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1.
J Cancer Res Clin Oncol ; 145(9): 2285-2292, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31372722

RESUMO

BACKGROUND: The cell adhesion molecule close homologue of L1 (CHL1) is a potential tumour suppressor and was recently detected in non-small cell lung cancer (NSCLC) specimens. The expression pattern, prognostic, and functional role of CHL1 in NSCLCs is unknown. METHODS: We evaluated the protein expression of CHL1 by immunohistochemistry in 2161 NSCLC patients based on a tissue microarray. The results were correlated with clinical, histopathological, and patient survival data (Chi square test, t test, and log-rank test, respectively). A multivariate analysis (Cox regression) was performed to validate its impact on patients' survival. RESULTS: CHL1 was expressed in NSCLC patients and was significantly overexpressed in lung adenocarcinomas and squamous cell carcinomas compared to neuroendocrine and large cell carcinomas of the lung (p < 0.001). CHL1 expression was associated with the T stage in adenocarcinomas (p = 0.011) and with metastatic lymph node status and UICC stage in squamous cell carcinomas (p = 0.034 and p = 0.035, respectively). Increased CHL1 expression was associated with improved survival in univariate (p = 0.031) and multivariate analyses (odds ratio 0.797, 95% confidence interval 0.677-0.939, p = 0.007). CONCLUSION: The prognostic significance of CHL1 makes it a potential prognostic and therapeutic target and underlines its role as a tumour suppressor. Further validation studies and functional analyses are needed to investigate its potential role in tumourigenesis and dissemination.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Moléculas de Adesão Celular/metabolismo , Neoplasias Pulmonares/mortalidade , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos
2.
Bioengineered ; 10(1): 345-352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411110

RESUMO

This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Ontologia Genética , Histona Desacetilase 1/sangue , Histona Desacetilase 1/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Anotação de Sequência Molecular , Análise Multivariada , Proteínas de Neoplasias/sangue , Prognóstico , Curva ROC , Recidiva , Transdução de Sinais , Análise de Sobrevida , Quinases da Família src/sangue , Quinases da Família src/genética
3.
Bone Joint J ; 101-B(8): 1024-1031, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31362545

RESUMO

AIMS: The aim of this study was to determine the risk of local recurrence and survival in patients with osteosarcoma based on the proximity of the tumour to the major vessels. PATIENTS AND METHODS: A total of 226 patients with high-grade non-metastatic osteosarcoma in the limbs were investigated. Median age at diagnosis was 15 years (4 to 67) with the ratio of male to female patients being 1.5:1. The most common site of the tumour was the femur (n = 103) followed by tibia (n = 66). The vascular proximity was categorized based on the preoperative MRI after neoadjuvant chemotherapy into four types: type 1 > 5 mm; type 2 ≤ 5 mm, > 0 mm; type 3 attached; type 4 surrounded. RESULTS: Limb salvage rate based on the proximity type was 92%, 88%, 51%, and 0% for types 1 to 4, respectively, and the overall survival at five years was 82%, 77%, 57%, and 67%, respectively (p < 0.001). Local recurrence rate in patients with limb-salvage surgery was 7%, 8%, and 22% for the types 1 to 3, respectively (p = 0.041), and local recurrence at the perivascular area was observed in 1% and 4% for type 2 and 3, respectively. The mean microscopic margin to the major vessels was 6.9 mm, 3.0 mm, and 1.4 mm for types 1 to 3, respectively. In type 3, local recurrence-free survival with limb salvage was significantly poorer compared with amputation (p = 0.025), while the latter offered no overall survival benefit. In this group of patients, factors such as good response to chemotherapy or limited vascular attachment to less than half circumference or longitudinal 10 mm reduced the risk of local recurrence. CONCLUSION: The proximity of osteosarcoma to major blood vessels is a poor prognostic factor for local control and survival. Amputation offers better local control for tumours attached to the blood vessels but does not improve survival. Limb salvage surgery offers similar local control if the tumour attachment to blood vessels is limited. Cite this article: Bone Joint J 2019;101-B:1024-1031.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Neoplasias Femorais/cirurgia , Imagem por Ressonância Magnética , Recidiva Local de Neoplasia/etiologia , Osteossarcoma/cirurgia , Cuidados Pré-Operatórios/métodos , Tíbia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Neoplasias Femorais/diagnóstico por imagem , Neoplasias Femorais/mortalidade , Neoplasias Femorais/patologia , Seguimentos , Humanos , Salvamento de Membro , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Tíbia/diagnóstico por imagem , Tíbia/patologia , Tíbia/cirurgia , Adulto Jovem
4.
Gene ; 716: 144034, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377317

