Effect of immune-modulating metronomic capecitabine as an adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma.

INTRODUCTION: Metronomic capecitabine used as an adjuvant therapy improves survival in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This therapeutic approach may also contribute to improving immune function, consequently enhancing overall therapeutic efficacy. AIM: We aimed to evaluate the effect of metronomic capecitabine as adjuvant therapy on immune function and survival in cases of LA-NPC. SUBJECTS AND METHODS: 28 patients with LA-NPC were enrolled in the study and equally assigned to two groups of 14 each: experimental and control group. The experimental group received induction chemotherapy + concurrent chemotherapy + adjuvant chemotherapy as well as oral capecitabine at a dose of 650 mg/m² of body surface area twice daily for 1 year, with the option to discontinue in case of intolerance. The control group did not receive additional chemotherapy or targeted drugs after the induction chemotherapy + concurrent chemoradiotherapy; however, they were followed up regularly. Changes in immune function and survival were compared between the two groups. RESULTS: The median follow-up time was 43.5 months. One year after adjuvant chemotherapy, the experimental group showed higher levels of CD8 + cells, CD28 + CD8 + cells, and activated CD8 + cells compared to the control group (P < 0.05). The CD4/CD8 ratio and proportion of monocyte-derived dendritic cells were also higher in the experimental group than in the control group, but the difference was not statistically significant (P ≥ 0.05). Comparisons of 3-year overall survival, local-regional recurrence-free survival, progression-free survival, and distant metastasis-free survival between the two groups showed percentages of 92.9% vs. 78.6%, 92.9% vs. 92.9%, 78.6% vs. 71.4%, and 85.7% vs. 0.78 0.6% respectively, but these differences were not significant (P > 0 0.05 ). CONCLUSION: Metronomic capecitabine chemotherapy was observed to induce an immunomodulatory effect in LA-NPC. TRIAL REGISTRATION: NCT02958111, date of registration 04-11-2016.

The circadian clock gene, BMAL1, promotes radiosensitization in nasopharyngeal carcinoma by inhibiting the epithelial-to-mesenchymal transition via the TGF-ß1/Smads/Snail1 axis.

Acquired radio-resistance is thought to be one of the main causes of recurrent metastasis after failure of nasopharyngeal carcinoma (NPC) radiotherapy, which may be related to X-ray-induced epithelial-mesenchymal transition (EMT) activation. The circadian clock gene, BMAL1, has been shown to correlate with the sensitivity of NPCs to radiotherapy, but the specific mechanism has not been reported. NPC cells were irradiated by conventional fractionation to generate radiotherapy-resistant cells. NPC cells with BMAL1 gene stabilization/overexpression and interference were obtained by lentiviral transfection. Western blotting, colony formation analysis, cell counting kit-8 assays, wound-healing tests, Transwell assays, flow cytometry, the EDU method, nuclear plasma separation experiments, HE staining, immunohistochemical staining and TUNEL staining were performed to explore the influence and molecular mechanism of the circadian clock gene, BMAL1, on NPC-acquired radio-resistance and EMT through in vitro and in vivo experiments. The results indicated that there was a gradual downregulation of BMAL1 gene protein expression during the routine dose induction of radio-resistance in NPC cells. EMT activation was present in the radiation-resistant cell line 5-8FR, and was accompanied by the significant enhancement of proliferation, migration and invasion. The BMAL1 gene significantly increased the radiosensitivity of the radiation-resistant cell line 5-8FR and reversed the acquired radio-resistance of NPCs, which was accomplished by inhibiting the TGF-ß1/Smads/Snail1 axis-mediated EMT.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in locally advanced nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy: a retrospective study with a 5-year follow-up.

Purpose: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods and materials: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at Guizhou Cancer Hospital. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a "MELODIE" multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n=35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusion: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Dickkopf-1 is an immune infiltration-related prognostic biomarker of head and neck squamous cell carcinoma.

