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In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .
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Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , China/epidemiología , Trasplante Autólogo , Anciano , Tasa de Supervivencia , Adulto Joven , Quimioterapia de Mantención , Autoinjertos , Inducción de Remisión , AdolescenteRESUMEN
STUDY QUESTION: Does fetal genetically determined birth weight associate with the timing of puberty? SUMMARY ANSWER: Lower fetal genetically determined birth weight was causally associated with an earlier onset of puberty, independent of the indirect effects of the maternal intrauterine environment. WHAT IS KNOWN ALREADY: Previous Mendelian randomization (MR) studies have indicated a potential causal link between birth weight, childhood BMI, and the onset of puberty. However, they did not distinguish between genetic variants that have a direct impact on birth weight through the fetal genome (referred to as fetal genetic effects) and those that influence birth weight indirectly by affecting the intrauterine environment (known as maternal genetic effects). It is crucial to emphasize that previous studies were limited because they did not account for the potential bias caused by unaddressed correlations between maternal and fetal genetic effects. Additionally, the proportion of birth weight variation explained by the fetal genome is considerably larger than that of the maternal genome. STUDY DESIGN, SIZE, DURATION: We performed two-sample MR analyses to investigate the causal effect of fetal genetically determined birth weight on puberty timing using summary data from large-scale genome-wide association studies (GWASs) in individuals of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the two most recent GWASs specifically centered on birth weight, which included 406â063 individuals and 423â683 individuals (63â365 trios) respectively, we identified genetic variants associated with fetal genetically determined birth weight, while adjusting for maternal genetic effects. We identified genetic variants associated with childhood BMI from an independent GWAS involving 21â309 European participants. On this basis, we employed two-sample MR techniques to examine the possible causal effects of fetal genetically determined birth weight on puberty timing using a large-scale GWAS of puberty timing (including 179â117 females of European ancestry). Furthermore, we employed advanced analytical methods, specifically MR mediation and MR-Cluster, to enhance our comprehension of the causal relationship between birth weight determined by fetal genetics and the timing of puberty. We also explored the pathways through which childhood BMI might act as a mediator in this relationship. MAIN RESULTS AND THE ROLE OF CHANCE: In the univariable MR analysis, a one SD decrease in fetal genetically determined birth weight (â¼ 418 g) was associated with a 0.16 (95% CI [0.07-0.26]) years earlier onset of puberty. The multivariable MR analysis including fetal genetically determined birth weight and childhood BMI in relation to puberty timing provided compelling evidence that birth weight had a direct influence on the timing of puberty. Lower birth weight (one SD) was associated with an earlier onset of puberty, with a difference of 0.23 (95% CI [0.05-0.42]) years. We found little evidence to support a mediating role of childhood BMI between birth weight and puberty timing (-0.07 years, 95% CI [-0.20 to 0.06]). LIMITATIONS, REASONS FOR CAUTION: Our data came from European ancestry populations, which may restrict the generalizability of our results to other populations. Moreover, our analysis could not investigate potential non-linear relationships between birth weight and puberty timing due to limitations in genetic summary data. WIDER IMPLICATIONS OF THE FINDINGS: Findings from this study suggested that low birth weight, determined by the fetal genome, contributes to early puberty, and offered supporting evidence to enhance comprehension of the fetal origins of disease hypothesis. STUDY FUNDING/COMPETING INTEREST(S): C.Z. was funded by the Sichuan Province Science and Technology Program [grant number 2021JDR0189]. J.Z. was supported by grants from the National Natural Science Foundation of China [grant number 82373588]. No other authors declare any sources of funding. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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Estudio de Asociación del Genoma Completo , Pubertad , Embarazo , Femenino , Humanos , Peso al Nacer/genética , Pubertad/genética , Atención Prenatal , Genética HumanaRESUMEN
