[Combination of anlotinib and irinotecan in the second-line treatment of metastatic colorectal cancer: a multicenter phase 1/2 trial].

Objective: To evaluate the safety and efficacy of anlotinib plus irinotecan in the second-line treatment of patients with metastatic colorectal cancer (mCRC). Methods: This prospective phase 1/2 study was conducted in 2 centers in China (Cancer Hospital of Chinese Academy of Medical Sciences and Jiangsu Province Hospital). We enrolled patients with mCRC whose disease had progressed after first-line systemic therapy and had not previously treated with irinotecan to receive anlotinib plus irinotecan. In the phase 1 of the trial, patients received anlotinib (8 mg, 10 mg or 12 mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180 mg/m(2), iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the phase 2, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Results: From May 2018 to January 2020, a total of 31 patients with mCRC were enrolled. Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1, and the RP2D was 12 mg. Thirty patients were evaluable for efficacy analysis. Eight patients achieved partial response, and 21 had stable disease, 1 had progressive disease. The ORR was 25.8% and the disease control rate was 93.5%. With a median follow-up duration of 29.5 months, the median progression-free survival and overall survival were 6.9 months (95% CI: 3.7, 9.3) and 17.6 months (95% CI: 12.4, not evaluated), respectively. The most common grade 3 treatment-related adverse events (≥10%) were neutropenia (25.8%) and diarrhea (16.1%). There was no treatment-related death. Conclusion: The combination of anlotinib and irinotecan has promising anti-tumor activity in the second-line treatment of mCRC with a manageable safety profile.

Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432.

BACKGROUND: High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1. PATIENTS AND METHODS: We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1-d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy. RESULTS: In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24-0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs. CONCLUSIONS: Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent. TRIAL REGISTRATION: ClinicalTrials.gov NCT02915432.

[Expression of HLA-DP in patients with neuromyelitis optica spectrum disorders].

Objective: To investigate the effect of HLA-DP gene expression on the susceptibility and disease status of neuromyelitis optica spectrum disorders (NMOSD). Methods: A total of 86 NMOSD patients (52 in acute phase and 34 in remission phase), 52 multiple sclerosis (MS) patients (20 in acute phase and 32 in remission phase) diagnosed in Department of Neurology, the Third Affiliated Hospital of Sun Yat-sen University and 29 healthy controls were enrolled prospectively. Genotyping of HLA-DP was performed. The expression levels of HLA-DP molecules in peripheral blood B cells and monocytes were measured by flow cytometry. The transcription levels of HLA-DPB1 mRNA in peripheral blood mononuclear cells (PBMC) were measured by real time-PCR. The results were compared among different groups Results: There was no statistically significant difference of the distributions of HLA-DPB1*0501/HLA-DPB1*0501, HLA-DPB1*0501/X and X/X genotypes and the frequencies of allele of HLA-DPB1*0501 among NMOSD, MS patients and healthy controls (P=0.96 and 0.71, respectively). The expression levels of HLA-DP on the surface of B cells in NMOSD patients, especially in remission phase patients, were significantly higher than those in healthy controls(212±328 and 374±394 vs 55±57, P=0.049 and 0.002, respectively). The expression levels of HLA-DP on the surface of monocytes in NMOSD patients in acute phase were significantly higher than those in healthy controls(158±175 vs 65±90, P=0.025). The transcription levels of PMBC HLA-DPB1 mRNA in acute phase and remission phase of NMOSD patients were significantly higher than those in healthy controls (3.0±1.4 and 2.9±1.3 vs 1.5±1.4, P=0.000 and 0.003, respectively). The expression levels of HLA-DP molecules on the surface of peripheral blood B cells and monocytes and the transcription levels of PMBC HLA-DPB1 mRNA in MS patients at the acute and remission stages were not significantly different from those in healthy controls. The expression levels of HLA-DP molecules on the surface of B cells in patients with HLA-DPB1*0501/HLA-DPB1*0501, HLA-DPB1*0501/X and X/X genotypes were statistically different (P=0.017). Conclusion: HLA-DP gene transcription and molecular expression levels in antigen presenting cells may affect the susceptibility and disease status of NMOSD patients, while HLA-DPB1*0501 allele may affect the transcription and molecular expression levels of HLA-DP gene in antigen presenting cells.

