Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma.

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.

Treatment of Abdominal Desmoplastic Small Round Cell Tumor Induces Acute Myeloid Leukemia-M5: A Case Report and Literature Review.

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive malignancy. Most patients are diagnosed at a late stage with poor prognosis. The treatment usually includes combined intensive chemotherapy, cytoreductive surgery, radiotherapy, and targeted therapy. Due to the low incidence rate and dismal survival, there is currently a lack of case reports on DSRCT with concurrent leukemia. We report a case of a young patient who achieved disease stabilization for 14 months after receiving 6 cycles of chemotherapy and whole abdominal radiation therapy (WART), followed by consolidation treatment with anlotinib. However, the treatment was terminated due to the development of Acute Myeloid Leukemia-M5 (AML-M5). Multimodal therapy may provide a survival benefit for rare tumors that lack standard treatment. However, intensive chemotherapy and extensive radiotherapy carry a risk of inducing secondary malignancies. This is the first reported case of concurrent DSRCT and AML-M5 with short intervals between onset.

Association between long non-coding RNA (lncRNA) GAS5 polymorphism rs145204276 and cancer risk.

OBJECTIVE: The long non-coding RNA (lncRNA) growth arrest­specific transcript 5 (GAS5) plays an important role in various tumors, and an increasing number of studies have explored the association of the GAS5 rs145204276 polymorphism with cancer risk with inconclusive results. METHODS: PubMed, Medline, EMBASE, Cochrane databases, and Web of Science were searched, and nine studies involving 6107 cases and 7909 controls were deemed eligible. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the relationship between rs145204276 and cancer risk in six genetic models. RESULTS: The pooled results suggest that the variant allele del was not associated with overall cancer risk. However, the subgroup analysis showed that allele del was significantly associated with a 22% decreased risk of gastrointestinal cancer (OR = 0.78, 95% CI: 0.72-0.85). Both sensitivity analyses and trial sequential analyses (TSA) demonstrated that the subgroup results were reliable and robust. Moreover, False-Positive Report Probability (FPRP) analysis indicated that the results had true significant correlations. CONCLUSION: These findings provide evidence that the GAS5 rs145204276 polymorphism is associated with the susceptibility to gastrointestinal cancer. Further studies with different ethnicities and larger sample sizes are warranted to confirm these results.

Complete Blood Count Score Model Predicts Inferior Prognosis in Primary Central Nervous System Lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL), an aggressive type of non-Hodgkin lymphoma, has a poor prognosis. Currently available prognostic scoring systems are inadequate. We therefore aimed to investigate the predictive values of complete blood counts (CBCs) in PCNSL. MATERIALS AND METHODS: The cohort of this retrospective study comprised 73 PCNSL patients. The predictive values of selected CBCs, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI), were analyzed. RESULTS: Ages and Memorial Sloan Kettering Cancer Center (MSKCC) scores of PCNSL patients correlated with NLR, PLR, and SII values (p <0.05). Both age and MSKCC scores correlated with inferior progression-free survival (PFS) and overall survival (OS) (p <0.05). High NLR, PLR, SII, and SIRI were significant predictors of shorter PFS and OS (p <0.05). NLR, PLR, SII, and SIRI were integrated to generate a "CBC score" model that accurately stratified PCNSL patients into three risk groups. The median PFS for low-risk, intermediate-risk, and high-risk groups were 24 ((12.458-35.542), 17 (10.626-23.374), and 9 (8.893-19.107) months, respectively (p = 0.011), and the median OS were 33 (19.175-46.825), 18 (16.368-19.632), and 9 (6.521-11.479) months, respectively (p = 0.008). Multivariate Cox regression model showed that MSKCC score (hazard ratio (HR) = 3.791, p <0.001), PLR (HR = 1.003, p = 0.013), and CBC score (HR = 1.873, p = 0.011) were independent predictors for PFS, whereas MSKCC score (HR = 4.128, p <0.001), PLR (HR = 1.003, p = 0.005), and CBC score (HR = 1.907, p = 0.004) were independent predictors for OS. CONCLUSION: The CBC score model may be a promising predictive system for PCNSL patients.

