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BACKGROUND: Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. METHODS: To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. RESULTS: ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. CONCLUSIONS: Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.
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Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Resultado do Tratamento , Haplótipos , Células Germinativas , Interferon lambda , Interleucinas/genéticaRESUMO
BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.
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Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Infecções por Citomegalovirus/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Taiwan/epidemiologia , Fatores de Risco , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Incidência , Adulto Jovem , Citomegalovirus/isolamento & purificação , Doença Enxerto-Hospedeiro/epidemiologia , Adolescente , Idoso , Transplante Homólogo/efeitos adversos , Criança , Pré-Escolar , Sistema de RegistrosRESUMO
The impact of platelet count on bleeding in hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected patients is unclear. We aimed to evaluate the relationship between platelet count and bleeding in patients with viral hepatitis. We selected patients with HBV and HCV infection. All esophagogastroduodenoscopy, colonoscopy, and brain imaging reports were reviewed to document upper gastrointestinal bleeding (UGIB), lower gastrointestinal bleeding (LGIB), and central nervous system bleeding (CNSB), respectively. We analyzed risk factors for first bleeding events by using Cox proportional hazards models. Incidence rate ratios (IRRs) were used to compare bleeding incidences between viral types and platelet levels. A total of 2522 HCV and 2405 HBV patients were enrolled. The HCV-to-HBV IRRs of UGIB, LGIB, and CNSB were significant at 1.797, 2.255, and 2.071, respectively. The common risk factors in both groups were thrombocytopenia, hypoalbuminemia, high alkaline phosphatase level, and cirrhosis for UGIB, whereas thrombocytopenia and hypoalbuminemia for LGIB. Hypoalbuminemia was the only risk for CNSB. After adjusting platelet count, the higher bleeding rates in the HCV patients diminished. Using a reference platelet count less than 100âxâ10 9 /l, bleeding risk elevated at platelet count less than 70âxâ10 9 /l and less than 40âxâ10 9 /l for UGIB and LGIB in the HCV patients, respectively, compared with less than 60âxâ10 9 /l for UGIB in the HBV patients. The incidence of CNSB was not related to platelet levels. HCV patients had a higher risk for major bleeding. Thrombocytopenia was a significant predictor. Monitoring and management of thrombocytopenia in addition to cirrhotic status was important in these patients.
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Hepatite B , Hepatite C , Hipoalbuminemia , Trombocitopenia , Humanos , Vírus da Hepatite B , Contagem de Plaquetas , Hepacivirus , Hipoalbuminemia/complicações , Hepatite C/complicações , Hemorragia Gastrointestinal/complicações , Trombocitopenia/complicações , Hepatite B/complicaçõesRESUMO
Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.
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Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/genética , Mutação , Calgranulina A/genética , Sequência de Bases , Fenótipo , Calreticulina/genética , Janus Quinase 2/genéticaRESUMO
Finding more metal complexes with outstanding water stability and high proton conductivity still has important research significance for the energy field. Herein, two highly proton-conductive complexes, one hydrogen-bonded supramolecular framework (HSF) [Cd(CBIA)2(H2O)4]·2H2O (1) and one coordination polymer (CP), {[Cd2(CBIA)2(4,4'-bipy)2(H2O)2]·(CBIA)·(OH)·2H2O}n (2) (4,4'-bipy = 4,4'-bipyridine), were triumphantly assembled using a zwitterionic organic compound, 2-(1-(carboxymethyl)-1H-benzo[d]imidazol-3-ium-3-yl)acetate (HCBIA). In the structure of HSF 1, there are several coordination and lattice H2O units except for the two monodentate CBIA- anions. CP 2 with a one-dimensional (1D) cylindrical structure has free CBIA- units and free H2O units located in the cavity. Thanks to the ability of the uncoordinated carboxyl groups and coordination/lattice water molecules to construct the rich H-bonding networks, both complexes exhibit super-high proton conductivities, reaching 5.09 × 10-3 and 3.41 × 10-3 S cm-1 under 100 °C/98% relative humidity (RH), respectively. Based on the exploration of crystal structure data, combined with the calculated activation energy, and adsorption/desorption plots of nitrogen and water vapor, the causes and differences in proton conductivity of the two complexes, especially the proton-conductive mechanism, are compared and analyzed. This study again confirms that the zwitterionic ligands can exert important effects on forming organo-inorganic hybrid materials with high proton conductivity.