[Analysis of clinical characteristics and prognosis of neuromyelitis optic spectrum disease complicated with malignant tumor].

Objective: To investigate the clinical features of patients involved with both malignant tumors and neuromyelitis optica spectrum disorders (NMOSD). Methods: The clinical data of 473 patients with NMOSD admitted into the Third Affiliated Hospital of Sun Yat-sen University and the Department of Neurology, Affiliated Hospital of Guizhou Medical University from June 2012 to March 2017 were retrospectively analyzed. Eleven NMOSD patients complicated with malignant tumors were screened out (3 with breast cancer, 2 with cervical cancer, 2 with rectal cancer, 2 with leukemia, 1 with nasopharyngeal carcinoma, 1 with thyroid cancer). Fifty patients without NMOSD were included as controls. Results: Most of the NMOSD patients were complicated by low-moderately differentiated squamous cell carcinoma/adenocarcinoma, mainly seen in breast, reproductive system, digestive system and hematological system. In terms of sex ratio and autoantibodies, the NMOSD patients with and without malignant tumors showed no significant difference. However, comparing to the patients without malignant tumor, the ones with malignant tumor showed a tendency of lower rate of initial brain symptoms and relapse rate, while with older onset age, higher initial EDSS score, protein content in cerebrospinal fluid (CSF), higher rates of initial symptom resulted from the focus of posterior region of the medulla and of significant image focus. Of the 8 NMOSD patients who diagnosed as malignant tumors in our hospital, 2 with breast cancer and 1 with cervical cancer had a good prognosis (follow-up EDSS score <3). All the 3 patients received aggressive surgery and chemotherapy treatment. However, the other 5 patients had poor prognosis (follow-up EDSS score ≥3 points). All the 11 patients received anti-tumor therapy, 4 patients had first NMOSD attack after anti-tumor treatment and no relapse. Only one case from the remaining 7 patients had relapse; Among the 9 patients received immunosuppressive therapy, 7 patients had no relapse, and 8 cases maintained stable; while, among all the 9 patients received immunosuppressive agents and anti-tumor therapy, only one case had relapse. Conclusions: There are some differences in the clinical features between the NMOSD patients with malignant tumors and the NMOSD patients without malignant tumors. Immunosuppressive therapy can improve the prognosis of patients with NMOSD and tumor, without increasing the risk of malignant tumor. The pathological type, staging and antitumor therapy may influence the prognosis of NMOSD. NMOSD patients with malignant tumor could be treated with anti-tumor and immunosuppressive agents if needed.

[Efficacy and safety of mycophenolate mofetil in treating neuromyelitis optica spectrum disorder: a multicenter, prospective, self-control study in Guangzhou City].

Objective: To evaluate the efficacy and safety of mycophenolate mofetil (MMF) in neuromyelitis optica spectrum disorder (NMOSD). Method: From September 2014 to February 2017, NMOSD patients with seropositive aquaporin4-IgG was enrolled through a multicenter, prospective study, and the annual recurrence rate (ARR), Expanded Disability Status Scale (EDSS) and MMF-related side effects before and after MMF treatment were compared. Results: Ninety patients were enrolled in the study. After being treated for a median of 12 months (1-30 months), the median ARR decreased from 1.1 pre-MMF to 0 post-MMF (P<0.001), and the median EDSS score decreased from 4.0 pre-MMF to 3.0 post-MMF (P<0.001). The EDSS score reduced significantly after 90 days' treatment (P<0.05). The main adverse events included the deranged liver enzymes (19%, 17/90), respiratory infection (11%, 10/90), urinary tract infection (6%, 5/90), varicella-zoster infection (6%, 5/90), anemia (6%, 5/90), leucopenia (6%, 5/90), diarrhea (2%, 2/90), hair loss (1%, 1/90); 11% (10/90) patients experienced severe adverse events, and 6% (5/90) patients discontinued MMF. Conclusions: MMF could significantly reduce the ARR and EDSS score of NMOSD. However, awareness on side effects should be raised.

First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.

BACKGROUND: Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. PATIENTS AND METHODS: Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. RESULTS: Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group. CONCLUSIONS: First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.

Efficacy and safety of fosaprepitant in the prevention of nausea and vomiting following highly emetogenic chemotherapy in Chinese people: A randomized, double-blind, phase III study.

