The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary ...to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.
The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It ...remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity‐modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein–Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five‐year progression‐free survival (PFS), overall survival (OS) and cancer‐specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA‐I (T1–T4 N0–N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA‐II (T1–T4 N0–N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA‐III (T1–T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA‐IVA (T3–T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1–T2 N0–N2; II: T3–T4 N0–N2 or T1–T2 N3 and III: T3–T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA‐based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups.
What's new?
The AJCC/UICC TNM stage classification is the most widely accepted common language to describe the magnitude and spread of cancer. However, a new pretreatment staging system comprising both anatomic and non‐anatomic factors is warranted to improve survival prediction. Here, the authors propose new stage groups incorporating pretreatment plasma Epstein–Barr virus (EBV) DNA for non‐metastatic nasopharyngeal carcinoma (NPC). Their prospective study measuring pretreatment plasma EBV DNA in 518 completely staged non‐metastatic NPC patients who were later treated with intensity‐modulated radiation therapy with/without adjunct chemotherapy demonstrates significantly better survival prediction with the newly proposed stages as compared to the current edition TNM.
Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with significantly high prevalence in Southern China. Unlike other head and neck cancers, mutations or deletions of tumor suppressor ...genes in NPC are not common. Recently, downregulation of tumor suppressor genes expression by microRNA (miRNA) is increasingly recognized as an important mechanism of nasopharyngeal tumorigenesis. In this study, we reported that microRNA-144 (miR-144) was frequently upregulated in NPC specimens and cell lines. Repression of miR-144 significantly decreased cell proliferation, clonogenicity, migration, invasion and tumor formation in nude mice, while restoring miR-144 in miR-144-attenuated NPC cells exhibited a strong tumorigenic role. Further, we found that miR-144 was inversely correlated with the tumor suppressor gene phosphatase and tensin homolog (PTEN) in NPC specimens and cell lines, and then we identified PTEN as a direct target of miR-144 in NPC cell lines. PTEN downregulation in miR-144-attenuated cells could increase cell growth, migration and invasion. Mechanistic investigations revealed that miR-144 suppressed the expression of PTEN to increase the expression of pAkt and cyclin D1 to promote G(1)-phase transition and decrease E-cadherin to promote migration and invasion. Taken together, we provide compelling evidence that miR-144 functions as an onco-miRNA in NPC, and its oncoeffects are mediated chiefly by repressing PTEN expression to activate the PI3K/Akt pathway.
Background
Time‐resolved magnetic resonance fingerprinting (MRF), or 4D‐MRF, has been demonstrated its feasibility in motion management in radiotherapy (RT). However, the prohibitive long acquisition ...time is one of challenges of the clinical implementation of 4D‐MRF. The shortening of acquisition time causes data insufficiency in each respiratory phase, leading to poor accuracies and consistencies of the predicted tissues’ properties of each phase.
Purpose
To develop a technique for the reconstruction of multi‐phase parametric maps in four‐dimensional magnetic resonance fingerprinting (4D‐MRF) through the optimization of local T1 and T2 sensitivities.
Methods
The proposed technique employed an iterative optimization to tailor the data arrangement of each phase by manipulation of inter‐phase frames, such that the T1 and T2 sensitivities, which were quantified by the modified Minkowski distance, of the truncated signal evolution curve was maximized. The multi‐phase signal evolution curves were modified by sliding window reconstruction and inter‐phase frame sharing (SWIFS). Motion correction (MC) and dot product matching were sequentially performed on the modified signal evolution and dictionary to reconstruct the multi‐parametric maps. The proposed technique was evaluated by numerical simulations using the extended cardiac‐torso (XCAT) phantom with regular and irregular breathing patterns, and by in vivo MRF data of three health volunteers and six liver cancer patients acquired at a 3.0 T scanner.
Results
In simulation study, the proposed SWIFS approach achieved the overall mean absolute percentage error (MAPE) of 8.62% ± 1.59% and 16.2% ± 3.88% for the eight‐phases T1 and T2 maps, respectively, in the sagittal view with irregular breathing patterns. In contrast, the overall MAPE of T1 and T2 maps generated by the conventional approach with multiple MRF repetitions were 22.1% ± 11.0% and 30.8% ± 14.9%, respectively. For in‐vivo study, the predicted mean T1 and T2 of liver by the proposed SWIFS approach were 795 ms ± 38.9 ms and 58.3 ms ± 11.7 ms, respectively.
Conclusions
Both simulation and in vivo results showed that the approach empowered by T1 and T2 sensitivities optimization and sliding window under the shortened acquisition of MRF had superior performance in the estimation of multi‐phase T1 and T2 maps as compared to the conventional approach with oversampling of MRF data.
