Anatomical changes and dosimetric analysis of the neck region based on FBCT for nasopharyngeal carcinoma patients during radiotherapy.

BACKGROUND: The study aimed to investigate anatomical changes in the neck region and evaluate their impact on dose distribution in patients with nasopharyngeal carcinoma (NPC) undergoing intensity modulated radiation therapy (IMRT). Additionally, the study sought to determine the optimal time for replanning during the course of treatment. METHODS: Twenty patients diagnosed with NPC underwent IMRT, with weekly pretreatment kV fan beam computed tomography (FBCT) scans in the treatment room. Metastasized lymph nodes in the neck region and organs at risk (OARs) were redelineation using the images from the FBCT scans. Subsequently, the original treatment plan (PLAN0) was replicated to each FBCT scan to generate new plans labeled as PLAN 1-6. The dose-volume histograms (DVH) of the new plans and the original plan were compared. One-way repeated measure ANOVA was utilized to establish threshold(s) at various time points. The presence of such threshold(s) would signify significant change(s), suggesting the need for replanning. RESULTS: Progressive volume reductions were observed over time in the neck region, the gross target volume for metastatic lymph nodes (GTVnd), as well as the submandibular glands and parotids. Compared to PLAN0, the mean dose (Dmean) of GTVnd-L significantly increased in PLAN5, while the minimum dose covering 95% of the volume (D95%) of PGTVnd-L showed a significant decrease from PLAN3 to PLAN6. Similarly, the Dmean of GTVnd-R significantly increased from PLAN4 to PLAN6, whereas the D95% of PGTVnd-R exhibited a significant decrease during the same period. Furthermore, the dose of bilateral parotid glands, bilateral submandibular glands, brainstem and spinal cord was gradually increased in the middle and late period of treatment. CONCLUSION: Significant anatomical and dosimetric changes were noted in both the target volumes and OARs. Considering the thresholds identified, it is imperative to undertake replanning at approximately 20 fractions. This measure ensures the delivery of adequate doses to target volumes while mitigating the risk of overdosing on OARs.

TSPAN1 inhibits metastasis of nasopharyngeal carcinoma via suppressing NF-kB signaling.

Nasopharyngeal carcinoma (NPC) originates in the epithelial cells of the nasopharynx and is a common malignant tumor in southern China and Southeast Asia. Metastasis of NPC remains the main cause of death for NPC patients even though the tumor is sensitive to radiotherapy and chemotherapy. Here, we found that the transmembrane protein tetraspanin1 (TSPAN1) potently inhibited the in vitro migration and invasion, as well as, the in vivo metastasis of NPC cells via interacting with the IKBB protein. In addition, TSPAN1 was essential in preventing the overactivation of the NF-kB pathway in TSPAN1 overexpressing NPC cells. Furthermore, reduced TSPAN1 expression was associated with NPC metastasis and the poor prognosis of NPC patients. These results uncovered the suppressive role of TSPAN1 against NF-kB signaling in NPC cells for preventing NPC metastasis. Its therapeutic value warrants further investigation.

Distribution of regional lymph lode metastasis in unilateral nasopharyngeal carcinoma and the suggestions for selective prophylactic irradiation with intensity-modulated radiotherapy.

PURPOSE: To address the regional lymph node (RLN) distribution and the long-term efficacy in unilateral nasopharyngeal carcinoma (NPC), providing elective irradiation for RLN with intensity-modulated radiotherapy (IMRT). METHODS: The involvement of clinical data of 136 patients with unilateral NPC, who underwent IMRT from November 2003 to December 2020 were analyzed retrospectively. The therapeutic effect and failure pattern of RLN metastasis were evaluated. RESULTS: Of 57.1% patients have bilateral RLN metastasis. The rate of contralateral RLNs metastasis is lower than that of ipsilateral RLNs. Contralateral RLN metastasis mainly occurs in level VIIa (39.0%) and II (38.2%). While level IVa is only 0.7%, and none of RLN metastasis was found in level IVb and Va. The median follow-up was 70 months, and the 3-, 5-and 10-year regional recurrence-free survival (RRFS) were 94.1%, 93.1%, and 93.1%, respectively. CONCLUSION: Routine prophylactic irradiation may not include contralateral lower neck LN and level Va for N0-1 unilateral NPC.

