Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

BACKGROUND: Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). AIM: To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC. METHODS: This multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups. RESULTS: The median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05). CONCLUSION: A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.

Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy.

Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P = 0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.

Chimeric Antigens Receptor T Cell Therapy Improve the Prognosis of Pediatric Acute Lymphoblastic Leukemia With Persistent/Recurrent Minimal Residual Disease in First Complete Remission.

Background: The presence of minimal residual disease (MRD) is an independent risk factor for poor prognosis in patients with acute lymphoblastic leukemia (ALL). Moreover, the role of chimeric antigen receptor T-cell (CAR-T) therapy in patients with MRD is currently unclear. Methods: We conducted a prospective study to investigate the role of CAR-T therapy in patients with persistent/recurrent MRD-positive ALL in first remission. Results: A total of 77 patients who had persistent/recurrent MRD were included. Of these patients, 43 were enrolled in the CAR-T group, 20 received chemotherapy as a bridge to allogeneic hematopoietic cell transplantation (allo-HSCT), and 14 patients received intensified chemotherapy. MRD negativity was achieved in 90.7% of the patients after CAR-T infusion. Patients who received CAR-T therapy had a higher 3-year leukemia-free survival (LFS) than patients who did not (77.8% vs. 51.1%, P = 0.033). Furthermore, patients in the CAR-T group had a higher 3-year LFS than those in the chemotherapy bridge-to-allo-HSCT group [77.8% (95% CI, 64.8-90.7%) vs. 68.7% (95% CI, 47.7-89.6%), P = 0.575] and had a significantly higher 3-year LFS than those in the intensified chemotherapy group [77.8% (95% CI, 64.8-90.7%) vs. 28.6% (95% CI, 4.9-52.3%), P = 0.001]. Among the patients who received CAR-T therapy, eight were not bridged to allo-HSCT, and six (75%) remained in remission with a median follow-up of 23.0 months after CAR-T infusion. Conclusions: Our findings show that CAR-T therapy can effectively eliminate MRD and improve survival in patients with a suboptimal MRD response.

Endoscopic trans-esophageal submucosal tunneling surgery: A new therapeutic approach for diseases located around the aorta ventralis.

AIM: To assess the efficiency of endoscopic trans-esophageal submucosal tunneling surgery (EESTS) technique for diseases located around the aorta ventralis. METHODS: Nine pigs were assigned to EESTs. The procedures were as follows: First, a long esophageal submucosal tunnel was established. Second, full-thickness myotomy was created. Third, an endoscope was entered into the abdominal cavity through a muscle incision and the endoscope was around the aorta ventralis. Eventually, celiac trunk ganglion neurolysis, partial hepatectomy and splenectomy, partial tissue resection in the area of the posterior peritoneum, and endoscopic submucosal dissection (ESD) combined with lymph node dissection were performed. The animals were given antibiotics for 5 d and necropsied 7 d after surgery. RESULTS: In all surgeries, one pig died from intraperitoneal hemorrhage after doing partial splenectomy, while the other pigs were alive after successfully operating other surgeries. For surgery of celiac trunk ganglion damage, at necropsy, there was no exudation in the abdominal cavity. Regarding surgery of partial hepatectomy, the wound with part healing was observed in the left hepatic lobe, and no bleeding or obvious exudation was seen. In surgery of partial splenectomy, massive hemorrhage was observed on the splenic wound surface, and the metal clips could not stop bleeding. After surgery of retroperitoneal tissue resection, mild tissue adhesion was observed in the abdominal cavity of one animal, and another one suffered from severe infection. For surgery of ESD and lymph node dissection, a moderate tissue adhesion was observed. CONCLUSION: EESTS is a feasible and safe technique for diseases located around the aorta ventralis.

FcRγ deficiency improves survival in experimental sepsis by down-regulating TLR4 signaling pathway.

