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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis, and there is little data available from the Chinese population. This retrospective study included 115 patients diagnosed with ATLL who were treated across five hospitals in China from June 2011 to December 2022. The median age at diagnosis was 53 years. Several genes involved in T-cell receptor-induced nuclear factor κB (TCR-NF-κB) signaling were commonly mutated, including PLCG1, CIC, PRKCB, CARD11, and IRF4. Eighty-seven patients received chemotherapy. Of these, 13 received a hematopoietic stem cell transplant (HSCT) (allogeneic-HSCT, n=9; autologous-HSCT, n=4) after chemotherapy. Following initial multiagent chemotherapy using EPOCH/CHOEP and other regimens, the overall response rates were 80.6% (complete response [CR], 44.4%) and 42.8% (CR, 14.2%), respectively. The 4-year survival rates (median survival time in days) for EPOCH/CHOEP (n=43), HSCT (n=13), and CHOP-based regimens (n=31) were 12.7% (138), 30.8% (333), and 0% (66), respectively. Lymphadenopathy, EPOCH/CHOEP, and hematopoietic stem cell transplantation were independent prognostic protective factors in patients with aggressive ATLL. Chinese patients exhibit a higher incidence of aggressive-type ATLL, sharing similar genetic alterations with Japanese patients. Etoposide-based chemotherapy (EPOCH or CHOEP) remains the preferred choice for aggressive ATLL, and upfront allogeneic HSCT should be considered in all eligible patients.
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OBJECTIVE: To investigate the effect of three different doses of oral pregabalin on minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Prospective, randomized, placebo-controlled, blinded, crossover trial. ANIMALS: A group of eight healthy adult cats aged 24-48 months. METHODS: Cats were randomly assigned to three oral doses of pregabalin (low dose: 2.5 mg kg-1, medium dose: 5 mg kg-1, high dose: 10 mg kg-1) or placebo 2 hours before MACISO determination, with the multiple treatments administered with a minimum 7 day washout period. Anesthesia was induced and maintained with isoflurane in oxygen until endotracheal intubation was achieved, and maintained with isoflurane with volume-controlled ventilation. MACISO was determined in triplicate using the bracketing technique and tail clamp method 120 minutes after pregabalin or placebo administration. Physiologic variables (including heart rate and blood pressure) recorded during MACISO determination were averaged and compared between the pregabalin and placebo treatments. One-way analysis of variance and the Friedman test were used to assess the difference for normally and non-normally distributed data, respectively. The Tukey test was used as a post hoc analysis. Values of p < 0.05 were considered significant. RESULTS: The MACISO with the medium- and high-dose pregabalin treatments were 1.33 ± 0.21% and 1.23 ± 0.17%, respectively. These were significantly lower than MACISO after placebo treatment (1.62 ± 0.13%; p = 0.014, p < 0.001, respectively), representing a decrease of 18 ± 9% and 24 ± 6%. The mean plasma pregabalin concentration was negatively correlated with MACISO values. Physiologic variables did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Doses of 5 or 10 mg kg-1 pregabalin, administered orally 2 hours before determining MACISO, had a significant isoflurane-sparing effect in cats.
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Anestésicos Inalatórios , Estudos Cross-Over , Isoflurano , Pregabalina , Alvéolos Pulmonares , Animais , Gatos , Feminino , Masculino , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Analgésicos/farmacocinética , Anestesia por Inalação/veterinária , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/farmacocinética , Anestésicos Inalatórios/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Isoflurano/administração & dosagem , Isoflurano/farmacocinética , Pregabalina/administração & dosagem , Pregabalina/farmacologia , Alvéolos Pulmonares/metabolismoRESUMO
Introduction: An increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma. Methods: We used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis. Results: The IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis. Discussion: In this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.