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Patients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little is known about their molecular basis. To explore further, we used whole exome sequencing to explore the genetic changes in the granulocytes of 26 paired MPN patients with or without SC. We noticed that MPN−SC patients harbor genomic variants of distinct genes, among which a unique pattern of co-occurrence or mutual exclusiveness could be identified. We also found that mutated genes in MPN−SC samples were enriched in immune-related pathways and inflammatory networks, an observation further supported by their increased plasma levels of TGF-ß and IL-23. Noteworthily, variants of KRT6A, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN−SC patients. Analysis through OncodriveCLUST disclosed that KRT6A replaces JAK2V617F as the more prominent disease driver in MPN−SC, whereas a major mutation in this gene (KRT6A c.745T>C) in our patients is linked to human carcinoma and predicted to be pathogenic in COSMIC database. Overall, we demonstrate that inflammation could be indispensable in MPN−SC pathogenesis.
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Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL migration. To explore further, we dissected the impacts of BET inhibition in DLBCL. We found that JQ1 abrogated amoeboid movement of DLBCL cells through both restraining RAS signaling and suppressing MYC-mediated RhoA activity. We also demonstrated that BET inhibition resulted in the upregulation of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3). IQGAP3 similarly exhibited an inhibitory effect on RAS activity in DLBCL cells. Through barcoded mRNA/protein profiling in clinical samples, we identified a specific subgroup of DLBCL tumors with enhanced phosphatidylinositol-3-kinase (PI3K) activity, which led to an inferior survival in these patients. Strikingly, a lower IQGAP3 expression level further portended those with PI3K-activated DLBCL a very dismal outcome. The inhibition of BET and PI3K signaling activity led to effective suppression of DLBCL dissemination in vivo. Our study provides an important insight into the ongoing efforts of targeting BET proteins as a therapeutic approach for DLBCL.
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BACKGROUND: Aberrant MYC and BCL2 expression, cell of origin (COO), and National Comprehensive Cancer Network international prognostic index (NCCN-IPI) are commonly used for risk assessment and treatment decision in patients with diffuse large B-cell lymphoma (DLBCL). Although obesity has been shown to be of predictive value in DLBCL patients, it remains unclear whether it retains its prognostic relevance after those aforementioned novel factors being taken into consideration. METHODS: Patients with DLBCL were identified retrospectively in a single institute and data were collected through electronic databases and pharmacy records. RESULTS: Fifteen (17.6%) out of the 85 patients with DLBCL in our cohort were categorized as obese. They had lower platelet counts, were younger and more likely to harbor either BCL2- or MYC-overexpressing tumors. The NCCN-IPI scores, COO, and other clinical parameters were not significantly different between obese and non-obese patients. In spite that obesity adversely affected the treatment response to immunochemotherapy, multivariate analysis showed that only NCCN-IPI risk categories [hazard ratio (HR) 2.83 for high-intermediate or high-risk, versus low-intermediate or low-risk, P=0.034] and BCL2/MYC expressional status (HR 4.12 for BCL2high and/or MYChigh, versus both low expressors, P=0.004) independently predicted progression-free survival (PFS) outcome, whereas obesity lost its prognostic value in this regard (HR 1.81 for obese patients, P=0.242). Similarly, high-intermediate to high NCCN-IPI risk (HR 3.11, P=0.034) and increased expression in either BCL2 or MYC (HR 5.63, P=0.001) both portended an inferior overall survival (OS), but the presence of obesity did not affect the outcome (HR 1.65, P=0.352). CONCLUSIONS: Our study has demonstrated that, for the first time, obesity increases the frequency of BCL2- or MYC-overexpressing tumors in patients with DLBCL.