RESUMO

BACKGROUND: Outcome in adjuvant chemotherapy of gastric cancer (GC) has considerable stage-independent variability, which underscores the need for prognostic or predictive molecular markers. CHAF1A promotes tumor growth while its impact on chemotherapy outcome remains unknown. METHODS: CHAF1A protein expression was measured in independent discovery and validation sets that included 86 and 325 patients respectively who received fluoropyrimidines-based adjuvant chemotherapy after radical gastrectomy. The chemosensitizing effect of CHAF1A knockdown was investigated in vitro. Bioinformatics analysis based on RNA-seq and proteome data from public database was performed to investigate the potential mechanisms and further validation was conducted. RESULTS: In both the discovery and validation sets, CHAF1A expression level was an independent predictor for disease-free survival (HR = 4.25; 95% CI: 2.31-7.79; P < 0.001; and HR = 1.91; 95% CI: 1.03-3.54; P = 0.039, respectively) and overall survival (HR = 3.25; 95% CI: 1.75-6.05; P < 0.001; and HR = 2.42; 95% CI: 1.12-5.20; P = 0.024, respectively) in patients with non-cardia GC but not in those with cardia GC. In GC cells, CHAF1A knockdown significantly decreased the IC50 of 5-FU. Bioinformatics analyses indicated that CHAF1A correlated with folate metabolism and the expression of thymidylate synthetase (TS). Furthermore, CHAF1A knockdown significantly reduced TS expression in GC cells and CHAF1A positively correlated with TS protein expression in tumor tissues. Finally, ten proteins potentially relevant to the regulation of TS expression by CHAF1A were identified using online tools based on RNA-seq and proteome data. CONCLUSIONS: CHAF1A may impact adjuvant chemotherapy outcome of GC by regulating the expression of TS.


Assuntos
Antineoplásicos/uso terapêutico , Chaperonas de Histonas/metabolismo , Pirimidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timidilato Sintase/metabolismo , Idoso , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Fator 1 de Modelagem da Cromatina/metabolismo , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Timidilato Sintase/genética , Resultado do Tratamento
5.
Medicine (Baltimore) ; 98(32): e16765, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393395

RESUMO

Primary septic arthritis of the hip is rare and potentially devastating in adults. Its optimal surgical treatment and clinical outcomes remain unclear.In this retrospective cohort study, we investigated mortality and reinfection rates after surgery of patients with septic hip arthritis. We reviewed patients treated for primary septic hip joints from October 2005 to December 2016. A total of 51 adult patients were identified, and 38 among them had destructive hip joints. A poor postoperative outcome was defined as mortality or recurrent infection within 2 years of surgery.After surgery, 7 (13.7%) patients died within 1 year and 5 (9.8%) patients developed a recurrent hip infection within 2 years. Therefore, poor outcomes occurred in 22% (n = 11) of the study cohort. Among the 38 patients with a destructive hip joint, 7 (18.4%) died within 1 year after surgery and 4 (10.5%) developed a recurrent hip infection within 2 years of surgery. Correlative infections other than infected hip joint and liver cirrhosis were identified as risk factors for poor outcomes.In conclusion, clinical physicians treating adult primary septic hip joints should be cognizant of the high failure rate of surgical treatment. In addition, the high mortality rate should be considered during the discussion of surgical treatment with these patients and their families.


Assuntos
Artrite Infecciosa/mortalidade , Artrite Infecciosa/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Infecciosa/complicações , Coinfecção/epidemiologia , Comorbidade , Desbridamento/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Análise de Sobrevida
6.
Gene ; 716: 144025, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31394177