Why subclinical involvement is prescribed the same high dose as gross tumor volume: A study on high-dose clinical target volume in intensity-modulated radiotherapy plan of nasopharyngeal carcinoma.

BACKGROUND: Most nasopharyngeal carcinoma (NPC) protocols define primary gross tumor volume (GTVnx) plus a range from 2 to 5 mm as the high-dose clinical target volume (hd-CTV). However, in China, hd-CTV is defined as GTVnx plus 0 mm. METHODS: A total of 40 patients with newly diagnosed nonmetastatic NPC (T1-T4 ten cases each) treated with IMRT were consecutively enrolled. Real and virtual treatment plans were designed according to the definitions of hd-CTV recommended by China and Radiation Therapy Oncology Group (RTOG), respectively. RESULTS: The hd-CTV in China was significantly smaller than that of RTOG. Exposure doses to 5 mm subclinical involvement and OARs as well as NTCP in the China treatment plan were significantly lower than those of RTOG. CONCLUSION: It could be recommended to divide the hd-CTV into GTV and subclinical target volume and to prescribe different doses for the GTV and subclinical involvement in the IMRT plan of NPC.

Correlated with better prognosis, CSTA inhibits metastasis of nasopharyngeal carcinoma cells via suppressing AKT signaling through promoting METTL3 degradation.

BACKGROUND: Metastasis is one of the main obstacles impeding the survival of nasopharyngeal carcinoma (NPC) patients, with the molecular mechanism underlying NPC metastasis still unclear. RESULTS: In this study, Cystatin A (CSTA) was found downregulated in NPC tissues with metastasis compared with those without metastasis. Shorter overall survival and distant metastasis-free survival were found in NPC patients with lower CSTA expression. Using functional assays, we found that CSTA prevented both the in vitro motility of NPC cells and their ability to metastasize in vivo. Transcriptome sequencing and western blot analysis revealed that CSTA inhibited the phosphorylation of AKT. Moreover, activating AKT using AKT agonist SG79 rescued the motility of CSTA-overexpressing NPC cells, whereas, treatment with AKT inhibitor MK2206 inhibited the motility of CSTA-knockdown NPC cells. Mechanically, immunoprecipitation coupled mass spectrometry found that CSTA interacted with the N6-adenosine-methyltransferase subunit METTL3 and promoted its ubiquitin-proteasome-mediated degradation following the upregulation of NKX3-1 and LHPP, which are negative regulators of AKT. Furthermore, knock-down of NKX3-1 and LHPP enhanced the motility of CSTA-overexpressing NPC cells. CONCLUSIONS: The inhibitory effect of CSTA upon NPC metastasis mainly depended on suppressing AKT signaling by the upregulation of NKX3-1 and LHPP expression resulting from the binding between CSTA and METLL3. Our study suggests that the CSTA-METLL3-NKX3-1/LHPP-AKT axis could be of therapeutic value for inhibiting NPC metastasis.

Clinical outcomes of non-nasopharyngeal lymphoepithelial carcinoma treated with a combined modality approach: A single-institution study.