Most mature B cells can be divided into four subtypes based on the expression of the surface markers IgD and CD27: IgD
CD27
naïve B cells, IgD
CD27
unswitched memory B cells, IgD
CD27
switched memory ...B cells, and IgD
CD27
double-negative (DN) B cells. Despite their small population size in normal peripheral blood, DN B cells play integral roles in various diseases. For example, they generate autoimmunity in autoimmune conditions, while these cells may generate both autoimmune and antipathogenic responses in COVID-19, or act in a purely antipathogenic capacity in malaria. Recently, DN B cells have been identified in nasopharyngeal carcinoma and non-small-cell lung cancers, where they may play an immunosuppressive role. The distinct functions that DN B cells play in different diseases suggest that they are a heterogeneous B-cell population. Therefore, further study of the mechanisms underlying the involvement of DN B cells in these diseases is essential for understanding their pathogenesis and the development of therapeutic strategies. Further research is thus warranted to characterize the DN B-cell population in detail.
Background and Aims
There are no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for HCC. This study aimed to evaluate the efficacy and safety of ...SBRT as bridging therapy, with comparison with transarterial chemoembolization (TACE) and high‐intensity focused ultrasound (HIFU).
Approach and Results
Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015 and compared with a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1 year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity, and posttransplant survival.
During the study period, 150 patients were evaluated (SBRT, n = 40; TACE, n = 59; HIFU, n = 51). The tumor control rate at 1 year was significantly higher after SBRT compared with TACE and HIFU (92.3%, 43.5%, and 33.3%, respectively; P = 0.02). With competing risk analysis, the cumulative incidence of dropout at 1 and 3 years after listing was lower after SBRT (15.1% and 23.3%) compared with TACE (28.9% and 45.8%; P = 0.034) and HIFU (33.3% and 45.1%; P = 0.032). Time‐to‐progression at 1 and 3 years was also superior after SBRT (10.8%, 18.5% in SBRT, 45%, 54.9% in TACE, and 47.6%, 62.8% in HIFU; P < 0.001). The periprocedural toxicity was similar, without any difference in perioperative complications and patient and recurrence‐free survival rates after transplant. Pathological complete response was more frequent after SBRT compared with TACE and HIFU (48.1% vs. 25% vs. 17.9%, respectively; P = 0.037). In multivariable analysis, tumor size <3 cm, listing alpha‐fetoprotein <200 ng/mL, Child A, and SBRT significantly reduced the risk of dropout.
Conclusions
SBRT was safe, with a significantly higher tumor control rate, reduced the risk of waitlist dropout, and should be used as an alternative to conventional bridging therapies.
Background
Most available four‐dimensional (4D)‐magnetic resonance imaging (MRI) techniques are limited by insufficient image quality and long acquisition times or require specially designed ...sequences or hardware that are not available in the clinic. These limitations have greatly hindered the clinical implementation of 4D‐MRI.
Purpose
This study aims to develop a fast ultra‐quality (UQ) 4D‐MRI reconstruction method using a commercially available 4D‐MRI sequence and dual‐supervised deformation estimation model (DDEM).
Methods
Thirty‐nine patients receiving radiotherapy for liver tumors were included. Each patient was scanned using a time‐resolved imaging with interleaved stochastic trajectories (TWIST)–lumetric interpolated breath‐hold examination (VIBE) MRI sequence to acquire 4D‐magnetic resonance (MR) images. They also received 3D T1‐/T2‐weighted MRI scans as prior images, and UQ 4D‐MRI at any instant was considered a deformation of them. A DDEM was developed to obtain a 4D deformable vector field (DVF) from 4D‐MRI data, and the prior images were deformed using this 4D‐DVF to generate UQ 4D‐MR images. The registration accuracies of the DDEM, VoxelMorph (normalized cross‐correlation NCC supervised), VoxelMorph (end‐to‐end point error EPE supervised), and the parametric total variation (pTV) algorithm were compared. Tumor motion on UQ 4D‐MRI was evaluated quantitatively using region of interest (ROI) tracking errors, while image quality was evaluated using the contrast‐to‐noise ratio (CNR), lung–liver edge sharpness, and perceptual blur metric (PBM).
Results
The registration accuracy of the DDEM was significantly better than those of VoxelMorph (NCC supervised), VoxelMorph (EPE supervised), and the pTV algorithm (all, p < 0.001), with an inference time of 69.3 ± 5.9 ms. UQ 4D‐MRI yielded ROI tracking errors of 0.79 ± 0.65, 0.50 ± 0.55, and 0.51 ± 0.58 mm in the superior–inferior, anterior–posterior, and mid–lateral directions, respectively. From the original 4D‐MRI to UQ 4D‐MRI, the CNR increased from 7.25 ± 4.89 to 18.86 ± 15.81; the lung–liver edge full‐width‐at‐half‐maximum decreased from 8.22 ± 3.17 to 3.65 ± 1.66 mm in the in‐plane direction and from 8.79 ± 2.78 to 5.04 ± 1.67 mm in the cross‐plane direction, and the PBM decreased from 0.68 ± 0.07 to 0.38 ± 0.01.