RESUMO

BACKGROUND: Existing meta-analysis have shown that the miR-200 family can be taken as a prognostic biomarker for many tumors. However, great heterogeneity was shown in predicting overall survival (OS) and progression-free survival (PFS). Emerging studies indicate that the expression levels of members of the miR-200 family are tissue-specific among various tumor tissues, which may be the main reason of the heterogeneity in predicting survival prognosis of tumor patients with the miR-200 family as biomarkers. By further analysis of heterogeneity of the miR-200 family as a biomarker for predicting survival prognosis of patients with different tumors, we expected to provide an accurate basis for the clinical application of the miR-200 family to predict the prognosis of patients with different tumors. METHODS: Eligible published studies were identified by searching the databases of PubMed, Embase and Web of Science. The clinical data of patients in the studies were pooled, and pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. The expressions of miRNAs were extracted from The Cancer Genome Atlas (TCGA). We presented the expressions of each member in miR-200 family in 15 types of cancer by boxplot, and analyzed the correlation among the members of miR-200 family by Spearman method. Different subgroup analyses were then performed based on the correlation among the members of miR-200 family, and the publication bias was assessed using the funnel plot of the Egger bias indicator test. RESULTS: Of 36 articles, including 15 tumor types and 4644 patients were included to perform meta-analysis. It was found that miR-200 family members can be used as independent protective factors in patients with various tumors but the miR-200 family has a higher heterogeneity in predicting prognosis: OS (HR = 0.82, 95% CI: 0.66-1.03, I2 = 85%, P < 0.01) and PFS (HR = 0.81, 95% CI: 0.57-1.16, I2 = 97%, P < 0.01). The data from TCGA database were used to analyze the expression levels of the miR-200 family and the results showed that the expression of miR-429 in different cancers is very different, and there are significant differences in expression levels compared with other miR-200 family members; the expression levels of miR-200a and miR-200b in various tumor tissues were similar to each other, respectively; miR-200c and miR-141 showed similar expression levels in each of most types of cancer tissues except ovarian cancer (OC). The expression levels of members of the miR-200 family in breast cancer (BRCA), cervical cancer (CESC), colon cancer (COAD), esophageal cancer (ESCA), head and neck cancer (HNSC), lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are relatively stable, but great variations can be found in the expression levels of miR-200 family members in ovarian cancer (OC), liver cancer (LIHC), renal clear cell carcinoma (KIRC) and renal papillary cell carcinoma (KIRP). Cluster analysis of expression of target genes of miR-200 family in different cancers yielded similar results to the expression level of the miR-200 family. Subgroup analysis of OC, LIHC, GC and LUAD based on expression levels and clustering results reduced or even eliminated the heterogeneity of miR-200 family members in predicting patient outcomes. CONCLUSIONS: Our results convincingly demonstrated that the miR-200 family could serve as a prognostic biomarker for cancers mentioned above and has potential value in clinical practice. MiR-200 family as prognostic biomarkers needs to be performed according to different tumor tissues and correlation between members in miR-200 family.


Assuntos
MicroRNAs/metabolismo , Neoplasias/mortalidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mineração de Dados , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Análise de Sobrevida
7.
Biol Res ; 52(1): 42, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399040

RESUMO

BACKGROUND: Prognosis remains one of most crucial determinants of gastric cancer (GC) treatment, but current methods do not predict prognosis accurately. Identification of additional biomarkers is urgently required to identify patients at risk of poor prognoses. METHODS: Tissue microarrays were used to measure expression of nine GC-associated proteins in GC tissue and normal gastric tissue samples. Hierarchical cluster analysis of microarray data and feature selection for factors associated with survival were performed. Based on these data, prognostic scoring models were established to predict clinical outcomes. Finally, ingenuity pathway analysis (IPA) was used to identify a biological GC network. RESULTS: Eight proteins were upregulated in GC tissues versus normal gastric tissues. Hierarchical cluster analysis and feature selection showed that overall survival was worse in cyclin dependent kinase (CDK)2, Akt1, X-linked inhibitor of apoptosis protein (XIAP), Notch4, and phosphorylated (p)-protein kinase C (PKC) α/ß2 immunopositive patients than in patients that were immunonegative for these proteins. Risk score models based on these five proteins and clinicopathological characteristics were established to determine prognoses of GC patients. These proteins were found to be involved in cancer related-signaling pathways and upstream regulators were identified. CONCLUSION: This study identified proteins that can be used as clinical biomarkers and established a risk score model based on these proteins and clinicopathological characteristics to assess GC prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/mortalidade , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Análise de Sobrevida , Análise Serial de Tecidos
8.
Braz J Med Biol Res ; 52(8): e8309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31411246