The prevention of chemotherapy-induced nausea and vomiting was one of the most challenging supportive care issues in oncology, especially to highly emetogenic chemotherapy (HEC). A total of 645 patients were randomized into fosaprepitant group (fosaprepitant/placebo 150 mg d1 in combination with granisetron and dexamethasone) or aprepitant group (aprepitant/placebo 125 mg d1; 80 mg d2-d3 plus granisetron and dexamethasone).The primary endpoint was the percentage of patients who had a complete response (CR) over the entire treatment course (0-120 hr, overall phase [OP]). It was assessed by using a non-inferiority model, with a non-inferiority margin of 10%. The difference of the CR rate was compared between two groups with chi-square analysis. Six hundred and twenty-six patients were included in the per protocol analysis. The percentage of patients with a CR in the fosaprepitant group was not inferior to that in the aprepitant group (90.85% versus 94.17%, p = .1302) during OP. Whether the cisplatin-based chemotherapy or not, the CR rate of the fosaprepitant group was not inferior to that of the aprepitant group. Both regimens were well tolerated. The most common adverse event was constipation. Fosaprepitant provided effective and well-tolerated control of nausea and vomiting associated with HEC in Chinese patients.

[Clinical analysis of acute disseminated encephalomyelitis in 44 cases].

Objective: To investigate the clinical features in 44 patients with acute disseminated encephalomyelitis (ADEM). Methods: Consecutive ADEM patients admitted to Neurology Department of the Third Affiliated Hospital of Sun yat-sen University during August 2009 to July 2014 were enrolled.Clinical and laboratory data of the patients were reviewed and analyzed. Results: Forty-four patients with ADEM based on the 2012 criteria were recruited, including 23 male and 21 female; 9 children, 11 teenagers and 24 adults.There were 23 monophasic ADEM (23/44, 52%) and 21 multiphasic ADEM (21/44, 48%). Fourteen patients (31.8%) had definite incentive factors within 2 weeks preceding the disease onset.The commonest presenting symptoms were fever (20/44, 45%), mental disorder (18/44, 41%), disturbance of consciousness (17/44, 39%) and seizure (12/44, 27%). The average EDSS score was (4.3±1.3), and the average mRS score was (2.7±0.9). Abnormal autoimmune antibodies were detected in 10 patients.Two patients were positive for NMO-IgG, and three patients were positive for oligoclonal bands.On MRI scanning, small lesions were observed in 18 of 44 patients (18/44, 41%); large confluent white matter lesions in 10 patients (10/44, 23%); symmetric bithalamic involvement in 12 patients (12/44, 27%). Patients were mainly treated with intravenous corticosteroids (40/44, 90.9%) and immunoglobulin G ( 13/44, 29.5%) in acute phase.Regular follow-up performed in 29 patients (65.9%), and the average follow-up time was (4.2±2.3) year.A monophasic course was found in 10 patients, and multiphasic course in 19 patients.After (2.5±2.3) years, patients with multiphasic ADEM experienced their first clinical relapse, and the relapse frequency was (3.3±1.4). The average EDSS score was (3.9±2.2), and the mRS score was (2.2±1.3) in their latest relapse.In follow-up MRI for (5.3±1.9) years, lesions in 18 patients (62.1%) were partially ameliorated, while 6 patients (20.7%) persisted, and new lesions appeared in 5 patients (17.2%). For the 13 multiphasic patients with regular treatment, intravenous corticosteroids (13/13, 100.0%) and immunoglobulin G (7/13, 53.8%) were still important treatments in the acute phase, while oral steroids (12/13, 92.3%) plus immunosuppressants including azathioprine, tacrolimus, cyclosporine and rituximab were chosen in the remission phase. Conclusions: ADEM is not uncommon in adults, presenting with multiphasic course, encephalopathy features and disseminated lesions on MRI.As it shows very heterogeneous characteristics, ADEM is best viewed as a "syndrome" rather than a specific disorder.

MiR-146a-5p level in serum exosomes predicts therapeutic effect of cisplatin in non-small cell lung cancer.