The Clinical Features and Survival Outcome of 107 Newly Diagnosed Advanced Stage Extranodal NK/T-Cell Lymphoma Cases: A Triple-Center Study.

OBJECTIVE: Advanced stage extranodal natural killer/T-cell lymphoma (ENKTL) is a distinct type of non-Hodgkin lymphoma and the prognosis of ENKTL is poor with current treatment. This study aimed to investigate the clinical features, treatment strategy and survival outcome in patients with advanced stage ENKTL. PATIENTS AND METHODS: A total of 107 patients with newly diagnosed advanced stage ENKTL between January 2010 and December 2014 were reviewed from three cancer centers. Survival probability was calculated using Kaplan-Meier and the survival curves were compared by Log rank test. Cox regression analyses was performed to investigate the prognostic factors in ENKTL. RESULTS: The median patient age in our cohort was 42.0 years, with a male to female ratio of around 2.3:1. Over half of the patients had B symptoms (n = 61), high IPI scores (≥ 2, n = 60) and high Prognostic Index of Natural Killer Lymphoma (PINK) scores (≥ 3, n = 69). Elevated LDH level was present in around half of the patients (44/91). Most patients (n = 88) in our cohort originated in upper aerodigestive tract and the remaining 19 cases presented with non-upper aerodigestive tract involvement at first diagnosis. Chemotherapy regimens used in our study mainly include CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (n = 26), L-asparaginase (L-asp) containing chemotherapy (GELOXD (gemcitabine, l-asparaginase, oxaliplatin and dexamethasone) and SMILE (L-asparaginase, methotrexate, ifosfamide, etoposide, and dexamethasone)) (n = 66). No significant difference between the baseline clinical characteristics was found between the L-asp and CHOP group. The CR rate after treatment was 39.3% (42/107) for the whole cohort. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) rate was 41.0% and 41.5%, respectively. The 3-year PFS (49.2% vs 26.5%, P = 0.048) and 3-year OS (49.4% vs 26.0%, P = 0.030) was significantly higher in the L-asp group than the CHOP group. Patient CR status and PINK score were proved to be significant independent factors affecting OS and PFS by multivariate analysis. The grade 3/4 hematologic toxicity (P = 0.0003) and non-hematologic toxicity (P = 0.0002) occurred more frequently in the SMILE group than the GELOXD group. CONCLUSION: Our results demonstrated that L-asp containing chemotherapy could provide favorable survival outcomes in patients with advanced stage ENKTL.

Optimal Courses of Chemotherapy Combined with Radiotherapy for Low-Risk Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Propensity Score Matching Analysis.

PURPOSE: This retrospective study compared effectiveness between ≤4 cycles and ≥5 cycles of L-asparaginase/pegaspargase-based chemoradiation in newly diagnosed low-risk extranodal natural killer/T-cell lymphoma (ENKTL), nasal type classified according to the Prognostic Index of Natural Killer (PINK) lymphoma model. PATIENTS AND METHODS: Patients were categorized into ≤4-cycle (2-4 chemotherapy cycles, n = 166) and ≥5-cycle groups (5-6 cycles, n = 86). Propensity score matching analysis was used to reduce potential confounding bias between the two groups. Treatment responses, adverse events, and survival outcomes between the two groups were analyzed. RESULTS: No matter before or after matching (65 in the ≤4-cycle group, 65 in the ≥5-cycle group), response rates and survival outcomes were similar between the ≤4-cycle and ≥5-cycle groups. Incidences of grade 1-2 anemia and transaminase elevation were higher in the ≥5-cycle group. After matching, for stage IE disease, there were no differences in response rates and survival outcomes between the two groups. For stage IIE disease, the complete response rate was higher in the ≥5-cycle group (72.4% vs 92.6%, p = 0.049), and the 3-year overall survival (65.5% vs 85.2%, p = 0.024) and 3-year progression-free survival (58.6% vs 81.5%, p = 0.027) rates were significantly extended in the ≥5-cycle group. CONCLUSION: When chemoradiotherapy strategies with L-asparaginase/pegaspargase-based regimens are applied to modern low-risk ENKTL patients classified according to the PINK model, it may be better to moderately extend chemotherapy courses in patients with stage IIE disease.