Fc receptor common γ signaling chain (FcRγ), a common subunit shared by Fc receptors (FcγRI, III, IV, FcαRI, and FcεRI), is an important immune regulator both in innate and adaptive immunity. Previous studies have shown that FcRγ was a potential target of inflammatory diseases, whereas the role of FcRγ in sepsis has been poorly understood. In this study, we found that deficiency of FcRγ resulted in increased survival in lipopolysaccharide (LPS)/D-galactosamine and E. coli-induced sepsis in mice. This protective effect was characterized by decreased TNF-α, IL-6, and IL-10. Further experiments in bone marrow-derived macrophages (BMDMs) in vitro also showed that FcRγ deficiency resulted in decreased production of TNF-α, IL-6, and IL-10 upon LPS stimulation. The mechanism study showed that FcRγ was physiologically associated with toll-like receptor 4 (TLR4), and tyrosine phosphorylation of FcRγ mediated TLR4 signaling pathway, followed by increased ERK phosphorylation upon LPS stimulation. Our results suggest that FcRγ might be a potential therapeutic target of sepsis.

[Roles of Tumor-infiltrating Lymphocytes in Non-small Cell Lung Cancer Recurrence and Metastasis:A Meta Analysis].

OBJECTIVE: To determine the prognostic value of tumor-infiltrating lymphocytes in the recurrence and metastasis of non-small cell lung cancer (NSCLC). METHODS: A PubMed, EMBASE, Cochrane Library databases, NIH databases, and China Biology Medicine disc, China National Knowledge Infrastructure, Chinese Science and Technology Periodical literature search strategy was designed. Studies on the prognostic values of intratumoural CD3⁺,CD4⁺,CD8⁺, and FoxP3+lymphocytes for NSLCL were retrieved. RevMan 5.1 was applied for Meta analysis. RESULTS: Totally 8 studies entered the final analysis. In pooled analysis of 1197 patients,the high expressions of CD3⁺ and CD8⁺ cells were correlated with the increase of overall survival (OS) (OR=0.52,95% CI=0.40- 0.68, P<0.0001; OR=0.52,95% CI=0.34-0.79,P=0.002), and the high expression of CD8⁺ was significantly correlated with the increase of disease-free survival (DFS) (OR=0.68,95% CI=0.51-0.91,P=0.01). The CD4⁺ cell expression level was not significantly correlated with OS or DFS (P=0.14, P=0.73). The high expression of FoxP3⁺ cells did not favor the DFS(OR=1.78,95% CI=1.36-2.31; P<0.0001). CONCLUSION: The expression levels of CD3⁺, CD8⁺ and FoxP3⁺ in NSCLC microenviroment are related with the prognosis of NSCLC, while the role of CD4⁺ in the development of NSCLC warrants further investigations.

Adoptive immunotherapy for small cell lung cancer by expanded activated autologous lymphocytes: a retrospective clinical analysis.

BACKGROUND: To investigate the clinical efficacy of expanded activated autologous lymphocytes (EAAL) in patients with small cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 32 SCLC patients were selected and randomly divided into EAAL treatment and control groups, 16 cases in each. EAAL were obtained by proliferation of peripheral blood mononuclear cells (PBMCs) of patients followed by phenotype determination. Clinical data of all patients were recorded. Patients of both groups were followed up and the overall survival (OS) were compared retrospectively. RESULTS: After culture and proliferation in vitro, the percentages of CD3+, CD3+CD8+, CD45RO+, CD28+, CD29+, CD8+CD28+ and CD3+CD16+/CD56+ cells increased markedly (p<0.05). The OS of the EAAL treatment group was longer than that of control group, but the difference was not statistically significant (p=0.060, HR=0.487, 95%CI 0.228~1.037). 1- to 3-year survival rates in EAAL treatment group were longer than those in control group, but there was still no significant difference (p>0.05). COX multivariate regression analysis showed that the number of chemotherapy cycles and the application of EAAL immunotherapy were independent prognostic factors for SCLC patients. The OS in females and chemotherapy≤6 cycles were obviously prolonged after EAAL immunotherapy. CONCLUSIONS: In vitro induction and proliferation of EAAL is easy and biologically safe. Generally, EAAL adoptive immunotherapy can evidently prolong the OS of SCLC patients.

Prolonged overall survival in gastric cancer patients after adoptive immunotherapy.

