Benefit of consolidative radiation in patients with extranodal limited-stage diffuse large B-cell lymphoma: a multicenter retrospective study in China.

Approximately 40% of limited-stage (stage I and II) diffuse large B-cell lymphoma (LS-DLBCL) presents with extranodal disease. Extranodal LS-DLBCL may have significant biological differences and associated with worse outcomes than nodal disease. Although rituximab based chemoimmunotherapy is standard of first-line treatment, the role of consolidative radiotherapy (RT) in this particular subgroup is controversial. In this multicenter retrospective study, we evaluated the survival benefit of consolidative RT in patients diagnosed with extranodal LS-DLBCL and received rituximab-based chemoimmunotherapy with or without consolidative RT. A total of 328 patients were included, 129 patients (39.3%) received chemoimmunotherapy and consolidative RT, and 199 patients (60.7%) received chemoimmunotherapy alone. With a median follow-up of 5.1 years (range, 0.3-14.8 years), 5-year progression-free survival (PFS) and overall survival (OS) for all patients were 75.4% and 83.9%, respectively. In multivariate analyses, the addition of consolidative RT was associated with superior OS (P = 0.004) and PFS (P = 0.005). High stage-modified International Prognosis Index (SM-IPI) risk predicted worse OS (P = 0.001) and PFS (P = 0.005). Also, propensity score-matched analyses showed RT improved both OS (hazard ratio [HR] 0.228, 95% confidence index [CI] 0.111-0.467, P < 0.001) and PFS (HR 0.308, 95% CI 0.167-0.566, P < 0.001). Among patients who achieved CR, 49 patients (16.6%) developed disease relapse, of which 30.6% relapsed at local sites. Consolidative RT significantly reduced relapse risk (P = 0.002). Our results demonstrated that consolidative RT significantly improved outcomes in patients with extranodal LS-DLBCL in the rituximab era.

Genomic features reveal potential benefit of adding anti-PD-1 immunotherapy to treat non-upper aerodigestive tract natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is a highly heterogeneous disease with a poor prognosis. However, the genomic characteristics and proper treatment strategies for non-upper aerodigestive tract NKTCL (NUAT-NKTCL), a rare subtype of NKTCL, remain largely unexplored. In this study, 1589 patients newly diagnosed with NKTCL at 14 hospitals were assessed, 196 (12.3%) of whom had NUAT-NKTCL with adverse clinical characteristics and an inferior prognosis. By using whole-genome sequencing (WGS) and whole-exome sequencing (WES) data, we found strikingly different mutation profiles between upper aerodigestive tract (UAT)- and NUAT-NKTCL patients, with the latter group exhibiting significantly higher genomic instability. In the NUAT-NKTCL cohort, 128 patients received frontline P-GEMOX chemotherapy, 37 of whom also received anti-PD-1 immunotherapy. The application of anti-PD-1 significantly improved progression-free survival (3-year PFS rate 53.9% versus 17.0%, P = 0.009) and overall survival (3-year OS rate 63.7% versus 29.2%, P = 0.01) in the matched NUAT-NKTCL cohort. WES revealed frequent mutations involving immune regulation and genomic instability in immunochemotherapy responders. Our study showed distinct clinical characteristics and mutational profiles in NUAT-NKTCL compared with UAT patients and suggested adding anti-PD-1 immunotherapy in front-line treatment of NUAT-NKTCL. Further studies are needed to validate the efficacy and related biomarkers for immunochemotherapy proposed in this study.

Membrane vesicles derived from Enterococcus faecalis promote the co-transfer of important antibiotic resistance genes located on both plasmids and chromosomes.

BACKGROUND: Bacterial membrane vesicles (BMVs) are novel vehicles of antibiotic resistance gene (ARG) transfer in Gram-negative bacteria, but their role in the spread of ARGs in Gram-positive bacteria has not been defined. The purpose of this study was to evaluate the role of MVs in the transmission of antimicrobial resistance in Gram-positive bacteria. METHODS: A linezolid-resistant Enterococcus faecalis CQ20 of swine origin was selected as the donor strain. Linezolid-susceptible E. faecalis SC032 of human origin, Enterococcus faecium BM4105 and Escherichia coli were selected as recipient strains. The presence of plasmids (pCQ20-1 and pCQ20-2) and an optrA-carrying transposon Tn6674 in CQ20, MVs and vesiculants was verified by WGS or PCR. MVs were isolated with density gradient centrifugation, and MV-mediated transformation was performed to assess the horizontal transferability of MVs. The MICs for CQ20 and its vesiculants were determined by the broth microdilution method. RESULTS: CQ20-derived MVs (CQ20-MV) were isolated, and PCR identified the presence of two plasmids and the optrA gene in the CQ20-MVs. MV-mediated transformation to E. faecalis SC032 and E. faecium BM4105 was successfully performed, and the WGS data also showed that both plasmids pCQ20-1 and pCQ20-2 and optrA-carrying transposon Tn6674 were transferred to E. faecalis SC032 and E. faecium BM4105, but failed for E. coli. Additionally, vesiculants that had acquired ARGs still had the ability to spread these genes via MVs. CONCLUSIONS: To our knowledge, this is the first report of MV-mediated co-transfer of ARG-carrying plasmids and transposons in the Gram-positive bacterium E. faecium.