Safety and efficacy of aprepitant as mono and combination therapy for the prevention of emetogenic chemotherapy-induced nausea and vomiting: post-marketing surveillance in China.

BACKGROUND: The goal of this study was to evaluate aprepitant usage in the context of routine clinical practice with dose/regimens at the discretion of prescribers for chemotherapy-induced nausea and vomiting (CINV) treatments. METHODS: In this single arm, multicenter prospective study 1,000 patients with solid malignancies were enrolled across 21 centers in China. The primary endpoint was the rate of adverse events (AEs), including drug related AEs and serious AEs (SAEs). Secondary efficacy endpoints included the proportion of patients achieving complete response (CR; no vomiting, no nausea, and no use of rescue medication) within 120 h after highly emetogenic chemotherapy, the rates of no nausea and no vomiting, as well as quality of life (QoL). Multivariable logistic regression analysis was carried out to determine factors associated with the overall (0-120 h), acute (0-24 h) and delayed (25-120 h) CR. RESULTS: Of the 1,000 highly emetogenic chemotherapy treated patients enrolled in the study ≥1 AE, ≥1 drug related AE, ≥1 SAE and drug related SAE rates in 998 patients were 45.9%, 2.5%, 4.0% and 0.1%, respectively. Approximately half of the patients (455/990, 46.0%) received aprepitant as part of a 3-drug anti-CINV regimen consistent with prescribing guidelines. The overall CR (0 to 120 h) for anti-emetic drug use was 41.0%, with an acute CR of 66.0% and a delayed CR of 46.5%. The rates of no vomiting and no nausea after solely aprepitant anti-emetic therapy from 0 to 120 h were 70.9% and 43.0%, for dual anti-emetic therapy 86.9% and 64.6%, and for triple therapy 86.4% and 69.5%, respectively. Multivariate regression analysis revealed that triple anti-emetic therapy (P=0.038), male gender (P<0.001) and a history of chemotherapy (P=0.016) were significantly associated with the overall acute CR. CONCLUSIONS: Especially as a combination treatment, aprepitant is safe and efficient for preventing CINV in patients receiving highly emetogenic chemotherapy.

An ssDNA aptamer specific for detection and purification of hexahistidine-tagged proteins.

Aptamers are small-sized RNA or ssDNA ligands with a unique structure, which have high specificity and affinity to their cognate targets. Thus, in addition to the extensive values in various bio-medical fields, aptamers can also be alternatively used as affinity ligands in the bioprocess, such as for protein purification. In the present study, a hexahistidine specific aptamer named AptHis-C, was developed through the SELEX methodology, which has high affinity to hexahistidine, and its dissociation constant was as low as 20.8 nM. The structural prediction revealed that AptHis-C contains two connected stem-loop conformations. AptHis-C can only specifically recognize recombinant proteins with the hexahistidine-tag in simple or complex situations, and not to those with other tags. When immobilized on magnetic beads, AptHis-C can be used as a tool for hexahistidine-tagged recombinant protein purification. Its effectiveness is as good as traditional Ni-based beads. Besides, due to the intrinsic characteristics of nucleic acids, such as high thermal/chemical stability, immobilized aptamer-magnetic beads can be reused many times without an obvious decrease of purification effectiveness. This aptamer may represent a novel method for the detection and purification of hexahistidine-tagged recombinant proteins.

The Role and Underlying Mechanism of Exosomal CA1 in Chemotherapy Resistance in Diffuse Large B Cell Lymphoma.

