After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-RT circulating plasma ...Epstein–Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM (tumor–lymph node–metastasis) stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy.
The prospective multicenter 0502 EBV DNA screening cohort (Hong Kong NPC Study Group 0502 trial) enrolled from 2006 to 2015 (n = 745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997 to 2006 (n = 340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009 to 2012 (n = 837). Eligible patients had histologically confirmed NPC of Union for International Cancer Control (UICC) 7th Edition stage II–IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-RT EBV DNA tested within 120 days after RT and received no adjuvant therapy. The primary end point was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low, intermediate, and high risk of death.
Combining post-RT EBV DNA level (0, 1–49, 50–499, and ≥500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate-, and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2%, respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. The RPA model (c-index 0.712) showed better risk discrimination than either the TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts.
Combining post-RT EBV DNA and TNM stage improved risk stratification in NPC.
•Integrating postradiotherapy plasma Epstein–Barr virus (EBV) DNA and tumor–lymph node–metastasis (TNM) stage improves the risk stratification of nasopharyngeal carcinoma.•Postradiotherapy plasma EBV DNA is a better predictor of early death in nasopharyngeal carcinoma than TNM stage.•The low-risk group by recursive partitioning model can spare more patients from unnecessary toxicity of adjuvant therapy.
Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker ...of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.
Objectives
A convolutional neural network (CNN) was adapted to automatically detect early-stage nasopharyngeal carcinoma (NPC) and discriminate it from benign hyperplasia on a non-contrast-enhanced ...MRI sequence for potential use in NPC screening programs.
Methods
We retrospectively analyzed 412 patients who underwent T2-weighted MRI, 203 of whom had biopsy-proven primary NPC confined to the nasopharynx (stage T1) and 209 had benign hyperplasia without NPC. Thirteen patients were sampled randomly to monitor the training process. We applied the Residual Attention Network architecture, adapted for three-dimensional MR images, and incorporated a slice-attention mechanism, to produce a CNN score of 0–1 for NPC probability. Threefold cross-validation was performed in 399 patients. CNN scores between the NPC and benign hyperplasia groups were compared using Student's
t
test. Receiver operating characteristic with the area under the curve (AUC) was performed to identify the optimal CNN score threshold.
Results
In each fold, significant differences were observed in the CNN scores between the NPC and benign hyperplasia groups (
p
< .01). The AUCs ranged from 0.95 to 0.97 with no significant differences between the folds (
p
= .35 to .92). The combined AUC from all three folds (
n
= 399) was 0.96, with an optimal CNN score threshold of > 0.71, producing a sensitivity, specificity, and accuracy of 92.4%, 90.6%, and 91.5%, respectively, for NPC detection.
Conclusion
Our CNN method applied to T2-weighted MRI could discriminate between malignant and benign tissues in the nasopharynx, suggesting that it as a promising approach for the automated detection of early-stage NPC.
Key Points
• The convolutional neural network (CNN)–based algorithm could automatically discriminate between malignant and benign diseases using T2-weighted fat-suppressed MR images.
• The CNN-based algorithm had an accuracy of 91.5% with an area under the receiver operator characteristic curve of 0.96 for discriminating early-stage T1 nasopharyngeal carcinoma from benign hyperplasia.
• The CNN-based algorithm had a sensitivity of 92.4% and specificity of 90.6% for detecting early-stage nasopharyngeal carcinoma.
Significant advances in physicochemical properties of polymeric micelles enable optimization of therapeutic drug efficacy, supporting nanomedicine manufacturing and clinical translation. Yet, the ...effect of micelle morphology on pharmacological efficacy is not adequately addressed. This work addresses this gap by assessing pharmacological efficacy of polymeric micelles with spherical and worm‐like morphologies. It is observed that poly(2‐oxazoline)‐based polymeric micelles can be elongated over time from a spherical structure to worm‐like structure, with elongation influenced by several conditions, including the amount and type of drug loaded into the micelles. The role of different morphologies on pharmacological performance of drug loaded micelles against triple‐negative breast cancer and pancreatic cancer tumor models is further evaluated. Spherical micelles accumulate rapidly in the tumor tissue while retaining large amounts of drug; worm‐like micelles accumulate more slowly and only upon releasing significant amounts of drug. These findings suggest that the dynamic character of the drug–micelle structure and the micelle morphology play a critical role in pharmacological performance, and that spherical micelles are better suited for systemic delivery of anticancer drugs to tumors when drugs are loosely associated with the polymeric micelles.
Small spherical micelles rapidly accumulate in tumors while carrying more drug than worm‐like micelles that accumulate slower and release drug in blood where it gets cleared. As a result, greater antitumor effects are seen with spherical micelles. Thereby, the dynamic character of drug–micelle species and control of micelle morphology play a critical role in their pharmacological performance in tumors.