OBJECTIVE: Lung cancer is the most common cause of death in cancer worldwide, and cisplatin plays an important role in its treatment. However, the response to chemotherapy is poorly attributable to drug resistance. Our present study aimed to investigate the relation of the exosomal miR-146a-5p level with the chemosensitivity of NSCLC to cisplatin and the molecular mechanism that miR-146a-5p mediated to effect on chemotherapy response. PATIENTS AND METHODS: The exosomes were isolated by ExoQuick kit. The exosomal morphology and particle size distribution were evaluated by the transmission electron microscopy and nanoSight assay respectively. Cell proliferation was detected using the MTT assay. NSCLC cells were infected with mimics or inhibitor to overexpress or downregulate miR-146a level. Besides, Quantitative real-time PCR, Western blot analysis, and immunohistochemistry were applied to detect the relative miRNA and protein levels. RESULTS: Advanced NSCLC patients with low serum exosomal miR-146a-5p levels had higher recurrence rates than those with high levels. A549/DDP cells and exosomes expressed higher miR-146a-5p than A549. In the process of cisplatin-induced drug resistance, the expression of miR-146a-5p decreased in either NSCLC cell lines or the exosomes gradually. What's more, the overexpression of miR-146a-5p could reverse the resistance of A549/DDP. And the possible mechanism of miR-146a-5p increasing chemosensitivity of NSCLC to cisplatin could be targeting Atg12 to inhibit autophagy. CONCLUSIONS: Serum exosomal miR-146a-5p may be a new biomarker predicting the efficacy of cisplatin for NSCLC patients and real-time monitoring drug resistance.

Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling.

Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.

Paclitacxel and carboplatin in advanced non-small-cell lung cancer.

To evaluate the efficacy and toxicity of the combination of paclitacxel and carboplatin on advanced non-small-cell lung cancer (NSCLC). Forty-eight patients with locally advanced (stage IIIb) or metastatic (stage IV) NSCLC were enrolled into the study. The patients received paclitacxel 55-60 mg/m(2) on day 1, 8, 15, carboplatin at an AUC of 5 on day 1, administreted in 28-day cycle. An objective response was obtained in 37.5% of patients (two complete and 16 partial responses). Significant difference existed between the naive patients and pretreated patients (46.4% vs. 25.0%, P<0.05). The main toxicities were bone marrow suppression, nausea/vomiting and alopecia. The combination of paclitacxel and carboplatin is an effective, well-tolerated scheme in the treatment of advanced NSCLC. The efficacy is higher in the naive group than in the pretreated group.

SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer.

The long noncoding RNA TINCR shows aberrant expression in human squamous carcinomas. However, its expression and function in gastric cancer remain unclear. We report that TINCR is strongly upregulated in human gastric carcinoma (GC), where it was found to contribute to oncogenesis and cancer progression. We also revealed that TINCR overexpression is induced by nuclear transcription factor SP1. Silencing TINCR expression inhibited cell proliferation, colony formation, tumorigenicity and apoptosis promotion, whereas TINCR overexpression promoted cell growth, as documented in the SGC7901 and BGC823 cell lines. Mechanistic analyses indicated that TINCR could bind to STAU1 (staufen1) protein, and influence KLF2 mRNA stability and expression, then KLF2 regulated cyclin-dependent kinase genes CDKN1A/P21 and CDKN2B/P15 transcription and expression, thereby affecting the proliferation and apoptosis of GC cells. Together, our findings suggest that TINCR contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.

Low expression of long noncoding RNA PANDAR predicts a poor prognosis of non-small cell lung cancer and affects cell apoptosis by regulating Bcl-2.

Recently, a novel class of transcripts, long noncoding RNAs (lncRNAs), is involved in diseases including cancer. Here, we investigated the the role of lncRNA PANDAR in the progression of non-small cell lung carcinoma (NSCLC). PANDAR, interacting with NF-YA, was generally downregulated in NSCLC tissues. In a cohort of 140 NSCLC patients, decreased PANDAR expression was negatively correlated with greater tumor size (P<0.001) and advanced TNM stage (P=0.002). Moreover, PANDAR could serve as an independent predictor for overall survival in NSCLC (P=0.015). Further experiments demonstrated that PANDAR expression was induced by p53, and chromatin immunoprecipitation (ChIP) assays confirmed that PANDAR was a direct transcriptional target of p53 in NSCLC cells. PANDAR overexpression significantly repressed the proliferation in vitro and in vivo. We also showed that PANDAR-mediated growth regulation is in part due to the transcriptional modulation of Bcl-2 by interacting with NF-YA, thus affecting NSCLC cell apoptosis. To our knowledge, this is the first report which showed the role of PANDAR in the progression of NSCLC. The p53/PANDAR/NF-YA/Bcl-2 interaction might serve as targets for NSCLC diagnosis and therapy.

