RESUMO
Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Progressão da Doença , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Fator de Transcrição STAT1 , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/imunologia , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/imunologia , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Fator de Transcrição STAT1/metabolismo , Animais , Camundongos , Humanos , Proliferação de Células/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologiaRESUMO
BACKGROUND & AIMS: Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients. METHODS: Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (nâ¯=â¯807) and validation (nâ¯=â¯797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models. RESULTS: The final presentation of the model was "linear predictorâ¯=â¯largest tumour diameter (cm)â¯+â¯tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively. CONCLUSIONS: The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required. LAY SUMMARY: There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.
Assuntos
Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica , Neoplasias Hepáticas/mortalidade , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Carga TumoralRESUMO
Endothelin-1 (ET-1), a member of endothelins family, binds to ETA receptor (ETAR) and ETB receptor to exert its role in multiple cellular processes. Although ET-1 and its receptors has been reported to be overexpressed in many cancers, and overexpression of ET-1 is able to trigger hepatocarcinogenesis in zebrafish, the functions of ET-1 and its receptors in hepatocellular carcinoma (HCC) cell migration and invasion remain unclear. In the present study, we found that ETAR was greatly expressed in HCC cells and HCC tissues. ETAR expression as well as ET-1 expression was associated with vascular invasion and tumor stage in HCC. Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells, while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion. Furthermore, ET-1 induced activation of ERK1/2 and AKT and increased MMP-3 production via ETAR. In addition, using inhibitors of ERK1/2 and AKT, we found that ERK1/2 and AKT pathways were both involved in ETAR-mediated migration, invasion, and MMP-3 production. Taken together, our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression. Thus, ETAR may play an important role in the progress of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Endotelina-1/metabolismo , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Endotelina/metabolismo , Transdução de Sinais , Adulto , Idoso , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Endotelina-1/genética , Feminino , Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Metaloproteinase 3 da Matriz/biossíntese , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Isoformas de Proteínas , Receptores de Endotelina/genética , Carga TumoralRESUMO
Glutathione S-transferases (GSTs) are enzymes which play an important role in the neutralization of toxic compounds and eradication of electrophilic carcinogens. Genetic polymorphisms within the genes encoding for GSTs may therefore cause variations in their enzyme activity, which may in turn influence the interindividual susceptibility to cancers. In this study, we aimed to investigate the association between genetic polymorphisms of GSTT1, GSTM1, and GSTP1 and the risk of colorectal cancer (CRC) in 264 cases and 317 controls in a Chinese population. Genotyping was performed by using multiplex PCR (for GSTT1 and GSTM1) and PCR-RFLP (for GSTP1) methods. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Our results showed that individuals with GSTT1 and GSTM1 null genotypes exhibited a higher risk of CRC (GSTT1, OR,1.66; 95% CI, 1.20-2.31, P=0.003; GSTM1, OR,1.57; 95% CI,1.13-2.18, P=0.007), while no association was observed for GSTP1 (P heterozygous=0.790 or P variant=0.261). Furthermore, individuals who simultaneously carried the null genotypes for both GSTT1 and GSTM1 showed a stronger risk association (OR, 1.95; 95% CI, 1.33-2.85; P<0.001). In conclusion, the GSTT1 and GSTM1 polymorphisms, but not GSTP1, may modulate the CRC risk among Chinese.
Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Idoso , Alelos , Neoplasias Colorretais/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , RiscoRESUMO
The specific molecular mechanism of neuroprotective effects of wnt-3a on spinal cord injury (SCI) has not been elucidated. In our study, we evaluated the recovery of motor function after SCI by BBB, observed neuronal apoptosis by western blot and TUNEL, observed the changes of neuronal inflammation by western blot and immunofluorescence staining, and observed the changes of motoneurons and spinal cord area in the anterior horn of the spinal cord via Nissl and HE staining. We found that wnt-3a could significantly promote the recovery of motor function, reduce the loss of motor neurons in the anterior horn of the spinal cord, promote the recovery of injured spinal cord tissue, inhibit neuronal apoptosis and inflammatory response, and ultimately promote neuronal function after SCI. However, when XAV939 inhibits the wnt/ß-catenin signaling pathway, the neuroprotective effects of wnt-3a are also significantly inhibited. The above results together indicated that wnt-3a exerts its neuroprotective effect on after SCI via activating the wnt/ß-catenin signaling pathway.
