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BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. Clonorchis sinensis (C. sinensis) infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis infection-related iCCA. METHODS: We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of C. sinensis-related iCCAs were validated through an in vitro co-culture system and in a mouse model of iCCA. RESULTS: We revealed that C. sinensis infection was significantly associated with iCCA patients' overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-related iCCAs. iCCA cell lines treated with excretory/secretory products of C. sinensis displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-related iCCAs than non-C. sinensis-related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from C. sinensis. CONCLUSIONS: We provide novel insights into metabolic alterations and the immune microenvironment in C. sinensis infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of C. sinensis-related iCCAs. IMPACT AND IMPLICATIONS: Clonorchis sinensis (C. sinensis)-infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non-C. sinensis-infected patients with iCCA. The underlying molecular characteristics of C. sinensis infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in C. sinensis-related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against C. sinensis-related iCCAs.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Clonorquíase , Clonorchis sinensis , Ácidos Graxos , Microambiente Tumoral , Colangiocarcinoma/imunologia , Colangiocarcinoma/parasitologia , Animais , Clonorchis sinensis/imunologia , Clonorchis sinensis/fisiologia , Clonorquíase/imunologia , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/parasitologia , Camundongos , Microambiente Tumoral/imunologia , Humanos , Ácidos Graxos/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/metabolismo , Masculino , Feminino , Linhagem Celular Tumoral , Modelos Animais de Doenças , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
BACKGROUND/OBJECTIVE: With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals. METHODS: A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review. RESULT: The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%). CONCLUSION: Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection.
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Aspergilose , Coinfecção , Criptococose , Aspergilose Pulmonar , Humanos , Coinfecção/complicações , Estudos Retrospectivos , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/diagnóstico , Criptococose/complicações , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Aspergilose/diagnósticoRESUMO
OBJECTIVES: We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). METHODS: Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. RESULTS: An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. CONCLUSIONS: Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.
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Aspergilose , Aspergilose Pulmonar Invasiva , Doença Pulmonar Obstrutiva Crônica , Humanos , Caspofungina/uso terapêutico , Aspergilose Pulmonar Invasiva/complicações , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/induzido quimicamente , Antifúngicos/efeitos adversos , Equinocandinas/efeitos adversos , Lipopeptídeos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
Purpose: The patterns and risk factors of postsurgical recurrence of patient with hepatocellular carcinoma (HCC) with microvascular invasion (MVI) are not clarified. This study aimed to decipher and compare the postoperative recurrent patterns and the risk factors contributing to recurrence between MVI positive (MVI(+)) and MVI negative (MVI(-)) HCC after hepatectomy. Patients and methods: Patients with HCC who underwent hepatectomy in three Chinese academic hospitals between January 1, 2009, and December 31, 2018, were enrolled. Recurrent patterns included early (≤2 years) or late (>2 years) recurrence, recurrent sites and number, and risk factors of recurrence were compared between the MVI(+)and MVI(-) groups by propensity score-matching (PSM). Results: Of 1756 patients included, 581 (33.1%) were MVI(+), and 875 (49.8%) patients developed early recurrence. Compared with the MVI(-) group, the MVI(+) group had a higher 2-year recurrence rate in the PSM cohort (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.59-2.10; P < 0.001), and more patients with multiple tumor recurrence. Patients with early recurrence in the MVI(+) group had a worse overall survival (OS) than those in the MVI(-) group (HR, 1.24; 95% CI, 1.02-1.50; P = 0.034). Resection margin (RM) ≤1.0 cm is a surgical predictor of early recurrence for the MVI(+) group (HR, 0.68; 95% CI, 0.54-0.87; P = 0.002), but not for the MVI(-) group. Conclusion: Compared to MVI(-) HCC, MVI(+) HCC tends to be early, multiple recurrence and lung and lymph node metastasis after resection. RM ≤1.0 cm is a surgical risk factor of early recurrence for patient with MVI.
