Abstract Background To better manage patients with de novo metastatic NPC (mNPC) including easily identifying individuals' survival outcomes and accurately choosing the most suitable treatment. ...Materials and methods Three independent cohorts of mNPC patients (a training set of n = 462, an internal prospective validation set of n = 272 and an external prospective validation set of n = 243) were studied. The radiological characteristics of distant metastases, including number of metastatic locations, number of metastatic lesions and size of metastatic lesions, were carefully defined based on imaging data. These three factors and other potential prognostic factors were comprehensively analysed and were further integrated into new subdivisions of stage M1 using a Cox proportional hazards model. Results We successfully subdivided the M1 stage into three categories: M1a, oligo metastasis without liver involvement; M1b, multiple metastases without liver involvement; and M1c, liver involvement irrespective of metastatic lesions. The 3-year overall survival ranged from 54.5% to 72.8%, from 34.3% to 41.6% and from 22.6.0%–23.6% for M1a, M1b and M1c, respectively ( P < 0.001). Systemic chemotherapy combined with radical loco-regional radiotherapy may benefit patients in M1a and M1b, not in M1c. Further aggressive treatment of metastatic lesions based on systemic chemotherapy and definitive loco-regional radiotherapy showed no survival benefit, even for patients in M1a ( P > 0.05). Conclusion The subdividing of M1 provided promising prognostic value and could aid clinicians in choosing the most suitable treatment for de novo mNPC patients.
Objectives
The value of using PET/CT for staging of stage I–II NPC remains unclear. Hence, we aimed to investigate the survival benefit of PET/CT for staging of early-stage NPC before radical ...therapy.
Methods
A total of 1003 patients with pathologically confirmed NPC of stages I–II were consecutively enrolled. Among them, 218 patients underwent both PET/CT and conventional workup (CWU, head-and-neck MRI, chest radiograph, liver ultrasound, bone scintigraphy) before treatment. The remaining 785 patients only underwent CWU. The standard of truth (SOT) for lymph node metastasis was defined by the change of size according to follow-up MRI. The diagnostic efficacies were compared in 218 patients who underwent both PET/CT and CWU. After covariate adjustment using propensity scoring, a cohort of 872 patients (218 with and 654 without pre-treatment PET/CT) was included. The primary outcome was overall survival based on intention to treat.
Results
Retropharyngeal lymph nodes were metastatic based on follow-up MRI in 79 cases. PET/CT was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions (72.2% 62.3–82.1 vs. 91.1% 84.8–97.4,
p
= 0.004). Neck lymph nodes were metastatic in 89 cases and PET/CT was more sensitive than MRI (96.6% 92.8–100.0 vs. 76.4% 67.6–85.2,
p
< 0.001). In the survival analyses, there was no association between pre-treatment PET/CT use and improved overall survival, progression-free survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival.
Conclusions
This study showed PET/CT is of little value for staging of stage I–II NPC patients at initial imaging.
Key Points
•
PET/CT was more sensitive than MRI in detecting neck lymph node lesions whereas it was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions.
•
No association existed between pre-treatment PET/CT use and improved survival in stage I–II NPC patients.
Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that ...methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m
A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction.
Cumulative doses of 200 mg/m
for concurrent cisplatin (DDP) were indicated by retrospective studies as sufficient in conferring survival benefit for locoregionally advanced nasopharyngeal carcinoma ...(LA-NPC). We performed an open-label, phase II, randomized, controlled trial to test the noninferiority of a two-cycle 100 mg/m
concurrent DDP regimen over three-cycle in patients with low-risk LA-NPC with pretreatment Epstein-Barr virus DNA levels < 4,000 copies/mL.
Eligible patients were randomly assigned 1:1 to receive two cycles or three cycles concurrent DDP-based chemoradiotherapy. The primary end point was 3-year progression-free survival (PFS). The secondary end points included overall survival, distant metastasis-free survival, locoregional relapse-free survival, etc.
