, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34170621

RESUMO

The characteristics of acidic polysaccharides extracted from Daucus carota L. var. sativa Hoffm were investigated and its hepatoprotective effects on alcoholic liver injury were determined in the mice model. A carrot polysaccharide (CPS-I: Carrot polysaccharide-I) with the molecular weight of 3.40×104  kDa was isolated from Daucus carota L. and purified by diethylaminoethyl-52 and Sephadex G-150 column chromatography. The components were analyzed by HPLC, which revealed that CPS-I consisted of galacturonic acid, rhamnose, xylose, arabinose, fructose, and galactose at a relative ratio of 1 : 3.16 : 1.13 : 5.53 : 3.45 : 7.76. Structural characterization analysis suggested that CPS-I was mainly composed of →6)-ß-D-Galp-(1→ and →5)-α-L-Araf-(1→. The hepatoprotective effect of CPS-I was evaluated by alcoholic liver injury mice model. The results showed that the administration of CPS-I (300 mg/kg/day) alleviated the alcoholic liver injury in mice by increasing the levels of ADH and ALDH and reducing oxidative stress. CPS-I ameliorated the pathological changes of liver characterized by lipid accumulation, and reduced the number of lipid droplets.


Assuntos
Daucus carota/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Polissacarídeos/química , Substâncias Protetoras/química , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Colesterol/sangue , Modelos Animais de Doenças , Fígado/patologia , Fígado/ultraestrutura , Hepatopatias Alcoólicas/patologia , Camundongos , Microscopia Eletrônica de Transmissão , Peso Molecular , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Triglicerídeos/sangue
14.
BMC Cancer ; 21(1): 697, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34126961

RESUMO

BACKGROUND: Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy. METHODS: Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytohubba plugin. Their prognostic values were assessed by Kaplan-Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. RESULTS: Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients. CONCLUSIONS: We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment.

15.
Cancer Med ; 10(10): 3388-3402, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939281

RESUMO

BACKGROUND: To compare the efficacy of first-line bevacizumab plus chemotherapy with cetuximab plus chemotherapy based on the stratification of metastatic colorectal cancer (mCRC) patients with mucinous adenocarcinoma (MA) or mucinous component (MC). METHODS: A retrospective study involving all mCRC patients receiving first-line bevacizumab-based or cetuximab-based chemotherapy at our hospital from September 2013 to January 2020 was conducted. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group on the basis of the conventional pathological classification of MA or MC. RESULTS: A total of 620 patients with mCRC were included in our study, consisting of 141 (22.7%) patients with MA/MC and 479 (77.3%) patients with non-mucinous adenocarcinoma (NMA). In the MA/MC cohort, patients who were treated with bevacizumab-based chemotherapy were associated with significantly better OS than those treated with cetuximab-base chemotherapy (30.0 vs. 26.3 months, p = 0.002), irrespective of tumor sites. The efficacy of bevacizumab-based chemotherapy was higher in nearly all subgroups as shown in the subgroup analysis. In the NMA cohort, median OS was better in the cetuximab plus chemotherapy group than that in the bevacizumab plus chemotherapy group (32.2 vs. 27.0 months, p = 0.005) for left-side mCRC patients, whereas OS was significantly longer in the bevacizumab plus chemotherapy group for right-side mCRC patients (26.0 vs. 20.9 months, p = 0.013). CONCLUSION: Conventional pathological classification (e.g. MA/MC) should be considered when tailoring the individualized optimal treatment for mCRC. Bevacizumab plus chemotherapy as first-line therapy may be the optimal option for patients with MA/MC.


Assuntos
Adenocarcinoma Mucinoso/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos
16.
Expert Rev Gastroenterol Hepatol ; 15(10): 1107-1114, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33878994

RESUMO

Introduction: Gallbladder carcinosarcoma (GBCS) is a rare neoplasm, and previous studies regarding to GBCS were case reports/case series, absence of large retrospective analyses, or systemic review. This review summarizes the current literature on accurate information of GBCS to assist clinicians to accurately diagnose and treat this malignancy.Areas covered: The authors retrieved relevant documents of GBCS from PubMed and Medline. This review elaborates on the knowledge of GBCS covering epidemiology, potential mechanism, clinical manifestation, diagnosis, treatment, and prognosis.Expert opinion: The majority of GBCS patients are easily misdiagnosed as GBC and usually treated as GBC. However, the biological behavior and outcome of GBCS is different from that of GBC. GBCS should be considered as a separate disease.

17.
Oncologist ; 26(8): e1320-e1326, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830591

RESUMO

LESSONS LEARNED: Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer. BACKGROUND: In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed. METHODS: This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion were eligible for this trial. Anti-epidermal growth factor receptor (EGFR) (for tumors with wild-type RAS) and anti-vascular endothelial growth factor (VEGF) therapy in the first or second line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day 1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m2 on day 1) every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: From September 2015 to November 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and the disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated. CONCLUSION: Bevacizumab combined with S-1 and raltitrexed showed promising antitumor activity and safety in refractory mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Quinazolinas/uso terapêutico , Tiofenos
18.
Medicine (Baltimore) ; 100(17): e25493, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907099