AIM: To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes (EAALs) in gastric cancer. METHODS: An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients, of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment (control group). EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination. Clinical data including age, gender, clinical stage, chemotherapeutic regimens, hospitalization, surgical, radiotherapy, and survival data were collected along with EAAL therapy details and side effects. Patients were followed and the relationship between treatment and overall survival (OS) data obtained for the immunotherapy and control groups were compared retrospectively. The safety of EAAL immunotherapy was also evaluated. RESULTS: After in vitro culture and proliferation, the percentages of CD3+, CD3+CD8+, CD8+CD27+, CD8+CD28+, and CD3+CD16+/CD56+ cells increased remarkably (P < 0.05), while the percentages of CD3+CD4+, CD4+CD25+, and CD3-CD16+/CD56+ (natural killer cells) were overtly decreased (P < 0.05); no significant change was observed in CD4+CD25+CD127- cells (P = 0.448). Interestingly, OS in the immunotherapy group was significantly higher than that in the control group, with 27.0 and 13.9 mo obtained for the two groups, respectively (P = 0.028, HR = 0.573, 95%CI: 0.347-0.945). These findings indicated a 42.7% decrease in the risk of death. In addition, we found that clinical stage and application of EAAL immunotherapy were independent prognostic factors for gastric cancer patients. Indeed, the OS in stage IIIc and IV patients that had received surgery was prolonged after EAAL immunotherapy (P < 0.05). Importantly, in vitro induction and proliferation of EAAL were easy and biologically safe. CONCLUSION: Overall, EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.

[Effect of FCGR3A Polymorphisms on Antibody-dependent Cetuximab-mediated Cytotoxicity in A549 Cells].

OBJECTIVE: To investigate the effect of FCGR3A polymorphisms on the antibody-dependent cell-mediated cytotoxicity (ADCC) activity induced by cetuximab against A549 cells. METHODS: A549 cell line was used as target cells and NKTm cells as effector cells. FCGR3A polymorphisms were detected by direct sequencing. The ADCC activity mediated by cetuximab was assessed by CCK-8 assay. RESULTS: Three genotypes of FCGR3A were detected:V/V,V/F,and F/F. The ADCC activity of NKTm cells with these three different genotypes mediated by cetuximab were significantly different (P=0.0015). NKTm cells with FCGR3A-158V/V genotypes had significantly higher ADCC activity than FCGR3A-V/F or F/F genotypes (P<0.01),whereas the ADCC activity between V/F and F/F genotype showed no statistical significance(P>0.05). CONCLUSION: FCGR3A polymorphisms have an impact on ADCC activity mediated by cetuximab in NKTm cells.

HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer.

BACKGROUND: In the Trastuzumab for GAstric cancer (ToGA) study, trastuzumab plus chemotherapy improved median overall survival by 2.7 months in patients with human epidermal growth factor receptor 2 (HER2)-positive [immunohistochemistry (IHC) 3+/fluorescence in situ hybridization-positive] gastric/gastroesophageal junction cancer compared with chemotherapy alone (hazard ratio 0.74). Post hoc exploratory analyses in patients expressing higher HER2 levels (IHC 2+/fluorescence in situ hybridization-positive or IHC 3+) demonstrated a 4.2-month improvement in median overall survival with trastuzumab (hazard ratio 0.65). The ToGA study provides the largest screening dataset available on HER2 overexpression/amplification in this indication. We further analyzed correlation(s) of HER2 overexpression/amplification with clinical and epidemiological factors. METHODS: HER2-positivity was analyzed by histological subtype, tumor location, geographic region, and specimen type. Exploratory efficacy analyses were performed. RESULTS: The HER2-positivity rate was 22.1 % across analyzed tumor samples. Rates were similar between European and Asian patients (23.6 % vs. 23.9 %), but higher in intestinal- vs. diffuse-type (31.8 % vs. 6.1 %), and gastroesophageal junction cancer versus gastric tumors (32.2 % vs. 21.4 %). Across all IHC scores, variability in HER2 staining (≤30 % stained cells) was observed in almost 50 % of cases, with increasing rates in lower IHC categories, and did not affect treatment outcome. The polysomy rate was 4 %. CONCLUSIONS: HER2 expression varies by tumor location and type. All patients with advanced gastric or gastroesophageal junction cancer should be tested for HER2 status, preferably using IHC initially. Due to the unique characteristics of gastric cancer, specific testing/scoring guidelines should be adhered to.