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Background: Lenvatinib or Sorafenib combined with programmed cell death protein-1 (PD-1) inhibitor as recommend treatment of advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM). We aimed to compared the prognosis of Lenvatinib plus PD-1 inhibitor (Len+PD-1) versus Sorafenib plus PD-1 (Sora+PD-1) as an initial therapy for HCC with EHM. Methods: Incorporating a sum of 229 HCC patients with EHM were encompassed within this study, with 127 in the Sora+PD-1 group and 102 in the Len+PD-1 group. Through propensity score matching (PSM), we compared overall survival (OS), progression-free survival (PFS), and patient safety between these two groups. Results: The median OS were 13.0 months and 14.2 months in the Sora+PD-1 group and Len+PD-1 group. The 6-, 12-, and 24-month OS rates were 92.9%, 58.9% and 5.6% in Sora+PD-1 group and 93.1%, 61.8% and 22.6% in Len+PD-1 group, respectively. The Len+PD-1 group had obviously better OS than the Sora+PD-1 group (P = 0.002). The 3-, 6-, and 12-month PFS rates were 76.4%, 27.6% and 1.6% in Sora+PD-1 group and 86.2%, 50.5% and 12.2% in Len+PD-1 group, respectively. Compared with Sora+PD-1 group, the Len+PD-1 group had obviously better PFS (P < 0.001). Analysis within subgroups showed that OS was significant in patients receiving TACE in Len+PD-1 group than Sora+PD-1 group (p = 0.003). Conclusion: Len+PD-1 group had longer OS and PFS than Sora+PD-1 group for patient with EHM. In addition, OS in patients received TACE was improved with Len+PD-1 treatment. For patients without TACE, there was no significance between Sora+PD-1 and Len+PD-1 groups.
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Background: Microvascular invasion (MVI) stands as a pivotal pathological hallmark of hepatocellular carcinoma (HCC), closely linked to unfavorable prognosis, early recurrence, and metastatic progression. However, the precise mechanistic underpinnings governing its onset and advancement remain elusive. Methods: In this research, we downloaded bulk RNA-seq data from the TCGA and HCCDB repositories, single-cell RNA-seq data from the GEO database, and spatial transcriptomics data from the CNCB database. Leveraging the Scissor algorithm, we delineated prognosis-related cell subpopulations and discerned a distinct MVI-related malignant cell subtype. A comprehensive exploration of these malignant cell subpopulations was undertaken through pseudotime analysis and cell-cell communication scrutiny. Furthermore, we engineered a prognostic model grounded in MVI-related genes, employing 101 algorithm combinations integrated by 10 machine-learning algorithms on the TCGA training set. Rigorous evaluation ensued on internal testing sets and external validation sets, employing C-index, calibration curves, and decision curve analysis (DCA). Results: Pseudotime analysis indicated that malignant cells, showing a positive correlation with MVI, were primarily concentrated in the early to middle stages of differentiation, correlating with an unfavorable prognosis. Importantly, these cells showed significant enrichment in the MYC pathway and were involved in extensive interactions with diverse cell types via the MIF signaling pathway. The association of malignant cells with the MVI phenotype was corroborated through validation in spatial transcriptomics data. The prognostic model we devised demonstrated exceptional sensitivity and specificity, surpassing the performance of most previously published models. Calibration curves and DCA underscored the clinical utility of this model. Conclusions: Through integrated multi-transcriptomics analysis, we delineated MVI-related malignant cells and elucidated their biological functions. This study provided novel insights for managing HCC, with the constructed prognostic model offering valuable support for clinical decision-making.
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Carcinoma Hepatocelular , Perfilação da Expressão Gênica , Neoplasias Hepáticas , Aprendizado de Máquina , Transcriptoma , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico , Prognóstico , Invasividade Neoplásica , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Microvasos/patologiaRESUMO
Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD. Methods: Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases. Results: A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1. Conclusions: Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.