Between September 2016 and October 2018, 332 patients were enrolled, with 166 in each arm. After a median follow-up of 37.7 months, the estimated 3-year PFS rates were 88.0% in the two-cycle group and 90.4% in the three-cycle group, with a difference of 2.4% (95% CI, -4.3 to 9.1,
= .014). No differences were observed between groups in terms of PFS, overall survival, and the cumulative incidences of locoregional relapse and distant metastasis. Patients in the three-cycle group developed significantly more grade 3-4 mucositis (41 24.8%
25 15.1%), hyponatremia (26 15.8%
14 8.4%), and dermatitis (9 5.5%
2 1.2%). The overall all-grade and grade 3-4 toxicity burdens were heavier in three-cycle group (T-scores, 12.33
10.57,
< .001 for all grades; 1.76
1.44,
= .05 for grade 3-4). Patients in the three-cycle group also showed more all-grade hearing impairment, dry mouth and skin fibrosis, and impaired long-term quality of life.
Intensity-modulated radiotherapy plus two cycles of concurrent 100 mg/m
DDP could be an alternative treatment option for patients with low-risk LA-NPC.
Background. MicroRNAs (miRNAs) have been demonstrated to exhibit important regulatory roles in multiple malignancies, including hepatocellular carcinoma (HCC). hsa-miR-497-5p was reported to involve ...in cancer progression and poor prognosis in many kinds of tumors. However, the expression and its clinical significance of hsa-miR-497-5p in HCC remain unclear. Methods. In the present study, we investigated the expression of hsa-miR-497-5p in HCC and analyzed the correction of clinical features with prognosis. The expression levels of hsa-miR-497-5p and potential target genes were analyzed in HCC and adjacent noncancerous tissues using The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze hsa-miR-497-5p levels in 328 HCC tissues and 30 paired adjacent noncancer tissues. Overall survival (OS) and progression-free survival (PFS) of patients with HCC were assessed using the Kaplan-Meier method and the log-rank test. Results. The hsa-miR-497-5p expression levels were decreased, and its target genes ACTG1, CSNK1D, PPP1CC, and BIRC5 were upregulated in HCC tissues compared with normal tissues. Lower levels of hsa-miR-497-5p expression and higher levels of the four target genes were significantly associated with higher tumor diameter. Moreover, patients with lower hsa-miR-497-5p expression and higher target genes levels had shorter OS. Conclusion. The expression levels of hsa-miR-497-5p may play an important regulatory role in HCC and are closely correlated with HCC progression and poor prognosis in patients. The hsa-miR-497-5p may be a specific therapeutic target for the treatment of HCC.
Abstract Objective To discuss the correlation between diffusion tensor imaging (DTI) measurements, diffusion tensor tractography and the clinical symptoms of cervical spondylotic myelopathy. Methods ...Based on the Japanese Orthopedics Association (JOA) score, 104 cervical spondylotic myelopathy cases were first divided into four groups: mild, moderate, severe and serious groups. According to lesion signal characteristics, all cases were again divided into three groups: A(N/N): normal signal in both T1WI and T2WI; B (N/H): normal signal in T1WI but high signal in T2WI; and C (L/H): low signal in T1WI and high signal in T2WI. The apparent diffusion coefficient (ADC), fractional anisotropy (FA), λ1, λ2, and λ3 were measured and diffusion tensor tractography was performed in the seriously compressed section of the spinal cord. Results The FA values were positively correlated with JOA scores ( r = 0.883, P < 0.05), and significantly different among four JOA groups ( P < 0.05). The ADC, λ2, and λ3 were significantly different among the moderate, severe and serious groups as well as among the A, B, and C groups ( P < 0.05). Declining FA values were found associated with increasing fiber bundle damage. Conclusions The FA values and the change patterns of fiber bundle were more sensitive than T2WI for spinal cord lesion, and were positively correlated with clinical symptoms.
In this study, a eukaryotic microalgae dominated microalgal-bacterial granular sludge process was explored for municipal wastewater treatment under simulated natural diel cycles. Different from ...previous studies with constant illumination, the excellent performances were obtained in terms of organics, ammonia-N and phosphate-P removal under simulated natural day-night conditions. It was found that about 94.9% of organics, 69.5% of ammonia-N and 90.6% of phosphate-P could be removed on average over a day-night cycle at a shorter hydraulic retention time of 2 h in the daytime, while 93.1% of organics, 62.5% of ammonia-N and 80.8% of phosphate-P removed at a hydraulic retention time of 4 h during the nighttime. Chlorophyceae were identified as the dominant microalgae, with Alphaproteobacteria and Sphingobacteriia being the major bacteria in MBGS. It was further revealed that microbial assimilation by microalgae and bacteria could serve as the main mechanism for the observed removal of organics, ammonia and phosphate, while the corresponding key metabolic pathways were also elucidated. Chlorophyceae were found to be the main player for the phosphorus removal via H+-exporting ATPase and H+-transporting two-sector ATPase, while Alphaproteobacteria were potentially responsible for the observed ammonia removal mediated by glutamine synthetase and glutamate dehydrogenase. It is expected that this study can offer an environmentally sustainable option for municipal wastewater treatment.