RESUMO

This study aimed to detect the expression of the long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) and evaluate its correlation with disease risk, stenosis degree, inflammation, as well as overall survival (OS) in coronary artery disease (CAD) patients. A total of 230 patients who underwent diagnostic coronary angiography were consecutively recruited and assigned to CAD group (n=125) or control group (n=105) according to presence or absence of CAD. Gensini score was calculated to assess the severity of coronary artery damage. Plasma samples were collected and the expression ANRIL was detected in all participants. High-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-8, IL-10, and IL-17 in CAD patients were measured and OS was calculated. The relative expression of ANRIL was higher in CAD patients compared to controls (P<0.001). Receiver operating characteristic disclosed that ANRIL could distinguish CAD patients from controls with an area under the curve of 0.789 (95%CI: 0.731-0.847). Spearman's rank correlation test revealed that expression of ANRIL was positively correlated with Gensini score (P=0.001), levels of hs-CRP (P=0.001), ESR (P=0.038), TNF-α (P=0.004), and IL-6 (P<0.001), while negatively correlated with IL-10 level (P=0.008) in CAD patients. Kaplan-Meier curve revealed that high expression of ANRIL was associated with shorter OS (P=0.013). In conclusion, circulating ANRIL presented a good diagnostic value for CAD, and its high expression was associated with increased stenosis degree, raised inflammation, and poor OS in CAD patients.


Assuntos
Doença da Artéria Coronariana/diagnóstico , RNA Longo não Codificante/genética , Idoso , Sedimentação Sanguínea , Proteína C-Reativa/análise , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Estenose Coronária/complicações , Citocinas/sangue , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Análise de Sobrevida
9.
Medicine (Baltimore) ; 98(33): e16871, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415425

RESUMO

Predicting long-term outcomes after sepsis is important when caring for patients with this condition. The purpose of the present study was to develop models predicting long-term mortality of patients with sepsis, including septic shock.Retrospective data from 446 patients with sepsis (60.8% men; median age, 71 years) treated at a single university-affiliated tertiary care hospital over 3 years were reviewed. Binary logistic regression was used to identify factors predicting mortality at 180 and 365 days after arrival at the emergency department. Long-term prognosis scores for the 180- and 365-day models were calculated by assigning points to variables according to their ß coefficients.The 180- and 365-day mortality rates were 40.6% and 47.8%, respectively. Multivariate analysis identified the following factors for inclusion in the 180- and 365-day models: age ≥65 years, body mass index ≤18.5 kg/m, hemato-oncologic diseases as comorbidities, and ventilator care. Patients with scores of 0 to ≥3 had 180-day survival rates of 83.8%, 70.8%, 42.3%, and 25.0%, respectively, and 365-day survival rates of 72.1%, 64.6%, 36.2%, and 15.9%, respectively (all differences P < .001; log-rank test). The areas under the receiver operating characteristic curves of the 180- and 365-day models were 0.713 (95% confidence interval [CI] 0.668-0.756, P < .001) and 0.697 (95% CI 0.650-0.740, P < .001), respectively.These long-term prognosis models based on baseline patient characteristics and treatments are useful for predicting the 6- and 12-month mortality rates of patients with sepsis.


Assuntos
Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Choque Séptico/mortalidade , Análise de Sobrevida , APACHE , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Comorbidade , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Respiração Artificial/efeitos adversos , Adulto Jovem
10.
Rev Col Bras Cir ; 46(3): e20192098, 2019 Aug 15.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31432981

RESUMO

OBJECTIVE: to evaluate the clinical and pathological differences between locally advanced colonic adenocarcinomas (LACA) with adhesions between adjacent organs or structures, and colonic adenocarcinomas with other clinical presentations. METHODS: we conducted a retrospective study from a convenience sample of patients with colonic adenocarcinoma, pathological stage pT3, distributed according to clinical and pathological characteristics in three groups: locally advanced tumors (LACA), pT3 tumors without adhesions or distant metastases (SF) and tumors with metastatic disease (M1). We evaluated clinical and pathological characteristics and the expression of seven immunohistochemical markers related to proliferation/apoptosis, cell invasion/migration and metastasis. RESULTS: we studied 101 patients: 30 LACA, 44 SF and 27 M1. Locally advanced tumors presented larger dimensions and were associated with increased lymphocyte infiltration rates, lower levels of bax expression, and CD 44v6 when compared with SF and M1 groups. We observed significant differences between LACA and M1 in relation to colonic location, histology, lymph node status and bax and CD44v6 expression. We found differences were observed between the three groups for tumor size and lymphocytic infiltrate. Survival was similar in the LACA and SF groups (p=0.66) and was lower in the M1 group (p<0.001). CONCLUSION: the data suggest that locally advanced colonic adenocarcinomas with adhesions between adjacent organs or structures represent a distinct entity.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Adenocarcinoma/mortalidade , Neoplasias do Colo/mortalidade , Humanos , Imuno-Histoquímica , Estudos Longitudinais , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Análise de Sobrevida
11.
N Engl J Med ; 381(8): 727-738, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31433920