Immunotherapy is currently one of the most viable therapies for head and neck squamous cell carcinoma (HNSCC), characterized by high immune cell infiltration. The Wnt-signaling inhibitor and immune activation mediator, Dickkopf-1 (DKK1), has a strong correlation with tumor growth, tumor microenvironment, and, consequently, disease prognosis. Nevertheless, it is still unclear how DKK1 expression, HNSCC prognosis, and tumor-infiltrating lymphocytes are related. To better understand these associations, we examined how DKK1 expression varies across different tumor and normal tissues. In our study, we investigated the association between DKK1 mRNA expression and clinical outcomes. Next, we assessed the link between DKK1 expression and tumor immune cell infiltration. Additionally, using immunohistochemistry, we evaluated the expression of DKK1 in 15 healthy head and neck tissue samples, and the expression of CD3, CD4, and DKK1 in 27 HNSCC samples. We also explored aberrant DKK1 expression during tumorigenesis. DKK1 expression was remarkably higher in HNSCC tissues than in healthy tissues, and was shown to be associated with tumor stage, grade, lymph node metastasis, histology, and a dismal clinical prognosis in HNSCC. DKK1 expression in HNSCC tissues was inversely correlated with CD3+ (P < 0.0001) and CD4+ (P < 0.0001) immune cell infiltration, while that in immune cells was inversely associated with HNSCC prognosis. These findings offer a bioinformatics perspective on the function of DKK1 in HNSCC immunotherapy and provide justification for clinical research on DKK1-targeted HNSCC treatments. DKK1 is a central target for improving the efficacy of HNSCC immunotherapy.

Association between PT, PT-INR, and in-hospital mortality in critically ill patients with tumors: A retrospective cohort study.

Objectives: Prothrombin time (PT) and PT-INR are independent predictors of mortality in patients with cancer. The PT and PT-INR of cancer patients are independent predictive variables of mortality. However, whether the PT or PT-INR is related to in-hospital mortality in severely ill patients with tumors remains unknown. Design: This was a case-control study based on a multicenter public database. Settings: This study is a secondary analysis of data extracted from 2014 to 2015 from the Electronic Intensive Care Unit Collaborative Research Database. Participants: The data relevant to seriously ill patients with tumors were obtained from 208 hospitals spread throughout the USA. This research included a total of 200,859 participants. After the samples were screened for patients with combination malignancies and prolonged PT-INR or PT, the remaining 1745 and 1764 participants, respectively, were included in the final data analysis. Primary and secondary outcome measures: The key evaluation methodology was the PT count and PT-INR, and the main outcome was the in-hospital mortality rate. Results: After controlling for confounding variables, we found a curvilinear connection between PT-INR and in-hospital mortality (p < 0.001), and the inflection point was 2.5. When PT-INR was less than 2.5, an increase in PT-INR was positively associated with in-hospital mortality (OR 1.62, 95% CI 1.24 to 2.13), whereas when PT-INR was greater than 2.5, in-hospital mortality was relatively stable and higher than the baseline before the inflection point. Similarly, our study indicated that the PT exhibited a curvilinear connection with in-hospital mortality. On the left side of the inflection point (PT <22), a rise in the PT was positively linked with in-hospital mortality (OR 1.08, 95% CI 1.04 to 1.13, p < 0.001). On the right side of the inflection point, the baseline PT was above 22, and the in-hospital mortality was stable and higher than the PT count in the prior range (OR 1.01, 95% CI 0.97 to 1.04, 0.7056). Conclusion: Our findings revealed that there is a curved rather than a linear link between the PT or PT-INR and in-hospital mortality in critically ill cancer patients. When these two laboratory results are below the inflection point, comprehensive therapy should be employed to reduce the count; when these two laboratory results are above the inflection point, every effort should be made to reduce the numerical value to a value below the inflection point.

Circadian clock gene BMAL1 inhibits the proliferation and tumor-formation ability of nasopharyngeal carcinoma cells and increases the sensitivity of radiotherapy.