Chemotherapy resistance plays a major role in treatment failure of diffuse large B cell lymphoma (DLBCL). Exosomes are closely related to tumor drug resistance. Herein, the expression of exosomal proteins in DLBCL and their roles in chemotherapy resistance of DLBCL are explored. Tandem mass tag labeling proteomics was used to perform proteomic profiling in exosomes from DLBCL patients' serum. The expression of carbonic anhydrase 1 (CA1) in parental, chemo-resistant DLBCL cells and DLBCL patient exosomes was detected. Proliferation of DLBCL following CA1 knockdown was investigated both in vitro and in vivo, along with the effects on nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. We identified 54 differentially expressed proteins. We validated that the expression level of exosomal CA1 was higher in chemo-resistant DLBCL cells than in chemo-sensitive counterparts. Knockdown of CA1 inhibited the growth of DLBCL via inhibiting the activation of NF-κB and STAT3 signaling pathways both in vitro and in vivo. An increased expression level of exosomal CA1 was associated with poorer prognosis, and exosomal CA1 could be used as a biomarker to predict chemotherapeutic efficacy. Our study suggests that exosomal CA1 can promote chemotherapy resistance in DLBCL via the NF-κB and STAT3 pathways, and it can serve as a biomarker for DLBCL prognosis.

HIV-negative plasmablastic lymphoma: report of 8 cases and a comprehensive review of 394 published cases.

BACKGROUND: Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma (PBL) is a rare entity of diffuse large B-cell lymphoma (DLBCL). The clinicopathological features of and optimal treatment for HIV-negative PBL remain largely unknown. METHODS: To gain insight into this distinct lymphoma, we summarized the clinicopathologic characteristics of 8 unpublished HIV-negative PBLs and performed a comprehensive review of 394 published cases. RESULTS: Of the 8 unpublished PBLs, the median patient age was 53.0 years. Four patients presented with stage IV disease. All 8 patients showed a plasma cell-like immunophenotype. Of the six patients who received anthracycline-based chemotherapy, including two who received bortezomib, three patients achieved a continuous complete response, two patients died due to disease progression, and one patient was lost to follow-up. The other two patients achieved continuous complete response after receiving chemotherapy combined with radiotherapy and surgery. Of the 402 patients, the majority were male, with a mean age of 58.0 years. EBV infection was detected in 55.7% of the patients. The median survival times of the patients who received CHOP or CHOP-like regimens and intensive regimens were not reached and 23.0 months, respectively, and the intensive regimen did not improve the survival outcome (P=0.981). Multivariate analysis showed that EBER remained the only independent factor affecting overall survival (OS). CONCLUSION: HIV-negative PBL is a distinct entity with a predilection for elderly and immunosuppressed individuals. Intensive chemotherapy had no apparent survival benefits over the CHOP regimen in terms of OS; the prognosis of this disease is poor with current chemotherapy methods, and treatment remains a challenge.

Cathepsin L interacts with CDK2-AP1 as a potential predictor of prognosis in patients with breast cancer.

Cathepsin L (CTSL) is a lysosomal acid cysteine protease that has been implicated in tumorigenesis and malignant progression. In the present study, the role of CTSL in tumorigenesis and prognosis of breast cancer was evaluated. The prognostic value of CTSL was analyzed using immunohistochemistry in patients with breast cancer, as well as online microarray datasets. CTSL expression was knocked down in the breast cancer cell line T-47D using RNA interference. MTT and colony formation assays were performed to assess the role of CTSL in the proliferation of breast cancer cells. Cell cycle progression and apoptosis were measured using flow cytometry. A physical interaction of CTSL and cyclin dependent kinase 2 associated protein 1 (CDK2-AP1) was determined using a glutathione S-transferase pull-down assay. Endogenous CTSL expression was high in breast cancer cells and exhibited an inverse association with CDK2-AP1 expression; aberrant expression of CTSL in breast cancer tissues predicted an improved clinical outcome and prognosis. In addition, CTSL knockdown decelerated the progression of breast cancer cells by arresting cell cycle progression and increasing apoptosis. Thus, CTSL may be a potential therapeutic target for treating patients with breast cancer.

linc01088 promotes cell proliferation by scaffolding EZH2 and repressing p21 in human non-small cell lung cancer.