RESUMO

BACKGROUND: A combination of fluoropyrimidines and platinum is widely accepted as the standard first-line treatment for advanced gastric and gastroesophageal adenocarcinomas. However, the benefit compared with platinum-free chemotherapeutic regimens remains controversial. We compared the efficacy and safety of capecitabine with oxaliplatin or docetaxel, as first-line therapy in advanced gastric cancer. METHODS: Eligible patients were randomly assigned to receive either capecitabine and oxaliplatin (XELOX) (capecitabine 1,000 mg/m2; twice daily for 14 days with oxaliplatin 130 mg/m2 on day 1, every 21 days), or DX (capecitabine 1,000 mg/m2; twice daily for 14 days with docetaxel 75 mg/m2 on day 1, every 21 days). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival, overall survival, and prespecified safety endpoints. RESULTS: Ninety patients were enrolled in the West China Hospital from April 2012 to August 2016; a total of 83 and 66 patients were eligible for safety and efficacy analyses, respectively. Between the XELOX and DX groups, ORR (24.2% vs 24.2%, p = 1.000), DCR (90.9% vs 75.8%, p = 0.099), progression-free survival (6.1m vs 4.1m, p = 0.346), and overall survival (8.8m vs 9.0m, p = 0.973) were similar. There was no significant difference in toxicity between the two regimens. The frequent grade 3 or higher toxicities in the XELOX and DX groups were peripheral neuropathy and hematological toxicity, respectively. Toxicity was tolerable; no treatment-related deaths occurred in either group. CONCLUSIONS: The DX regimen was not superior to XELOX, but instead, similar. The platinum-containing regimen remains the preferred first-line option for advanced gastric and gastroesophageal adenocarcinomas, and DX might be considered as an alternative for patients unsuitable for platinum-containing chemotherapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaloacetatos/uso terapêutico , Intervalo Livre de Progressão , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida
19.
Oncologist ; 26(8): 649-e1313, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33749934

RESUMO

LESSONS LEARNED: MET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for response rate and progression-free survival. Whether MET overexpression can be considered a potential predictive biomarker and be used as an inclusion criterion is worth investigating in a future study. BACKGROUND: Metatinib tromethamine tablet (metatinib) is a small molecule receptor kinase inhibitor targeting both c-MET and vascular endothelial growth factor receptor 2. This phase I trial aimed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of metatinib in patients with advanced solid tumors. METHODS: Eligible patients received a single dose of metatinib in a 3 + 3 dose-escalation design with dose levels of 25-800 mg/day, after a single dose on day 1, then 2 days off, and then a multidose schedule of once-daily doses for 25 consecutive days (days 4-28). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), efficacy, and biomarkers. RESULTS: Eighteen patients (including nine patients with hepatocellular carcinoma [HCC]) received at least one dose of study drug (one patient quit the study without continuous multiple-dose administration after receiving a single dose of metatinib). Hand-foot skin reaction, diarrhea, and liver dysfunction were the DLTs, and 200 mg/day was the MTD. The most common treatment-related adverse events (TRAEs) were skin toxicity (50%), diarrhea (33.3%), and liver dysfunction (27.8%). Three patients (only one of six in the 200 mg/day cohort; the other two in the 300 mg/day cohort) experienced severe TRAEs: one patient with severe liver dysfunction and two patients with severe liver dysfunction and skin toxicity, respectively. Pharmacokinetics assessment indicated that metatinib was rapidly absorbed and metabolized to the formation of reactive metabolite, SCR-1510, after single-dose administration. The mean time taken to achieve maximum concentration and terminal elimination half-life of SCR-1510 was approximately 2.0-3.0 hours and ranged from 8 to 14 hours. Two patients had partial responses. The objective response rate and disease control rate (DCR) were 11.1% and 61.1%, respectively. The median progression-free survival (PFS) was 2.75 months. CONCLUSION: Metatinib administration of 200 mg/day was well tolerated, safe, and effective. The MTD was 200 mg/day, which should be recommended in further investigations.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Comprimidos , Trometamina , Fator A de Crescimento do Endotélio Vascular
20.
Phytother Res ; 35(6): 3298-3309, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33570219

RESUMO

Abscisic acid (ABA), a well-known natural phytohormone reportedly exerts anti-inflammatory and anti-oxidative properties in diabetes and colitis. However, the efficacy of ABA against allergic airway inflammation and the underlying mechanism remain unknown. Herein, an OVA-induced murine allergic airway inflammation model was established and treated with ABA in the presence or absence of PPAR-γ antagonist GW9662. The results showed that ABA effectively stunted the development of airway inflammation, and concordantly downregulated OVA-induced activation of NLRP3 inflammasome, suppressed oxidative stress and decreased the expression of mitochondrial fusion/fission markers including Optic Atrophy 1 (OPA1), Mitofusion 2 (Mfn2), dynamin-related protein 1 (DRP1) and Fission 1 (Fis1). Moreover, ABA treatment further increased OVA-induced expression of PPAR-γ, while GW9662 abrogated the inhibitory effect of ABA on allergic airway inflammation as well as on the activation of NLRP3 inflammasome and oxidative stress. Consistently, ABA inhibited the activation of NLRP3 inflammasome, suppressed oxidative stress and mitochondrial fusion/fission in LPS-stimulated Raw264.7 cells via PPAR-γ. Collectively, ABA ameliorates OVA-induced allergic airway inflammation in a PPAR-γ dependent manner, and such effect of ABA may be associated with its inhibitory effect on NLRP3 inflammasome and oxidative stress. Our results suggest the potential of ABA or ABA-rich food in protecting against asthma.


Assuntos
Ácido Abscísico/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/metabolismo , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7 , Sistema Respiratório/metabolismo
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