[Outcome of radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type].

Objective: To evaluate the prognosis and determine the failure patterns after radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL). Methods: A total of 557 patients from 2000-2015 with low-risk early-stage ENKTCL who received radiotherapy (RT) with or without chemotherapy (CT) from China Lymphoma Collaborative Group were retrospectively reviewed. Among them, 427 patients received combined modality therapy, whereas 130 patients received RT alone. Survivals were calculated by Kaplan-Meier method and compared with Log-rank test. Overall survival (OS) was compared with age and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Cox stepwise regression model was used for multivariate analysis. Results: The 5-year OS and progression-free survival (PFS) were 87.2% and 77.2%. The SMR was 3.59 (P<0.001) at 1 year after treatment, whereas it was 1.50 at 4 years after treatment, without significant difference between ENKTCL group and country-matched general population (P=0.146). Compared with RT alone, CMT did not result in significantly superior 5-year OS (87.0% vs 87.4%, P=0.961) or PFS (76.1% vs 80.7%, P=0.129). Local failure (11.5%, 64/557) and distant failure (10.8%, 60/557) were the main failure modes, while regional failure was rare (2.9%, 16/557). The 5-year locoregional control rate (LRC) was 87.2% for the whole group, with 89.5% for ≥50 Gy versus 73.7% for <50 Gy (P<0.001). Radiotherapy dose was an independent factor affecting LRC(P<0.05). Conclusions: Radiotherapy achieves a favorable prognosis in patients with low-risk early-stage ENKTCL. The incidence of either locoregional or distant failure is low. Radiation dose still is an important prognostic factor for LRC.

[Clinical features and treatment outcome of extranodal nasal-type NK/T-cell lymphoma of the extra-upper aerodigestive tract].

Objective: To investigate the clinical features and prognosis of extranodal nasal-type NK/T-cell lymphoma of the extra-upper aerodigestive tract (extra-UADT NKTCL). Methods: The clinical data of 159 patients with extra-UADT NKTCL from the China Lymphoma Collaborative Group (CLCG) database between November 2001 and December 2015 were retrospectively analyzed. Kaplan-Meier survival analysis and Log-rank test were used to evaluate the prognosis. The Cox regression model is used for multi-factor analysis. Results: Extra-UADT NKTCL commonly occurs in skin and soft tissues (106/159, 66.7%) and gastrointestinal tract (31/159, 19.5%). The incidences of elevated lactate dehydrogenase (LDH) and Ann Arbor Ⅲ~Ⅳ stage were 47.8% (76/159) and 64.2% (102/159), respectively. The 3-year overall survival (OS) and progression-free survival (PFS) rates were 43.6% and 27.9%, respectively. The corresponding OS rates of primary skin/soft tissue site and gastrointestinal tract site were 41.0% and 59.4% (P=0.281), while the PFS rates were 24.8% and 48.3%, respectively (P=0.109). Combined modality treatment improved the 3-year OS of all the patients (58.4% vs 33.9%, P=0.001) and 3-year PFS (40.7% vs 20.7%, P=0.008) when compared with chemotherapy alone. LDH elevation, Ann Arbor synthesising and ≥2 junction external bits were intrusive as independent risk factors for total survival (P<0.05), LDH elevation and ≥2 junction outer bits were intrusive as independent risk factors for progressionless survival(P<0.05). The distant extranodal dissemination was the primary failure patterns. Conclusions: Extra-UADT NKTCL appears to have distinct clinical characteristics and poor outcome. Compared with chemotherapy alone, combined modality treatment may improve the prognosis of patients with extra-UADT NKTCL.

[The effects of sequence of radiotherapy and chemotherapy on prognosis of patients with early-stage extranodal NK/T cell lymphoma (nasal type) and its individualized application].