The clinical and genomic distinctions of Class1/2/3 BRAF-mutant colorectal cancer and differential prognoses.

BRAF mutations are the oncogenic drivers in colorectal cancer and V600 mutations (Class1), which lead to RAS-independent active monomers, are the most common mutation types. BRAF non-V600 mutants can be further classified as RAS-independent active dimers (Class2) and RAS-dependent impaired kinase (Class3). We retrospectively reviewed the mutational profiles of 328 treatment-naïve colorectal tumors with BRAF mutations detected using capture-based hybrid next-generation sequencing targeting 400 + cancer-related genes. The clinical and genetic distinctions of patients harboring Class1/2/3 BRAF mutations were investigated, which revealed that tumors with Class1 BRAF mutations showed more unique genomic profiles than those with Class2/3 mutations. Also, by using an external dataset from cBioPortal, we demonstrated that patients with Class3 BRAF mutations had the best survival outcomes compared to the other two subgroups. These findings promoted the development of anti-BRAF strategies by distinguishing BRAF mutant subgroups.

Corrigendum to "Epidemiological Trends of Head and Neck Cancer: A Population-Based Study".

[This corrects the article DOI: 10.1155/2021/1738932.].

Epidemiological Trends of Head and Neck Cancer: A Population-Based Study.

BACKGROUND: Over the past decades, lots of advance have occurred in the prevention, diagnosis, and treatment of head and neck cancer (HNC). However, the contemporaneous incidence and survival trends, on the basis of population-based registry, have not been reported. METHODS: The HNC cancer cases were accessed from the Surveillance, Epidemiology, and End Results (SEER) database. The incidence trend was analyzed by joinpoint analysis, with the survival trend being analyzed by period analysis of relative survival rate (RSR) and Kaplan-Meier analyses. Cox regression analysis was performed to identify the prognostic factors for overall survival. RESULTS: The general incidence trend of HNC increases slightly, with an average annual percentage change of 0.6%, along with five fluctuating segments. The improvement of net survival over the past decades was showed by increasing 60-month RSR, from 54.1% to 56.0% to 60.9% to 66.8%, which was further confirmed by Kaplan-Meier analyses. Moreover, disparities in incidence and survival patterns can be observed in different subgroups. CONCLUSION: A fluctuating incidence pattern and an ever-improving survival were observed in HNC over time.

Human glioma cells-conditioned medium promotes proliferation and migration of human bone marrow mesenchymal stromal cells in vitro.

PURPOSE: To investigate changes in cell proliferation and migration of human bone marrow-derived mesenchymal stromal cells (hMSCs) in glioma environment, in order to assess the tumorigenic risk of hMSCs in the clinical application to treat human gliomas. METHODS: hMSCs were obtained from normal adult persons and identified by their morphological characteristics and test of their stemness. The U251 glioma cell-conditioned medium (U251-CM) was obtained to simulate the human glioma environment in vitro. hMSCs were cultured in the U251-CM or the control medium in the same conditionzs and changes in cell proliferation and migration were detected by MTT assay and wound healing assay. RESULTS: The results of MTT assay showed that, compared with the control group, the proliferation of hMSCs cultured in U251-CM increased significantly, and the results of wound healing assay showed that the migration of hMSCs cultured in U251-CM also increased significantly. CONCLUSIONS: Human glioma cell-conditioned medium may promote the proliferation and migration of hMSCs, and we are concerned about the tumorigenic risk of hMSCs in glioma environment before their clinical application.

The regulation of cancer cell migration by lung cancer cell-derived exosomes through TGF-ß and IL-10.

