Phase II Study of Gemcitabine, Peg-Asparaginase, Dexamethasone and Methotrexate Regimen for Newly Diagnosed Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Final Analysis With Long-Term Follow-Up and Rational Research for the Combination.

Patients with extranodal natural killer/T-cell lymphoma (ENKTL), nasal type are benefit from peg-asparaginase, gemcitabine, and methotrexate. Therefore, we conducted a prospective phase II trial using a combination of these drugs as GAD-M regimen in naïve ENKTL patients, simultaneously, explored the combinational mechanism. The GAD-M regimen was administered for 6 cycles sandwiched by radiotherapy for stage I/II and 6 cycles for stage III/IV patients. After 6 cycles, the overall response rate of 36 patients was 91.6%, and the complete remission rate increased to 83.3%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 74.8% and 77.8%, respectively. The 5-year PFS and OS were 68.3% and 77.8%. No patient suffered from the central nervous system (CNS) relapse. Most patients experienced recoverable liver dysfunction and anemia in this study. The plasma MTX concentration ratio at 12 to 24 hr during the first cycle could be an early predictor of outcomes in ENKTL (PFS, P=0.005; OS, P=0.002). Additionally, we found that high dose MTX (HD-MTX) and gemcitabine had the synergistic effect of ENKTL cell in vitro. Mechanistically, we demonstrated that the combination could lead to obviously apoptosis in ENKTL cell with extremely release of reactive oxygen spices (ROS), which mediated by endoplasmic reticulum stress. In conclusion, the GAD-M regimen could be a new choice to newly diagnosed ENKTL, especially for stage I/II patients. Furthermore, our results showed the synergy effect of HD-MTX with gemcitabine in ENKTL. CLINICAL TRIAL REGISTRATION: This trial was registered at www.clinicaltrials.gov as #NCT01991158.

The beneficial effect of Escalated-R-CHOP-21 for the treatment of diffuse large B-cell lymphoma in elderly male patients: A propensity-matched cohort study.

PURPOSE: Some studies have indicated that using 500 mg/m2 rituximab combined with CHOP-14 may be beneficial for elderly men but not women with diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to investigate the potential benefit of escalated doses of rituximab with CHOP-21 as the first-line treatment in male patients with DLBCL. METHODS: We performed a retrospective cohort study to analyze the survival benefit of rituximab 500 mg/m2 plus the CHOP-21 regimen (Escalated-R-CHOP-21) as the first-line treatment compared with using rituximab 375 mg/m2 plus the CHOP-21 regimen (Standard-R-CHOP-21) in men with DLBCL. We used propensity score matching to maximize the balance of the observed covariables. The primary endpoints of this study were the progression-free survival (PFS) rate and overall survival (OS) rate at 3 years. RESULTS: After a median follow-up of 47 months (IQR 31-65), no significant difference in PFS and OS was found for men treated with Escalated-R-CHOP-21 compared with Standard-R-CHOP-21 [3-year PFS: 69.7% versus 71.9%, p = 0.867; 3-year OS: 83.0% versus 82.4%, p = 0.660]. After 1:1 propensity score matching, we found that the patients using Escalated-R-CHOP-21 had statistically significant survival benefits relative to Standard-R-CHOP-21 among the 96 matched elderly male patients for 3-year PFS [75.5% (95% CI 62.8-88.2) versus 58.2% (95% CI 44.3-72.1); p = 0.019] and 3-year OS [86.6% (95% CI 76.4-96.8) versus 65.8% (95% CI 52.1-79.5); p = 0.017]. However, no differences in survival were observed for younger male patients. Furthermore, the dose effect in PFS of Escalated-R-CHOP-21 was more obvious for elderly male patients with no high-risk extranodal sites (p = 0.005 and interaction p = 0.030). CONCLUSION: Escalated-R-CHOP-21 could be a safe and effective option for treating elderly male patients with DLBCL. This study provides new insight into optimizing the standard treatment regimen, which may have important therapeutic implications in elderly male patients with DLBCL.

PFKFB4 Overexpression Facilitates Proliferation by Promoting the G1/S Transition and Is Associated with a Poor Prognosis in Triple-Negative Breast Cancer.