Objectives
MRI can detect early-stage nasopharyngeal carcinoma (NPC), but the detection is more challenging in early-stage NPCs because they must be distinguished from benign hyperplasia in the ...nasopharynx. This study aimed to determine whether intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) MRI could distinguish between these two entities.
Methods
Thirty-four subjects with early-stage NPC and 30 subjects with benign hyperplasia prospectively underwent IVIM DWI. The mean pure diffusion coefficient (
D
), pseudo-diffusion coefficient (
D
*), perfusion fraction (
f
) and apparent diffusion coefficient (ADC) values were calculated for all subjects and compared between the 2 groups using Student’s
t
test. Receiver operating characteristics with the area under the curve (AUC) was used to identify the optimal threshold for all significant parameters, and the corresponding diagnostic performance was calculated. A
p
value of < 0.05 was considered statistically significant.
Results
Compared with benign hyperplasia, early-stage NPC exhibited a significantly lower
D
mean (0.64 ± 0.06 vs 0.87 ± 0.11 × 10
−3
mm
2
/s), ADC
0–1000
mean (0.77 ± 0.08 vs 1.00 ± 0.13 × 10
−3
mm
2
/s), ADC
300–1000
(0.63 ± 0.05 vs 0.86 ± 0.10 × 10
−3
mm
2
/s) and a higher
D
* mean (32.66 ± 4.79 vs 21.96 ± 5.21 × 10
−3
mm
2
/s) (all
p
< 0.001). No significant difference in the
f
mean was observed between the two groups (
p
= 0.216). The
D
and ADC
300–1000
mean had the highest AUC of 0.985 and 0.988, respectively, and the D mean of < 0.75 × 10
−3
mm
2
/s yielded the highest sensitivity, specificity and accuracy (100%, 93.3% and 96.9%, respectively) in distinguishing early-stage NPC from benign hyperplasia.
Conclusion
DWI has potential to distinguish early-stage NPC from benign hyperplasia and
D
and ADC
300–1000
mean were the most promising parameters.
Key Points
• Diffusion-weighted imaging has potential to distinguish early-stage nasopharyngeal carcinoma from benign hyperplasia in the nasopharynx.
• The pure diffusion coefficient, pseudo-diffusion coefficient from intravoxel incoherent motion model and apparent diffusion coefficient from conventional diffusion-weighted imaging were significant parameters for distinguishing these two entities in the nasopharynx.
• The pure diffusion coefficient, followed by apparent diffusion coefficient, may be the most promising parameters to be used in screening studies to help detect early-stage nasopharyngeal carcinoma.
Purpose
Convolutional neural networks (CNNs) show potential for delineating cancers on contrast-enhanced MRI (ce-MRI) but there are clinical scenarios in which administration of contrast is not ...desirable. We investigated performance of the CNN for delineating primary nasopharyngeal carcinoma (NPC) on non-contrast-enhanced images and compared the performance to that on ce-MRI.
Materials and methods
We retrospectively analyzed primary NPC in 195 patients using a well-established CNN, U-Net, for tumor delineation on the non-contrast-enhanced fat-suppressed (fs)-T2W, ce-T1W and ce-fs-T1W images. The CNN-derived delineations were compared to manual delineations to obtain Dice similarity coefficient (DSC) and average surface distance (ASD). The DSC and ASD on fs-T2W were compared to those on ce-MRI. Primary tumor volumes (PTVs) of CNN-derived delineations were compared to that of manual delineations.
Results
The CNN for NPC delineation on fs-T2W images showed similar DSC (0.71 ± 0.09) and ASD (0.21 ± 0.48 cm) to those on ce-T1W images (0.71 ± 0.09 and 0.17 ± 0.19 cm, respectively) (
p
> 0.05), and lower DSC but similar ASD to ce-fs-T1W images (0.73 ± 0.09,
p
< 0.001; and 0.17 ± 0.20 cm,
p
> 0.05). The CNN overestimated PTVs on all sequences (
p
< 0.001).
Conclusion
The CNN showed promise for NPC delineation on fs-T2W images in cases where it is desirable to avoid contrast agent injection. The CNN overestimated PTVs on all sequences.