AIMS: Non-small cell lung cancer (NSCLC), characterized by extensive metastasis and poor prognosis, is the most common type of lung cancer. Dysregulation of certain lncRNAs is known to be linked to the tumorigenesis of NSCLC. However, the specific roles in NSCLC for many other lncRNAs, such as linc01088, remain largely unknown. MATERIALS AND METHODS: The expression patterns of linc01088, p21 and EZH2 were examined both in NSCLC tissues and cell lines using RT-qPCR assay. CCK-8, colony formation, immunofluorescence staining, and flow cytometry assays were employed to evaluate the effects of linc01088 on NSCLC cell proliferation properties. RNA immunoprecipitation (RIP) assay was performed to determine the direct binding relationship between linc01088 and zeste homolog 2 (EZH2). Western blot and RT-qPCR analysis were performed to assess p21 level within knockdown of either linc01088 or EZH2. Nude mouse subcutaneous NSCLC models were constructed for further validating the effects and mechanisms of linc01088 in vivo. KEY FINDINGS: linc01088 and EZH2 were highly expressed both in NSCLC tissues and cell lines. Knockdown of linc01088 suppressed the proliferation of NSCLC cells, and prolonged the G1 phase while shortened S and G2-M phases. RIP assay revealed the direct binding relationship between linc01088 and EZH2. Knockdown of either linc01088 or EZH2 induced up-regulation of p21 expression, which subsequently inhibited the tumor growth. SIGNIFICANCE: We demonstrated that linc01088 could promote cell proliferation via binding with EZH2 to repress p21, which aggravates the tumorigenesis of NSCLC. Therefore, linc01088 might be a potential oncogene and target for novel anti-tumor therapies.

Neoadjuvant dose-modified docetaxel in squamous cell carcinoma of the head and neck: A phase 3 study.

OBJECTIVE: To evaluate the efficacy and safety of dose-modified docetaxel plus cisplatin and 5-fluorouracil (TPF) in Chinese patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: This Phase III, open-label, multi-center study included Chinese adults with previously untreated TNM Stage III or IV SCCHN (NCT00995293). Patients were randomized (1:1) to induction chemotherapy with TPF (docetaxel 60 mg/m2 and cisplatin 60 mg/m2 on day 1 and 5-FU 750 mg/m2  per day continuous IV infusion on days 1-5) or PF (cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2  per day on days 1-5) every 3 weeks for 3-4 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS in the TPF (n = 108) and PF (n = 111) groups was 400 days and 342 days (HR = 0.75; 95% CI, 0.53─1.06; p = .227), respectively. Overall response rate was higher for TPF versus PF (76.3% vs. 52.9%; p = .001), although this equalized following radiotherapy (75.0% vs. 73.9%). In the TPF and PF groups, ≥1 treatment-emergent adverse event was experienced by 104 (94.5%) and 110 (93.2%) patients, respectively. CONCLUSION: Adding dose-modified docetaxel to PF did not significantly improve PFS but may increase anti-tumor activity in Chinese patients with locally advanced SCCHN.

Antitumor effects and mechanisms of 1,25(OH)2D3 in the Pfeiffer diffuse large B lymphoma cell line.

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non­Hodgkin lymphoma in China. 1,25­Dihydroxyvitamin D3 [1,25(OH)2D3] has been shown to possess significant antitumor potential and is degraded by 25­hydroxyvitamin D­24­hydroxylase (CYP24A1). In the present study, the role of CYP24A1 and autophagy, and their underlying mechanisms in the anticancer effects of 1,25(OH)2D3 in DLBCL cells, were investigated. It was found that the levels of CYP24A1 in DLBCL lymph node tissues were higher than in hyperplasia lymphadenitis tissue. Moreover, the expression of CYP24A1 was positively associated with the Ann Arbor stage and the International Prognostic Index in patients with DLBCL, and negatively associated with the clinical response to treatment. Patients >60 years of age were found to have a higher level of CYP24A1. 1,25(OH)2D3 inhibited the proliferation of the Pfeiffer DLBCL cell line and increased the G1 phase population of Pfeiffer cells. Rapamycin (RAPA) in combination with 1,25(OH)2D3 increased the G1 phase distribution of Pfeiffer cells. Furthermore, RAPA blocked the increase of CYP24A1 and vitamin D receptor (VDR) expression induced by 1,25(OH)2D3. 1,25(OH)2D3 induced the formation of autophagosomes, increased the expression of autophagy related protein light chain (LC)3II/LC3I and reduced the expression of the ubiquitin binding protein P62. In addition, 1,25(OH)2D3 decreased the phosphorylation of AKT and mammalian target of RAPA (mTOR), and downstream targets eukaryotic translation imitation factor 4E­binding protein 1 and ribosomal protein S6 kinase ß­1 in Pfeiffer cells. The results from the present study suggested that CYP24A1 may be a novel prognostic indicator for DLBCL. 1,25(OH)2D3 inhibited proliferation and induced autophagy of Pfeiffer cells. In addition, 1,25(OH)2D3 increased the G1 phase population of Pfeiffer cells. These effects may be mediated by inhibition of the AKT/mTOR/PI3K signaling pathway. RAPA increased the cell cycle arrest induced by 1,25(OH)2D3 by blocking the upregulated expression of CYP24A1 and VDR.