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BACKGROUND: Somatic mutations of Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) are the major clonal molecules that drive the pathogenesis of myeloproliferative neoplasms (MPN). It is well recognized that MPN patients carry an excessive risk of thrombohemorrhagic complications. However, little is known about the prevalence of these clonal markers in patients with cerebral vascular disease. METHODS: To address this issue, 153 consecutive stroke patients in Taiwan were enrolled in the study. Allele-specific PCR (AS-PCR), real-time AS-PCR, and Illumina paired-end sequencing were employed to detect the presence of MPL, JAK2V617F, and CALR exon 9 mutations, respectively. RESULTS: JAK2V617F mutation was detectable in 13 samples (8.5%), but the allele burdens (AB) were greater than 1% in only six (3.9%) of them. Compared to JAK2-unmutated patients, those with JAK2V617F AB > 1% had significantly higher white blood count (p = 0.01), although four of the six did not exhibit MPN phenotypes. Two patients had a heterozygous CALR exon9 mutation locating outside the coding region and did not alter the amino acid sequence of this protein. On the other hand, there were no patients carrying the MPL mutations. Using patient age, baseline hemogram, and stroke-relevant risk factors, we developed a predictive model that could successfully identify stroke patients at risk of carrying clonal JAK2V617F mutation. CONCLUSION: The prevalence of JAK2V617F mutation in stroke patients was higher than that seen in general population. Based on our newly developed probability stratification model, genotyping of JAK2V617F mutation in selected patients with stroke might be warranted.
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Calreticulina/genética , Janus Quinase 2/genética , Mutação/genética , Receptores de Trombopoetina/genética , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Éxons/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos , Estatísticas não Paramétricas , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Taiwan/epidemiologiaRESUMO
High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2 Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.
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Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Janus Quinase 2/genética , MicroRNAs/genética , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Fenótipo , Transdução de Sinais , Adulto , Idoso , Apoptose/genética , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Cromossomos Humanos Par 12 , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Estudos de Associação Genética , Humanos , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/mortalidade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Interferência de RNA , Fatores de Transcrição STAT/metabolismo , Translocação GenéticaRESUMO
OBJECTIVES: Complex and multiple mechanisms are involved in the etiology of Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP). Many hematopoietic growth factors affect the thrombopoiesis. The aim of this study was to clarify the interaction of the thrombopoietic factors in patients with HCV-ITP. METHODS: We selected 33 patients with HCV-ITP and 17 normal individuals. We compare serum interleukin (IL)-3, IL-6, IL-11, thrombopoietin (Tpo), stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-α (TNFα), and spleen size between these two groups. RESULTS: Our study shows that Tpo, IL-6, and TNFα significantly increased in patients with HCV-ITP compared to the normal population (Tpo:122.577 vs. 40.602; IL-6: 2.175 vs. 0.943; TNFα: 2.460 vs. 1.322). IL-11 was significantly lower in the HCV-ITP group (10.829 vs. 15.042). HCV-ITP patients had a higher spleen index (21.121 vs 13.498, P = 0.003). According to regression analysis and multiple linear regression analysis, only IL-11 had a significantly positive correlation with platelet count, while TNFα showed a negative correlation. DISCUSSIONS: Tpo and IL-6 increased in patients with HCV-ITP, suggesting a positive feedback of low platelet count. TNFα-associated immune response is suspected to have an impact on low platelet count. IL-11 is assumed to directly affect thrombopoiesis. CONCLUSIONS: This study is the most comprehensive study to evaluate the interaction between platelet count and the important thrombopoetic factors in patients with HCV-ITP. The thrombopoietic factors clearly play an important role in HCV-ITP.