BACKGROUND: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphate-4 (PFKFB4) is a key factor that plays an important role in tumorigenesis. However, its role in triple-negative breast cancer (TNBC) progression needs to be further validated. We investigated whether PFKFB4 is directly involved in the oncogenic signaling networks of TNBC. METHODS: First, we assessed the expression level of PFKFB4 in tumor tissue specimens by immunohistochemistry and evaluated its prognostic value. Next, the effect of PFKFB4 on TNBC cell growth and associated mechanisms were investigated. Finally, the results were further verified in vivo. RESULTS: We found that PFKFB4 overexpression was associated with an unfavorable prognosis in TNBC patients. PFKFB4 was overexpressed in TNBC cell lines in hypoxic environments, and its overexpression promoted tumor progression in vitro and in vivo. Further analyses demonstrated that the possible mechanism might be that PFKFB4 overexpression facilitates TNBC progression by enhancing the G1/S phase transition by increasing the protein level of CDK6 and phosphorylation of Rb. CONCLUSIONS: These data suggest that PFKFB4 plays significant roles in the tumorigenesis and development of TNBC.

Bortezomib in combination with fludarabine plus cyclophosphamide for patients with relapsed or refractory mantle-cell lymphoma: results of the LYM-4003 study.

This study aimed to identify the maximum-tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine (B-FC) in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL (rrMCL). Forty patients were enrolled between April 8, 2011, and October 10, 2015. The MTD of cyclophosphamide was identified to be 250 mg/m2 days 1-2. At a median follow-up of 31.6 months (13.5-47.4), among 32 patients in phase 2, 10 (31%) had a complete response and 13 (41%) had a partial response. The median progression-free survival was 21 months (95% CI 7.3-34.7), and the median overall survival was 32.4 months (95% CI 17.8-47.0). Grade 3-4 hematologic AEs included neutropenia (27%) and thrombocytopenia (39%). The B-FC regimen has satisfactory responses and manageable toxicities in rrMCL patients (ClinicalTrials.gov NCT01322776).

R-split-EPOCH plus high dose methotrexate in untreated diffuse large B cell lymphoma with MYC rearrangement or double expression of MYC and BCL-2.

Purpose: Diffuse large B cell lymphoma (DLBCL) with MYC rearrangement or double expression of MYC and BCL-2 (DE DLBCL) has a relatively poor prognosis and does not respond well to standard R-CHOP. In the current study, we aimed to investigate the efficacy and safety of R-split-EPOCH plus high dose methotrexate (HD-MTX) in the particular patient population. Methods: A total of 28 patients diagnosed with DE DLBCL or DLBCL with MYC rearrangement between January 2015 and December 2018 were included and retrospectively analyzed. All the participants underwent R-split-EPOCH plus HD-MTX as introduction therapy, with split infusion of etoposide, doxorubicin, and vincristine for 48 hours on D1-2 and D10-11, respectively. Results: The overall objective response (ORR) rate was 100%, with 24 (85.7%) complete response (CR) and 4 (14.3%) partial response (PR). The CR rate was 76.9% and 93.3% for DLBCL patients with MYC rearrangement and DE DLBCL patients, respectively. The 1- and 3-year PFS rate was 100% and 74.9%, respectively. The 1- and 3-year OS rate was 100% and 92.9%, respectively. Grade 3/4 non-hematological toxicity and grade 3/4 hematological toxicity occurred in 50% and 85.7% of patients, respectively. No treatment-related death was reported. Conclusions: R-split-EPOCH plus HD-MTX regimen is an effective and feasible treatment option for DE DLBCL and DLBCL with MYC rearrangement.

Re-instatement of Sorbus harrowiana (Rosaceae), based on morphometric analysis.

Sorbus harrowiana (≡Pyrus harrowiana), previously considered a synonym of Sorbus insignis (≡Pyrus insignis) in the Flora of China, is re-instated here and shown to be distinct from S. insignis, based on morphometric analysis, coupled with herbarium and field investigation. We also present for the first-time full descriptions, distributional records and notes for S. harrowiana and S. insignis.