Tumorigenesis has been considered to be as a result of abnormal cell-cell communication. It has been proposed that exosomes act as communicators between tumors and their microenvironment and have been demonstrated to be involved in tumorigenesis and subsequent metastasis. However, the mechanisms underlying the role of exosomes in these processes remains elusive. The present study sought to determine the underlying mechanisms. Using two lung cancer cell lines, it was demonstrated that exosomes derived from metastatic small cell lung cancer cells (NCI-H1688) have greater effects on cancer cell migration, compared with exosomes derived from primary non-small cell lung cancer cells (NCI-H2228). Further characterization of the contents of the exosomes demonstrated that there were increased levels of TGF-ß and IL-10 in exosomes from NCI-H1688 cells compared with exosomes derived from NCI-H2228 cells, in particular under hypoxia. Blockade of TGF-ß and IL-10 with antibodies confirmed that these cytokines were essential for the regulation of cancer cell migration. Taken together, the results of the present study indicated that exosomes derived from cancer cells regulated the cellular migration of tumor cells through TGF-ß and IL-10, which may provide a novel approach for developing therapeutic methods against cancer.

Structural and functional characterization of neuromedin S in the teleost fish, zebrafish (Danio rerio).

Neuromedin S (NMS) has been demonstrated to have important roles in many vertebrate physiological processes. However, the function of NMS in teleost fishes remains unclear. We explored the physiological roles of the NMS gene in the zebrafish model. An NMS cDNA was cloned from zebrafish brain tissue, and the full-length cDNA sequence was 521 bp in length and encoded a precursor of 110 amino acid residues. Interestingly, fish prepro-NMS is predicted to generate a short 34-residue peptide, designated as NMS-related peptide (NMSRP). Zebrafish prepro-NMS does not contain the NMS peptide which is found in the NMS precursors of mammals, and just retains the MNSRP peptide. A multiple-species sequence alignment showed that NMSRPs are conserved among the other sampled vertebrates. Zebrafish NMS mRNA was detected by RT-PCR revealing a tissue-specific distribution with high levels of expression in the brain, spleen, ovary, pituitary, and muscle. Furthermore, the locations of NMS-expressing cells in the zebrafish brain were detected by in situ hybridization in the parvocellular preoptic nucleus (PPa), the ventral zone of the periventricular hypothalamus (Hv), and lateral hypothalamic nucleus (LH). The levels of NMS mRNA in the hypothalamus were significantly increased after three days of food deprivation. Administration of zebrafish NMSRP by intraperitoneal injection significantly promoted the expression of neuropeptide Y (NPY) and orexin, suggesting an orexigenic role for NMSRP in zebrafish. The present study offers a new understanding of the NMS gene in vertebrates and increases our knowledge of the neuroendocrine regulation of feeding.

Controversies regarding T status and N status for non-small cell lung cancer.

According to the newest version of NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer (NSCLC), increasing attentions are paid to the role of nodal status and other high-risk factors, including vascular invasion, wedge resection, tumors > 4 cm, visceral pleural involvement, and incomplete lymph node sampling in the individual clinical treatment. Precise definitions of T status and N status, closely associated with prognosis and treatment, are worth expanding further. However, complexity arises because no unity definition exists regarding individual T and N descriptors. In an attempt to explore the potential prognostic values of the T status and N status, we systematically review relevant literature and found that there still remained some disputes about the definitions and prognosis. The adjacent lobe invasion regarded as T2 or T3 has not been reached consensus yet so far. Lymph node spread patterns are associated with the treatment strategies of NSCLC. This review mainly focus on the role of T status and N status and tried to seek appropriate and individual treatment strategies in NSCLC.

Metformin inhibits the growth of nasopharyngeal carcinoma cells and sensitizes the cells to radiation via inhibition of the DNA damage repair pathway.

Nasopharyngeal carcinoma (NPC) is a leading cause of cancer-related mortality. Radiotherapy is one of the primary modalities for NPC treatment. However, in patients in the late stages of the disease, the local control rate and overall survival rate remain low. Therefore, it is urgent to identify new targets that can improve the outcome of radiotherapy in this neoplasm. In the present study, we investigated the effects of metformin on the radiosensitivity of NPC cells and explored the potential mechanisms. The radiosensitizing effects of metformin on NPC cells were measured by colony formation assay. Cell apoptosis was assessed by Hoechst 33342 staining analysis. DNA damage was detected by monitoring γ-H2AX foci with immunofluorescence. The changes in apotosis-related and DNA damage repair-related proteins were detected by western blotting. Our study demonstrated that metformin significantly reduced the cell viability, enhanced radiosensitivity and potentiated radiation-induced caspase-9/-3 cleavage in the NPC cells. In addition, metformin plus radiation significantly upregulated the expression of p-ATM, p-ATR, γ-H2AX and downregulated the expression of ATM, ATR, p95/NBS1, Rad50, DNA-PK, Ku70 and Ku80. Therefore, our results suggest that metformin possesses a strong radiosensitizing potential in NPC cells. This radiosensitizing effect was associated with inhibition of DNA double-strand break repair processes through HR repair and the NHEJ repair signaling pathway, thereby enhancing radiation-induced cell apoptosis. These findings imply that metformin is a potent radiation-sensitizing agent and may be a promising candidate for clinical evaluation as part of a combined regimen for the treatment of nasopharyngeal carcinoma.