Assuntos
Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Proteína Wnt3A , Animais , Ratos , Apoptose , Neurônios Motores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Via de Sinalização Wnt/fisiologia , Proteína Wnt3A/metabolismo , Proteína Wnt3A/uso terapêuticoRESUMO
Nobiletin (NOB), a polymethoxylated flavone isolated from citrus peels, is a promising dietary treatment for lung diseases, such as pulmonary fiborsis. In this work, the underlying mechanisms of NOB's preventative effect on pulmonary fibrosis were explored using bleomycin-exposed mice and IL-4-induced M2 polarization of the macrophages. Results showed that NOB treatment could significantly ameliorate lung fibrosis by suppressing pathological damages, collagen deposition, and fibroblat activation. Moreover, NOB obviously reduced the M2 macrophage-related proteins, including CD206, Arg1, and pro-fibrotic mediators such as TGF-ß and CTGF, which might contribute to the antifibrosis effect of NOB. Network analysis of the differentially expressed genes in NOB-treated M2 macrophages showed that autophagy, mTOR signaling pathway, and AMPK signaling pathway might be involved in the effects of NOB. Further exploration illustrated that autophagy was enhanced in NOB-treated lung and M2 macrophages.The addition of 3MA, an autophagy inhibitor, could significantly weaken the effect of NOB on lung fibrosis and macrophage M2 polarization. Additionally, NOB also markedly decreased the expression of p-AMPK, p-mTOR, and p-P70S6K in the M2 macrophages and lung tissues of BLM-exposed mice. Compound C, an AMPK agonist, significantly suppressed NOB-induced activation of AMPK and mTOR signals, as well as its inhibitory effect on autophagy, M2 macrophages and lung fibrosis both in vitro and in vivo, supporting the requirement of AMPK-mTOR-mediated autophagy for the NOB's antifibrosis activity. Taken together, this study suggests that NOB ameliorates pulmonary fibrosis likely involving the inhibition of M2 macrophage via activating AMPK-mTOR-mediated autophagy.
Assuntos
Proteínas Quinases Ativadas por AMP , Autofagia , Bleomicina , Flavonas , Macrófagos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Flavonas/farmacologia , Flavonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Pulmão/patologia , Pulmão/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
CONTEXT/OBJECTIVE: This study aimed to explore the anti-inflammatory and neuroprotective effects of protocatechuic aldehyde (PCA) in rats with spinal cord injury (SCI) and to clarify the molecular mechanisms underlying its pharmacological effects. DESIGN: Male Sprague Dawley rat model of moderate spinal cord contusion were established. SETTING: Third-class first-class hospital. OUTCOME MEASURES: The Basso, Beattie, and Bresnahan scores and performance on the inclined plane test were evaluated. Histological analyses were performed via hematoxylin and eosin staining. Apoptosis in the spinal cord and neurons was detected by 5 terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining. Apoptotic factors (Bax, Bcl-2, and cleaved caspase-3) were also evaluated. INOS, IL-1ß, IL-10, TNF-α, Wnt-3α, ß-catenin, iBA-1, and NeuN were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting (WB), and enzyme-linked immunosorbent assay. Cell viability and the immunofluorescence of IL-1ß were measured in PC-12 cells. RESULTS: Using WB and quantitative reverse transcription-PCR, we confirmed that PCA treatment activated the Wnt/ß-catenin signaling axis in vivo and in vitro. Hematoxylin and eosin staining and hindlimb motor functional evaluation revealed that treatment with PCA improved tissue protection and functional recovery via the Wnt/ß-catenin axis. The upregulation of TUNEL-positive cells, downregulation of neurons, elevated apoptosis-associated factors in rats, and increased apoptotic rates were observed in microglia and PC-12 after PCA application. Finally, PCA mitigated SCI-induced inflammation by targeting the Wnt/ß-catenin axis. CONCLUSION: This study provided preliminary evidence that PCA inhibits neuroinflammation and apoptosis through the Wnt/ß-catenin pathway, thereby attenuating the secondary injury after SCI and promoting the regeneration of injured spinal tissues.