BMAL1 is a core circadian clock gene that is expressed rhythmically in a variety of tumor cells and is related to cancer cell proliferation and chemoradiotherapy sensitivity. Radiotherapy plays an important role in the treatment of nasopharyngeal carcinoma (NPC). However, the rhythmicity of BMAL1 in NPC, as well as its precise role in radiotherapy, remains unclear. We assessed changes in BMAL1 expression over 48 h in NPC cells and normal nasopharyngeal epithelial cells NP69 using real-time quantitative polymerase chain reaction (RT-PCR) and western blotting (WB). Then, we induced the overexpression and knocked-down the levels of BMAL1 in NPC cells, and subsequently used Cell Counting Kit-8 assays to assess the proliferation of NPC cells. Xenograft tumour growth was used to evaluate the effect of BMAL1 in vivo. Immunohistochemical staining was used to detect the expression of BMAL1 protein in transplanted tumors. Gene Set Enrichment Analysis (GSEA) was performed to explore the biological signaling pathway. Finally, RT-PCR and WB were used to detect the expressions of BMAL1, p53 and p21. The results showed that the mRNA expression levels of circadian clock gene BMAL1 fluctuated rhythmically with time, and the expression levels of BMAL1 also changed depending on the protein levels in NPC and NP69 cells. Overexpression of BMAL1 inhibited the proliferation of NPC cells, while knockdown BMAL1 had the opposite effects. In a xenograft model, we observed that the upregulation of BMAL1 inhibited tumor growth and enhanced the sensitivity of NPC cells to radiotherapy. Ultimately, the downregulation of BMAL1 promoted tumor growth and decreased radiosensitivity. GSEA analysis suggested that BMAL1 significantly affected the p53 pathway. Overexpression of BMAL1 promoted the expression of p53 and p21, while the knockdown of BMAL1 inhibited the expression of p53 and p21. We speculate that BMAL1 has the potential to be a prognostic biomarker and therapeutic target for NPC.

The Treatment Combining Antiangiogenesis with Chemoradiotherapy Impinges on the Peripheral Circulation Vascular Endothelial Cells and Therapeutic Effect in the Patients with Locally Advanced Nasopharyngeal Carcinoma.

This study was implemented for the evaluation on the circulating endothelial cells' (CECs) clinical significance in the locally advanced nasopharyngeal carcinoma treatment with endostatin-combined chemoradiotherapy. This study enrolled 47 patients with locally advanced nasopharyngeal carcinoma who were hospitalized from May 9, 2012 to March 10, 2013. These patients were split up into the observation group (25 patients) and control group (22 patients). Patients in the observation group received the endostatin combined with induction chemotherapy and subsequently with concurrent chemoradiotherapy with endostatin. Patients in the control group were treated with inductive chemotherapy followed by concurrent chemoradiotherapy. CECs in peripheral blood were conducted separately before or after inductive chemotherapy and additionally in the end of concurrent chemoradiotherapy. The CEC values of the observation group showed significant statistical differences (p < 0.05) before or after different therapies, whereas those data in the control group were not statistically different. And, the mostly importantly, the CEC values in the observation group and control group turned out a statistical difference. The combination of endostatin and chemoradiotherapy significantly reduced parameters of peripheral blood CECs in these patients. According to the CEC parameters' variety that we observed in the combined therapies, this study demonstrated that the CECs might be a clinical clue to evaluate this antiangiogenic chemoradiotherapy. And the clinical value of CECs will be further determined along with increasing comparative studies and clinical long-term efficacy observation.

Association between platelets and in-hospital mortality in critically ill patients with tumours: a retrospective cohort study.