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Reposicionamento de Medicamentos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doença Pulmonar Obstrutiva Crônica , Locos de Características Quantitativas , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: The prevalence of invasive pulmonary aspergillosis (IPA) among patients with chronic obstructive pulmonary disease (COPD) is steadily increasing, leading to high mortality. Although early diagnosis can significantly reduce mortality, the efficacy of current diagnostic methods is limited. Consequently, there is a need for novel approaches for early IPA detection. Methods: This retrospective study involved 383 hospitalized COPD patients with GOLD stages III and IV. The IPA group (67 patients) and non-IPA group (316 patients) were identified at the First Affiliated Hospital of Guangzhou Medical University between January 2016 and February 2022. We analyzed common serological indicators in our hospital to identify predictive indicators for the early diagnosis of IPA in COPD patients. Results: The sensitivity and specificity of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), lactate dehydrogenase (LDH), and ceruloplasmin (CER) for diagnosing IPA in COPD patients were as follows: CRP (91.2%, 57.7%), ESR (77.5%, 73.0%), PCT (60.5%, 71.4%), LDH (50.0%, 88.8%), and CER (60.7%, 74.3%). Combinations of biomarkers, such as CRP-ESR, CRP-LDH, ESR-LDH, ESR-CER, and LDH-CER, showed promising diagnostic potential, with larger area under the curve (AUC) values for IPA diagnosis in COPD patients. However, no statistically significant difference was observed between the diagnostic efficacy of single biomarkers and combined biomarkers. Notably, compared to those in the unassisted ventilation group, the patients in the assisted ventilation group (including noninvasive ventilation and tracheal intubation/incision-assisted ventilation group) exhibited significantly greater PCT and LDH levels, while the CER significantly decreased (p=0.021). There were no significant differences in biomarker levels between the ICU group and the non-ICU group. CRP (p<0.01), ESR (p=0.028), PCT (p<0.01), and CER (p<0.01) were positively correlated with hospitalization duration, whereas LDH was not correlated with hospitalization duration. Conclusion: Our study highlights the diagnostic potential of CRP, ESR, PCT, LDH, and CER for IPA in COPD patients. CRP and LDH can also initially predict the need for assisted ventilation, while CRP can initially estimate the length of hospitalization. This study represents the first report of the potential of CER for diagnosing IPA, suggesting its significance for further research.
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Aspergilose Pulmonar Invasiva , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudos Retrospectivos , Proteína C-Reativa/análise , Biomarcadores , Pró-CalcitoninaRESUMO
Research on how thermal exposure affects the microstructure and mechanical properties of the Ti-48Al-3Nb-1.5Ta (at. %) alloy, which is prepared via powder hot isostatic pressing (P-HIP), is essential since this low-density alloy shows promise for use in high-temperature applications, particularly for aero-engines, which require long-term stable service. In this study, a P-HIP Ti-48Al-3Nb-1.5Ta (at. %) alloy was exposed to high temperatures for long durations. The phase, microstructure and mechanical properties of the P-HIP Ti-48Al-3Nb-1.5Ta alloy after thermal exposure under different conditions were analyzed using XRD, SEM, EBSD, EPMA, TEM, nanomechanical testing and tensile testing. The surface scale is composed of oxides and nitrides, primarily Al2O3, TiO2, and TiN, among which Al2O3 is preferentially generated and then covered by rapidly growing TiO2 as the thermal exposure duration increases. The nitrides appear later than the oxides and exist between the oxides and the substrate. With increasing exposure temperature and duration, the surface scale becomes more continuous, TiO2 particles grow larger, and the oxide layer thickens or even falls off. The addition of Ta and Nb can improve the oxidation resistance because Ta5+ and Nb5+ replace Ti4+ in the rutile lattice and weaken O diffusion. Compared with the P-HIP Ti-48Al-3Nb-1.5Ta alloy, after thermal exposure, the grain size does not increase significantly, and the γ phase increases slightly (by less than 3%) with the decomposition of the α2 phase. With increasing thermal exposure duration, the γ phase exhibits discontinuous coarsening (DC). Compared with the P-HIP Ti-48Al-3Nb-1.5Ta alloy, the hardness increases by about 2 GPa, the tensile strength increases by more than 50 MPa, and the fracture strain decreases by about 0.1% after thermal exposure. When the depth extends from the edge of the thermally exposed specimens, the hardness decreases overall.