Objective: To analyze the effects of the sequence of radiotherapy and chemotherapy on the efficacy of early-stage extranodal NK/T-cell lymphoma (nasal type, ENKTCL) patients, and to provide a quantitative evaluation method for individualized radiotherapy and chemotherapy. Methods: The Chinese Lymphoma Collaborative Group (CLCG) collected the clinical data of 2 008 patients with early-stage Ⅰ/Ⅱ ENKTCL who received radiotherapy and chemotherapy from January 2000 to early September 2019 from 21 hospitals across the country, including 1 417 males and 591 females, aged 2 to 83 (42±14) years. According to the sequence of radiotherapy and chemotherapy, patients were divided into radiotherapy-first group (388 cases) and chemotherapy-first group (1 620 cases). Survival rate was estimated using Kaplan-Meier method, and multivariate Cox proportional risk model was used to screen and identify independent prognostic factors. The prognostic prediction models of the two therapies were constructed separately, and the models were used to predict the individualized mortality risk of all patients to determine the appropriate radiotherapy and chemotherapy regimen for each patient. Results: The 5-year overall survival rate was 74.2% (95%CI: 69.6%-79.2%) in the radiotherapy-first group and 69.7% (95%CI: 67.1%-72.4%) in the chemotherapy-first group. Although the 5-year overall survival rate of patients in the radiotherapy-first group was numerically higher than that of the chemotherapy-first group, the difference was not statistically significant (χ2= 2.26, HR=0.84 (95%CI: 0.68-1.05), P=0.133). Six variables including age, gender, ECOG score, LDH, Ann Arbor staging, and PTI (primary tumor invasion) were screened out as independent prognostic factors (the chemotherapy-first group: HR were 1.01, 1.25, 2.07, 0.77, 1.34, 1.49, respectively, all P<0.05; radiotherapy-first group: HR were 1.02, 1.31, 1.66, 0.78, 1.37, 1.29, all P>0.05). The mean 5-year predicted mortality risk for all patients receiving radiotherapy-first regimen was lower than those receiving chemotherapy-first regimen (26.8% vs 30.2%, P<0.001). There were individualized differences in the predicted mortality risk of patients with different clinical characteristics who received radiotherapy-first regimen or chemotherapy-first regimen. Conclusion: Patients with stage Ⅰ/Ⅱ ENKTCL treated with radiotherapy-first regimen had a better expected prognosis than patients treated with chemotherapy-first regimen. The quantitative assessment of the differential effects of the sequence of radiotherapy and chemotherapy on the mortality risk of individual patients based on their clinical characteristics was helpful for the clinical development of the optimal radiotherapy and chemotherapy plan for each patient.

[Impacts of EGFR 19 exon mutations on brain metastases in treatment-naïve patients with lung adenocarcinoma].

Objective: To investigate the relationship between the status of epidermal growth factor receptor (EGFR) mutations and brain metastases in patients with lung adenocarcinoma. Methods: From August 2010 to May 2015, a total of 1 063 lung adenocarcinoma patients with identified status of EGFR mutations in Shanxi Cancer Hospital were enrolled, of which 456 patients had EGFR mutations. Multivariate Logistic regression model was used to analyze the correlation between EGFR mutation status and brain metastases in patients with lung adenocarcinoma. Results: In 125 patients with brain metastases before initial treatment, 65 patients had EGFR mutations, including 36 patients with deletion mutations in exon 19. The frequency of EGFR 19 exon mutation was 28.8% (36/125). Among 456 patients with EGFR mutations, 65(14.3%) patients were with brain metastases, in which 36(55.0%) had deletion mutations in exon 19. The multivariate analysis showed that age, Eastern Cooperative Oncology Group (ECOG) score, EGFR mutations and N staging were associated with brain metastases(P<0.05). Further subgroup multivariate analyses showed that age, ECOG score, mutation status in exon 19 and N staging were associated with brain metastases (P<0.05). Conclusions: EGFR mutation status is related to brain metastases. Mutations in EGFR exon 19 is an independent risk factor for brain metastases.

[Technical advancement improves survival in patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving definitive radiotherapy].