Transcriptional profiling of long-intergenic noncoding RNAs in lung squamous cell carcinoma and its value in diagnosis and prognosis.

BACKGROUND: Long intergenic noncoding RNAs (lincRNAs) are a series of novel transcribed regions expressed in cancers that may represent candidate biomarkers for lung squamous cell carcinoma (LSqCC) treatment. In this study, we evaluated the lincRNA profile in LSqCC patients and screened valuable lincRNAs for diagnosis and prognosis. METHODS: Transcriptome profiling of 549 samples derived from 501 LSqCC patients were identified in TCGA database. 48 patients had paired primary tumor (PT) and solid normal (SN) tissue samples, while 453 patients had only PT samples. 1,771 lincRNA candidates were evaluated. Paired test (Wilcoxon two-sample paired signed rank tests) was performed in paired PT and SN samples. Logistic regression analysis were performed in independent 453 PT samples and 48 SN samples to screen the significant lincRNAs candidates for malignances. Independent 501 PT samples were further used to screen the significant lincRNAs candidates for prognosis. RESULTS: Among 1,771 lincRNAs, 10 lincRNAs were significant highly-expressed risk candidates in PT samples, and 10 protective lincRNAs candidates were significant lowly-expressed in PT samples. Among 10 highly-expressed risk lincRNAs, a small panel of LINC00487, LINC01927, and C10orf143 (LINC00959) could effectively predict malignancies in paired samples (AUC = 0.7274, 95%CI = (0.6264, 0.8285)). When combined with protective lincRNA candidates LINC02315, LINC00491, and LINC01697, the predictive efficiency was greatly improved in both paired samples (AUC = 0.8030, 95%CI = (0.7250, 0.8810)) and independent samples (AUC = 0.7481, 95%CI= (0.6642, 0.8320)). Additionally, three highly-expressed risk lincRNAs, LINC01031, LINC01088, and LINC01931, were significantly associated with poor prognosis in PT samples, suggesting potential targets for anti-LSqCC treatment. CONCLUSION: Therefore, lincRNAs could be promising biomarkers for predicting malignancies and potential anti-LSqCC targets for drug development.

Comprehensive Genomic Profiling of EBV-Positive Diffuse Large B-cell Lymphoma and the Expression and Clinicopathological Correlations of Some Related Genes.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare type of lymphoma with a high incidence in elderly patients, poor drug response, and unfavorable prognosis. Despite advances in genomic profiling and precision medicine in DLBCL, EBV+ DLBCL remain poorly characterized and understood. We include 236 DLBCL patients for EBV-encoded mRNA (EBER) in situ hybridization detection and analyzed 9 EBV+ and 6 EBV negative cases by next-generation sequencing (NGS). We then performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to analyze chromosome rearrangements and gene expressions in 22 EBV+ and 30 EBV negative cases. The EBER results showed a 9.3% (22/236) positive rate. The NGS results revealed recurrent alterations in MYC and RHOA, components of apoptosis and NF-κB pathways. The most frequently mutated genes in EBV+ DLBCL were MYC (3/9; 33.3%), RHOA (3/9; 33.3%), PIM1 (2/9; 22.2%), MEF2B (2/9; 22.2%), MYD88 (2/9; 22.2%), and CD79B (2/9; 22.2%) compared with KMT2D (4/6; 66.7%), CREBBP (3/6; 50.0%), PIM1 (2/6; 33.3%), TNFAIP3 (2/6; 33.3%), and BCL2 (2/6; 33.3%) in EBV-negative DLBCL. MYC and KMT2D alterations stood out the most differently mutated genes between the two groups. FISH detection displayed a lower rearrangement rate in EBV+ cohort. Furthermore, KMT2D expression was highly expressed and associated with poor survival in both cohorts. MYC was only overexpressed and related to an inferior prognosis in the EBV+ DLBCL cohort. In summary, we depicted a distinct mutation profile for EBV+ and EBV-negative DLBCL and validated the differential expression of KMT2D and MYC with potential prognostic influence, thereby providing new perspectives into the pathogenesis and precision medicine of DLBCL.