RESUMO
Background: Certain medication categories may increase the risk of stroke. Nonetheless, the evidence regarding the causal relationship of medication-taking in promoting stroke and subtypes is deficient. Methods: We evaluated the causal effect of a genetic predisposition for certain medication categories on stroke and subtypes (ischemic and hemorrhagic categories) by a two-sample Mendelian randomization (MR) analysis. Data for 23 medication categories were gathered from a genome-wide association study (GWAS) involving 318,177 patients. The Medical Research Council Integrative Epidemiology Unit Open GWAS database and the FinnGen consortium were used to gather GWAS data for stroke and subtypes. Inverse variance weighted, MR-Egger, and weighted median were used for the estimation of causal effects. Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were used for sensitivity analyses. Results: Ten medication categories were linked to a high stroke risk. Nine categories were linked to a high-risk ischemic stroke. Five categories were associated with small vessel ischemic stroke. Nine categories were positively associated with large artery atherosclerotic ischemic stroke. Three categories causally increased the possibility of cardioembolic ischemic stroke. Four categories were associated with intracerebral hemorrhage. Four categories were associated with nontraumatic intracranial hemorrhage. Three categories were causally associated with subarachnoid hemorrhage (SAH). Four categories were associated with the combination of SAH, unruptured cerebral aneurysm, and aneurysm operations SAH. Conclusions: This study confirms that some medication categories lead to a greater risk of strokes. Meanwhile, it has an implication for stroke screening as well as direct clinical signiï¬cance in the design of conduction of future randomized controlled trials.
RESUMO
Purpose: The treatment of hepatocellular carcinoma (HCC) patients with high-risk features (Vp4, and/or tumor occupancy≥50%) has not been standardized and has poor outcomes. The present study aimed to assess the safety, efficacy, and prognostic impact of lenvatinib, hepatic arterial infusion chemotherapy (HAIC), and humanized programmed death receptor-1 (PD-1) in treating high-risk patients and to explore the biomarkers that may predict the efficacy. Methods: HCC patients with high-risk features treated with lenvatinib, HAIC, and PD-1 were analyzed retrospectively. Overall survival (OS), progression-free survival (PFS), duration of response (DOR), objective response rate (ORR), and disease control rate (DCR) were calculated to evaluate the antitumor efficacy. Treatment-related adverse events (TRAEs) were analyzed to assess the safety profiles. Results: Between February 2020 and July 2022, 97 patients were enrolled in this retrospective cohort study. The median follow-up time was 447 days. During analysis, 65 patients had disease progression, and 39 patients died. The median PFS and OS were 295 and 579 days, respectively. According to RECIST 1.1 and mRECIST, the ORR was 64.9% and 78.3%, respectively, and the DCR was 92.8%. The median and intrahepatic DOR was 363 and 462 days, respectively. Treatment-related grade 3 or 4 adverse events occurred in 64 (65.9%) patients, and the most common adverse events were hypertension (9.3%), thrombocytopenia (7.2%), and elevated aspartate transaminase (7.2%). Participants with low levels of serum procalcitonin (PCT) had satisfactory prognosis. Conclusion: Lenvatinib, HAIC, and PD-1 were safe and showed promising antitumor activity against HCC with high-risk features. The initial levels of procalcitonin might be the predictive biomarkers for the combined treatment.
RESUMO
Observational studies have provided evidence of a correlation between alterations in gut microbiota composition and infertility. However, concrete proof supporting the causal relationship is still lacking. We performed a Mendelian randomization study to assess whether genetically gut microbiota composition influences the risk of infertility. The genetic data pertaining to gut microbiota were obtained from a genome-wide association study meta-analysis, which was conducted among 24 cohorts (18,340 participants) from the international MiBioGen consortium. By the primary method of assessing causality, we have identified 2 family taxa, 2 genus taxa, and 1 order taxa that were linked to a low risk of male infertility, while 1 genus taxa were associated with a high risk of male infertility. Furthermore, we have discovered 6 genus taxa, 1 phylum taxa, 1 class taxa, 1 order taxa, and 1 family taxa that were associated with a low risk of female infertility, while 1 genus taxa were linked to a high risk of female infertility. This study successfully confirmed that there was a causal link between gut microbiota and infertility. The identification of these specific strains through genetic prediction offers a valuable insight for early diagnosis, prevention, and treatment of infertility.