RESUMO

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Dexametasona/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidrazinas/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Triazóis/efeitos adversos , Adulto Jovem
12.
Anticancer Res ; 39(7): 3295-3301, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262849

RESUMO

The development of effective human epidermal growth factor receptor 2 (HER2)-targeted therapies has been heralded as a significant milestone in breast cancer treatment, resulting in improvement of the outcome for those with HER2-positive metastatic breast cancer. Despite these advantages, metastatic breast cancer is still regarded as an incurable disease. In heavily pretreated patients with increasingly limited options for palliative management, ensuring control of disease and maintenance of quality of life is an important goal. Vinorelbine and lapatinib is a combination used in later-line treatment of metastatic HER2-positive breast cancer. The current article presents a systematic review and meta-analysis of prospective series of the vinorelbine/lapatinib doublet for efficacy and toxicity in metastatic HER2-positive breast cancer. Altogether seven prospective trials involving 235 evaluable patients were retrieved for analysis. Pooled estimates of response rate and disease control rate were 24.4% and 63.3% respectively. Furthermore, overall survival was 20.1 months and progression-free survival was 5.44 months. The most common grade 3 and 4 toxicities were seen in fewer than 10% of cases. Vinorelbine/ lapatinib combination regimen may serve as an option for pre-treated patients with metastatic HER2-positive breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lapatinib/uso terapêutico , Vinorelbina/uso terapêutico , Neoplasias da Mama/patologia , Humanos , Receptor ErbB-2 , Análise de Sobrevida , Resultado do Tratamento
13.
Am Surg ; 85(6): 645-653, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267907

RESUMO

The purpose of this meta-analysis was to determine the value of quantitative dynamic contrast-enhanced (DCE) MRI (DCE-MRI) in evaluating the response of breast cancer to neoadjuvant chemotherapy (NAC). PubMed, Embase, and Cochrane Library databases (from building to July 31, 2018) were searched to collect articles about the therapeutic evaluation of NAC using the quantitative DCE-MRI in patients with breast cancer. The sensitivities and specificities of quantitative DCE-MRI in the evaluation of NAC for breast cancer were extracted from the articles. Meta-DiSc1.4 was applied to evaluate the efficacy of the sensitivity and specificity; forest figure and summary receiver operating characteristics (SROC) were created. A total of 356 articles were enrolled in this study, including 739 cases in total, in which 218 cases were effective and the other 521 cases were ineffective to NAC, considering the pathological results as the gold standard. The sensitivity and specificity in the included 14 articles of quantitative DCE-MRI (Ktrans, Kep, and ve) in comprehensively evaluating NAC for breast cancer were 84 per cent (95% confidence interval (CI): 78-88%) and 83 per cent (95% CI: 79-86%), respectively. The area under SROC was 0.899 (95% CI: 0.867-0.943). The sensitivity and specificity in the three articles of Ktrans evaluating NAC for breast cancer were 84.1 per cent (95% CI: 71.0-92.1%) and 81.3 per cent (95% CI: 70.5%-88.5%), respectively. The area under SROC was 0.899 (95% CI: 0.834-0.962). Our study confirmed that the quantitative DCE-MRI is able to monitor NAC treatment for breast cancer because of its high sensitivity and specificity. However, there is a high degree of heterogeneity in published studies, highlighting the lack of standardization in the field.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Meios de Contraste , Imagem por Ressonância Magnética/métodos , Terapia Neoadjuvante/métodos , Intensificação de Imagem Radiográfica/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Neoplasias da Mama/mortalidade , Estudos de Avaliação como Assunto , Medicina Baseada em Evidências , Feminino , Humanos , Pessoa de Meia-Idade , Curva ROC , Medição de Risco , Sensibilidade e Especificidade , Análise de Sobrevida , Resultado do Tratamento
14.
Am Surg ; 85(6): 671-675, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267910