P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression.

Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.

The effect of monosialotetrahexosylganglioside (GM1) in prevention of oxaliplatin induced neurotoxicity: a retrospective study.

Oxaliplatin is a key agent in the treatment of colorectal cancer. However, peripheral neuropathy markedly limits the use of oxaliplatin. This retrospective study was performed to assess the efficacy of monosialotetrahexosylganglioside (GM1) for preventing oxaliplatin induced neurotoxicity. Patients with colorectal cancer treated with oxaliplatin based chemotherapy (FOLFOX or XELOX) were retrospectively divided into two groups according to the use of GM1. The severity of neurotoxicity and efficacy of oxaliplatin were evaluated. A total of 278 cases were included, 114 in GM1 group and 164 in control group. A significantly lower incidence of grade 1-3 acute neurotoxicity (81% vs 92%, p=0.006), grade 2 acute neurotoxicity (26% vs 45%, p=0.002) was observed in GM1 group. Similarly, incidence of grade 1-3 (30% vs 48%, p=0.003) and grade 3 chronic neurotoxicity (4% vs 13%, p=0.021) was also lower in GM1 group. No difference was detected in objective response rate, progress free survival, and median overall survival between GM1 group and control group. The retrospective study demonstrated that GM1 significantly reduced the incidence of oxaliplatin induced neuropathy, especially severe neuropathy, without impairment of efficacy. Prospective trials of GM1 as neuroprotective of oxaliplatin treatment in colorectal cancer are warranted.

Expression of livin in gastric cancer and induction of apoptosis in SGC-7901 cells by shRNA-mediated silencing of livin gene.

BACKGROUND: Because of increased resistance to apoptosis in tumor cells, inhibition of specific anti-apoptotic factors may provide a rational approach for the development of novel therapeutic strategies. Livin, a novel inhibitor of apoptosis protein family, has been found to be expressed in various malignancies and is suggested to have poorly prognostic significance. However, no data are available concerning the significance of livin in gastric cancer. In this study, we detected the expression of livin in human gastric carcinoma and investigated the apoptotic susceptibility of SGC - 7901 cell by shRNA-mediated silencing of the livin gene. METHODS: The mRNA and protein expression of livin were analyzed by RT-PCR and western blot assay. The relationship between livin expression and clinical pathologic parameters was investigated. The small interfering RNA eukaryotic expression vector specific to livin was constructed by gene recombination, and the nucleic acid was sequenced. Then it was transfected into SGC-7901 cells by Lipofectamin 2000. RT-PCR and Western blot assay were used to validate gene-silencing efficiency of livin in SGC-7901 cells. Stable clones were obtained by G418 screening. The cell apoptosis was assessed by flow cytometry (FCM). Cell growth state and 50 % inhibition concentration (IC50) of 5-FU and cisplatin was determined by MTT method. RESULTS: The expression of livin mRNA and protein were detected in 19 of 40 gastric carcinoma cases (47.5%) and SGC-7901 cells. No expression of livin was detected in tumor adjacent tissues and benign gastric lesion. The positive correlation was found between livin expression and poor differentiation of tumors as well as lymph node metastases (P<0.05). Four small interfering RNA eukaryotic expression vector specific to livin were constructed by gene recombination. And one of them can efficiently decrease the expression of livin, the inhibition of the gene was not less than 70% (P<0.01). The recombinated plasmids were extracted and transfected gastric cancer cells. The stable clones were obtained by G418 screening, and were amplified and cultured. When livin gene was silenced, the reproductive activity of the gastric cancer cells was significantly lower than the control groups(P<0.05). The study also showed that IC50 of 5-Fu and cisplatin on gastric cancer cells treated by shRNA was decreased and the cells were more susceptible to proapoptotic stimuli (5-Fu and cisplatin) (P<0.01). CONCLUSIONS: Livin is overexpressed in gastric carcinoma with a relationship to tumor differentiation and lymph node metastases, which is suggested to be one of the molecular prognostic factors for some cases of gastric cancer. ShRNA can inhibit livin expression in SGC-7901 cells and induce cell apoptosis. Livin may serve as a new target for apoptosis-inducing therapy of gastric cancer.