Conclusion
This novel DDEM method successfully generated UQ 4D‐MR images based on a commercial 4D‐MRI sequence. It shows great promise for improving liver tumor motion management during radiation therapy.
Objectives
To compare the intravoxel incoherent motion (IVIM) diffusion and perfusion characteristics of nasopharyngeal carcinoma (NPC) and post-chemoradiation fibrosis to aid in their ...differentiation.
Methods
Fifty-three (64 %) patients with newly diagnosed NPC and 30 (36 %) patients with biopsy-proven post-chemoradiation fibrosis were recruited into tumour and fibrosis groups respectively. Diffusion-weighted magnetic resonance (MR) imaging was performed using 13
b
values (0–1,000 s/mm
2
). Their respective IVIM parameters (
D
, pure diffusion;
f
, perfusion fraction;
D
*, pseudodiffusion coefficient) were obtained.
Results
D
and
f
were significantly lower in NPC (
D
= 0.752 ± 0.194 × 10
-3
mm
2
/s,
P
<0.001;
f
= 0.122 ± 0.095,
P
<0.001) than in fibrosis (
D
= 1.423 ± 0.364 × 10
-3
mm
2
/s;
f
= 0.190 ± 0.120); while
D
* was significantly higher in NPC (111.366 ± 65.528 × 10
-3
mm
2
/s,
P
<0.001) than in fibrosis (77.468 ± 62.168 × 10
-3
mm
2
/s). Respective cut-off values with sensitivity, specificity and accuracy were:
D
= 1.062 × 10
-3
mm
2
/s (100 %, 100 %, 100 %);
f
= 0.132 (66.0 %, 100 %, 78.3 %);
D
* = 85.283 × 10
-3
mm
2
/s (100 %, 90.7 %, 96.4 %).
Conclusion
NPC and post-chemoradiation fibrosis have distinctive IVIM parameters. IVIM MR imaging is potentially useful in discrimination between NPC and fibrosis.
Key Points
•
New MRI techniques offer greater help in the assessment of nasopharyngeal carcinoma
.
•
Tumour and post
-
chemoradiation fibrosis have distinctive intravoxel incoherent motion diffusion
/
perfusion parameters
.
•
Non
-
invasive IVIM MRI may help differentiate between tumour and fibrosis
.
•
Pure diffusion is a robust independent discriminating factor which improves diagnostic confidence
.
(1) Background: Central venous access devices (CVADs) have been commonly employed during various courses of anticancer treatment. Currently, there are a few types of clinically available CVADs, which ...are associated with short-term and long-term complications. However, little is known about the complication rates when CVADs are used only in palliative care settings. We therefore performed a systematic review and meta-analysis of all the published literature to evaluate the complication rates of CVADs in this clinical setting. (2) Methods: A systematic review and meta-analysis were conducted to identify publications from PubMed/MEDLINE, Embase (Ovid), Scopus, Cochrane Library, CINAHL, Google Scholar, and trial registries. Publications reporting the complication rates of PICCs, central lines, and PORTs in palliative settings for terminally ill cancer patients were included, while those on the use of systemic anticancer therapy and peripheral venous catheters were excluded. The outcome measures included overall complication rate, rate of catheter-related bloodstream infection (CRBSI), and rate of thromboembolism (TE). This systematic review was registered with PROSPERO (CRD42023404489). (3) Results: Five publications with 327 patients were analyzed, including four studies on PICCs and one study on central lines. No studies on PORTs were eligible for analysis. The overall complication rate for PICCs (pooled estimate 7.02%, 95% CI 0.27–19.10) was higher than that for central lines (1.44%, 95% CI 0.30–4.14, p = 0.002). The risk of CRBSI with PICCs (2.03%, 95% CI 0.00–9.62) was also higher than that with central lines (0.96%, 95% CI 0.12–3.41, p = 0.046). PICCs also had a trend of a higher risk of TE (2.10%, 95% CI 0.00–12.22) compared to central lines (0.48%, 95% CI 0.01–2.64, p = 0.061). (4) Conclusions: PICCs for palliative cancer care were found to have greater complications than central lines. This might aid in the formulation of future recommendation guidelines on the choice of CVAD in this setting.
Multiple factors, including host genetics, environmental factors, and Epstein–Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility ...genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage- stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germ-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10−12). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident-macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.
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