OBJECTIVES: Platelet count is an independent predictor of mortality in patients with cancer. It remains unknown whether the platelet count is related to in-hospital mortality in severely ill patients with tumours. DESIGN: A retrospective study based on a dataset from a multicentre cohort. SETTING: This was a secondary analysis of data from one Electronic Intensive Care Unit Collaborative Research Database survey cycle (2014-2015). PARTICIPANTS: The data pertaining to severely ill patients with tumours were collected from 208 hospitals located across the USA. This study initially a total of 200 859 participants. After the population was limited to patients with combined tumours and platelet deficiencies, the remaining 2628 people were included in the final data analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The main measure was the platelet count, and the main outcome was in-hospital mortality. RESULTS: After adjustment for the covariates, the platelet count had a curvilinear relationship with in-hospital mortality (p<0.001). The first inflection point was 18.4 (per 10 change). On the left side of the first inflection point (platelet count ≤184 'x10ˆ9/L), an increase of 10 in the platelet count was negatively associated with in-hospital mortality (OR 0.92, 95% CI 0.89 to 0.95, p<0.001). The second inflection point was 44.5 (per 10 change). Additional increases of 10 in the platelet count thereafter were positively associated with hospital mortality (OR 1.13, 95% CI 1.00 to 1.28, p=0.0454). The baseline platelet count was in the range of 184 'x10ˆ9/L-445 'x10ˆ9/L(p=0.0525), and the hospital mortality was lower than the baseline platelet count in other ranges. CONCLUSIONS: The relationship between platelet count and in-hospital mortality in critically ill patients with tumours was curvilinear. The lowest in-hospital mortality was associated with platelet count between 184 'x10ˆ9/Land 445 'x10ˆ9/L. This indicates that both high and low platelet count should receive attention in clinical practice.

[Clinical results of recombinant human endostatin combined with chemoradiotherapy for locally advanced nasopharyngeal carcinoma].

OBJECTIVE: To compare the short-term efficacy and observe the tolerability and safety of recombinant human endostatin combined with induction chemotherapy followed by chemoradiotherapy for locally advanced nasopharyngeal carcinoma. METHODS: Fifty-three patients with locally advanced nasopharyngeal carcinoma, who received recombinant human endostatin combined with induction chemotherapy followed by chemoradiotherapy, treated in our department from December 2011 to March 2013 were included in the study group of this study. Another 48 patients, who received induction chemotherapy followed by chemoradiotherapy alone in the same period, were chosen as a control group. The short-term outcome, overall survival (OS), progression-free survival (PFS), and acute side effects of the two groups were compared. RESULTS: The complete remission rates of nasopharyngeal tumor in the study and control groups were 77.4% and 72.9%, respectively (P=0.154). The complete remission rates of patients with and without cervical lymph node metastasis were 75.5% and 62.6%, respectively, showing a significant difference (P=0.037). The 2-year OS, PFS, and DMFS rates for the study group were 82.3%, 77.2%, and 82.2%, respectively, versus 87.2%, 84.3% and 84.2% for the control group, showing a non-significant differences between the two groups (P=0.938, P=0.551, and P=0.725). CONCLUSIONS: The short-term results of recombinant human endostatin (Endostar) combined with induction chemotherapy followed by concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma are slightly better than that of induction chemotherapy followed by concurrent chemoradiotherapy alone, with tolerable treatment-related toxicity and no more side effects.

[Phase II clinical trial of two different modes of administration of the induction chemotherapy for locally advanced nasopharyngeal carcinoma].