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Solute carrier family 27 member 2 (SLC27A2) is involved in fatty acid metabolism in tumors and represents a prospective target for cancer therapy. However, the role and mechanism of action of SLC27A2 in acute lymphoblastic leukemia (ALL) remain unclear. In this study, we aimed to explore the intrinsic associations between SLC27A2 and ALL and evaluate the prognostic significance, biological functions, and correlation with immune infiltration. We used the transcriptome and clinical data from the TARGET dataset. Differentially expressed genes (DEGs) in the SLC27A2 low- and high-expression groups were analyzed for prognostic implications and functional enrichment. Furthermore, we analyzed the relationship between SLC27A2 gene expression and immune cell infiltration using the ESTIMATE method, which was evaluated using the TIGER platform. Finally, we knocked down SLC27A2 in the Jurkat ALL cell line and conducted cell proliferation, western blotting, flow cytometry, and CCK-8 assays to elucidate the biological function of SLC27A2 in ALL. Patients with ALL who have higher expression levels of SLC27A2 have poorer overall survival and event-free survival. According to gene set enrichment analysis, the DEGs were primarily enriched with immune system processes and the PI3K-Akt signaling pathway. There was an inverse relationship between SLC27A2 expression and immune cell invasion, suggesting involvement of the former in tumor immune evasion. In vitro experiments showed that knockdown of SLC27A2 inhibited cell proliferation and protein expression and altered the Akt pathway, with a reduced proportion of B cells. In conclusion, SLC27A2 plays a vital role in the development of ALL.
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BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. MATERIALS AND METHODS: By performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. RESULTS: The 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10-34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27-103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10-2). CONCLUSIONS: The PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.
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Lesões Encefálicas , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patologia , Estudos Retrospectivos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Estudo de Associação Genômica Ampla , Lesões Encefálicas/etiologia , Radioterapia de Intensidade Modulada/efeitos adversos , Medição de RiscoRESUMO
BACKGROUND: Aedes albopictus is an invasive vector of serious Aedes-borne diseases of global concern. Habitat management remains a critical factor for establishing a cost-effective systematic strategy for sustainable vector control. However, the community-based characteristics of Ae. albopictus habitats in complex urbanization ecosystems are still not well understood. METHODS: A large-scale investigation of aquatic habitats, involving 12 sites selected as representative of four land use categories at three urbanization levels, was performed in Guangzhou, China during 2015-2017. The characteristics and dynamics of these Ae. albopictus habitats were assessed using habitat-type composition, habitat preference, diversity indexes and the Route index (RI), and the temporal patterns of these indexes were evaluated by locally weighted scatterplot smoothing models. The associations of RI with urbanization levels, land use categories and climatic variables were inferred using generalized additive mixed models. RESULTS: A total of 1994 potential habitats and 474 Ae. albopictus-positive habitats were inspected. The majority of these habitats were container-type habitats, with Ae. albopictus showing a particularly higher habitat preference for plastic containers, metal containers and ceramic vessels. Unexpectedly, some non-container-type habitats, especially ornamental ponds and surface water, were found to have fairly high Ae. albopictus positivity rates. Regarding habitats, the land use category residential and rural in Jiangpu (Conghua District, Guangzhou) had the highest number of Ae. albopictus habitats with the highest positive rates. The type diversity of total habitats (H-total) showed a quick increase from February to April and peaked in April, while the H-total of positive habitats (H-positive) and RIs peaked in May. RIs mainly increased with the monthly average daily mean temperature and monthly cumulative rainfall. We also observed the accumulation of diapause eggs in the winter and diapause termination in the following March. CONCLUSIONS: Ecological heterogeneity of habitat preferences of Ae. albopictus was demonstrated in four land use categories at three urbanization levels. The results reveal diversified habitat-type compositions and significant seasonal variations, indicating an ongoing adaptation of Ae. albopictus to the urbanization ecosystem. H-positivity and RIs were inferred as affected by climatic variables and diapause behavior of Ae. albopictus, suggesting that an effective control of overwintering diapause eggs is crucial. Our findings lay a foundation for establishing a stratified systematic management strategy of Ae. albopictus habitats in cities that is expected to complement and improve community-based interventions and sustainable vector management.
