Non-keratinizing nasopharyngeal carcinoma, the major subtype of nasopharyngeal carcinoma, is characterized by low differentiation and a close relation to Epstein-Barr virus infection, which indicates a link between Epstein-Barr virus oncogenesis and loss of differentiation, and raises our interest in investigating the involvement of Epstein-Barr virus in nasopharyngeal carcinoma dedifferentiation. Our previous study showed abundant expression of an Epstein-Barr virus-encoded microRNA, BART10-3p, in nasopharyngeal carcinoma tissues, but the association between BART10-3p and nasopharyngeal carcinoma differentiation remains unknown. Here, we examined the expression and prognostic value of BART10-3p, and undertook bioinformatics analysis and functional assays to investigate the influence of BART10-3p on nasopharyngeal carcinoma differentiation and proliferation and the underpinning mechanism. Microarray analysis identified BART10-3p as the most significantly upregulated Epstein-Barr virus-encoded microRNA in nasopharyngeal carcinoma tissues and the upregulation was confirmed in two public datasets. The expression of BART10-3p was an independent unfavorable prognosticator in nasopharyngeal carcinoma and its integration with the clinical stage showed improved prognosis predictive performance. Bioinformatics analysis suggested a potential role of BART10-3p in tumor differentiation and progression. Functional assays demonstrated that BART10-3p could promote nasopharyngeal carcinoma cell dedifferentiation, epithelial-mesenchymal transition, and proliferation in vitro, and tumorigenicity in vivo. Mechanistically, BART10-3p directly targeted the 3′UTR of ALK7 and suppressed its expression. Reconstitution of ALK7 rescued BART10-3p-induced malignant phenotypes. Overall, our study demonstrates that BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7, suggesting a promising therapeutic opportunity to reverse the malignant phenotypes of nasopharyngeal carcinoma.
BackgroundInhibitory checkpoints are promising antitumor targets and predictive biomarkers in a variety of cancers. We aimed to identify the expression levels and prognostic value of multiple inhibitory checkpoints supported by preclinical and clinical evidence in head and neck lymphoepithelioma-like carcinoma (HNLELC).MethodsThe expression of seven inhibitory checkpoints were evaluated in the tumor nest (TN) and tumor stroma (TS) of 102 HNLELC specimens using immunohistochemistry and digital pathology, and an inhibitory checkpoint-based signature (ICS) was subsequently constructed using the LASSO Cox regression model.ResultsPD-L1, B7H3, and IDO-1 were mostly expressed in the TN, with median H-score of TN vs TS: 63.6 vs 14.6; 8.1 vs 1.0; 61.5 vs 34.7 (all P < 0.001), whereas PD-1, TIM-3, LAG-3, and VISTA were mainly observed in the TS, with median H-score of TN vs TS: 0.2 vs 12.4, 3.4 vs 7.1, 6.2 vs 11.9, 16.4 vs 47.2 (all P < 0.001), respectively. The most common simultaneously expressed combinations consisted of PD-L1 + B7H3 + IDO-1 + TIM-3 + LAG-3 + VISTA and B7H3 + IDO-1 + TIM-3 + LAG-3 in the TN (both occurring in 8.8% of patients) and PD-L1 + B7H3 + IDO-1 in the TS (4.9%). In addition, high-ICS patients had shorter 5-year disease-free (40.6% vs 81.7%; P < 0.001), regional recurrence-free (63.5% vs 88.2%; P = 0.003), and overall survival (73.5% vs 92.9%; P = 0.006) than low-ICS patients. Multivariate analysis revealed that ICS represented an independent predictor, which could significantly complement the predictive performance of TNM stage for 3-year (AUC 0.724 vs 0.619, P = 0.014), 5-year (AUC 0.727 vs 0.640, P = 0.056), and 10-year disease-free survival (AUC 0.815 vs 0.709, P = 0.023).ConclusionsThe expression of inhibitory checkpoints and ICS classifier may increase the prognostic value of the TNM staging system and guide the rational design of personalized inhibitory checkpoint blockade therapy in HNLELC.