Heterogeneity of epidermal growth factor receptor mutations in lung adenocarcinoma harboring anaplastic lymphoma kinase rearrangements: A case report.

Lung cancer is a heterogeneous and complex disease that remains the leading cause of cancer-related mortality worldwide. The identification of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangements has changed the treatment of non-small cell lung cancer, creating a personalized treatment era that is based on the appropriate molecular selection of patients. In spite of the efficacy of tyrosine kinase inhibitors (TKIs), acquired resistance remains inevitable due to various mechanisms. The present study reports the case of a 30-year-old patient with stage IV lung adenocarcinoma initially harboring an EGFR mutation. However, following disease progression and a series of treatments, the wild-type EGFR gene was observed and the ALK rearrangements were revealed. Erlotinib administration resulted in a good response in the patient initially, but crizotinib did not. This indicated an association between the secondary mutations in kinases and the drug resistance to TKIs. This case should also highlight the clinical significance of repeat biopsies for the subsequent therapeutic choices at the onset of clinical progression.

A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers.

INTRODUCTION: The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m(2) or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m(2) (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. CONCLUSIONS: Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable.

A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC).

BACKGROUND: The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. METHODS: This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. RESULTS: Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. CONCLUSIONS: The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting.

Measurement of serum antibodies against NY-ESO-1 by ELISA: A guide for the treatment of specific immunotherapy for patients with advanced colorectal cancer.

NY-ESO-1 has been identified as one of the most immunogenic antigens; thus, is a highly attractive target for cancer immunotherapy. The present study analyzed the expression of serum antibodies (Abs) against NY-ESO-1 in patients with advanced colorectal cancer (CRC), with the aim of guiding the treatment of NY-ESO-1-based specific-immunotherapy for these patients. Furthermore, the present study was the first to evaluate the kinetic expression of anti-NY-ESO-1 Abs and investigate the possible influencing factors. A total of 239 serum samples from 155 pathologically confirmed patients with advanced CRC (stages III and IV) were collected. The presence of spontaneous Abs against NY-ESO-1 was analyzed using an enzyme-linked immunosorbent assay (ELISA). The results demonstrated that 24.5% (38/155) of the investigated patients were positive for NY-ESO-1-specific Abs. No statistically significant correlations were identified between the expression of anti-NY-ESO-1 Abs and clinicopathological parameters, including age and gender, location, grading, local infiltration, lymph node status, metastatic status and K-ras mutation status (P>0.05). In 59 patients, the kinetic expression of anti-NY-ESO-1 Abs was analyzed, of which 14 patients were initially positive and 45 patients were initially negative. Notably, 16/59 (27.1%) patients changed their expression status during the study period, and the initially positive patients were more likely to change compared with the initially negative patients (85.7 vs. 8.8%; P<0.001). Therefore, monitoring serum Abs against NY-ESO-1 by ELISA is an easy and feasible method. The high expression rate of NY-ESO-1-specific Abs in CRC patients indicates that measuring the levels of serum Abs against NY-ESO-1 may guide the treatment of NY-ESO-1-based specific immunotherapy for patients with advanced CRC.

Efficacy analysis of tyrosine kinase inhibitors on rare non-small cell lung cancer patients harboring complex EGFR mutations.

The efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small cell lung cancer (NSCLC) is related to EGFR mutations. Although the p.L858R point mutation in exon 21 and the in-frame deletion mutation in exon 19 are well known, efficacy of EGFR-TKI in patients with more than one EGFR mutation is not well understood. 799 NSCLC patients were screened for EGFR mutations. Of the 799 patients, 443 (55.4%) had mutations, out of which 22 (2.75%) had multiple complex mutations. Most multiple mutations (20/22) harbored common mutations such as the p.L858R point mutation in exon 21 and the in-frame deletion mutation in exon 19. 11 out of 22 patients who had multiple EGFR mutations underwent TKI therapy and primary end-points of progression free and overall survival were determined. Our analysis revealed that cases with multiple mutations had similar end-point outcomes as single mutation to TKI therapy. Report of these cases will be helpful in decision making for treatment of NSCLC patients harboring multiple EGFR mutations.