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Hepacivirus/metabolismo , Púrpura Trombocitopênica Idiopática/complicações , Trombopoetina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Induction chemotherapy with docetaxel improved outcome in advanced head and neck squamous cell carcinoma (HNSCC) patients, but docetaxel was not recommended in liver dysfunction patients for treatment toxicities. Severe neutropenic events (SNE) including severe neutropenia (SN) and febrile neutropenia (FN) still developed in these patients with normal serum transaminases. Ultrasonography (US) fibrotic score represented degree of hepatic parenchymal damage and showed good correlation to fibrotic changes histologically. This study aims to evaluate the association of US fibrotic score with docetaxel treatment-related SNE in advanced HNSCC patients with normal serum transaminases. Between 1 January 2011 and 31 December 2013, a total of 47 advanced HNSCC patients treated with induction docetaxel were enrolled. The clinical features were collected to assess predictive factors for SNE. The patients were divided into two groups by the US fibrotic score with a cutoff value of 7. The Mann-Whitney U test and logistic regression method were used for the risk factor analysis. The background, treatment, and response were similar in both groups except for lower lymphocyte and platelet count in patients with higher US score. Twenty-seven patients (51 %) developed grade 3/4 neutropenia, and more SNE developed in patients with US score â§7. In multivariate analysis, only US score ≥7 was independent predictive factor for developing SN (hazard ratio 7.71, p = 0.043) and FN (hazard ratio 20.95, p = 0.008). US score ≥7 is an independent risk factor for SNE in advanced HNSCC patients treated with induction docetaxel. US score could be used for risk prediction of docetaxel-related SNE.
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Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Febre/etiologia , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/diagnóstico , Quimioterapia de Indução/efeitos adversos , Fígado/diagnóstico por imagem , Neutropenia/etiologia , Taxoides/efeitos adversos , Ultrassonografia/métodos , Adulto , Idoso , Docetaxel , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoAssuntos
Janus Quinase 2/genética , Mutação Puntual , Púrpura Trombocitopênica Idiopática/genética , Adolescente , Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Humanos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/cirurgia , Baço/cirurgia , EsplenectomiaRESUMO
OBJECTIVE: Myelofibrosis (MF) is a pathologic entity of myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms that severely affect the quality of life accompanied with the risk of leukemia development. Conventional treatment is usually ineffective and has limited impact on prolongation of survival. Dysregulated Janus kinase (JAK) signaling is common in MPN. In two randomized controlled trials, ruxolitinib, a potent pan-JAK inhibitor, has been shown to be highly effective in patients with intermediate- and high-risk MF. METHOD: We retrospectively analyzed the therapeutic outcome of 10 MF patients treated with ruxolitinib in our institute. Basic clinical data, JAK2V617F mutational status and Myelofibrosis Symptoms Assessment Form (MF-SAF) to evaluate disease-related symptoms were recorded initially, and at every visit. RESULT: Among these patients, only half of the patients harbored JAK2V617F mutation. After treatment with ruxolitinib, all patients had reduction of splenic size and reached nadir by week 24. Nine patients had body weight increment, and four of them had body weight increment more than 10%. Seven patients had their total symptom score reduced by more than 50% after therapy. The efficacy of ruxolitinib was irrelevant to JAK2V617F mutational status. Adverse events were mainly hematological and easily manageable. DISCUSSION AND CONCLUSION: Ruxolitinib is both safe and efficacious in a cohort of Asian patients with MF. The efficacy of ruxolitinib is irrelevant to the mutational status of JAK2V617F.