OBJECTIVE: This study aimed to evaluate the impact of technical advancement of radiation therapy in patients with LA-NSCLC receiving definitive radiotherapy (RT). METHODS: Patients treated with definitive RT (≥50 Gy) between 2000 and 2010 were retrospectively reviewed. Overall survival (OS), cancer specific survival (CSS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) were calculated and compared among patients irradiated with different techniques. Radiation-induced lung injury (RILI) and esophageal injury (RIEI) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0 (NCI-CTCAE 3.0). RESULTS: A total of 946 patients were eligible for analysis, including 288 treated with two-dimensional radiotherapy (2D-RT), 209 with three-dimensional conformal radiation therapy (3D-CRT) and 449 with intensity-modulated radiation therapy (IMRT) respectively. The median follow-up time for the whole population was 84.1 months. The median OS of 2D-RT, 3D-CRT and IMRT groups were 15.8, 19.7 and 23.3 months, respectively, with the corresponding 5-year survival rate of 8.7%, 13.0% and 18.8%, respectively (P<0.001). The univariate analysis demonstrated significantly inferior OS, LRPFS, DMFS and PFS of 2D-RT than those provided by 3D-CRT or IMRT. The univariate analysis also revealed that the IMRT group had significantly loger LRPFS and a trend toward better OS and DMFS compared with 3D-CRT. Multivariate analysis showed that TNM stage, RT technique and KPS were independent factors correlated with all survival indexes. Compared with 2D-RT, the utilization of IMRT was associated with significantly improved OS, LRPFS, DMFS as well as PFS. Compared with 3D-CRT, IMRT provided superior DMFS (P=0.035), a trend approaching significance with regard to LRPFS (P=0.073) but no statistically significant improvement on OS, CSS and PFS in multivariate analysis. The incidence rates of RILI were significantly decreased in the IMRT group (29.3% vs. 26.6% vs.14.0%, P<0.001) whereas that of RIET rates were similar (34.7% vs. 29.7% vs. 35.3%, P=0.342) among the three groups. CONCLUSIONS: Radiation therapy technique is a factor affecting prognosis of LA-NSCLC patients. Advanced radiation therapy technique is associated with improved tumor control and survival, and decreased radiation-induced lung toxicity.

EIF5A2 predicts outcome in localised invasive bladder cancer and promotes bladder cancer cell aggressiveness in vitro and in vivo.

BACKGROUND: EIF5A2, eukaryotic translation initiation factor 5A2, is associated with several human cancers. In this study, we investigated the role of EIF5A2 in the metastatic potential of localised invasive bladder cancer (BC) and its underlying molecular mechanisms were explored. METHODS: The expression pattern of EIF5A2 in localised invasive BC was determined by immunohistochemistry. In addition, the function of EIF5A2 in BC and its underlying mechanisms were elucidated with a series of in vitro and in vivo assays. RESULTS: Overexpression of EIF5A2 was an independent predictor for poor metastasis-free survival of localised invasive BC patients treated with radical cystectomy. Knockdown of EIF5A2 inhibited BC cell migratory and invasive capacities in vitro and metastatic potential in vivo and reversed epithelial-mesenchymal transition (EMT), whereas overexpression of EIF5A2 promoted BC cells motility and invasiveness in vitro and metastatic potential in vivo and induced EMT. In addition, we found that EIF5A2 might activate TGF-ß1 expression to induce EMT and drive aggressiveness in BC cells. EIF5A2 stabilized STAT3 and stimulated nuclear localisation of STAT3, which resulted in increasing enrichment of STAT3 onto TGF-ß1 promoter to enhance the transcription of TGF-ß1. CONCLUSIONS: EIF5A2 overexpression predicts tumour metastatic potential in patients with localised invasive BC treated with radical cystectomy. Furthermore, EIF5A2 elevated TGF-ß1 expression through STAT3 to induce EMT and promotes aggressiveness in BC.

[Prognostic value of the age-adjusted Charlson comorbidity index in patients over 60 years old with laryngeal squamous cell carcinoma].

Objective: To evaluate the value of the age-adjusted Charlson comorbidity Index (ACCI) in predicting the prognosis and guiding the clinical treatment of laryngeal squamous cell carcinoma (LSCC) in patients over 60 years old. Methods: Retrospective analysis of 249 cases of LSCC in Shanxi Provincial Cancer Hospital and First Hospital of Shanxi Medical University from 2008 to 2015 was performed. There were 234 males and 15 females, aged from 60 to 88 years. The clinical characteristics, treatment information and follow-up data were collected. ACCI was used to score the comorbidities of the patients. Receiver operating characteristic (ROC) curve was drawn and the patients were divided into high ACCI group and low ACCI group according to the cut-off value of ACCI. Prognostic factors were analyzed. Kaplan-Meier method was used for survival analysis, rank sum test was used for comparison between groups, χ2 test was used for enumeration data. Results: Overall survival (OS) was 54.6%, progression-free survival (PFS) was 59.4%, and cancer-specific survival (CSS) was 58.6%. Both the median survival time and PFS time were 60 months. The best cutoff point of the ACCI group was 5. Cox multivariate analysis showed that ACCI was an independent risk factor for OS, PFS and CSS (OR=1.553, 1.499 and 1.534,respectively, all P<0.05). In the high ACCI group, OS (χ2=4.120 and 4.115,P<0.05) and CSS (χ2=4.510 and 5.009,P<0.05) of patients treated with surgery plus radiotherapy and patients with radiotherapy alone were better than those of patients with surgery alone (P<0.05). But in the low ACCI group, there was no significant difference in prognosis among the three treatment regimens (P>0.05). Conclusion: High ACCI offors important prognostic information for LSCC in patients over 60 years old, and can guide clinical treatment options.