Display omitted
•Microalgal-bacterial granular sludge process was demonstrated under day-night cycles.•85% of organics and P were removed during diel cycles.•Ammonia removal was organic source-dependent, with 75% removed for acetate.•The removal mechanisms of organics, N and P were identified with key metabolic pathways.•Metabolic pathways of organics, N and P were related to the functions of microbial taxa.
DNA origami enables the manipulation of objects at nanoscale, and demonstrates unprecedented versatility for fabricating both static and dynamic nanostructures. In this work, we introduce a new ...strategy for transferring modular reconfigurable DNA nanostructures from two‐dimensional to three‐dimensional. A 2D DNA sheet could be modularized into connected parts (e.g., two, three, and four parts in this work), which can be independently transformed between two conformations with a few DNA “trigger” strands. More interestingly, the transformation of the connected 2D modules can lead to the controlled, resettable structural conversion of a 2D sheet to a 3D architecture, due to the constraints induced by the connections between the 2D modules. This new approach can provide an efficient mean for constructing programmable, higher‐order, and complex DNA objects, as well as sophisticated dynamic substrates for various applications.
We demonstrated a new strategy for constructing modular DNA nanostructures that are reconfigurable from two‐dimensional to three‐dimensional. This strategy demonstrates an efficient means for constructing programmable, higher‐order, and complex DNA objects, as well as sophisticated dynamic substrates for various applications.
The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in ...nasopharyngeal carcinoma (NPC) patients.
One hundred fifty-six patients with stage III–IVb and pretreatment Epstein–Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years.
After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62–1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score.
The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients.
NCT02421640
•Adoptive immunotherapy with autologous TILs following CCRT was safe.•Additional TIL infusion does not improve PFS in high-risk NPC patients.•A potential survival benefit was observed with CCRT plus TILs in selected patients.•Provide evidence for trials investigating the TILs plus immune checkpoint inhibitors.
Recent studies have emphasized microRNAs (miRs) as crucial regulators in the occurrence and development of pancreatic cancer that continues to be one of the deadliest malignancies with few effective ...therapies. The study aimed to investigate the functional role of miR-873 and its associated mechanism to unravel the biological characteristics of pancreatic cancer stem cells in tumor growth. The expression patterns of pleckstrin-2 (PLEK2) and miR-873 were detected in the pancreatic cancer tissues. Then to further investigate specific role of miR-873, the pancreatic cancer stem cells were treated with miR-873 mimic, PLEK2, small interfering RNA against PLEK2, LY294002 (inhibitor of phosphatidylinositol 3-kinase/protein kinase B PI3K/AKT pathway) to detect the relative gene expression as well as their effects on cell self-renewal, proliferation and apoptosis. Finally, the tumor formation in nude mice was measured to verify the preceding results in vivo. Pancreatic cancer tissues exhibited a decline of miR-873 expression and an enhancement of PLEK2 expression. miR-873 targeted PLEK2 and downregulated its expression, leading to inhibition of PI3K/AKT pathway. Overexpressed miR-873 or silenced PLEK2 inhibited the self-renewal and proliferation while promoting the apoptosis of pancreatic cancer stem cells. Tumor formation was inhibited by overexpressed miR-873 or silenced PLEK2 in nude mice. Overall, miR-873 can suppress the self-renewal and proliferation of pancreatic cancer stem cells by blocking PLEK2-dependent PI3K/AKT pathway. Hence, this study contributes to understanding the role of miR-873 in pancreatic cancer stem cells and its underlying molecular mechanisms to aid in the development of effective pancreatic cancer therapeutics.
•The mechanism of miR-873 in self-renewal, proliferation and apoptosis of pancreatic cancer stem cells was investigated.•Pancreatic cancer tissues exhibited lower level of miR-873 and higher level of PLEK2.•This study contributes to understanding the role of miR-873 in pancreatic cancer stem cells and its underlying molecular mechanisms to aid in the development of effective pancreatic cancer therapeutics.
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