Fatal interstitial lung disease after addition of sorafenib to a patient with lung adenocarcinoma who had failed to improve with erlotinib alone.

Interstitial lung disease (ILD) induced by epidermal growth factor receptor tyrosine kinase inhibitors has been extensively documented with decreasing incidence after appropriate patient selection due to increasing awareness over the years. However, ILD induced by sorafenib was mentioned with lower frequency only in patients with hepatocellular and renal cell carcinoma living in Japan but not in patients with other carcinomas or living outside Japan, and it has been overlooked in clinical practice. In the present case, sorafenib was added to the treatment of a 60-year-old non-smoking patient with non-small cell lung cancer (NSCLC). After his failing to improve with erlotinib alone, erlotinib was continued to be given in combination with sorafenib as a salvage therapy. Although clinical signs of ILD were observed 2 weeks after the addition of sorafenib, the radiological diagnosis of ILD was only made 41 days after the initiation of the combination treatment, and the patient died 56 days after treatment onset. It was concluded that ILD was indeed induced by sorafenib. This is the first report of ILD induced by sorafenib in a patient with NSCLC living outside Japan. Oncologists should be aware of this fatal complication for its early detection in order to avoid a severe course of ILD leading to a decrease in the ILD mortality rate.

Activating transcription factor 3 promotes colon cancer metastasis.

Colorectal cancer is one of the commonest of solid malignancy in the world. Activating transcription factor 3 (ATF3), a homolog of the mouse TI-241 and rat LFR-1, is a stress responsive gene that has been widely indicated in different malignancies. However, the role of ATF3 in colon cancer is paradoxical with both a suggested pro- and anti-tumorigenic role. The objective of the current study was to investigate the role of ATF3 in colon cancer metastasis using HT29 and CaCO2 colon cancer cell lines. Expression of ATF3 was initially evaluated in five pairs of colon cancer and matched noncancerous colon tissues. The role of ATF3 in promoting in vitro migration and invasion were evaluated by siRNA-mediated knockdown and adenovirus-mediated overexpression of ATF3. In addition, the role of ATF3 in promoting in vivo tumor growth and hepatic metastasis was investigated by shRNA-mediated knockdown of ATF3. Expression of ATF3 was more in the colon cancer tissues as compared with the pooled noncancerous control colon tissue. Our results showed that in both HT29 and CaCO2 cells, ATF3 promoted in vitro motility and invasion. Furthermore, knockdown of ATF3 attenuated subcutaneous tumor growth and CD31(+) neovasculature in xenograft assays with HT29 and CaCO2 cells and inhibited hepatic metastasis. Cumulatively, our results unequivocally show that ATF3 promotes colon cancer metastasis.

[Role of epidermal growth factor receptor expression level in cetuximab cytotoxicity and antibody-dependent cell-mediated cytotoxicity effect against A549 lung cancer cell line].

OBJECTIVE: To investigate the role of epidermal growth factor receptor (EGFR) expression level in cetuximab cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) effect against A549 lung cancer cell line. METHODS: A549 cell line and NKTm cells were used as the target cell and the effector cell, respectively. pEGFR-EGFP plasmids were transfected into A549 cells by nucleofector method. EGFR expression levels were measured by immunohistochemistry. The ADCC activity induced by cetuximab was assessed by cell counting kit-8 assay. RESULTS: A549 cells transfected with pEGFR-EGFP plasmids expressed higher level of EGFR protein on membrane and were more sensitive to ADCC activity mediated by cetuximab (P<0.05). The inhibition rate of A549 cells showed no significant difference between transfection group and wild-type group when treated with cetuximab alone (P> 0.05). CONCLUSION: EGFR expression level influences the sensitivity of A549 lung cancer cell line to ADCC activity mediated by cetuximab but not to cetuximab alone.

TGF-ß1 precursor and CD8 are potential prognostic and predictive markers in operated breast cancer.