Assuntos
Microbioma Gastrointestinal , Infertilidade Feminina , Infertilidade Masculina , Feminino , Masculino , Humanos , Infertilidade Feminina/genética , Análise da Randomização Mendeliana , Microbioma Gastrointestinal/genética , Estudo de Associação Genômica Ampla , Infertilidade Masculina/genéticaRESUMO
The aim of this study was to evaluate the incidence of deep vein thrombosis (DVT) in patients with suspected pulmonary embolism (PE) and the relation between PE and the site of DVT by using technetium-99m-macroaggregated human serum albumin ((99m)Tc-MAA) radionuclide venography (RNV). Technetium-99m-MAA RNV was performed simultaneously with lung perfusion scintigraphy in 123 patients with suspected PE. The incidence of DVT in patients with suspected PE was 58.54%. The incidence of DVT in patients with PE was 77.46%, while in patients without PE was 32.69%. The rate of proximal DVT in patients with PE was 74.55%, while in patients without PE was 47.06%. The average embolic lung segments in patients with proximal DVT and patients with distal DVT were 6.2±2.3 and 3.1±1.2, respectively. In conclusion, lower limb (99m)Tc-MAA RNV demonstrated a high incidence (58.54%) of DVT in patients with suspected PE. The prevalence of DVT was higher in patients with PE than in patients without PE. Pulmonary embolism was more likely to occur in patients with proximal DVT, and more embolic lung segments were detected in patients with proximal DVT.
Assuntos
Pulmão/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/epidemiologia , Agregado de Albumina Marcado com Tecnécio Tc 99m , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/epidemiologia , Adulto , Idoso , China/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Cintilografia , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
Spinal cord injury (SCI) is a complex central traumatic disease. STAT3 signal transduction pathway plays an important role in SCI. Wogonin has been reported to exhibit neuroprotection. However, the molecular mechanism of its potential therapeutic effect after SCI remains unclear. In this study, rats were divided into the following groups: Sham; SCI; SCI + wogonin; and SCI + wogonin + colivelin (Colivelin is an effective activator of the STAT3 pathway). Motor function was evaluated by Basso Beattie Bresnahan (BBB) score. Histomorphological changes in the spinal cords were observed by Hematoxylin-eosin (HE) staining and Nissl staining. Western blot, Transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, and immunofluorescence were used to detect changes in the neuronal inflammation, apoptosis, and STAT3 signal pathway. Western blot and immunofluorescence techniques were also performed to detect the regulatory effect and the underlying mechanism of wogonin on the inflammation and apoptosis of PC12 cells. Experimental results in vivo and in vitro showed that wogonin could promote the recovery of motor function, improve the histopathological morphology, inhibit the activation of the STAT3 signal pathway, and reduce the neuronal inflammation and apoptosis in the rats with SCI. Activation of the STAT3 signal pathway by colivelin reversed the therapeutic effect of wogonin. Therefore, wogonin could inhibit inflammation and apoptosis by inhibiting the STAT3 signal pathway and promote the functional recovery of rats with SCI.
Assuntos
Traumatismos da Medula Espinal , Animais , Apoptose , Flavanonas , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismoRESUMO
Many aggregating animals use aposematic signals to advertise their toxicity to predators. However, the coordination between aposematic signals and toxins is poorly understood. Here, we reveal that phenylacetonitrile (PAN) acts as an olfactory aposematic signal and precursor of hypertoxic hydrogen cyanide (HCN) to protect gregarious locusts from predation. We found that PAN biosynthesis from phenylalanine is catalyzed by CYP305M2, a novel gene encoding a cytochrome P450 enzyme in gregarious locusts. The RNA interference (RNAi) knockdown of CYP305M2 increases the vulnerability of gregarious locusts to bird predation. By contrast, the elevation of PAN levels through supplementation with synthetic PAN increases the resistance of solitary locusts to predation. When locusts are attacked by birds, PAN is converted to HCN, which causes food poisoning in birds. Our results indicate that locusts develop a defense mechanism wherein an aposematic compound is converted to hypertoxic cyanide in resistance to predation by natural enemies.
Assuntos
Acetonitrilas/metabolismo , Aves , Doenças Transmitidas por Alimentos , Gafanhotos/metabolismo , Cianeto de Hidrogênio/intoxicação , Comportamento Predatório , Olfato/fisiologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Técnicas de Silenciamento de Genes , Interferência de RNARESUMO
OBJECTIVE: To evaluate the efficacy and safety of raltitrexed plus oxaliplatin-based transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). METHODS: A total of 123 patients with unresectable HCC were recruited into the prospective cohort study. Raltitrexed plus oxaliplatin-based TACE was performed according to the traditional method at monthly intervals and was repeated for up to 4 cycles if no disease progression or intolerable toxicity occurred. The primary efficacy endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and tumor response rate. The Cox proportional-hazards regression model was used to assess the independent prognostic factors of OS. Adverse events were also observed. RESULTS: The median OS time and PFS were 623 days (95% CI: 461, 785) and 338 days (95% CI: 302, 704), respectively. The disease control rate was 95.5% (118/123). The Cox proportional-hazards regression model indicated that age, ECOG performance status and response to TACE as independent prognostic factors of OS. No treatment-related mortality occurred within 30 days of treatment procedure. The most common complications included postembolization syndrome, liver dysfunction and hematological toxicity. Grade 3 pain, transglutaminase abnormality and thrombocytopenia were observed in 16 (13%), 15 (12.2%) and 3 (2.4%) patients, respectively. No grade 4 adverse events were observed. CONCLUSION: Raltitrexed plus oxaliplatin-based TACE led to high tumor response rate and promising PFS and OS, and was considered safe and tolerable in patients with unresectable HCC.