RESUMO

This study aims to provide some experience in diagnosis and treatment of unexpected gallbladder cancer (UGBC) and find the major risk factors. Retrospective data were collected and analyzed on 22 patients who were diagnosed with UGBC during or after laparoscopic cholecystectomy from January 2013 to January 2018 at our hospital. Average age of the patients was (60.2 ± 12.8) years (range, 42-83 years). Among them, there were 6 men and 16 women. Gallbladder stones, atrophic gallbladder, uneven thickened wall of the gallbladder, and choledocholithiasis were found to be the major risk factors. Eight patients (36.4%) were diagnosed intraoperatively. Seven cases (31.8%) were at the T1 stage; of these, three were treated with laparoscopic cholecystectomy; two were converted to cholecystectomy; and two underwent cholecystectomy, lymph node dissection, and liver resection. Eight (36.4%) T2 patients, five (22.7%) T3 patients, and one T4 patient had radical cholecystectomy. Partial cholecystectomy and cholecystotomy were carried out in another T4 patient. T1 patients did not receive chemotherapy or radiotherapy. Eleven had chemotherapy and four received chemoradiotherapy. The follow-up period ranged from six months to five years. The one-year survival rate for T1 to T4 patients was 100 per cent, 75 per cent, 40 per cent, and 0 per cent, respectively. A high index of clinical suspicion of UGBC is needed if one patient suffered from both gallbladder stones and choledocholithiasis with atrophic gallbladder or uneven thickened wall of the gallbladder preoperatively. To avoid more UGBC and reoperation, imaging examinations combined with tumor marker tests and intraoperative histopathologic examination are highly recommended.


Assuntos
Causas de Morte , Colecistectomia Laparoscópica/métodos , Colelitíase/cirurgia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Achados Incidentais , Adulto , Fatores Etários , Idoso , Colecistectomia Laparoscópica/efeitos adversos , Colelitíase/diagnóstico por imagem , Bases de Dados Factuais , Feminino , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Incidência , Complicações Intraoperatórias/patologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Prognóstico , Reoperação/métodos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Análise de Sobrevida
15.
Tumour Biol ; 41(7): 1010428319860728, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31264534

RESUMO

Colon cancer represents one of the most common cancers in the world. Despite improved treatment, mortality remains high. In order to improve the assessment of prognosis for colon cancer patients, identifying new prognostic markers remains necessary. We analyzed preoperative serum samples from 148 colon cancer patients surgically treated at Helsinki University Hospital from 1998 through 2002 using a multiplex proximity extension assay (Oncology II panel, Olink Bioscience, Uppsala, Sweden), a panel constituting 92 immunological and oncological markers. We performed univariate and multivariate analyses on these patients and calculated the disease-specific survival among patients using the log-rank test for Kaplan-Meier estimates. In the univariate survival analysis of 92 biomarkers, 26 resulted in p < 0.1. Among these, eight biomarkers emerged as statistically significant (p < 0.05). Patients with low levels of kallikrein 13 had a poor prognosis. Moreover, patients with high levels of amphiregulin, carcinoembryonic antigen-related adhesion molecule 5, interleukin 6, mucin 16, syndecan 1, transforming growth factor alpha, and vimentin also had a poor prognosis. In the multivariate analysis, kallikrein 13 and mucin 16 emerged as independent prognostic markers. The role of kallikrein 13, a member of the serine protease kallikrein biomarker family, in tumorigenesis remains unclear. Mucin 16 is also known as carbohydrate antigen 125, a well-known ovarian cancer biomarker. Patients with low levels of kallikrein 13 (hazard ratio: 0.36; 95% confidence interval: 0.14-0.92; p = 0.033) and high levels of mucin 16 (hazard ratio: 3.15; 95% confidence interval: 1.68-5.93; p < 0.005) had a poor prognosis. Mucin 16 and kallikrein 13 represent independent prognostic markers for colon cancer. Furthermore, the clinical utility of mucin 16 and kallikrein 13 serum tests warrants additional investigation.


Assuntos
Antígeno Ca-125/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Calicreínas/metabolismo , Proteínas de Membrana/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imunoensaio/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Análise de Sobrevida
16.
Medicine (Baltimore) ; 98(26): e15682, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261491