BACKGROUND: This study presents a summary of the clinical characteristics of non-nasopharyngeal lymphoepithelial carcinoma (NNPLEC), effects of combined modality treatment and prognostic value of plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) load, with the aim of providing a reference framework for optimizing treatment practices and outcomes. METHODS: Patients with NNPLEC treated by our center between January 2000 and December 2020 were retrospectively reviewed. RESULTS: In total, 728 patients were included. The lung was identified as the most common primary tumor site (64.0%), followed by the salivary gland (19.2%). A total of 539 (74.0%) patients underwent surgery, 459 (63.0%) received chemotherapy, and 361 (49.6%) were subjected to radiotherapy. The median follow-up time was 45 months (range, 6-212 months) and 5-year overall survival (OS) was 79.1%. Increased plasma EBV-DNA load of >513.5 copies/mL was predictive of disease progression, with a specificity of 98.1% and a sensitivity of 98.9%. In multivariate Cox analysis, N stage, surgery, and radiotherapy were independent prognostic factors for both OS and PFS. Radiotherapy significantly improves OS in comparison with no radiotherapy group for salivary LEC, while surgery significantly improves OS for pulmonary LEC. CONCLUSION: Based on our analysis, surgery and radiotherapy are associated with better OS and PFS for NNPLEC. Radiotherapy could be recommended for salivary LEC, while surgery remains the primary treatment strategy for pulmonary LEC patients. An increased plasma EBV-DNA load of >513.5 copies/mL is strongly predictive of disease progression, supporting the importance of regular evaluation of plasma EBV-DNA as part of the diagnostic routine.

Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies.

Background/Purpose: Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT). Materials/Methods: Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration. Results: Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group. Conclusions: FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.

Novel long noncoding RNA LINC02820 augments TNF signaling pathway to remodel cytoskeleton and potentiate metastasis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China. However, there are no targets to treat ESCC because the molecular mechanism behind the cancer is still unclear. Here, we found a novel long noncoding RNA LINC02820 was upregulated in ESCC and associated with the ESCC clinicopathological stage. Through a series of functional experiments, we observed that LINC02820 only promoted the migration and invasion capabilities of ESCC cell lines. Mechanically, we found that LINC02820 may affect the cytoskeletal remodeling, interact with splice factor 3B subunit 3 (SF3B3), and cooperate with TNFα to amplify the NF-κB signaling pathway, which can lead to ESCC metastasis. Overall, our findings revealed that LINC02820 is a potential biomarker and therapeutic target for the diagnosis and treatment of ESCC.

Electron ultra-high dose rate FLASH irradiation study using a clinical linac: Linac modification, dosimetry, and radiobiological outcome.

PURPOSE: Ultra-high dose rate FLASH irradiation (FLASH-IR) has been shown to cause less normal tissue damage compared with conventional irradiation (CONV-IR), this is known as the "FLASH effect." It has attracted immense research interest because its underlying mechanism is scarcely known. The purpose of this study was to determine whether FLASH-IR and CONV-IR induce differential inflammatory cytokine expression using a modified clinical linac. MATERIALS AND METHODS: An Elekta Synergy linac was used to deliver 6 MeV CONV-IR and modified to deliver FLASH-IR. Female FvB mice were randomly assigned to three different groups: a non-irradiated control, CONV-IR, or FLASH-IR. The FLASH-IR beam was produced by single pulses repeated manually with a 20-s interval (Strategy 1), or single-trigger multiple pulses with a 10 ms interval (Strategy 2). Mice were immobilized in the prone position in a custom-designed applicator with Gafchromic films positioned under the body. The prescribed doses for the mice were 6 to 18 Gy and verified using Gafchromic films. Cytokine expression of three pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukin-6 [IL-6]) and one anti-inflammatory cytokine (IL-10) in serum samples and skin tissue were examined within 1 month post-IR. RESULTS: The modified linac delivered radiation at an intra-pulse dose rate of around 1 × 106 Gy/s and a dose per pulse over 2 Gy at a source-to-surface distance (SSD) of 13 to 15 cm. The achieved dose coverage was 90%-105% of the maximum dose within -20 to 20 mm in the X direction and 95% within -30 to 30 mm in the Y direction. The absolute deviations between the prescribed dose and the actual dose were 2.21%, 6.04%, 2.09%, and 2.73% for 6, 9, 12, and 15 Gy as measured by EBT3 films, respectively; and 4.00%, 4.49%, and 2.30% for 10, 14, and 18 Gy as measured by the EBT XD films, respectively. The reductions in the CONV-IR versus the FLASH-IR group were 4.89%, 10.28%, -7.8%, and -22.17% for TNF-α, IFN-γ, IL-6, and IL-10 in the serum on D6, respectively; 37.26%, 67.16%, 56.68%, and -18.95% in the serum on D31, respectively; and 62.67%, 35.65%, 37.75%, and -12.20% for TNF-α, IFN-γ, IL-6, and IL-10 in the skin tissue, respectively. CONCLUSIONS: Ultra-high dose rate electron FLASH caused lower pro-inflammatory cytokine levels in serum and skin tissue which might mediate differential tissue damage between FLASH-IR and CONV-IR.

Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2.

BACKGROUND: The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social. The ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health and economic stability worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19. METHODS: We first established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus spike protein and its host receptor ACE2. Two compound libraries of 2,864 molecules were screened with this platform. Selected candidate compounds were validated by SARS-CoV-2_S pseudotyped lentivirus and ACE2-overexpressing cell system. Molecular docking was used to analyze the interaction between S protein and compounds. RESULTS: We identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S protein and the human cell ACE2 receptor. Additionally, tannic acid showed moderate inhibitory effect on the interaction of S protein and ACE2. CONCLUSION: This platform is a rapid, sensitive, specific, and high throughput system, and available for screening large compound libraries. TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug.

Individualized clinical target volume delineation and efficacy analysis in unilateral nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT): 10-year summary.

PURPOSE: To evaluate the long-term local control, failure patterns, and toxicities after individualized clinical target volume (CTV) delineation in unilateral nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). METHODS: Unilateral NPC was defined as a nasopharyngeal mass confined to one side of the nasopharynx and did not exceed the midline. From November 2003 to December 2017, 95 patients were retrospectively included. All patients received IMRT. The CTVs were determined based on the distance from the gross tumor. The contralateral para-pharyngeal space and skull base orifices were spared from irradiation. RESULTS: There were three local recurrences and eight regional recurrences in 10 patients during an 84-month follow-up. All local recurrences were within PGTVnx, and all in-field recurrences. No recurrences were found in traditional high-risk areas including contralateral the para-pharyngeal space and skull base orifices. The 10-year local-recurrence-free survival, regional-recurrence-free survival and overall survival were 96.2%, 90.5% and 84.7%, respectively. The dosimetry parameters of the tumor-contralateral organs were all lower than the values of the tumor-ipsilateral side (P < 0.05). The late toxicities occurred mainly in the tumor-ipsilateral organs, including radiation-induced temporal lobe injury, impaired visuality, hearing loss and subcutaneous fibrosis. CONCLUSION: Individualized CTV delineation in unilateral NPC could yield excellent long-term local control with limited out-of-field recurrences, reduced dose to tumor- contralateral organs and mild late toxicities, which is worthy of further exploration.

Radioprotective effect of X-ray abdominal FLASH irradiation: Adaptation to oxidative damage and inflammatory response may be benefiting factors.

BACKGROUND: Ultrahigh dose-rate irradiation (FLASH-IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still unclear. Besides, the FLASH experiments using high energy X-ray, the most common modality in clinical radiotherapy, are rarely reported. This study aims to investigate the radiobiological response using 6 MV X-ray FLASH-IR or conventional dose-rate IR (CONV-IR). METHODS: The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH-IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X-ray FLASH-IR or CONV-IR, the prescribed dose was 15 Gy or 10 Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post-IR to evaluate acute tissue responses or followed up for 6 weeks to observe late-stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed. RESULTS: The mean dose rate of >150 Gy/s and instantaneous dose rate of >5.5 × 105  Gy/s was reached in FLASH-IR at the center of mice body. After 6 weeks' follow-up of mice that received 15 Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH-IR induced less acute intestinal damage than CONV-IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro-inflammatory cytokine concentrations were elevated at the acute stage after both FLASH-IR and CONV-IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro-inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage. CONCLUSIONS: The radioprotective effect of 6 MV X-ray FLASH-IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH-IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.