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Aedes , Ecossistema , Animais , Urbanização , Mosquitos Vetores , Óvulo , LarvaRESUMO
OBJECTIVE: To evaluate the efficacy and safety of idarubicin combined with high-dose cytarabine as a post-remission therapy for elderly patients with acute myeloid leukemia (AML). METHODS: From November 2017 to June 2021, 24 AML patients aged ≥60 years who were in complete remission for the first time were enrolled in consolidation chemotherapy with idarubicin (10 mg/m2 intravenously once for day 1) combined with high-dose cytarabine (1.5 g/m2 intravenously over 3 hours every 12 hours for day 1-3), and the efficacy and safety were observed. RESULTS: Among the 24 patients, there were 12 males and 12 females, the median age was 65 (60-78) years old, and the median follow-up time was 23.3 (2-42.7) months. By the end of the follow-up, 15 patients relapsed and 11 patients died. The median disease-free survival (DFS) was 9 months and there were 3 cases of 2-year DFS. The median overall survival (OS) was 16.2 months, and there were 4 cases of 2-year OS. In terms of safety, 6 patients had grade 1-2 non-hematological adverse reactions, 12 patients had grade 3-4 hematological adverse reactions, and a total of 6 patients developed infection after consolidation chemotherapy. Multivariate analysis showed that two induction cycles and high-risk cytogenetic abnormalities were the adverse factors of DFS and OS in elderly patients with AML in this study. CONCLUSION: For AML patients ≥60 years old in first complete remission, idarubicin combined with high-dose cytarabine as post-remission therapy has a better safety, but compared with other regimens does not improve the prognosis of elderly patients, which needs further exploration.
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Idarubicina , Leucemia Mieloide Aguda , Idoso , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idarubicina/uso terapêutico , Estudos Retrospectivos , Citarabina , Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Indução de RemissãoRESUMO
Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors' long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93-10.18, P = 9.51 × 10-08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals' identification for personalized prevention and treatment.
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Surdez , Perda Auditiva , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Cisplatino/efeitos adversos , Estudo de Associação Genômica Ampla , Qualidade de Vida , Perda Auditiva/induzido quimicamente , Perda Auditiva/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/induzido quimicamenteRESUMO
PURPOSE: This single-centre study aimed to determine the clinicopathological characteristics and prognosis for patients with co-existing FL and DLBCL components (FL/DLBCL). METHODS: We retrospectively analysed the clinical characteristics and prognosis of patients diagnosed with FL/DLBCL (n = 56) and with pure FL (n = 260) or de novo DLBCL (n = 812) (controls) between January 2013 and December 2021. RESULTS: The median age of patients with FL/DLBCL was 52 years. The amount of the DLBCL component ranged from 5 to 95%. Among the 56 FL/DLBCL cases analysed, 67.9% were of germinal centre B-cell (GCB) origin, 26.8% non-GCB origin, and 5.3% were unclassified. The clinical features of patients with FL/DLBCL were intermediate, falling between those of FL and DLBCL. Propensity-score matching was performed for patients with similar baseline characteristics who were receiving the rituximab plus cyclophosphamide, doxorubicin or epirubicin, vindesine, and prednisone (R-CHOP) regimen. Patients with FL/DLBCL showed inferior outcomes compared to those with FL, with a lower complete remission (CR) rate, progression-free survival (PFS), and overall survival (OS). Bone marrow involvement and B symptoms were identified as independent adverse prognostic factors for PFS among patients with FL/DLBCL. Patients with FL/DLBCL presented a lower CR rate and PFS but similar OS to those with DLBCL when receiving the R-CHOP regimen. CONCLUSION: Patients with FL/DLBCL showed inferior treatment response and survival than those with pure FL and had a lower CR rate and PFS, but similar OS to those with DLBCL in the rituximab era.