OBJECTIVE: To compare the therapeutic effects, toxic side effects and influence on the immune function in patients treated with TPF [docetaxel (DOC) + cisplatin (DDP) + 5-fluorouracil (5-Fu)] induction chronochemotherapy and conventional chemotherapy for locally advanced nasopharyngeal (NPC). METHODS: Seventy patients with locally advanced nasopharyngeal carcinoma were treated in our department at their first visit from April 2013 to December 2013. They were divided randomly into two groups: the chronochemotherapy group (38 patients) and conventional chemotherapy group (32 patients). All of the patients were treated with TPF regimen with 2 cycles of induction chemotherapy in a 21-28-days/cycle. The chronochemotherapy group: DOC: 75 mg/m2, i. v. gtt, d1 (03: 30-04: 30); DDP: 75 mg/m2, 10 am-10 pm, c.i.v, d1-d5; 5-Fu: 750 mg·m(-2)·d(-1), 10 pm-10 am, c. i.v., d1-d5, both chemotherapies were administered by intravenous infusion using an automatic electric pump. The conventional chemotherapy group: Both DOC and DDP were administered intravenously at a dose of 75 mg/m2 on d1. 5-Fu was given at a dose of 750 mg/m2 for 24 hours from d1-d5 with continuous infusion in a total of 120 hours. In this procedure, prescribing the conventional intravenous infusion, intensity modulated radiation therapy was used after the induction chemotherapy. The prescribed nasopharyngeal lesion dose (GTVnx) was 69.96 Gy/33 fractions for the T1-T2 nasopharygeal cancer, while 73.92 Gy/33 fractions nasopharynx lesion dose (GTVnx) for the T3-T4 nasopharyngeal cancer. The planning target volume (PTV) of positive lymph node (PTVnd) dose was 69.96 Gy/33 fractions. Concurrent chemoradiotherapy: cisplatin 100 mg/m2, i. v. gtt. d1-d2, and there were two cycles in total and 21 days each cycle. RESULTS: Sixty-six patients were evaluable for the response assessment. There were 36 patients in the chronochemotherapy group and 30 patients in the conventional chemotherapy group. After the induction chemotherapy, no CR case was found in both of the two groups. The PR was 80.6% in the chronochemotherapy group and 50.0% in the conventional chemotherapy group (P=0.009). After concurrent chemoradiotherapy, the CR rate in the chronocheotherapy group was 45.5%, significantly higher than 20.7% in the conventional chemotherapy group (P=0.040). Secondly, the incidence rates of adverse reactions including bone marrow suppression, nausea, vomiting, diarrhea, constipation, oral mucositis, fatigue, anorexia in the chrono-chemotherapy group were significantly lower than that in the conventional group (P<0.05 for all). Finally, compared the two groups, the CD4+ /CD8+ ratio was significantly lower in the chronochemotherapy group than that in the conventional chemotherapy group (P<0.05). The lymphocytes CD19+ and CD4+/CD8+ were decreased and CD3+, CD4+, CD8+, CD16++CD56+ were increased in the chronochemotherapy group, while only CD3+ and CD8+ were increased in the conventional chemotherapy group. CONCLUSIONS: Compared with the conventional chemotherapy, the chronochemotherapy may be more favorable in the treatment of NPC, with a better therapeutic effects and effectiveness than that of conventional chemotherapy after induction chemotherapy, with less side effects, and can improve the immune function in the patients.

Expressions of CD147, MMP-2 and MMP-9 in laryngeal carcinoma and its correlation with poor prognosis.

The objectives of this study are to investigate the expressions of matrix metalloproteinase inducing factor (CD147), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) in laryngeal tumor tissues and its significant correlation with tumor infiltration, metastasis and prognosis. Laryngeal tumor tissue from 48 laryngeal cancer patients with complete clinical information was collected. The laryngitis tissue from 15 patients were collected as control group. Immunohistochemical analysis for CD147, MMP-2 and MMP-9 was performed for all the tissue. The results showed the expression rates of CD147, MMP-2 and MMP-9 in laryngeal carcinoma were 87.5 %, 75.0 % and 79.2 % respectively, significantly higher than those (26.7 %, 6.7 %, and 33.3 % respectively) in the control group are (P < 0.01). High expression of CD147, MMP-2 and MMP-9 related to the clinical stages and lymphatic metastasis of laryngeal carcinoma. Univariate survival analysis showed that the 5-year survival of laryngeal carcinoma patients with low expression of CD147, MMP-2 and MMP-9was 83.3 %, 83.3 % and 90 % respectively, while the patients with high expression had 5-year survival at 25 %, 7.7 % and 18.2 % respectively (P < 0.05). Multiple regression analysis showed that high expression of MMP-9 was independently associated with poor prognosis (P < 0.05). High expression of CD147, MMP-2 and MMP-9 were related with laryngeal carcinoma invasion and metastasis. High expressions of CD147, MMP-2 and MMP-9 were all predictive factors of poor prognosis of laryngeal carcinoma.