Clinical target volume design of postoperative intensity-modulated radiotherapy for major salivary gland tumours according to surgical principles: an innovative method.

BACKGROUND: No international consensus has been reached regarding delineation of postoperative intensity-modulated radiotherapy (PO-IMRT) clinical target volumes (CTV) for major salivary gland carcinoma (SGC). The purpose of this article was to report our experience according to surgical principles. METHODS: Between June 2010 and June 2018, 54 consecutive patients were enrolled. Reserved tissues around the margin of resection that were less than 5 mm from the invasive tumour edge before surgery were defined as high-risk clinical target volumes (CTV-HD), those less than 10 mm away were defined as medium-risk CTV (CTV1), and those 10-20 mm away were defined as low-risk CTV (CTV2), and were irradiated with 63-65 Gy, 59.5-61 Gy, and 45-54 Gy, respectively. Target volume distributions of reserved tissues were analysed and actuarial estimates of overall survival (OS), recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were obtained with the Kaplan-Meier method. RESULTS: In parotid gland tumours, the percentages of defined CTV-HD in the styloid process, mandibular ramus, posterior venter of the digastric muscle, carotid sheath and stylomastoid foramen reached 34.29%, 25.71%, 54.29%, 40.00%, and 37.10%, respectively. The median follow-up was 33 months (range, 5-98 months). The 3-year and 5-year Kaplan-Meier estimates of OS, RFS and DMFS were 85.4% and 77.8%, 97.4%, and 97.4%, and 82.0% and 82.0%, respectively. CONCLUSIONS: It is feasible to delineate CTVs according to distances between various reserved tissues and the primary tumour edge before operation.

MMP12 knockout prevents weight and muscle loss in tumor-bearing mice.

BACKGROUND: Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12-/- mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12-/- mice on a weekly basis, their weight were not significantly different from those of WT mice. METHODS: ApcMin/+; MMP12-/- mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 -/-) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. RESULTS: MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. CONCLUSIONS: MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.

Efficacy of concurrent chemoradiotherapy in subgroups of stage III nasopharyngeal carcinoma: an analysis based on 10-year follow-up.

PURPOSE: To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) in subgroups of stage III nasopharyngeal carcinoma (NPC) in the context of intensity-modulated radiotherapy (IMRT). METHODS: A total of 272 patients with stage III NPC who underwent IMRT with or without concurrent chemotherapy were retrospectively reviewed. Clinicopathological features were evaluated by a Cox regression model to identify independent prognostic factors. Survival outcomes were assessed using the Kaplan-Meier method and log-rank test. RESULTS: The median follow-up time was 108 months. The 10-year locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 87.8%, 80.7%, 68.8%, and 74.9%, respectively. Multivariate analysis showed that the N classification was significantly associated with DMFS (hazard ratio [HR] 3.616, 95% confidence interval [CI] 1.387-9.428, P = 0.009), DFS (HR 2.417, 95% CI 1.291-4.423, P = 0.006), and OS (HR 3.024, 95% CI 1.385-6.602, P = 0.005). In patients with T1-3N2 disease, CCRT was associated with improved 10-year LRFS (89.6% vs. 65.4%, P = 0.005), DFS (71.9% vs. 39.4% P = 0.001) and OS (80.0% vs. 50.5%, P = 0.004) compared with IMRT alone. However, in patients with T3N0-1 disease, no significant survival differences were observed between patients treated with IMRT alone and CCRT (P > 0.05). CONCLUSIONS: CCRT is an effective therapy in stage III NPC, especially for patients with N2 disease, but IMRT alone may be adequate for N0-1 disease. Individualized treatment strategies are essential for patients with varying disease risks.

Postponing tumor onset and tumor progression can be achieved by alteration of local tumor immunity.