Association of improved overall survival with decreased distant metastasis following asparaginase-based chemotherapy and radiotherapy for intermediate- and high-risk early-stage extranodal nasal-type NK/T-cell lymphoma: a CLCG study.

BACKGROUND: This study evaluated the survival benefit of asparaginase (ASP)-based versus non-ASP-based chemotherapy combined with radiotherapy in a real-world cohort of patients with early-stage extranodal nasal-type natural killer/T-cell lymphoma (ENKTCL). PATIENTS AND METHODS: We identified 376 patients who received combined radiotherapy with either ASP-based (ASP, platinum, and gemcitabine; n = 286) or non-ASP-based (platinum and gemcitabine; n = 90) regimens. The patients were stratified into low-, intermediate-, and high-risk groups using the early stage-adjusted nomogram-revised risk index. Overall survival (OS) and distant metastasis (DM)-free survival (DMFS) between the chemotherapy regimens were compared using inverse probability of treatment weighting (IPTW) and multivariable analyses. RESULTS: ASP-based (versus non-ASP-based) regimens significantly improved 5-year OS (84.5% versus 73.2%, P = 0.021) and DMFS (84.4% versus 74.5%, P = 0.014) for intermediate- and high-risk patients, but not for low-risk patients in the setting of radiotherapy. Moreover, ASP-based regimens decreased DM, with a 5-year cumulative DM rate of 14.9% for ASP-based regimens compared with 25.1% (P = 0.014) for non-ASP-based regimens. The survival benefit of ASP-based chemotherapy and radiotherapy remained consistent after adjusting the confounding variables using IPTW and multivariate analyses; additional sensitivity analyses confirmed these results. CONCLUSIONS: The findings provided support for ASP-based chemotherapy and radiotherapy as a first-line treatment strategy for intermediate- and high-risk early-stage ENKTCL.

Circ-0104631 promotes cell proliferation and invasion in colorectal cancer and predicts poor prognosis.

OBJECTIVE: The aim of this study was to elucidate the effect of Circ-0104631 on the progression of colorectal cancer (CRC) and to demonstrate the underlying mechanism. Our research might provide new biological markers and molecular therapeutic targets for the diagnosis and therapy of CRC. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to detect Circ-0104631 expression in human colorectal cancer tissues and normal control tissues. To further explore the effect of Circ-0104631 on CRC in vitro, we first knocked down Circ-0104631 in colorectal cancer cells (SW480 and LoVo) by shRNA transfection. Subsequently, we detected its effect on cell proliferation and invasion by cell counting kit-8 (CCK-8) assay, colony formation assay and cell invasion assay, respectively. The regulation of Circ-0104631 on the expressions of phosphate and tension homology deleted on chromosome ten (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway-related proteins was detected by Western blot. Besides, the regulatory mechanism of Circ-0104631 on the progression and metastasis of CRC was further verified by recovery experiments. RESULTS: QRT-PCR results showed that Circ-0104631 was highly expressed in tissues of patients with CRC when compared with that of normal control tissues. At the same time, we also found that the expression of Circ-010463 was significantly up-regulated in CRC tissues with high topography lymph node metastasis (TNM) stage and distant metastasis. Survival curve analysis indicated that high expression of Circ-010463 predicted poor prognosis of CRC patients. In vitro experiment demonstrated that inhibition of Circ-0104631 in SW480 and LoVo cells could markedly decrease cell growth and metastasis abilities. Meanwhile, Western blot results indicated that the protein expression of PTEN increased significantly, while p-Akt and p-mTOR decreased remarkably after knock-down of Circ-0104631 in CRC cells. Furthermore, recovery experiments illustrated that knockdown of PTEN in SW480 and LoVo cells partially attenuated the inhibitory effect of shRNA-Circ-0104631 on cell growth and metastasis. CONCLUSIONS: Circ-0104631 was highly expressed in CRC tissues. Furthermore, knockdown of Circ-0104631 could inhibit the growth and metastasis of CRC cells by regulating PTEN/Akt/mTOR signaling pathway.

Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4+ and CD8+ T-lymphocytes.