Lectin from Agrocybe aegerita as a glycophenotype probe for evaluation of progression and survival in colorectal cancer.

BACKGROUND: Agrocybe aegerita Lectin (AAL) has been identified to have high affinity for sulfated and α2-3- linked sialic acid glycoconjugates, especially the sulfated and sialyl TF (Thomsen-Friedenreich) disaccharide. This study was conducted to investigate the clinicopathological and prognostic value of AAL in identifying aberrant glycosylation in colorectal cancer (CRC). MATERIALS AND METHODS: Glycoconjugate expression in 59 CRC tissues were detected using AAL-histochemistry. Clinicopathological associates of expression were analyzed with chi- square test or Fisher's exact test. Relationships between expression and the various clinicopathological parameters was estimated using Kaplan-Meier analysis and Cox regression models. RESULTS: AAL specific glycoconjugate expression was significantly higher in tumor than corresponding normal tissues (66.1% and 46.1%, respectively, p=0.037), correlating with depth of invasion (p=0.015) and TNM stage (p=0.024). Patients with lower expression levels had a significantly higher survival rate than those with higher expression (p=0.046 by log rank test and p=0.047 by Breslow test for overall survival; p=0.054 by log rank test and P=0.038 by Breslow test for progress free survival). A marginally significant association was found between AAL specific glycoconjugate expression and overall survival by univariate Cox regression analysis (p=0.059). CONCLUSIONS: Lower AAL specific glycoconjugate expression is a significant favorable prognostic factor for overall and progress free survival in CRC. This is the first report about the employment of AAL for histochemical analysis of cancer tissues. The binding characteristics of AAL means it has potential to become a powerful tool for the glycan investigation and clinical application.

An updated meta-analysis of fatal adverse events caused by bevacizumab therapy in cancer patients.

BACKGROUND: The risk of fatal adverse events (FAEs) due to bevacizumab-based chemotherapy has not been well described; we carried out an updated meta-analysis regarding this issue. METHODS: An electronic search of Medline, Embase and The Cochrane Central Register of Controlled Trials was conducted to investigate the effects of randomized controlled trials on bevacizumab treatment on cancer patients. Random or fixed-effect meta-analytical models were used to evaluate the risk ratio (RR) of FAEs due to the use of bevacizumab. RESULTS: Thirty-four trials were included. Allocation to bevacizumab therapy significantly increased the risk of FAEs; the RR was 1.29 (95% CI:1.05-1.57). This association varied significantly with tumor types (P=0.002) and chemotherapeutic agents (P=0.005) but not with bevacizumab dose (P=0.90). Increased risk was seen in patients with non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. However, FAEs were lower in breast cancer patients treated with bevacizumab. In addition, bevacizumab was associated with an increased risk of FAEs in patients who received concomitant agents of taxanes and/or platinum. CONCLUSION: Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs among patients with special tumor types, particularly when combined with chemotherapeutic agents such as platinum.

BIRB796, the inhibitor of p38 mitogen-activated protein kinase, enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cells.

ATP-binding-cassette family membrane proteins play an important role in multidrug resistance. In this study, we investigated BIRB796, an orally active inhibitor of p38 mitogen-activated protein kinase, reversed MDR induced by ABCB1, ABCG2 and ABCC1. Our results showed that BIRB796 could reverse ABCB1-mediated MDR in both the drug selected and transfected ABCB1-overexpressing cell models, but did not enhance the efficacy of substrate-chemotherapeutical agents in ABCC1 or ABCG2 overexpression cells and their parental sensitive cells. Furthermore, BIRB796 increased the intracellular accumulation of the ABCB1 substrates, such as rhodamine 123 and doxorubicin. Moreover, BIRB796 bidirectionally mediated the ATPase activity of ABCB1, stimulating at low concentration, inhibiting at high concentration. However, BIRB796 did not alter the expression of ABCB1 both at protein and mRNA level. The down-regulation of p38 by siRNA neither affected the expression of ABCB1 nor the cytotoxic effect of paclitaxel on KBV200. The binding model of BIRB796 within the large cavity of the transmembrane region of ABCB1 may form the basis for future lead optimization studies. Importantly, BIRB796 also enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBV200 cell xenografts in nude mice. Overall, we conclude that BIRB796 reverses ABCB1-mediated MDR by directly inhibiting its transport function. These findings may be useful for cancer combinational therapy with BIRB796 in the clinic.

Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo.

Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a Phase II clinical trial for the treatment of ovarian cancer. In our study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the doxorubicin (Dox) and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic.

Comparison of KRAS/BRAF mutations between primary tumors and serum in colorectal cancer: Biological and clinical implications.

In colorectal cancer (CRC), KRAS and BRAF mutations in primary tumors are associated with resistance to anti-epidermal growth factor receptor (anti-EGFR)-based therapies. However, the correlation between KRAS/BRAF mutation in primary tumors and serum has not been well studied. To evaluate the degree of concordance of KRAS/BRAF mutations between the primary tumors and the matched serum samples in CRC, serum and tumor tissues were collected from 115 patients with CRC and KRAS/BRAF mutations were examined by nested polymerase chain reaction (PCR) and direct sequencing. BRAF mutations were present in 3.5% (4/115) of the primary tumor tissue samples and 0.87% (1/115) of the serum samples. In the 4 primary tumors with BRAF mutations, identical mutations were not observed in the corresponding serum samples (κ=-0.016). KRAS mutations were observed in 32.2% (37/115) of the primary tumors and 11.3% (13/115) of the serum samples. Of the 37 tumor cases with KRAS mutations, 9 had identical mutations in the corresponding serum sample, with a concordance rate of 24.3% (9/37). Discordance was observed in 32 (27.8%) patients. The concordance between KRAS mutations in the primary tumors and KRAS mutations in the matched serums was low (κ=0.231). The results of the present study suggest that the possibility of differences in the mutational status of KRAS/BRAF between primary tumors and matched serum samples should be considered when patients are selected for anti-EGFR-based therapies.

Effect of dicycloplatin, a novel platinum chemotherapeutical drug, on inhibiting cell growth and inducing cell apoptosis.

Dicycloplatin, a new supramolecular platinum-based antitumor drug, has been approved by the State Food and Administration (SFDA) of China. In this study, we investigated the anticancer activity of dicycloplatin in cancer cells and signaling pathways involved in dicycloplatin-induced apoptosis. Dicycloplatin inhibited the proliferation of cancer cells and increased the percentage of apoptosis in a concentration-dependent manner. Besides, some apoptosis related events were observed after treatment with dicycloplatin, including increase of reactive oxygen species (ROS), collapse of mitochondrial membrane potential (Δψm), release of cytochrome c from the mitochondria to the cytosol, upregulation of p53, which were accompanied by activation of caspase-9, caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage in a concentration-dependent manner. The role of apoptosis in dicycloplatin-mediated cell death was further confirmed by the concomitant treatment with caspase-8 or caspase-9 inhibitors, which inhibited apoptosis and PARP cleavage. Intracellular glutathione (GSH) was also found to inhibit the cytotoxic effect of dicycloplatin. In conclusion, these findings suggest that dicycloplatin induces apoptosis through ROS stress-mediated death receptor pathway and mitochondrial pathway which is similar to carboplatin.

Axitinib targeted cancer stemlike cells to enhance efficacy of chemotherapeutic drugs via inhibiting the drug transport function of ABCG2.

Stemlike cells have been isolated by their ability to efflux Hoechst 33342 dye and are called the side population (SP). We evaluated the effect of axitinib on targeting cancer stemlike cells and enhancing the efficacy of chemotherapeutical agents. We found that axitinib enhanced the cytotoxicity of topotecan and mitoxantrone in SP cells sorted from human lung cancer A549 cells and increased cell apoptosis induced by chemotherapeutical agents. Moreover, axitinib particularly inhibited the function of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) and reversed ABCG2-mediated multidrug resistance (MDR) in vitro. However, no significant reversal effect was observed in ABCB1-, ABCC1- or lung resistance-related protein (LRP)-mediated MDR. Furthermore, in both sensitive and MDR cancer cells axitinib neither altered the expression of ABCG2 at the mRNA or protein levels nor blocked the phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2. In nude mice bearing ABCG2-overexpressing S1-M1-80 xenografts, axitinib significantly enhanced the antitumor activity of topotecan without causing additional toxicity. Taken together, these data suggest that axitinib particularly targets cancer stemlike cells and reverses ABCG2-mediated drug resistance by inhibiting the transporter activity of ABCG2.