Assuntos
Carcinoma Hepatocelular/terapia , Catéteres , Embolização Terapêutica/instrumentação , Óleo Etiodado/metabolismo , Fluordesoxiglucose F18 , Neoplasias Hepáticas/terapia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Artérias , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Neoplasia Residual , Resultado do TratamentoRESUMO
Chemical communication plays an important role in density-dependent phase change in locusts. However, the volatile components and emission patterns of the migratory locust, Locusta migratoria, are largely unknown. In this study, we identified the chemical compositions and emission dynamics of locust volatiles from the body and feces and associated them with developmental stages, sexes and phase changes. The migratory locust shares a number of volatile components with the desert locust (Schistocerca gregaria), but the emission dynamics of the two locust species are significantly different. The body odors of the gregarious nymphs in the migratory locust consisted of phenylacetonitrile (PAN), benzaldehyde, guaiacol, phenol, aliphatic acids and 2,3-butanediol, and PAN was the dominant volatile. Volatiles from the fecal pellets of the nymphs primarily consist of guaiacol and phenol. Principal component analysis (PCA) showed significant differences in the volatile profiles between gregarious and solitary locusts. PAN and 4-vinylanisole concentrations were significantly higher in gregarious individuals than in solitary locusts. Gregarious mature males released significantly higher amounts of PAN and 4-vinylanisole during adulthood than mature females and immature adults of both sexes. Furthermore, PAN and 4-vinylanisole were completely lost in gregarious nymphs during the solitarization process, but were obtained by solitary nymphs during gregarization. The amounts of benzaldehyde, guaiacol and phenol only unidirectionally decreased from solitary to crowded treatment. Aliphatic aldehydes (C7 to C10), which were previously reported as locust volatiles, are now identified as environmental contaminants. Therefore, our results illustrate the precise odor profiles of migratory locusts during developmental stages, sexes and phase change. However, the function and role of PAN and other aromatic compounds during phase transition need further investigation.
Assuntos
Locusta migratoria/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Animais , Comportamento Animal , Fezes/química , Feminino , Locusta migratoria/crescimento & desenvolvimento , Masculino , Ninfa/metabolismo , Densidade Demográfica , Fatores Sexuais , Comportamento SocialRESUMO
Apatinib is a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. Previous studies have suggested that apatinib is safe and effective in some solid tumors. We report one case with advanced hepatocellular carcinoma (HCC), who received apatinib combined with transhepatic arterial chemotherapy and embolization (TACE), and chemotherapy respectively. TACE was administered three times once a month, using lipiodol 10ml, oxaliplatin 150mg, and tegafur 1g. The dose of apatinib was 500 mg/d from day 4 to 24. After TACE, the patient received chemotherapy of regimen FOLFOX4, oxaliplatin intravenously at 85 mg/m2 on day 1, calcium levofolinate 200 mg/m2 on day 1 and 2, 5-fluorouracil 400 mg/m2 intravenously and 5-fluorouracil 600 mg/m2 intravenously pumped for 22h on day 1 and 2, cycled every two weeks for seven cycles. He took concurrently apatinib with a dose of 500mg daily from 1 to 10 days per cycle. He was confirmed as partial response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST). The level of serum alpha-fetoprotein (AFP) decreased from 60500 ng/ml to 12.7 ng/ml, and the progression free survival (PFS) time was more than eight months. It indicated that apatinib may be a superior choice for HCC patients.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Piridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioembolização Terapêutica , Intervalo Livre de Doença , Óleo Etiodado/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Tegafur/administração & dosagemRESUMO