PURPOSE: Patients with peripheral T-cell lymphomas (PTCL) in the relapsed or refractory (r/r) setting have only a limited number of therapies available, and the prognosis is extremely poor. SHR2554 is an oral inhibitor against EZH2, a rational therapeutic target for lymphomas. PATIENTS AND METHODS: This was a multicenter, two-part, phase I study of SHR2554 in r/r mature lymphoid neoplasms. In part I, 350 mg twice daily was established as the recommended phase II dose (RP2D) based on the findings during dose escalation and expansion; subsequently, selected lymphoma subtypes were recruited in clinical expansion cohorts to receive SHR2554 at RP2D. Here, we provide an in-depth assessment of SHR2554 at RP2D in subpopulation with r/r PTCL. RESULTS: Twenty-eight patients were included for analysis (17 angioimmunoblastic T-cell lymphoma and 11 not otherwise specified). Eighteen (64%) patients had received ≥2 lines of previous anticancer therapies. The objective response rate was 61% [95% confidence interval (CI), 41-78]. Responses were still ongoing in 59% (10/17) of the responders; estimated median duration of response was 12.3 months (95% CI, 7.4-not reached). Median progression-free survival was 11.1 months (95% CI, 5.3-22.0), and 12-month overall survival rate was 92% (95% CI, 72-98). The most common grade 3 or 4 treatment-related adverse events were decreased platelet count [nine (32%)] as well as decreased white blood cell count, decreased neutrophil count, and anemia [four (14%) for each]. No treatment-related deaths were reported. CONCLUSIONS: This extended follow-up analysis further supports SHR2554 as a therapeutic opportunity for patients with r/r PTCL.
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Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patología , Resultado del Tratamiento , Proteína Potenciadora del Homólogo Zeste 2 , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
Objective: Bronchoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are two essential methods for obtaining the pathological diagnosis of central lung masses or hilar and mediastinal lymphadenopathy. We can observe that many patients have a fever after examinations, but the pathogenesis is not yet fully clear. We tried to comprehensively assess the occurrence of postoperative fever and bacterial infections in patients undergoing bronchoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) procedures. Methods: We retrospectively analyzed 512 patients undergoing bronchoscopy or EBUS-TBNA examination. According to examination methods, all patients were classified into three groups: Only perform bronchoscopy examination (BO) group (122 cases)ï¼both perform bronchoscopy and biopsy (BB) group (262 cases), and EBUS-TBNA after bronchoscopy (EBUS) group (128 cases). Peripheral blood leucocyte, neutrophil count, and serum IL-6 test results were obtained before and after the examination. A blood culture was performed when the body temperature was higher than 38.5°C. Results: Among the three groups, the onset time (5.5h), average duration (6h), and peak temperature (37.7°C) of fever in the BO group were lower than those in the BB and EBUS groups. Still, there was no significant difference in onset time (11.66h, 11.83h), average duration (12.86h, 13.56h), and peak temperature (39.1°C, 39.1°C) between the BB group and EBUS group. There was no significant difference in the peripheral blood leukocyte count, neutrophil count or IL-6 level before the operation (P > .05). Compared with the preoperative, the leukocyte count, neutrophil count and IL-6 level in the three groups were increased after the operation (P < .05). Positive blood cultures were diagnosed as normal oropharyngeal flora. Conclusions: Postoperative fever after bronchoscopy is a relatively common complication, most of which do not require special treatment. Individuals with concomitant diseases such as diabetes may have postoperative infections after EBUS-TBNA, and they should be emphatically observed. The findings could potentially extend to similar diagnostic procedures or situations in pulmonary medicine. Understanding the risk factors associated with postoperative fever can help healthcare providers manage patient expectations and monitor certain groups more closely.
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Broncoscopía , Interleucina-6 , Humanos , Broncoscopía/efectos adversos , Broncoscopía/métodos , Estudios Retrospectivos , Ganglios Linfáticos/patología , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/efectos adversos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodosRESUMEN
BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.