ANGPTL4 overexpression inhibits tumor cell adhesion and migration and predicts favorable prognosis of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) patients have relatively poor clinical outcomes. A marker predicting the prognosis of patients with TNBC could help guide treatment. Extensive evidence demonstrates that angiopoietin-like 4 (ANGPTL4) is involved in the regulation of cancer growth, metastasis and angiogenesis. Therefore, its role in TNBC is of interest. METHODS: We tested the ANGPTL4 expression level in tumor tissues by immunohistochemistry (IHC) and detected its association with the clinical features of TNBC patients. Next, the effects and mechanisms of ANGPTL4 on TNBC cell migration and adhesion were investigated. RESULTS: We found that ANGPTL4 overexpression was associated with favorable outcomes in TNBC patients. ANGPTL4 upregulation inhibited cell adhesion, migration and invasion in vitro. Further analyses demonstrated that the possible mechanism might involve suppression of TNBC progression by interacting with extracellular matrix-related genes. CONCLUSIONS: The present findings demonstrated that enhancement of ANGPTL4 expression might inversely correlate with TNBC progression. ANGPTL4 is a promising marker of TNBC and should be evaluated in further studies. TRIAL REGISTRATION: Retrospectively registered.

Expression of PD-L1 on Monocytes Is a Novel Predictor of Prognosis in Natural Killer/T-Cell Lymphoma.

Background: Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive lymphoma with a dismal prognosis, and novel therapeutic targets are urgently needed. Programmed death-ligand 1 (PD-L1) has become a promising therapeutic target for various cancers, but most of the studies have focused on expression of PD-L1 on tumor cells. Expression of PD-L1 on tumor-infiltrating non-malignant cells, especially monocytes, has not been studied in NKTCL, and its prognostic value remains unknown. Materials and Methods: Expression of PD-L1 on tumor-infiltrating stromal cells was measured in NKTert and HS5 cells when cultured alone or co-cultured with NKTCL cell lines. Clinical samples were collected from 42 patients with newly diagnosed NKTCL. Expression of PD-L1 on monocytes was analyzed in patients' peripheral blood and tumor tissues using flow cytometry and immunofluorescent staining, respectively. Survival data were retrospectively collected and the prognostic significance of PD-L1 expression on monocytes was analyzed. Results: PD-L1 expression on tumor-infiltrating stromal cells was remarkably elevated when co-cultured with NKTCL cells. The percentage of PD-L1+ monocytes among all monocytes in peripheral blood was significantly higher in NKTCL patients than that in healthy individuals. Among NKTCL patients, percentage of PD-L1+ monocytes in blood positively correlated with that in tumor tissues. Patients with a higher percentage (≥78.2%) of PD-L1+ monocytes in blood or with a higher percentage (≥24.2%) of PD-L1+ monocytes in tumor tissues exhibited a significantly inferior survival, compared with their counterparts. A higher percentage of PD-L1+ monocytes in blood or tumor tissues was an independent adverse prognostic factor. Conclusions: Expression of PD-L1 on monocytes is up-regulated and has significant prognostic value in patients with NKTCL.

Aurora B induces epithelial-mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis.

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3ß to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3ß/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3ß/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3ß/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.

Metronomic combination chemotherapy using everolimus and etoposide for the treatment of non-Hodgkin lymphoma.

Patients with Non-Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP-16) alone and that of MCC using both VP-16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI-LY-10 and SU-DHL-6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low-dose VP-16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP-16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy-related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP-16 48 hours + RAD001 24 hours is the optimal method for treating NHL.

Characteristics, Prognostic Factors, and Survival of Patients with NK/T-Cell Lymphoma of Non-upper Aerodigestive Tract: A 17-Year Single-Center Experience.