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BACKGROUND: Onradivir (ZSP1273) is a novel anti-influenza A virus inhibitor. Preclinical studies show that onradivir can inhibit influenza A H1N1 and H3N2 replication and increase the survival rate of infected animals. In this study, we aimed to evaluate the safety and efficacy of three onradivir dosing regimens versus placebo in outpatients with acute uncomplicated influenza A virus infection. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial at 20 clinical sites in China. Eligible participants were adults (18-65 years) with an influenza-like illness screened by rapid antigen testing at the first clinical visit, had the presence of a fever (axillary temperature ≥38·0°C), and had the presence of at least one moderate systemic and one respiratory symptom within 48 h of symptom onset. Patients were excluded if they were pregnant, allergic to onradivir, or had received any influenza antiviral medication within 7 days before enrolment. Participants were randomly assigned (1:1:1:1) into four groups by an interactive web response system: onradivir 200 mg twice per day group, onradivir 400 mg twice per day group, onradivir 600 mg once per day group, and a matching placebo group. A 5-day oral treatment course was initiated within 48 h after symptoms onset. The primary outcome was the time to alleviate influenza symptoms in the modified intention-to-treat population. Safety was a secondary outcome. We evaluated the patients' self-assessed severity of seven influenza symptoms on a 4-point ordinal scale, and the treatment-emergent adverse events in all patients. This trial is registered with ClinicalTrials.gov, number NCT04024137. FINDINGS: Between Dec 7, 2019, and May 18, 2020, a total of 205 patients were screened; of whom, 172 (84%) were randomly assigned to receive onradivir (n=43 in the 200 mg twice per day group; n=43 in the 400 mg twice per day group; and n=43 in the 600 mg once per day group), or placebo (n=42). Median age was 22 years (IQR 20-26). All three onradivir groups showed decreased median time to alleviate influenza symptoms (46·92 h [IQR 24·00-81·38] in the 200 mg twice per day group, 54·87 h [23·67-110·62] in the 400 mg twice per day group, and 40·05 h [17·70-65·82] in the 600 mg once per day) compared with the placebo group (62·87 h [36·40-113·25]). The median difference between the onradivir 600 mg once per day group and the placebo group was -22·82 h (p=0·0330). The most frequently reported treatment-emergent adverse event was diarrhoea (71 [42%] of 171), ranging from 33-65% of the patients in onradivir-treated groups compared with 10% in the placebo group; no serious adverse events were observed. INTERPRETATION: Onradivir showed a safety profile comparable to placebo, as well as higher efficacy than placebo in ameliorating influenza symptoms and lowering the viral load in adult patients with uncomplicated influenza infection, especially the onradivir 600 mg once per day regimen. FUNDING: National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, National Natural Science Foundation of China, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project, Emergency Key Program of Guangzhou Laboratory, Macao Science and Technology Development Fund, and Guangdong Raynovent Biotech.
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Antivirais , Influenza Humana , Humanos , Influenza Humana/tratamento farmacológico , Adulto , Masculino , Método Duplo-Cego , Feminino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Adulto Jovem , Adolescente , Idoso , Resultado do Tratamento , China , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacosRESUMO
Anti-interferon-γ autoantibody (AIGA) syndrome may be the basis of disseminated Talaromyces marneffei infection in human immunodeficiency virus (HIV)-negative adults. However, the pathogenesis of Th1 cell immunity in T. marneffei infection with AIGA syndrome is unknown. A multicenter study of HIV-negative individuals with T. marneffei infection was conducted between September 2018 and September 2020 in Guangdong and Guangxi, China. Patients were divided into AIGA-positive (AP) and AIGA-negative (AN) groups according to the AIGA titer and neutralizing activity. The relationship between AIGA syndrome and Th1 immune deficiency was investigated by using AP patient serum and purification of AIGA. Fifty-five HIV-negative adults with disseminated T. marneffei infection who were otherwise healthy were included. The prevalence of AIGA positivity was 83.6%. Based on their AIGA status, 46 and 9 patients were assigned to the AP and AN groups, respectively. The levels of Th1 cells, IFN-γ, and T-bet were higher in T. marneffei-infected patients than in healthy controls. However, the levels of CD4+ T-cell STAT-1 phosphorylation (pSTAT1) and Th1 cells were lower in the AP group than in the AN group. Both the serum of patients with AIGA syndrome and the AIGA purified from the serum of patients with AIGA syndrome could reduce CD4+ T-cell pSTAT1, Th1 cell differentiation and T-bet mRNA, and protein expression. The Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients. Inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome.IMPORTANCEThe pathogenesis of Th1 cell immunity in Talaromyces marneffei infection with anti-interferon-γ autoantibody (AIGA) syndrome is unknown. This is an interesting study addressing an important knowledge gap regarding the pathogenesis of T. marneffei in non-HIV positive patients; in particular patients with AIGA. The finding of the Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients, and inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome, which presented in this research could help bridge the current knowledge gap.
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Autoanticorpos , Interferon gama , Micoses , Talaromyces , Células Th1 , Humanos , Talaromyces/imunologia , Células Th1/imunologia , Interferon gama/imunologia , Autoanticorpos/imunologia , Autoanticorpos/sangue , Masculino , Adulto , Feminino , China , Micoses/imunologia , Micoses/microbiologia , Pessoa de Meia-Idade , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/genéticaRESUMO
Importance: Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence. Objective: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus. Design, Setting, and Participants: This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included. Interventions: Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib. Main Outcomes and Measures: The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment. Results: Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group. Conclusion and Relevance: In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04143191.