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Linfoma de Células T Periférico , Adulto , Humanos , Masculino , Femenino , Adolescente , Persona de Mediana Edad , Linfoma de Células T Periférico/tratamiento farmacológico , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Progresión de la Enfermedad , Janus Quinasa 1/genética , Tirosina/uso terapéuticoRESUMEN
OBJECTIVES: This study aimed to integrate positron emission tomography/computed tomography (PET/CT) metrics and genetic mutations to optimize the risk stratification for diffuse large B-cell lymphoma (DLBCL) patients. METHODS: The data of 94 primary DLBCL patients with baseline PET/CT examination completed in the Shandong Cancer Hospital and Institute (Jinan, China) were analyzed to establish a training cohort. An independent cohort of 45 DLBCL patients with baseline PET/CT examination from other hospitals was established for external validation. The baseline total metabolic tumor volume (TMTV) and the largest distance between two lesions (Dmax) standardized by patient body surface area (SDmax) were calculated. The pretreatment pathological tissues of all patients were sequenced by a lymphopanel including 43 genes. RESULTS: The optimal TMTV cutoff was 285.3 cm3 and the optimal SDmax cutoff was 0.135 m-1 . TP53 status was found as an independent predictive factor significantly affecting complete remission (p = 0.001). TMTV, SDmax, and TP53 status were the main factors of the nomogram and could stratify the patients into four distinct subgroups based on their predicted progression-free survival (PFS). The calibration curve demonstrated satisfactory agreement between the predicted and actual 1-year PFS of the patients. The receiver operating characteristic curves showed this nomogram based on PET/CT metrics and TP53 mutations had a better predictive ability than the clinic risk scores. Similar results were identified upon external validation. CONCLUSIONS: The nomogram based on imaging factors and TP53 mutations could lead to a more accurate selection of DLBCL patients with rapid progression, to increase tailor therapy.
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Linfoma de Células B Grandes Difuso , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Nomogramas , Pronóstico , Carga Tumoral , Fluorodesoxiglucosa F18 , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/genética , Estudios Retrospectivos , Mutación , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Leucemia Linfocítica Crónica de Células B , Linfocitosis , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfocitosis/inducido químicamente , Linfocitosis/diagnóstico , Piperidinas , Pirazoles/efectos adversosRESUMEN
PURPOSE: To investigate the efficacy and safety of the novel orally active PI3Kδ inhibitor in relapsed and/or refractory patients with follicular lymphoma (FL) who had received at least two prior systemic treatments. PATIENTS AND METHODS: Histologically confirmed relapsed and/or refractory patients with FL with disease progression after receiving second-line or greater systemic therapy were enrolled. Linperlisib was administered at 80 mg every day, orally in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome for the study was the objective response rate (ORR), with secondary outcomes including the duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate, and drug safety profile. RESULTS: Of 114 screened relapsed and/or refractory patients with FL, 84 were enrolled in the full analysis set (FAS). The ORR of the 84 FAS patients was 79.8% [95% confidence interval (CI), 69.6-87.8, 67 patients], with 13 patients (15.5%) achieving a complete response and 54 patients (64.3%) with a partial response. The median DOR was 12.3 months (95% CI, 9.3-15.9). The median PFS was 13.4 months (95% CI, 11.1-16.7). The 12-month OS rate was 91.4% (95% CI, 82.7-95.8) and a median OS not reached by 42 months. The most frequent (>3%) treatment-related adverse events Grade ≥3 were infectious pneumonia (19.0%), neutropenia (15.5%), decreased lymphocyte count (4.8%), decreased leukocyte count (4.8%), increased lipase (3.6%), decreased platelet count (3.6%), hypertriglyceridemia (3.6%), and interstitial lung disease (3.6%). CONCLUSIONS: Linperlisib demonstrated compelling clinical activity and manageable tolerability for relapsed and/or refractory patients with FL who had received at least two prior systemic therapies.