The front pointer provides a twofold function: a crosshair shadow and an extended FSD measurement at the same time. The crosshair shadow is cast from two perpendicular 3D printed components blocking the light field. An indexing rod was integrated with crosshair components along the central axis to provide extended FSD reading. Results: The simulation workflow is as follows, (A) insert the light field accessory, (B) select proper applicator for the treatment site, (C) adjust Xstrahl gantry till the light field covers desired treatment area, (D) attach the front pointer accessory and record the FSD, (E) mark the field light edge and crosshair. The treatment workflow is as follows, (A) insert the light field accessory and treatment applicator, (B) adjust Xstrahl gantry till the crosshair and the light field match marks, and (C) start the treatment. Conclusion: With custom light field and front pointer accessories extended FSD treatments are feasible and reproducible for Xstrahl 150 units. The extended FSD setup helps avoid physical contact between cone and patient skin especially in open wound scenarios. The light field capability improves treatment area determination especially for uneven surfaces and simplifies patient setup for better reproducibility. The front pointer provides quick and accurate extended FSD measurements for treatment planning during simulation and optional second check for treatment setup.
Purpose/Objective(s): Modalities such as image-guided radiation therapy and better understanding of tumor motion have enhanced tumor targeting, enabling a decrease in target volume margins. With newer imaging/treatment technologies, it is unclear the extent to which clinicians can reduce standard margins for inoperable non-small cell lung cancer (NSCLC), especially in the setting of concurrent chemotherapy which should treat microscopic disease. We hypothesized that smaller target volume margins, when used in conjunction with 4-dimensional computed tomography (4DCT) simulation and daily cone beam computed tomography (CBCT), would not compromise locoregional control and would decrease acute toxicity. Materials/Methods: We conducted a retrospective review of 82 patients with Stage II-III (n Z 73) or Stage IV oligometastatic (n Z 9) NSCLC who received definitive and concurrent chemoradiation therapy (CRT) and underwent 4DCT simulation and daily CBCT. Real time fluoroscopy with abdominal compression was used before delineation of an internal target volume (ITV) on the 4DCT, which was further expanded to a clinical target volume and planning target volume (PTV). ITV to PTV margins were typically 6 mm-10 mm. As another way to quantify variations in margins, a standard PTV was generated by expanding the original gross tumor volume (GTV) with a 10 mm margin, and a margin deviation index (MDI) was calculated as the percentage change in equivalent uniform dose between the original PTV and standard PTV. Grade 3 radiation esophagitis (RE3) and pneumonitis (RP3) were assessed with CTCAE v4.03. Spearman rank correlation tests, the cumulative incidence method, Gray's test, and Fine-Gray method were used. Results: Median MDI was 2.1% (range,-4.0-55.7%), with MDI 5.8% for 33% (n Z 27/82) of patients. Median ITV to PTV margin was 8 mm (range, 0-15 mm). A greater MDI correlated with a smaller ITV to PTV margin (p < 0.001), a larger GTV (p < 0.001), and use of intensitymodulated radiation therapy (IMRT) (p Z 0.002). A tighter target volume margin (greater MDI and smaller ITV to PTV margin) did not increase the risk of locoregional progression (MDI 2.1% vs < 2.1%, HR 0.59, p Z 0.15; MDI 5.8% vs < 5.8%, HR 0.82, p Z 0.62; ITV to PTV margin < 8 mm vs 8 mm, HR 0.61, p Z 0.21). MDI 5.8% vs < 5.8% was associated with a marginal decrease in 1-year cumulative incidences of RE3 (4% vs 24%, p Z 0.025) and either RE3 or RP3 (11% vs 31%, p Z 0.043), while MDI 2.1% vs < 2.1%, ITV to PTV margin < 8 mm vs 8 mm, and IMRT were not significantly associated with these toxicities. Conclusion: Smaller target volume margins were used for larger tumors, yet did not increase the risk of locoregional progression. Additional studies are needed to determine if smaller margins, when used alongside 4DCT simulation and daily CBCT, can be employed consistently to decrease toxicity during definitive CRT for inoperable NSCLC.
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