PURPOSE: The extranodal natural killer (NK)/T-cell lymphoma (NKTCL) of non-upper aerodigestive tract (NUAT) was found to have clinical heterogeneity compared with NKTCL of the upper aerodigestive tract (UAT) in small scale studies. We conducted this study in a much larger cohort to analyze the clinical characteristics, prognostic factors, treatment modality, and clinical outcomes of patients with NUAT-NKTCL. MATERIALS AND METHODS: From January 2001 to December 2017, a total of 757 NKTCL patients were identified and included in this study, including 92 NUAT-NKTCL patients (12.2%) and 665 UAT-NKTCL patients (87.8%). RESULTS: NUAT-NKTCL patients had relatively poorer performance status, more unfavorable prognostic factors, and more advanced stage, compared with UAT-NKTCL patients. The 5-year overall survival (OS) was 34.7% for NUAT-NKTCL, which was significantly worse than UAT-NKTCL (64.2%, p<0.001). The median OS duration was 30.9 months for NUAT-NKTCL. Multivariate analysis showed that presence with B symptoms and elevated serum lactate dehydrogenase independently predicted worse OS. International prognostic index score and prognostic index of natural killer lymphoma score still had prognostic values in NUAT-NKTCL, while the Ann Arbor system could not accurately predict the OS. CONCLUSION: NUAT-NKTCL is a distinctive subtype of NKTCL in many aspects. Patients with NUAT-NKTCL have relatively poorer performance status, more unfavorable prognostic factors, more advanced stage, and poorer prognosis.

Mutation Profiling of Malignant Lymphoma by Next-Generation Sequencing of Circulating Cell-Free DNA.

Background: Malignant lymphomas are a group of distinct lymphoid neoplasms, exhibiting marked diversity in biological behaviors and clinical outcomes. Liquid biopsy, such as circulating cell-free DNA (cfDNA), has recently been attempted to be used for mutation profiling of lymphomas using next-generation sequencing (NGS). However, only limited data about cfDNA are restricted in Hodgkin's lymphoma and B cell lymphoma, and there is no report in the T cell lymphoma so far. Patient and Methods: Medical records of a total of 50 lymphoma patients were retrospectively reviewed, and cfDNA samples were analyzed by capture-based NGS targeting 390 lymphoma- and cancer- relevant genes. We sought to explore the clinical utility of cfDNA in establishing the mutation profiles of different lymphoma subtypes and analyze the correlation between cfDNA concentration and other clinical indices such as serum LDH and IPI. Results: Somatic alterations were identified in cfDNA samples with a median of 64 variants per sample. The concentration of cfDNA in the plasma was found to be significantly correlated with the clinical indices in diffuse large B cell lymphoma (DLBCL). The genetic heterogeneity of different lymphoma subtypes was clearly observed in cfDNAs from germinal center B-cell (GCB) DLBCL, non-GCB DLBCL and natural killer/T-cell lymphoma (NKTCL), confirming that distinct molecular mechanisms are involved in the pathogenesis of different lymphomas. Conclusion: Our findings demonstrate that NGS-based cfDNA mutation profiling reveals genetic heterogeneity across lymphoma subtypes, with potential implications for the discovery of therapeutic targets, the exploration of genome evolution and the development of risk-adapted treatment.

Trends in survival of patients with stage I/II Burkitt lymphoma in the United States: A SEER database analysis.

The treatment strategy for management of Burkitt lymphoma (BL) has evolved during the past decades and the clinical outcome for this disease as a whole has also improved. Due to limited information reported on survival trends of patients with stage I/II (limited-stage) BL, here we used the Surveillance, Epidemiology, and End Results (SEER) database to conduct our study. The time period was divided into two eras (1983-2001 and 2002-2014) as the recent era reflected more intensive chemotherapy regimens, the availability of rituximab, the widespread use of antiretroviral therapy (ART) and improvements in supportive care. Patients with limited-stage BL had a significantly better 5-year overall survival (OS) in the 2002-2014 era in both univariate analysis and multivariate analysis, compared with those in the 1983-2001 era (64.1% vs 57.4%). However, clinical outcomes of elderly patients (≥60 years) and children patients (0-19 years) did not significantly improve. Older age and race of black were correlated with poorer OS in multivariate analysis, whereas sex, primary sites, and application of radiotherapy did not significantly influence OS. In conclusion, the prognosis of patients with limited-stage BL has improved in the 2002-2014 era, but the outcome was still much poorer in elderly patients, which needs to be improved by identifying newly molecular-targeted drugs and developing novel personalized therapeutic approaches.

Differential clinical significance of pre-, interim-, and post-treatment plasma Epstein-Barr virus DNA load in NK/T-cell lymphoma treated with P-GEMOX protocol.