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Linfoma Folicular , Humanos , Linfoma Folicular/patología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Progresión de la Enfermedad , Resultado del TratamientoRESUMEN
Background: Accumulating evidence shows that immunogenic cell death (ICD) enhances immunotherapy effectiveness. In this study, we aimed to develop a prognostic model combining ICD, immunity, and long non-coding RNA biomarkers for predicting hepatocellular carcinoma (HCC) outcomes. Methods: Immune- and immunogenic cell death-related lncRNAs (IICDLs) were identified from The Cancer Genome Atlas and Ensembl databases. IICDLs were extracted based on the results of differential expression and univariate Cox analyses and used to generate molecular subtypes using ConsensusClusterPlus. We created a prognostic signature based on IICDLs and a nomogram based on risk scores. Clinical characteristics, immune landscapes, immune checkpoint blocking (ICB) responses, stemness, and chemotherapy responses were also analyzed for different molecular subtypes and risk groups. Result: A total of 81 IICDLs were identified, 20 of which were significantly associated with overall survival (OS) in patients with HCC. Cluster analysis divided patients with HCC into two distinct molecular subtypes (C1 and C2), with patients in C1 having a shorter survival time than those in C2. Four IICDLs (TMEM220-AS1, LINC02362, LINC01554, and LINC02499) were selected to develop a prognostic model that was an independent prognostic factor of HCC outcomes. C1 and the high-risk group had worse OS (hazard ratio > 1.5, p < 0.01), higher T stage (p < 0.05), higher clinical stage (p < 0.05), higher pathological grade (p < 0.05), low immune cell infiltration (CD4+ T cells, B cells, macrophages, neutrophils, and myeloid dendritic cells), low immune checkpoint gene expression, poor response to ICB therapy, and high stemness. Different molecular subtypes and risk groups showed significantly different responses to several chemotherapy drugs, such as doxorubicin (p < 0.001), 5-fluorouracil (p < 0.001), gemcitabine (p < 0.001), and sorafenib (p < 0.01). Conclusion: Our study identified molecular subtypes and a prognostic signature based on IICDLs that could help predict the clinical prognosis and treatment response in patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Pronóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Muerte Celular Inmunogénica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapiaRESUMEN
Colon cancer is a malignant neoplasm with high mortality that has seriously threatened human life. Accumulating evidence reveals that the ß-glucuronidase (GLU), a lysosomal exoglycosidase enzyme, plays important roles in the pathological progression of colon cancer. Unfortunately, understanding the pathological roles of GLU remains a challenge due to the lack of effective detection methods for visualization the fluctuations of GLU in tissues. In this paper, based on hydrolysis function of GLU, an enzyme-activated ratiometric two-photon (TP) fluorescent probe (RN-GLU) was designed. RN-GLU was synthesized by introducing a glucopyranuronic acid methyl ester as the recognition group and 1, 8-naphthalimide as a TP fluorophore. In the presence of GLU, the trigger group was removed made an ICT process occurred induced enhancement of fluorescence ratio (I553 nm/I441 nm, 214-fold). Probe RN-GLU displayed low detection limit (1.2 × 10-2 µg/L) and rapid detection to GLU in vitro through a ratiometric response mode. Meanwhile, RN-GLU exhibited high selectivity for GLU and showed nearly no response to other relevant biological species. The imaging results demonstrated that RN-GLU could be applied for ratiometric monitoring of endogenous GLU levels in HCT116 cells with good lysosome targetable ability. Due to its two-photon excitation, RN-GLU could monitor GLU in colon cancer tumor tissue with good penetration ability (imaging depth of 200 µm). RN-GLU could be developed as a potential method for evaluating and confirming the functions of GLU in colon cancer diagnosis and complex biosystem.
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Neoplasias del Colon , Colorantes Fluorescentes , Neoplasias del Colon/diagnóstico por imagen , Glucosa/análogos & derivados , Glucuronidasa , Humanos , LisosomasAsunto(s)
Leucemia Prolinfocítica Tipo Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Lenalidomida/uso terapéutico , Leucemia Prolinfocítica Tipo Células B/tratamiento farmacológico , Piperidinas , Pirazoles , Pirimidinas/uso terapéutico , Rituximab/uso terapéutico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Introduction: Double-expressor diffuse large B-cell lymphoma (DEL), harboring double expression of MYC and BCL2, has an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). We initiated a clinical trial to treat newly diagnosed DEL with R-CHOP plus Bruton's tyrosine kinase (BTK) inhibitor (BTKi) zanubrutinib (ZR-CHOP) and achieved a high complete response (CR) rate while four patients progressed during therapy, one of them carrying ATM and CD58 mutations. We applied an in vitro high-throughput drug sensitivity test for the prediction of clinical responses to different drugs in this patient. Case presentation: We report a 30-year-old female patient diagnosed with stage III (DEL), with ATM and CD58 mutations. The patient achieved partial response (PR) after two cycles of ZR-CHOP and remained PR after four cycles of ZR-CHOP, while the disease progressed after six cycles of ZR-CHOP. High-throughput drug screening using a panel of 117 compounds identified a range of therapies with efficacy for this patient. The primary tumor cells showed moderate sensitivity to bortezomib, thalidomide, and gemcitabine as a single agent and bortezomib, thalidomide, and dexamethasone (VTD) as a combined regimen. The patient was treated with two cycles of VTD regimen (bortezomib 1.3 mg/m2, d1, 4, 8, 11; thalidomide 100 mg, d1-21; dexamethasone 20 mg, d1, 2, 4, 5, 8, 9) and achieved PR with only a small lesion left. Another two cycles of VTD plus gemcitabine were then administered, and the patient achieved CR. Stem cells were mobilized, and autologous hematopoietic stem cell transplantation was carried out afterward. The patient remained CR for more than 3 months after transplantation. Conclusion: In this article, we present a first-line chemoresistant DEL patient with ATM and CD58 mutations who was treated successfully with VTD plus gemcitabine under the guidance of in vitro high-throughput drug sensitivity test.