The transforming growth factor ß1 (TGF-ß1) and CD8-positive T cells are two important immune factors that function at opposite directions. The purpose of this study was to verify the relationship between the two factors and their associations with long-term effects of adjuvant chemotherapy or endocrine therapy in breast cancer. Expression of TGF-ß1 precursor and CD8 was immunohistochemically detected on surgically-obtained tumor samples of 130 (stage I-III) invasive breast carcinomas from Chinese subjects, who were followed up for a mean time of 112 months. Interstitial CD8-positive cells and TGF-ß1 precursor-positive cells adjacent to tumor nests were counted. Infiltration of CD8-positive lymphocytes into tumor nests and TGF-ß1 precursor expression in tumor cells were observed and survival analysis was performed. Our results showed that density of interstitial CD8-positive lymphocytes was an independent adverse prognostic factor for distant disease-free survival (DDFS) (HR=8.416, 95% CI=1.636-43.292, P=0.011) in hormone receptor-positive patients who were on adjuvant endocrine therapy. For breast cancer patients who did not receive adjuvant chemotherapy, those without infiltration of CD8-positive cells into tumor nests had a shorter overall survival (OS) than their counterparts with CD8-positive cell infiltration into tumor nests (Log-Rank, P=0.003). But OS of patients without infiltration of CD8-positive cells into tumor nests was significantly prolonged by adjuvant chemotherapy (Log-Rank, P=0.013) and paralleled that of patients with CD8-positive cell infiltration. Although OS was shorter in the tumor cell TGF-ß1 precursor (t-TGF-ß1-pre)-positive patients than in the negative patients in patients without receiving chemotherapy (P=0.053), OS of t-TGF-ß1-pre-positive patients was significantly prolonged by adjuvant chemotherapy (P=0.035) and was longer than that of t-TGF-ß1-pre-negative patients. Analysis showed that t-TGF-ß1-pre was an independent positive prognostic factor for DDFS (HR=0.392 95% CI=0.157-0.978, P=0.045) in patients who received adjuvant chemotherapy. This study suggested that density of interstitial CD8-positive lymphocytes was of prognostic value in hormone receptor-positive patients who received adjuvant endocrine therapy. Our study verified that adverse immunologic signatures consisting of absence of CD8-positive cells in tumor nests or expression of TGF-ß1 precursor in tumor cells in breast cancer were associated with worse prognosis and significantly improved long-term survival with adjuvant chemotherapy, respectively.

Analysis on survival and prognostic factors for cancer patients with malignancy-associated hypercalcemia.

OBJECTIVE: To explore the incidence, clinical characteristics, diagnosis and treatment strategies, prognosis of patients with malignancy-associated hypercalcemia (MAH). METHODS: The data of 115 patients with MAH who were treated at the Medical Oncology Department of Chinese PLA General Hospital from Jan., 2001 to Dec., 2010 was retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazard model with statistic software SPSS 18.0. RESULTS: The patients had blood calcium levels ranging from 2.77 to 4.87 mmol/L. Except for 9 cases who died or were discharged within 5 days after admission, all other patients recovered to normal blood calcium level after treatment with bisphosphonates or intravenous hydration and diuretics; their survival after occurrence of MAH was from 1 day to 4,051 days, and the median survival time was only 50 days. In the log-rank test, the male, renal metastasis, central nervous system symptoms and hypercalcemia occurring over 140 days after cancer diagnosis were predictors of poor survival (P=0.002, P=0.046, P=0.000, P=0.009). In the COX analysis, being male, central nervous system symptoms and hypercalcemia lasting over 140 days after cancer diagnosis were independent prognostic factors for survival time (RR=2.131, P=0.027; RR=3.054, P=0.002; RR=2.403, P=0.001). According to these factors, a score system was established to predict the patient prognosis and adjust the treatment. CONCLUSION: Cancer patients with MAH have an extremely poor median survival. Some independent factors indicate poor prognosis, including male gender, central nervous system symptoms and hypercalcemia lasting over 140 days after cancer diagnosis. The prognostic score can serve as a reference for MAH prognosis and treatment, worthy of further investigation.