Circulating EBV-DNA is an accurate biomarker of tumor load in extranodal natural killer (NK)/T cell lymphoma (ENKTL); however, its role in patients treated with P-GEMOX has not been evaluated. In this study, we examined plasma EBV-DNA of 99 patients at different time points by real-time quantitative polymerase chain reaction. Multivariate analysis revealed that ECOG PS score, response rate, and post-treatment EBV-DNA level were independent predictors of progression-free survival (PFS) and overall survival (OS). Positive post-treatment plasma EBV-DNA was associated with poor OS in ENKTL patients. The 3-year OS for patients with positive pre-, interim-, post-treatment EBV-DNA was significantly lower than that for patients with negative EBV-DNA; the values were 70.2% vs. 93.9% (p = .022), 53.8% vs. 99.1% (p < .001), and 40.6% vs. 91.8% (p < .001), respectively. We conclude that monitoring dynamic changes in plasma EBV-DNA in ENKTL patients treated with P-GEMOX could predict important outcomes such as OS.

A novel Bcl-2 inhibitor, BM-1197, induces apoptosis in malignant lymphoma cells through the endogenous apoptotic pathway.

BACKGROUND: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. METHODS: The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. RESULTS: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase - 9, - 3, and - 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. CONCLUSIONS: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.

The Clinical Utility of Circulating Epstein-Barr Virus DNA Concentrations in NK/T-Cell Lymphoma: A Meta-Analysis.

BACKGROUND: Circulating Epstein-Barr virus (EBV) DNA concentrations were reported to have prognostic value for NK/T-cell lymphoma patients in limited small-scale studies. In this study, we aimed to evaluate the clinical utility of circulating EBV-DNA concentrations to a large sample of NK/T-cell lymphoma patients. METHODS: We conducted this meta-analysis, which included a total of 15 prospective and retrospective comparable studies to assess the association between pretreatment EBV-DNA (pre-DNA), posttreatment EBV-DNA (post-DNA), and clinical outcomes of NK/T-cell lymphoma patients. We chose overall survival (OS) as the primary endpoint and progression-free survival (PFS), complete response (CR), and overall response rate (ORR) as secondary endpoints. RESULTS: High pre-DNA and detectable post-DNA were both significantly correlated with poorer OS in NK/T-cell lymphoma patients (P < 0.05), with hazard radios (HRs) equal to 3.45 and 2.30, respectively. High pre-DNA and detectable post-DNA also predicted poorer PFS. Additionally, high pre-DNA was found to be significantly correlated with both worse CR and ORR, which indicated worse treatment response. CONCLUSION: Circulating EBV-DNA concentrations provides prognostic values of survival and treatment response in NK/T-cell lymphoma patients.

Trends in Survival of Patients with Primary Gastric Diffuse Large B-Cell Lymphoma: An Analysis of 7051 Cases in the SEER Database.

Treatment modalities for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) have changed significantly during the past decades. However, limited information on the trends of clinical outcome of PG-DLBCL patients has been reported. Here, we conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database to compare the survival trends of PG-DLBCL patients from 1973 to 2014. Patients were divided into 2 eras based on the year of diagnosis in relation to immunotherapy with the anti-CD20 antibody rituximab that was approved in 1997 and became a widely used drug in 2000. There was a significant improvement in survival among PG-DLBCL patients diagnosed in the 2001-2014 era (n = 4186) compared to patients diagnosed in the 1973-2000 era (n = 2865), with the 5-year overall survival rates of 53% and 47%, respectively (p = 0.001). Multivariable analysis revealed that the 2001-2014 era (HR = 0.892, p = 0.001) was associated with lower mortality and that patients of older age, Black race, advanced stage, and male gender were associated with poor prognosis. Although outcome of PG-DLBCL has significantly improved over time, more effective therapies are needed for older patients to further improve their survival.

Expressions and prognostic values of the E2F transcription factors in human breast carcinoma.