RESUMO

To compare the efficacy of drug-eluting bead transarterial chemoembolization combined with radiofrequency ablation (DEB-TACE+RFA) versus DEB-TACE alone in Chinese hepatocellular carcinoma (HCC) patients.The 28 patients receiving DEB-TACE+RFA and 74 HCC patients receiving DEB-TACE were recruited in this study. Treatment responses, progression-free survival (PFS), and overall survival (OS) were evaluated.One to 3 months after treatments, the proportion of patients achieving complete response (CR) (78.6% vs 33.8%, P <.001) and objective response rate (ORR) (92.9% vs 78.4%, P =.010) were elevated in DEB-TACE+RFA group compared with DEB-TACE group. Multivariate logistic regression displayed that DEB-TACE+RFA was an independently predicting factor for better CR (P = .006). Subgroup analysis of CR achievement illuminated that DEB-TACE+RFA disclosed better CR achievement in patients with history of cirrhosis (P <.001), tumor located in right liver (P = .003), bilobar disease (P = .013), tumor size <3.3 cm (P = .001), no portal vein invasion (P = .001), no hepatic vein invasion (P <.001), Child-pugh stage A (P <.001), Barcelona Clinic Liver Cancer (BCLC) stage 0, A-B (P <.001), abnormal alpha-fetoprotein (AFP) (P = .001) and normal AFP (P = .016). The PFSs were similar between 2 groups (P = .112), however, the OS was more prolonged in DEB-TACE+RFA group (P = .025) compared with DEB-TACE group. And subgroup analysis displayed that PFS of patients with largest nodule size >3.3 cm (P = .025) was longer and patients with unilobar disease (P = .009), and patients with no hepatic invasion (P = .019) and Child-pugh stage A (P = .037) had more favorable OS in DEB-TACE+RFA group compared with DEB-TACE group.DEB-TACE+RFA achieved better treatment responses and OS compared with DEB-TACE alone in Chinese HCC patients.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Ablação por Radiofrequência , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/métodos , China , Terapia Combinada , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento
17.
Medicine (Baltimore) ; 98(26): e15872, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261495

RESUMO

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for ∼20% of invasive breast cancers and is associated with poor prognostics. The recent outcome of HER2+ breast cancer treatment has been vastly improved owing to the application of antibody-targeted therapies. Trastuzumab (Herceptin) is a monoclonal antibody designed to target HER2+ breast cancer cells. In addition to improved survival in the adjuvant treatment of HER2+ breast cancer, trastuzumab treatment has also been associated with cardiotoxicity side effect. However, the molecular mechanisms of trastuzumab action and trastuzumab-mediated cardiotoxicity are still not fully understood. Previous research utilized bulk transcriptomics analysis to study the underlining mechanisms, which relied on averaging molecular signals from bulk tumor samples and might have overlooked key expression features within breast cancer tumor. In contrast to previous research, we compared the single cancer cell level transcriptome profile between trastuzumab-treated and nontreated patients to reveal a more in-depth transcriptome profile. A total of 461 significantly differential expressed genes were identified, including previously defined and novel gene expression signatures. In addition, we found that trastuzumab-enhanced MGP gene expression could be used as prognostics marker for longer patient survival in breast invasive carcinoma patients, and validated our finding using TCGA (The Cancer Genome Atlas) breast cancer dataset. Moreover, our study revealed a 48-gene expression signature that is associated with cell death of cardiomyocytes, which could be used as early biomarkers for trastuzumab-mediated cardiotoxicity. This work is the first study to look at single cell level transcriptome profile of trastuzumab-treated patients, providing a new understanding of the molecular mechanism(s) of trastuzumab action and trastuzumab-induced cardiotoxicity side effects.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Transcriptoma/efeitos dos fármacos , Trastuzumab/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Projetos Piloto , Prognóstico , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Análise de Sobrevida
18.
Medicine (Baltimore) ; 98(26): e15886, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261497

RESUMO

There is limited information about the effects of corticosteroids on severe drug-induced liver injury (DILI). This study aimed to investigate the efficacy and safety of prednisone in severe DILI.Ninety patients with severe DILI were enrolled and studied retrospectively. They were divided into prednisone (n = 66) and control groups (n = 24), undergoing the same treatment regimen except that patients in the prednisone group received a median daily dose of 40 mg prednisone. The primary endpoint was severity reduction (serum total bilirubin [TBIL] <86 µmol/L).During the study, the cumulative rates of severity reduction at 4-, 8-, and 12 days were comparable between the 2 groups (prednisone versus control: 7.6%, 33.3%, and 60.6% versus 12.5%, 37.5%, and 66.7%, P = .331), and were markedly lower in the high-dose group than in the low-dose group (0%, 28.6%, and 35.7% versus 9.6%, 34.6%, and 67.3%, P = .012) or in the control group (0%, 28.6%, and 35.7% versus 12.5%, 37.5%, and 66.7%, P = .023). The 30-day overall survival rate in the prednisone group was significantly higher than in the control group (100% versus 91.7%, P = .018). Serum bilirubin and transaminase values gradually decreased in both groups, which were not significantly different mostly. Cox-regression models revealed that baseline TBIL (hazard ratio: 0.235; 95% confidence interval: 0.084-0.665; P = .006) was the only predictor for severity reduction. No severe adverse event was noted in both groups.Prednisone therapy is safe but not beneficial, and even detrimental at a daily dose > 40 mg for the treatment of severe DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucocorticoides/uso terapêutico , Prednisona/uso terapêutico , Adolescente , Adulto , Idoso , Bilirrubina/sangue , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Falha de Tratamento , Adulto Jovem
19.
Medicine (Baltimore) ; 98(26): e16029, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261506