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Antineoplásicos/uso terapêutico , Janus Quinase 2/genética , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Esplenomegalia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Peso Corporal/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/enzimologia , Medula Óssea/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Mutação , Nitrilas , Mielofibrose Primária/etnologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Baço/efeitos dos fármacos , Baço/enzimologia , Baço/patologia , Esplenomegalia/etnologia , Esplenomegalia/genética , Esplenomegalia/patologia , Taiwan , Resultado do TratamentoRESUMO
BACKGROUND/PURPOSE: Cytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy. METHODS: Between January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors. RESULTS: The overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both p < 0.001) and less infection-free catheter longevity (p < 0.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (p < 0.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida. CONCLUSION: Infection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line-associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings.
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Infecções Relacionadas a Cateter/epidemiologia , Cateteres Venosos Centrais/efeitos adversos , Neoplasias/complicações , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateteres Venosos Centrais/microbiologia , Tratamento Farmacológico/métodos , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Modelos de Riscos Proporcionais , Fatores de Risco , Taiwan , Adulto JovemRESUMO
In this study, we aimed to assess the neuroprotective effect of sevoflurane preconditioning in a cerebral focal ischemia-reperfusion rat model. Sixty Sprague Dawley rats were divided into six groups: sham operated group, cerebral focal ischemia-reperfusion (CIR) group, CIR+sevoflurane preconditioning (SP) (2%) group, CIR+sevoflurane preconditioning (2.5%) group, CIR+sevoflurane preconditioning (3%) group, and CIR+sevoflurane preconditioning (3.5%) group. All subjects were euthanized 2days post-surgery and their hippocampus tissues were removed. Tissue malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) levels were measured and hippocampus tissue samples were examined histopathologically. Results showed that significant difference in antioxidant, immunity indexes, and apoptosis-related protein expression was detected in hippocampus tissue between sham-operated control and CIR groups. Sevoflurane preconditioning significantly dose-dependently reduced MDA, IL-1ß, IL-6, IL-10 and TNF-α levels and enhanced antioxidant enzyme activities in hippocampus tissue of CIR+SP groups compared to CIR group. In addition, sevoflurane preconditioning significantly dose-dependently upregulated PI3K, p-Akt and Bcl-2 levels and downregulated caspase-3 and Bax levels in hippocampus tissue of CIR+SP groups compared to CIR group. It can be concluded that sevoflurane preconditioning demonstrates a strong and ameliorative effect on cerebral I/R damage in rats. The neuroprotective mechanisms of sevoflurane preconditioning are associated with its properties of anti-apoptosis and anti-oxidation as well as regulation of PI3K and p-Akt signal activation.
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Isquemia Encefálica/tratamento farmacológico , Éteres Metílicos/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Traumatismo por Reperfusão/patologia , Sevoflurano , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Patients with hepatitis C virus (HCV) infection have been associated with development of diffuse large B-cell lymphoma (DLBCL), yet its impact on several clinical aspects, including phenotypic characteristics and treatment-related toxicities as well as survival outcome after rituximab-based immunochemotherapy, remains controversial. METHODS: To elucidate the characteristics of HCV-positive DLBCL in the context of a new prognostic model, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), we retrospectively analyzed DLBCL patients diagnosed and treated with immunochemotherapy at our institute during the last decade. RESULTS: In all, HCV infection was identified in 22 (17.7%) of 124 DLBCL patients. Except for being more likely to present with an advanced stage of disease, patients with HCV infection were phenotypically indistinguishable from HCV-negative cases. Multivariate analysis showed 3 factors independently predicted a dismal overall survival (OS) outcome: lower albumin level (<3 g/dL vs. ≥3 g/dL, p<0.001; HR=13.21, 95% CI=2.69-64.98, p=0.001), presence of HCV infection (vs. HCV-negative; HR=9.75, 95% CI=1.97-48.34, p=0.005), and poor NCCN-IPI risk (high-intermediate or high vs. low-intermediate or low; HR=5.56, 95% CI=1.17-26.55, p=0.031). CONCLUSIONS: Our study has demonstrated that HCV infection status and low serum albumin level add important prognostic values to the newly proposed NCCN-IPI model for patients with DLBCL.