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Linfoma Folicular , Linfoma Difuso de Grandes Células B , Humanos , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Resultado do Tratamento , Estudos Retrospectivos , Intervalo Livre de Doença , Prognóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Vincristina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêuticoRESUMO
This study aimed to assess the efficacy and safety of hypomethylating agent (HMA)-based regimens in the treatment of older adult patients with acute myeloid leukaemia (AML), unfit for standard induction chemotherapy. Treatment outcomes and prognostic factors of 140 older adult patients with AML who were unfit for intensive chemotherapy and were treated with HMA-based therapies were retrospectively analysed. The median age of the group was 70 years, and poor-risk cytogenetics and secondary/treatment-related AML (s/t-AML) accounted for 45.6% and 34.3% of these patients, respectively. The overall response rate was 48.6%, and 40.1% for patients who achieved complete remission (CR) or CR with incomplete blood count recovery. The median overall survival (OS) was 10.4 months, and the 1-, 2-, and 5-year OS rates were 42.6%, 19.9%, and 4.9%, respectively. Early mortality accounted for 4.3% of all cases, and infection occurred in 87.1% of all patients during induction therapy. Patients who received HMA and low-dose chemotherapy presented with significantly superior response and long-term survival rates compared to those who received HMA alone. They also showed comparable outcomes to those treated with the azacitidine plus venetoclax protocol. Low-dose chemotherapy in combination with decitabine or azacitidine showed a similar response rate and prognosis. Age ≥ 75years and a white blood cell (WBC) count ≥ 10 × 109 cells/L were identified as independent adverse prognostic factors for OS, while poor-risk cytogenetics, percentage of bone marrow blasts, and s/tAML had no significant impact on OS when patients were treated with HMA-based regimens. In conclusion, HMA combined with low-dose chemotherapy was effective and safe in older adults with AML who were unfit for intensive chemotherapy, and no difference was observed between decitabine and azacitidine.
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Azacitidina , Leucemia Mieloide Aguda , Humanos , Idoso , Decitabina/efeitos adversos , Estudos Retrospectivos , Azacitidina/uso terapêutico , Resultado do Tratamento , Leucemia Mieloide Aguda/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Background: It remains controversial who would benefit from adjuvant chemotherapy (ACT) in patients with early-stage non-small cell lung cancer (NSCLC). We aim to construct a polygenic hazard score (PHS) to predict prognosis and ACT benefit among NSCLC patients. Methods: We conducted a retrospective study including 1,395 stage I-II NSCLC patients. We performed a genome-wide association study (GWAS) on overall survival (OS) in patients treated with ACT (SYSUCC ACT set, n=404), and then developed a PHS using LASSO Cox regression in a random subset (training, n=202) and tested it in the remaining set (test, n=202). The PHS was further validated in two independent datasets (SYSUCC surgery set, n=624; PLCO cohort, n=367). Results: The GWAS-derived PHS consisting of 37 single-nucleotide polymorphisms (SNPs) was constructed to classify patients into high and low PHS groups. For patients treated with ACT, those with low PHS had better clinical outcomes than high PHS (test set: HR =0.21, P<0.001; PLCO ACT set: HR =0.33, P=0.260). Similar results were found in the extended validation cohorts including patients with or without ACT (SYSUCC: HR =0.48, P<0.001; PLCO: HR =0.60, P=0.033). Within subgroup analysis by treatment or clinical factors, we further observed consistent results for the prognostic value of the PHS. Notably, ACT significantly improved OS in stage II patients with low PHS (HR =0.26, P<0.001), while there was no ACT survival benefit among patients with high PHS (HR =0.97, P=0.860). Conclusions: The PHS improved prognostic stratification and could help identify patients who were most likely to benefit from ACT in early-stage NSCLC.
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BACKGROUND: Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. METHODS: We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218). RESULTS: Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%). CONCLUSIONS: This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Masculino , Humanos , Carcinoma Nasofaríngeo/genética , Sequenciamento do Exoma , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/genética , Predisposição Genética para Doença , Herpesvirus Humano 4/genética , Estudos de Casos e Controles , Proteína Grupo D do Xeroderma Pigmentoso/genéticaRESUMO
Patients with hematological malignancies (HM) often develop the invasive fungal disease (IFD), causing important morbidity/mortality. While treatment guidelines are available, risk stratification models for optimizing antifungal therapy strategies are few. Clinical records from 458 HM patients with IFD were retrospectively analyzed. Following Chinese treatment guidelines, patients received empirical (n = 239) or diagnostic-driven therapy (n = 219). The effectiveness rate was 87.9% for the empirical and 81.7% for the diagnostic-driven therapy groups (P ≥ 0.05). The incidence of adverse reactions was 18.4% and 16.9%, respectively (P ≥ 0.05). All risk factors of IFD in HM patients were estimated in the univariate analyses and multivariate analyses by the chi-square test and logistic regression model. Duration ≥14 days (OR = 18.340, P=0.011), relapsed/refractory disease (OR = 11.670, P=0.005), IFD history (OR = 5.270, P=0.021), and diabetes (OR = 3.120, P=0.035) were significantly associated with IFD in the multivariate analysis. Patients with more than 3 of these factors have a significant difference in effective rates between the empirical (85.7%) and diagnostic-driven (41.6%) therapy (P=0.008). Empirical and diagnostic-driven therapy effective rates were 80.6% and 70.9% in the patients with two risk factors (P > 0.05) and 85.1% and 85.4% in the patients with one risk factor (P > 0.05). Thus, there was no significant difference in effectiveness in patients with one or two risk factors. The abovementioned risk stratification can guide clinical antifungal therapy. The patients with 3 or more risk factors benefit from empirical therapy.