RESUMO

BACKGROUND: To study the occurrence and prognosis of acute respiratory distress syndrome (ARDS) using single nucleotide polymorphisms (SNPs) of TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci in the TLR4/NF-κB pathway. METHODS: Genotypes were analyzed for TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci. Plasma TNF-α and IL-6 levels and MyD88 mRNA expression in peripheral blood mononuclear cells (PBMCs) of 300 ARDS patients and 300 non-ARDS patients (control group) were examined. The patients were followed up for 60 days, and the prognosis outcome was recorded. RESULTS: The TNF-α rs1800629 locus A allele and the IL-6 rs1800796 locus G allele were found to be risk factors for ARDS (adjusted OR = 1.452, 95% CI: 1.211-1.689, P < .001 and adjusted OR = 1.205, 95% CI: 1.058-1.358, P = .005, respectively). The G allele at MyD88 rs7744 locus was a protective factor against ARDS (adjusted OR = 0.748, 95% CI: 0.631-0.876, P < .001). Compared with the other groups, homozygotes for TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci had higher expression levels, of which homozygotes for TNF-α rs1800629 and IL-6 rs1800796 loci had lower 60-day survival rates, while MyD88 rs7744 locus homozygotes had a higher 60-day survival rate. CONCLUSION: The effect of TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 SNPs on gene expression level is a likely cause of ARDS occurrence and poor prognosis.


Assuntos
NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Síndrome do Desconforto Respiratório do Adulto/genética , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Biomarcadores/sangue , Feminino , Expressão Gênica/genética , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/sangue , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/sangue , Prognóstico , RNA Mensageiro/sangue , Síndrome do Desconforto Respiratório do Adulto/sangue , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Transdução de Sinais , Análise de Sobrevida , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangue
20.
Medicine (Baltimore) ; 98(26): e16065, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261514

RESUMO

BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Some clinical trials have demonstrated that apatinib is efficacious against advanced nonsquamous NSCLC. OBJECTIVE: This study aimed to probe efficacy and safety of apatinib plus docetaxel, as the second or above line treatment, in advanced nonsquamous NSCLC. DESIGN: Multicenter, prospective, single arm study. SETTING: Three teaching hospitals centers in the Sichuan. PARTICIPANTS: Fourteen patients with stage IVA/B nonsquamous NSCLC had previously received at least 1 platinum-based chemotherapy regimen. INTERVENTION: Patients who were enrolled between November 2016 and January 2018 were given docetaxel (75 mg/m, i.v., d1) plus oral apatinib (250 mg/d), 4 weeks as one cycle, until disease progression or intolerance to adverse events (AE). MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival (PFS). The secondary endpoints comprised objective response rate (ORR), disease control rate (DCR), overall survival (OS), and AE incidence rate. RESULTS: All patients carried adenocarcinoma by pathological type. The median follow-up duration was 9.76 months. Out of 14 cases, 12 were evaluable, showing ORR of 33.33%, DCR of 66.67%, DCR of 50% in cases with brain metastasis, median PFS of 2.92 months (95% CI: 1.38-4.48), and 6-month OS of 80%. Primary AEs encompassed: leukopenia in 7 cases (58.33%), hand-foot skin reaction in 5 cases (41.67%), and diarrhea in 4 cases (33.33%). Among them, grade 3 AEs were: leukopenia in 4 cases (33.33%), and hand-foot skin reaction in 1 case (8.33%). No grade 4/5 AEs were reported. Univariate and multivariate analysis were conducted respectively for PFS and OS. These factors encompassed: gender, age, gene mutations, clinical stage, ECOG scores, quantity of metastatic foci, brain metastasis, and hand-foot skin reaction. Results demonstrated zero risk factors for PFS or OS. CONCLUSION: Apatinib plus docetaxel, as the second or above line treatment, is effective and safe against advanced nonsquamous NSCLC, with good tolerance profile. TRIAL REGISTRATION: NCT03416231.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Docetaxel/efeitos adversos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Dados Preliminares , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Retratamento , Análise de Sobrevida , Resultado do Tratamento , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/uso terapêutico
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