Prognostic Factors and Treatment Strategies for Intrahepatic Cholangiocarcinoma from 2004 to 2013: Population-Based SEER Analysis.

BACKGROUND: Seventy percent of intrahepatic cholangiocarcinoma (ICC) patients are inoperable. Treatment for unresectable patients is essential to improve poor survival. AIMS: We aimed to evaluate the prognostic factors for ICC patients, and investigate the potential treatment strategies for unresectable patients. METHODS: ICC patients were identified in SEER registry in 2004-2013. Univariate and multivariate Cox proportional hazard regression analysis were performed to evaluate the effect of treatment strategies. RESULTS: Of 2248 cases diagnosed in 2010-2013 and staged according to the American Joint Committee on Cancer (AJCC) 7th edition, 1706 (76.13%) did not receive cancer-directed surgery. This portion increased compared to those diagnosed between 2004 and 2009 and staged according to the AJCC 6th edition (72.87%). In addition, the percentage of stage 4 cases increased, while stage 3 cases decreased, because AJCC 7th staging system categorized both T4 and N1 patients into stage IV, which were previously categorized into stage III by AJCC 6th staging system. Patients with radiofrequency ablation (RFA) showed a poorer survival in 2004-2009 (P = .0213), but an almost the same survival as patients with tumor resection in 2010-2013 (P = .51), suggesting that RFA performed better in recent years. Lymphadenectomy showed protective effect for unresectable patients. Radiotherapy improved cancer-specific survival in non-surgery patients (P < .0001).The proportion of stage IV patients increased tremendously from 37.4% in 2004-2009 to 58.7% in 2010-2013. Among 1319 stage IV patients (2010-2013), surgery at distant metastatic sites improved cancer-specific survival. CONCLUSIONS: For unresectable tumors, RFA, radiotherapy, lymphadenectomy, and surgery of distant metastases showed significant benefits to improve cancer-specific survival.

Investigation of expressions of PDK1, PLK1 and c-Myc in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Because the prognosis of DLBCL patients varies considerably, there is an urgent need to identify novel prognostic factors. In this study, we investigated the expression levels of the signalling enzyme 3-phosphoinositide-dependent protein kinase-1 (PDK1), the cell cycle regulatory enzyme Polo-like kinase 1 (PLK1) and the transcription factor (c-Myc) in DLBCL tissues and evaluated their clinical and prognostic significance. PDK1, PLK1 and c-Myc were detected by immunohistochemical staining of paraffin-embedded specimens from 152 DLBCL and 48 lymphadenitis patients. Expression levels were correlated with clinicopathological factors. PDK1, PLK1 and c-Myc were more commonly expressed in DLBCL specimens than in lymphadenitis specimens, and the expression of each protein correlated positively with that of the other two molecules. High PDK1, PLK1 and c-Myc expression, high international prognostic index score, high lactate dehydrogenase levels and late Ann Arbor stage were shown to correlate with shorter overall survival time. A multivariate Cox regression model showed that high expression levels of PLK1 and c-Myc were independent prognostic factors for DLBCL. Our findings indicate that PLK1 and c-Myc expression might be promising predictive biomarkers for DLBCL patients.