BACKGROUND: It has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their life spans with unknown mechanisms. METHODS: We used a MMTV-PyMT mouse model with different genetic backgrounds (FVB/NJ vs. C57BL/6J) to generate different cancer onset phenotypes, then profiled and analyzed the gene expression of three tumor stages in both Fvb.B6 and Fvb mice to explore the underlying mechanisms. RESULTS: We found that in contrast with the FVB/N-Tg (MMTV-PyMT) 634Mul mice (Fvb mice), mammary tumor initiation was significantly delayed and tumor progression was significantly suppressed in the Fvb.B6 mice (generated by crossing FVB/NJ with C57BL/6J mice). Transcriptome sequencing and analysis revealed that the differentially expressed genes were enriched in immune-related pathways. Flow cytometry analysis showed a higher proportion of matured dendritic cells in the Fvb.B6 mice. The plasma levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) were significantly reduced in the Fvb.B6 mice. IL-6 also impaired the maturation of bone marrow dendritic cells (BMDCs) of the Fvb mice in vitro. CONCLUSION: All these findings suggest that immunity levels (characterized by a reduced IL-6 level and intact DC maturation in Fvb.B6 mice) are the key factors affecting tumor onset in a murine mammary cancer model.

Is Surgery an Inevitable Treatment for Advanced Salivary Lymphoepithelial Carcinoma? Three Case Reports.

Lymphoepithelial carcinoma (LEC) of the salivary gland is a rare malignancy which is identical to undifferentiated nasopharyngeal carcinoma. However, most patients are treated with surgery as primary treatment, which is impossible for some very locoregionally advanced patients. And there are few reports of patients treated by an induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) approach. This report describes 3 cases of advanced stage LEC of the salivary gland. All patients presented with a palpable mass of variable duration and underwent induction CCRT. All cases were positive for Epstein-Barr virus-encoded small RNAs. After IC, all cases had reached partial response and all achieved complete response after CCRT. All patients remained local-regional recurrence-free after 6-month follow-up for case 1, 50-month for case 2, and 14-month for case 3 up to our last follow-up. No serious adverse events were found.

LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival.

Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.

Failure patterns and prognostic factors for cervical node-negative nasopharyngeal carcinoma in the intensity-modulated radiotherapy era.

BACKGROUND: To evaluate the failure patterns and prognostic factors in patients with cervical node-negative nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. METHODS: Patients with cervical node-negative NPC treated with IMRT at the Sun Yat-sen University Cancer Center between February 2001 and December 2008 were retrospectively reviewed. The failure patterns, prognostic factors, and efficacy of additional chemotherapy were assessed. RESULTS: The median follow-up time was 78 months for 298 patients. The 5-year local recurrence-free survival (LRFS), nodal recurrence-free survival (NRFS), distant metastasis-free survival (DMFS), failure-free survival (FFS), and overall survival (OS) were 95.2%, 99.3%, 94.8%, 89.8%, and 92.9%, respectively. The rate of treatment failure remained high in patients with T4 disease (35.4%, 17/48), including eight of local recurrence, two of nodal recurrence, and seven of distant metastasis. Multivariate analyses showed that the primary gross tumor volume (GTVp) was significantly associated with LRFS, DMFS, FFS, and OS. Subgroup analysis revealed that patients with GTVp ≤ 42.5 cc had better 5-year LRFS (98.7% vs 81.4%, P < .001), 5-year DMFS (97.8% vs 82.5%, P < .001), 5-year FFS (96.1% vs 65.4%, P < .001), and 5-year OS (96.6% vs 78.2%, P < .001) than patients with GTVp > 42.5 cc. However, additional chemotherapy showed no significant survival benefit in stratification analysis. CONCLUSIONS: Cervical node-negative NPC has a good prognosis in the IMRT era, and the primary tumor volume is the most important prognostic factor. Further exploration is needed to determine the optimal treatment strategy for patients with a high tumor burden.