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Esophageal cancer is the eighth most common malignancy and the sixth leading cause of cancer-related deaths worldwide. Chemotherapy based on platinum drugs, 5-fluorouracil, adriamycin, paclitaxel, gemcitabine, and vinorelbine, as well as targeted treatment and immunotherapy with immune checkpoint inhibitors improved the prognosis in a portion of patients with advanced esophageal cancer. Unfortunately, a number of esophageal cancer patients develop drug resistance, resulting in poor outcomes. Multiple mechanisms contributing to drug resistance of esophageal cancer have been reported. Notably, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), have been identified to play crucial roles in modulating esophageal cancer drug resistance. In the present review, we highlight the underlying mechanisms how miRNAs, lncRNAs, and circRNAs impact the drug resistance of esophageal cancer. Several miRNAs, lncRNAs, and circRNAs may have potential clinical implications as novel biomarkers and therapeutic targets for esophageal cancer.
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YY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20-200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted.Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1 .
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Linfoma de Células B/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B , Inhibidores de las Quinasa Fosfoinosítidos-3/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Chemotherapy-induced neutropenia is commonly encountered in clinical practice. The management of neutropenia has been evolving from short-acting granulocyte colony-stimulating factors (G-CSFs) to long-acting G-CSFs. However, an evaluation of the safety and effectiveness of long-acting G-CSFs in clinical practice is still lacking. METHODS: This multicenter, non-interventional study was aimed at exploring the safety and effectiveness of mecapegfilgrastim in different cancer patients in China. All patients provided written informed consent prior to the study and were treated according to routine clinical practice. Different prophylactic strategies (primary or secondary prophylaxis) were also compared. RESULTS: This study included 638 patients from May 2019 to November 2020. More than half of the participants were breast cancer patients. The mean age of all the patients was 56 years. White blood cell increase (6.2%) was the most frequently reported adverse event (AE) possibly related to the study drug. No unexpected AEs were reported. Grade ≥3 neutropenia in chemotherapy treatment cycle 1 was reported in 36 (5.6%) patients. Incidence of grade ≥3 neutropenia in cycle 1 in the primary and secondary prophylaxis subgroups were of 4.3% and 9.2%, respectively. A decreasing trend of severe neutropenia incidence was observed from cycle 1 to cycle 4. CONCLUSIONS: Mecapegfilgrastim was generally well tolerated, and no unexpected AEs were observed in this study. Primary administration of mecapegfilgrastim led to a lower incidence of neutropenia than did secondary administration. Continuous administration of mecapegfilgrastim could keep the incidence of neutropenia to a relatively low level.