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Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10-7 to 4.79 × 10-44). By incorporating the PRS into EBV-serology-based NPC screening, the test's positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.
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Estudo de Associação Genômica Ampla , Neoplasias Nasofaríngeas , Estudos de Casos e Controles , Humanos , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta-IgA, in healthy males from NPC endemic area. METHODS: HLA alleles of 1078 healthy males in southern China from the 21-RCCP study were imputed using genome-wide single nucleotide polymorphism data. EBV Zta-IgA in blood samples were measured using an enzyme-linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta-IgA serological status and its potential joint association with smoking. The binding affinity for Zta-peptide was predicted using NetMHCIIpan 4.0. RESULTS: HLA-DRB1*09:01 was found to be associated with a higher risk of Zta-IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32-2.45; p = 1.82 × 10-4 ). Compared with non-smokers without HLA-DRB1*09:01, the effect size increased to 2.19- and 3.70-fold for the light and heavy smokers carrying HLA-DRB1*09:01, respectively. Furthermore, HLA-DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA-DRB1 alleles. CONCLUSIONS: Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA-DRB1*09:01 have a significantly higher risk of being Zta-IgA seropositive, which indicates the necessity of smoking cessation in certain high-risk populations and also provide clues for further research on the etiology of NPC.
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Infecções por Vírus Epstein-Barr/imunologia , Antígenos HLA/genética , Herpesvirus Humano 4/imunologia , Imunoglobulina A/imunologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Transativadores/imunologia , Adulto , Alelos , Anticorpos Antivirais/imunologia , Povo Asiático/genética , Infecções por Vírus Epstein-Barr/virologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Voluntários Saudáveis , Humanos , Imunoglobulina A/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/imunologia , Fumar/efeitos adversos , Proteínas Virais/imunologiaRESUMO
The characteristics and survival of 218 patients with extranodal natural killer/T-cell lymphoma (ENKTCL) were analyzed in this retrospective study. The median progression-free survival (PFS) and overall survival (OS) were 10.9 months and 50.5 months, respectively. Sequential chemoradiotherapy achieved a 74.5% overall response rate (ORR) and a 30.9% 5-year PFS rate in patients with localized stage. Asparaginase-containing protocols demonstrated superior prognosis in advanced cases, with a median FPS at 5.7 months, compared to 1.9 months without asparaginase. Initial treatment with P-GEMOX regimens showed superior ORR and PFS compared to the SMILE regimen, with lower toxicities. Hematopoietic stem cell transplantation (HSCT) improved the PFS and OS of refractory or relapsed (R/R) cases. PD-1/PD-L1 antibody could achieve a median PFS at 4.0 months and a median OS at 14.6 months in R/R patients for whom salvage therapies failed. High-risk PINK-E score was the only independent adverse prognostic factor for PFS and OS.
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Linfoma Extranodal de Células T-NK , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Quimiorradioterapia , Intervalo Livre de Doença , Humanos , Células Matadoras Naturais , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/terapia , Prognóstico , Estudos RetrospectivosRESUMO
Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, environmental factor, and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein-Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have two or more relatives affected with NPC, in 116 high-risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent-offspring pairs and sibling-sibling pairs (P < .001), but not in distant kin relationship pairs. Interestingly, after excluding the shared environmental factor within families, host genetics contributes significantly to NP EBV loads with a heritability of 56.41% (P = 1.00 × 10-7 ), and its effect was slightly elevated (68.86%, P = 3.40 × 10-6 ) in families with more NPC cases (≥3). These findings indicate that additional host-genetic variants involved in the EBV local NP mucosal behavior may be especially important for the development of NPC.