OBJECTIVE: To investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in Chinese hepatocellular carcinoma (HCC) patients with low serum HBV DNA level, and to analyze the factors related to HBV reactivation in HCC patients with low serum HBV DNA level. METHODS: From November 2011 to January 2014, 109 patients newly diagnosed with HCC with an HBV DNA level less than 2,000 IU/mL were enrolled in the study. These patients underwent at least two TACE procedures and were followed-up for at least 3 months to assess the reactivation of HBV DNA. Ten variables were compared in patients with and without HBV reactivation to evaluate the factors related to HBV reactivation in HCC patients with low serum HBV DNA level. RESULTS: Of 109 HCC patients with low level HBV DNA, nine patients were HBeAg-positive, the other 100 patients were HBeAg-negative. Twenty-three of 109 (21.1%) patients developed HBV reactivation after TACE. Of nine HBeAg-positive patients, 55.6% (5/9) developed HBV reactivation, while in 100 HBeAg-negative patients, the rate of HBV reactivation was 18% (18/100) (P=0.019). Of ten variables of patients with low level HBV DNA, the levels of AFP and HBeAg status were found to be significantly correlated with HBV reactivation. Nevertheless, on binary logistic regression analysis, only HBeAg-positive status was the independent predictor of HBV reactivation in HCC patients with low serum HBV DNA level (odds ratio, 7.41; P=0.013). CONCLUSION: HCC patients with low serum HBV DNA level still remain associated with risk of viral reactivation after TACE, and HBeAg-positive HCC patients have a higher risk than patients with HBeAg-negative status.
RESUMO
Sorafenib has been demonstrated to improve survival rate in patients with advanced hepatocellular carcinoma (HCC); however, the survival benefit remains modest and the response rates remain poor. Transarterial chemoembolization (TACE) may be used for the treatment of advanced HCC with well-preserved liver function and has a high local tumor control rate. We hypothesized that patients with advanced HCC may benefit from the combination of sorafenib with TACE. A retrospective study was conducted involving patients with advanced HCC, who had received at least one TACE session. Patients subsequently received 400 mg sorafenib twice per day and were monitored monthly. A dose reduction from 400 to 200 mg of sorafenib twice per day was permitted. The overall survival and side effects were subsequently followed up. In total, 38 patients were included from April 1st, 2009 to March 31st, 2012. All patients were treated with sorafenib after TACE was performed. As of March 31st, 2013, seven patients remained on sorafenib, and were censored at that time point. The median overall survival time was 12 months (95% confidence interval, 6.3-17.7 months). The sorafenib dose was reduced temporarily in 32 patients (84.2%). The most common toxicities were dermatological adverse effects (94.7%), diarrhea (63.2%) and alopecia (26.3%). The survival benefit of sorafenib combined with TACE for advanced HCC is promising, with no intolerable adverse events, provided that dose adjustment is permitted.
RESUMO
RATIONAL AND OBJECTIVE: Radioembolization with yttrium-90 microspheres is a therapy that is used for hepatic tumors. 20-30 µm microspheres loaded with Y90 are supposedly occluding tumor vessels at the capillary level. Then, these spheres deliver high-dose radiation to the tumor. However, this theoretical embolic effect has never been appreciated in imaging. Dual-Phase cone-beam computed tomography (DPCBCT) is a multi-phasic intra-procedural scan that uses only one contrast media injection to visualize early (feeding vessel) and delayed (capillary level) tumor enhancement. The purpose of this study was to determine whether there is a micro-embolic effect induced by TheraSpheres® (MDS Nordion, Ottawa, Ontario, Canada) at the capillary level by using DPCBCT imaging. MATERIALS AND METHODS: 14 patients with 72 carcinoid or neuroendocrine tumors were treated with radioembolization, and all underwent DPCBCT (Allura Xper, Philips Healthcare) imaging before and immediately after radioembolization with TheraSpheres®. Tumor enhancement was measured in each phase by drawing a region of interest within the tumors. RESULTS: 72 tumors were evaluated: average tumor density in the early arterial phase was 241 and 230 Hounsfield units (HU) (p<0.001) before and after radioembolization, respectively; the average density in the delayed arterial phase was 226 and 161 HU (p<0.001) before and after radioembolization, respectively. Average difference in tumor attenuation before and after radioembolization in early arterial and delayed phase was 11 HU and 64 HU (p<0.001), respectively. CONCLUSION: The significant decrease in tumor enhancement in the DPCBCT delayed phase after TheraSpheres® injection indicates that there is an appreciable microembolic effect at the tumor capillary bed level.