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OBJECTIVE: To assess the efficacy and safety of the novel histone deacetylase inhibitor, chidamide, in combination with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (Chi-CHOEP) for untreated peripheral T-cell lymphoma (PTCL). METHODS: A prospective, multicenter, single arm, phase 1b/2 study was conducted. A total of 128 patients with untreated PTCL (18-70 years of age) were enrolled between March 2016 and November 2019, and treated with up to 6 cycles with the Chi-CHOEP regimen. In the phase 1b study, 3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximum-tolerated dose and recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 study was 2-year progression-free survival (PFS). RESULTS: Fifteen patients were enrolled in the phase 1b study and the RP2D for chidamide was determined to be 20 mg, twice a week. A total of 113 patients were treated at the RP2D in the phase 2 study, and the overall response rate was 60.2%, with a complete response rate of 40.7%. At a median follow-up of 36 months, the median PFS was 10.7 months, with 1-, 2-, and 3-year PFS rates of 49.9%, 38.0%, and 32.8%, respectively. The Chi-CHOEP regimen was well-tolerated, with grade 3/4 neutropenia occurring in approximately two-thirds of the patients. No unexpected adverse events (AEs) were reported and the observed AEs were manageable. CONCLUSIONS: This large cohort phase 1b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients.
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Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Factor 88 de Diferenciación Mieloide/genética , Proteínas de Neoplasias/genética , China/epidemiología , Femenino , Humanos , Incidencia , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Masculino , PronósticoRESUMEN
Macrophages play important roles in angiogenesis; however, previous studies on macrophage angiogenesis have focused on traditional 2D cultures. In this study, we established a 3D culture system for macrophages using collagen microcarriers and assessed the effect of 3D culture on their angiogenic capabilities. Macrophages grown in 3D culture displayed a significantly different morphology and arrangement under electron microscopy compared to those grown in 2D culture. Tube formation assays and chick embryo chorioallantoic membrane assays further revealed that 3D-cultured macrophages were less angiogenic than those in 2D culture. Whole-transcriptome sequencing showed that nearly 40% of genes were significantly differently expressed, including nine important angiogenic factors of which seven had been downregulated. In addition, the expression of almost all genes related to two important angiogenic pathways was decreased in 3D-cultured macrophages, including the two key angiogenic factors, VEGFA and ANG2. Together, the findings of our study improve our understanding of angiogenesis and 3D macrophage culture in tissues, and provide new avenues and methods for future research on macrophages.
Asunto(s)
Técnicas de Cultivo Tridimensional de Células/métodos , Macrófagos/patología , Ribonucleasa Pancreática/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inductores de la Angiogénesis , Animales , Células Cultivadas , Embrión de Pollo , Membrana Corioalantoides , Colágeno/metabolismo , Regulación de la Expresión Génica , Ratones , Microscopía Electrónica , Células RAW 264.7 , Ribonucleasa Pancreática/genética , Factor A de Crecimiento Endotelial Vascular/genética , Secuenciación del ExomaRESUMEN
BACKGROUND AND AIMS: Stool DNA testing is an emerging and attractive option for colorectal cancer (CRC) screening. We previously evaluated the feasibility of a stool DNA (sDNA) test of methylated SDC2 for CRC detection. The aim of this study was to assess its performance in a multicenter clinical trial setting. METHODS: Each participant was required to undergo a sDNA test and a reference colonoscopy. The sDNA test consists of quantitative assessment of methylation status of SDC2 promoter. Results of real-time quantitative methylation-specific PCR were dichotomized as positive and negative, and the main evaluation indexes were sensitivity, specificity, and kappa value. All sDNA tests were performed and analyzed independently of colonoscopy. RESULTS: Among the 1110 participants from three clinical sites analyzed, 359 and 38 were diagnosed, respectively, with CRC and advanced adenomas by colonoscopy. The sensitivity of the sDNA test was 301/359 (83.8%) for CRC, 16/38 (42.1%) for advanced adenomas, and 134/154 (87.0%) for early stage CRC (stage I-II). Detection rate did not vary significantly according to age, tumor location, differentiation, and TNM stage, except for gender. The follow-up testing of 40 postoperative patients with CRC returned negative results as their tumors had been surgically removed. The specificity of the sDNA test was 699/713 (98.0%), and unrelated cancers and diseases did not seem to interfere with the testing. The kappa value was 0.84, implying an excellent diagnostic consistency between the sDNA test and colonoscopy. CONCLUSION: Noninvasive sDNA test using methylated SDC2 as the exclusive biomarker is a clinically viable and accurate CRC detection method. CHINESE CLINICAL TRIAL REGISTRY: Chi-CTR-TRC-1900026409, retrospectively registered on October 8, 2019; http://www.chictr.org.cn/edit.aspx?pid=43888&htm=4 .