E2F transcription factors (E2Fs) are a family of transcription factors involved in cell proliferation, differentiation, and apoptosis. Their important roles in the development and metastasis of breast carcinoma (BC) have been discovered by previous in vitro and in vivo studies. Yet, expressions and distinct prognostic values of these eight E2Fs in human BC remain unclear in many respects. In this study, we aimed to reveal their roles in BC through analyzing the transcription and survival data of the E2Fs in BC patients from four online databases including ONCOMINE, Breast Cancer Gene-Expression Miner v4.1, cBioPortal for Cancer Genomics, and Kaplan-Meier Plotter. We found the overexpression of E2Fs in BC tissues compared with normal breast tissues, except for E2F4. Higher expression levels of E2Fs, except for E2F4 and E2F6, were associated with higher levels of Scarff-Bloom-Richardson grade of BC. Alterations of E2Fs were found to be significantly correlated with poorer overall survival of BC patients. Through plotting the survival curve in the Kaplan-Meier Plotter, it was found that higher mRNA levels of E2F1, E2F3, E2F7, and E2F8 were associated with poorer relapse-free survival in all BC patients, indicating that they are potential targets for individualized treatments of BC patients. Conversely, higher mRNA expression level of E2F4 predicted better RFS in BC patients, suggesting E2F4 as a new biomarker for BC prognosis. Considering currently available limited evidence, further studies need to be performed to investigate the roles of E2Fs in BC.

The role of protein p16INK4a in non-oropharyngeal head and neck squamous cell carcinoma in Southern China.

Cyclin-dependent kinase inhibitor 2A (p16INK4a) protein is a surrogate immunohistochemical marker of human papillomavirus infection in oropharynx squamous cell carcinoma (OPSCC). However, the effects of p16INK4a in non-OPSCC require additional analysis. In addition, major gaps remain in the literature, including small volumes of data for China. Therefore, the present study evaluated the frequency of p16INK4a positivity in patients with non-OPSCC in Southern China, and assessed its prognostic value. p16INK4a expression status in patients with non-OPSCC was determined by immunohistochemistry. p16INK4a-positive expression was defined as a strong and diffuse staining in ≥70% of the tumor cells. Then, the diagnostic value of p16INK4a in predicting overall survival (OS) and disease-free survival (DFS) rate was determined. The positive rate of p16INK4a was 26.3% in larynx cancer and 24.8% in oral cavity cancer. Multivariate analysis revealed that the protein status independently predicted improved OS rate, but not DFS rate (P=0.096). Comparing different disease stages, patients at an early stage with p16INK4a-positive non-OPSCC exhibited improved DFS and OS rates compared with those exhibited by patients who were negative. The p16INK4a-positive rate in patients with non-OPSCC was 25.1% [26.3% in Laryngeal squamous cell carcinoma (LSCC) and 24.8% in Oropharyngeal squamous cell carcinomas (OSCC)] in the present cohort from South China. The present study suggested that p16INK4a expression in non-OPSCC predicts favorable clinical outcomes, particularly in early stage non-OPSCC and oral cancer.

Persistent peripheral blood EBV-DNA positive with high expression of PD-L1 and upregulation of CD4 + CD25 + T cell ratio in early stage NK/T cell lymphoma patients may predict worse outcome.

Although gemcitabine, oxaliplatin and L-asparaginase/pegylated asparaginase (P-GEMOX) treatment for early-stage extranodal natural killer/T cell lymphoma (ENKTL) is effective, some patients die within 1 year of diagnosis. We attempted to determine an optimal biomarker for identifying such patients. We enrolled 71 patients with ENKTL who received P-GEMOX between January 2011 and January 2014. We classified the patients according to the outcome into worse (died within 1 year) or better groups (survival time ≥ 3, 4 or 5 years). The area under the curve (AUC) was determined to identify the optimal biomarker for differentiating the groups. The AUC was highest in patients who were plasma Epstein-Barr virus (EBV) DNA-positive post-treatment. The AUC was 0.82, 0.86 and 0.86 when the worse group was compared to the better group, respectively. Among the post-treatment EBV DNA-positive patients, as compared to EBV DNA-negative patients, pre-treatment EBV DNA-positive patients had a higher proportion of CD4 + CD25 + T cells. There was higher programmed cell death protein ligand-1(PD-L1) expression in post-treatment EBV DNA-positive patients. Post-treatment positive EBV DNA status maybe a useful biomarker of worse outcomes in early stage ENKTL.