Background: Prophylactic treatment for severe hemophilia A is likely to be more effective than treatment when bleeding occurs, however, prophylaxis is costly. We studied an inception cohort of 25 ...boys using a tailored prophylaxis approach to see if clotting factor use could be reduced with acceptable outcomes. Methods: Ten Canadian centers enrolled subjects in this 5‐year study. Children were followed every 3 months at a comprehensive care hemophilia clinic. They were initially treated with once‐weekly clotting factor; the frequency was escalated in a stepwise fashion if unacceptable bleeding occurred. Bleeding frequency, target joint development, physiotherapy and radiographic outcomes, as well as resource utilization, were determined prospectively. Results: The median follow‐up time was 4.1 years (total 96.9 person‐years). The median time to escalate to twice‐weekly therapy was 3.42 years (lower 95% confidence limit 2.05 years). Nine subjects developed target joints at a rate of 0.09 per person‐year. There was an average of 1.2 joint bleeds per person‐year. The cohort consumed on average 3656 IU kg−1year−1 of factor (F) VIII. Ten subjects required central venous catheters (three while on study); no complications of these devices were seen. One subject developed a transient FVIII inhibitor. End‐of‐study joint examination scores – both clinically and radiographically – were normal or near‐normal. Conclusions: Most boys with severe hemophilia A will probably have little bleeding and good joint function with tailored prophylaxis, while infusing less FVIII than usually required for traditional prophylaxis.
Purpose To evaluate the utility of amide proton transfer (APT) imaging in the characterization of head and neck tumors. Materials and Methods This retrospective study of APT imaging included 117 ...patients with 70 nasopharyngeal undifferentiated carcinomas (NUCs), 26 squamous cell carcinomas (SCCs), eight non-Hodgkin lymphomas (NHLs), and 13 benign salivary gland tumors (BSGTs). Normal tissues were examined in 25 patients. The APT means of malignant tumors, normal tissues, and benign tumors were calculated and compared with the Student t test and analysis of variance. The added value of the mean APT to the mean apparent diffusion coefficient (ADC) for differentiating malignant and benign tumors was evaluated by using receiver operating characteristic analysis and integrated discrimination index. Results The mean APT of malignant tumors (2.40% ± 0.97 standard deviation) was significantly higher than that of brain tissue (1.13% ± 0.43), muscle tissue (0.23% ± 0.73), and benign tumors (1.32% ± 1.20) (P < .001). There were no differences between malignant groups (NUC, 2.37% ± 0.90; SCC, 2.41% ± 1.16; NHL, 2.65% ± 0.89; P = .45 to P = .86). The mean ADC of malignant tumors (0.85 ± 0.17 × 10
mm
/sec) was significantly lower than that of benign tumors (1.46 ± 0.47 × 10
mm
/sec) (P = .001). Adding APT to ADC increased the area under the curve from 0.87 to 0.96, with an integrated discrimination index of 7.6% (P = .13). Conclusion These preliminary data demonstrate differences in amide proton transfer (APT) mean of malignant tumors, normal tissues, and benign tumors, although APT mean could not be used to differentiate between malignant tumor groups. APT imaging has the potential to be of added value to apparent diffusion coefficient in differentiating malignant from benign tumors.
Poor human-to-human transmission of influenza A H5N1 virus has been attributed to the paucity of putative sialic acid α2-3 virus receptors in the epithelium of the human upper respiratory tract, and ...thus to the presumed inability of the virus to replicate efficiently at this site. We now demonstrate that ex vivo cultures of human nasopharyngeal, adenoid and tonsillar tissues can be infected with H5N1 viruses in spite of an apparent lack of these receptors.
To study the dynamic changes in plasma Epstein-Barr virus (pEBV) DNA after radiotherapy in nasopharyngeal cancer (NPC).
We conducted a randomized controlled trial of adjuvant chemotherapy versus ...observation in patients with NPC who had detectable pEBV DNA at 6 weeks post-radiotherapy. Randomized patients had a second pEBV DNA checked at 6 months post-randomization. The primary endpoint was progression-free survival (PFS).
We prospectively enrolled 789 patients. Baseline post-radiotherapy pEBV DNA was undetectable in 573 (72.6%) patients, and detectable in 216 (27.4%) patients, of whom 104 (13.2%) patients were eligible for randomization to adjuvant chemotherapy (
= 52) versus observation (
= 52). The first post-radiotherapy pEBV DNA had a sensitivity of 0.48, specificity of 0.81, area under receiver-operator characteristics curve (AUC) of 0.65, false positive (FP) rate of 13.8%, and false negative (FN) rate of 14.4% for disease progression. The second post-radiotherapy pEBV DNA had improved sensitivity of 0.81, specificity of 0.75, AUC of 0.78, FP rate of 14.3%, and FN rate of 8.1%. Patients with complete clearance of post-radiotherapy pEBV DNA (51%) had survival superior to that of patients without post-radiotherapy pEBV DNA clearance (5-year PFS, 85.5% vs. 23.3%; HR, 9.6;
< 0.0001), comparable with patients with initially undetectable post-radiotherapy pEBV DNA (5-year PFS, 77.1%), irrespective of adjuvant chemotherapy or observation.
Patients with NPC with detectable post-radiotherapy pEBV DNA who experienced subsequent pEBV DNA clearance had superior survival comparable with patients with initially undetectable post-radiotherapy pEBV DNA. Post-radiotherapy pEBV DNA clearance may serve as an early surrogate endpoint for long-term survival in NPC.
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