While the role of mitochondrial metabolism in controlling T-lymphocyte activation and function is becoming more clear, the specifics of how mitochondrial redox signaling contributes to T-lymphocyte regulation remains elusive. Here, we examined the global effects of elevated mitochondrial superoxide (O2-) on T-lymphocyte activation using a novel model of inducible manganese superoxide dismutase (MnSOD) knock-out. Loss of MnSOD led to specific increases in mitochondrial O2- with no evident changes in hydrogen peroxide (H2O2), peroxynitrite (ONOO-), or copper/zinc superoxide dismutase (CuZnSOD) levels. Unexpectedly, both mitochondrial and glycolytic metabolism showed significant reductions in baseline, maximal capacities, and ATP production with increased mitochondrial O2- levels. MnSOD knock-out T-lymphocytes demonstrated aberrant activation including widespread dysregulation in cytokine production and increased cellular apoptosis. Interestingly, an elevated proliferative signature defined by significant upregulation of cell cycle regulatory genes was also evident in MnSOD knock-out T-lymphocytes, but these cells did not show accelerated proliferative rates. Global disruption in T-lymphocyte DNA methylation and hydroxymethylation was also observed with increased mitochondrial O2-, which was correlated to alterations in intracellular metabolite pools linked to the methionine cycle. Together, these results demonstrate a mitochondrial redox and metabolic couple that when disrupted may alter cellular processes necessary for proper T-lymphocyte activation.

Prognostic nomogram for overall survival in previously untreated patients with extranodal NK/T-cell lymphoma, nasal-type: a multicenter study.

The aim of this study was to develop a widely accepted prognostic nomogram for extranodal NK/T-cell lymphoma, nasal-type (NKTCL). The clinical data from 1383 patients with NKTCL treated at 10 participating institutions between 2000 and 2011 were reviewed. A nomogram was developed that predicted overall survival (OS) based on the Cox proportional hazards model. To contrast the utility of the nomogram against the widely used Ann Arbor staging system, the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI), we used the concordance index (C-index) and a calibration curve to determine its predictive and discriminatory capacity. The 5-year OS rate was 60.3% for the entire group. The nomogram included five important variables based on a multivariate analysis of the primary cohort: stage; age; Eastern Cooperative Oncology Group performance status; lactate dehydrogenase; and primary tumor invasion. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.72 for both cohorts, which was superior to the predictive power (range, 0.56-0.64) of the Ann Arbor stage, IPI and KPI in the primary and validation cohorts. The proposed nomogram provides an individualized risk estimate of OS in patients with NKTCL.

[Clinical and experimental studies of the dynamic changes in neuropeptides after trauma].

Dynamic changes of contents of beta-endorphin, leu-enkephalin and oxytocin in plasma were determined in seventeen fracture patients with shock, fascial space syndromes, or infection postoperation. There was significant rise of contents in beta-endorphin and leu-enkephalin but not in oxytocin after trauma, Of those accompanied by infection postoperation, beta-endorphin and oxytocin remained high. The contents of beta-endorphin and enkephalin decreased gradually in non-infectious group, but were still higher than normal. The most obvious change was seen in beta-endorphin, suggesting that beta-endorphin plays a more important role in trauma. This was also confirmed in rat injury model.

Long-term ethanol and nicotine treatment elicit tolerance to ethanol.

Several previous studies have shown that 1 to 2 weeks of treatment with ethanol elicits tolerance to several effects produced by ethanol and cross-tolerance to nicotine-induced hypothermia. Similarly, short-term, high-dose nicotine treatment produces tolerance to nicotine and cross-tolerance to ethanol-induced hypothermia. In the studies reported here, C57BL/6 mice were force-fed ethanol, nicotine, or an ethanol/nicotine combination in the drinking water for 6 months. All of the chronic drug-treated mice developed tolerance to ethanol as measured by open-field activity, body temperature, and sleep-time tests. Ethanol tolerance is due, in part, to enhanced metabolism and reduced CNS sensitivity in the two ethanol-treated groups but only to reduced CNS sensitivity in the nicotine-treated group. Similar levels of tolerance to nicotine developed in those two groups that were nicotine-treated, but no tolerance to nicotine was seen in those animals treated with ethanol alone. The tolerance to nicotine may be related to an upregulation of brain (cortex, hippocampus, and hypothalamus) [3H]-nicotine binding, but ethanol tolerance is not readily explained by changes in the number of the brain high affinity nicotine binding sites.