Anlotinib Versus Sunitinib as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Randomized Phase II Clinical Trial.

BACKGROUND: Anlotinib is a tyrosine kinase inhibitor inhibiting angiogenesis. This multicenter, randomized phase II trial aimed to investigate the efficacy and safety of anlotinib in comparison with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Patients with mRCC from 13 clinical centers were randomly assigned in a 2:1 ratio to receive anlotinib (n = 90) or sunitinib (n = 43). Anlotinib was given orally at a dose of 12 mg once daily (2 weeks on/1 week off), and sunitinib was given orally at 50 mg once daily (4 weeks on/2 weeks off). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: The median PFS was similar with anlotinib and sunitinib (17.5 vs. 16.6 months, p > .05). The median OS (30.9 vs. 30.5 months, p > .05), ORR (30.3% vs. 27.9%), and 6-week DCR (97.8% vs. 93.0%) were similar in the two groups. Adverse events (AEs) of grade 3 or 4 were significantly less frequent with anlotinib than with sunitinib (28.9% vs. 55.8%, p < .01), especially in terms of thrombocytopenia and neutropenia. AEs occurring at a lower frequency with anlotinib were hand-foot syndrome, eyelid edema, hair depigmentation, skin yellowing, neutropenia, thrombocytopenia, and anemia. The incidence of serious AEs was lower with anlotinib than with sunitinib. CONCLUSION: The clinical efficacy of anlotinib was similar to that of sunitinib as the first-line treatment for mRCC, but with a more favorable safety profile. IMPLICATIONS FOR PRACTICE: This study evaluated the efficacy and safety of anlotinib for the first-line treatment of metastatic renal cell carcinoma. Anlotinib, which was developed independently in China, is a new tyrosine kinase inhibitor inhibiting multiple kinases involved in angiogenesis and tumor proliferation. Results indicated that the efficacy of anlotinib is comparable to and the safety is better than that of sunitinib.

Efficacy and safety of first-line sunitinib in Chinese patients with metastatic renal cell carcinoma.

AIM: We report the first prospective study of sunitinib for metastatic renal cell carcinoma (mRCC) in China. METHODS: Chinese mRCC patients received first-line sunitinib 50 mg daily (4/2 regimen). Overall survival (OS), progression-free survival (PFS), objective response rate and safety were assessed. Potential efficacy biomarkers were explored in post hoc analyses. RESULTS: Median PFS was 61.7 weeks; median OS was 133.4 weeks; objective response rate was 31.1%. Most frequent adverse events (AEs) were: hand-foot syndrome (63.8%), decreased white blood cell count (52.4%), fatigue (51.4%) and decreased platelet count (51.4%). AEs were identified that predicted longer PFS and OS. CONCLUSION: Sunitinib showed efficacy and manageable AE profile in treatment-naive Chinese mRCC patients. Larger prospective studies are required to confirm identified AEs as predictors of efficacy.

Effects of ulinastatin on early postoperative cognitive function after one-lung ventilation surgery in elderly patients receiving neoadjuvant chemotherapy.

We investigated the effects of ulinastatin on early postoperative cognitive dysfunction (POCD) after one-lung ventilation (OLV) surgery in elderly patients receiving neoadjuvant chemotherapy. Eighty elderly patients with preoperative neoadjuvant chemotherapy scheduling for radical esophagectomy under OLV were recruited. They were randomly divided into an ulinastatin pretreatment group (U group, n = 40) and a control group (C group, n = 40). The U group received 10,000 U/kg ulinastatin before anesthesia and 5000 U/kg daily on postoperative days 1 to 3, while C group received saline. Levels of interleukin (IL)-6, IL-10, C-reactive protein (CRP), and S-100ß protein were assayed before surgery, at the end of surgery, and on postoperative days 1 and 3. Patients underwent cognitive assessment 1 day before and 7 days after surgery. 38 patients in U group and 37 patients in C group completed the neuropsychological tests. The U group had a lower incidence of POCD than C group (23.7 % versus 45.9 %, P = 0.043). The levels of S-100ß protein, IL-6, IL-10, and CRP in both groups increased after surgery. The postoperative concentrations of S-100ß protein, IL-6, and CRP in U group were lower than those in C group. On postoperative day 3, compared with C group, the level of CRP in U group was lower, while that of IL-10 was higher. These findings demonstrate that ulinastatin can attenuate the elevation of S100ß protein levels and the incidence of POCD, most likely by the mechanism of reducing serum IL-6 and CRP levels and increasing IL-10 levels.

Primary hepatic angiosarcoma and potential treatment options.

Angiosarcomas account for a mere 2-3% of adult soft tissue sarcomas, with an overall poor outcome. Depending on the primary site, angiosarcomas have distinct prognosis. Primary hepatic angiosarcomas (PHAs) are much rare tumors, with worse prognosis compared with other angiosarcomas. PHA is reported to be associated with vinyl chloride, but the majority of patients were still with unknown etiology. As PHA lacks specific symptoms, signs, or images, pathological diagnosis is necessary. The review summarizes 25 articles published from January 2000 to December 2012, including 64 cases of PHA with detailed information. Survival curves are estimated using the Kaplan-Meier method by SPSS 21.0. We find that the median survival time is 5 months; local excision alone or combination with adjuvant therapy is the optimal choice, with median survival time of 17 months. In addition, liver transplant is abandoned for high recurrence rate; emergent transcatheter arterial embolization is thought to be an efficient method for controlling intra-abdominal bleeding; and transcatheter arterial chemoembolization and chemotherapy may be helpful in improving survival.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome.

Non-small cell lung cancer (NSCLC) is found worldwide with high incidence and poor prognoses. Nowadays, insights in the interaction between tumors and immune system have led to the development of immunotherapy as a fundamentally new concept for the treatment of NSCLC. Adoptive cell transfer represents an important advancement in cancer immunotherapy such as cytokine-induced killer and γδ T-cells. Recent clinical research studies provide evidence for the positive effects of adoptive immunotherapy, which is probably associated with levels of cytokines, cell doses, and immune microenvironment. This review summarizes the current condition of adoptive immunotherapy in NSCLC and the long-standing confusion in this field.

Role of SOCS1 in tumor progression and therapeutic application.

SOCS1, a prototype molecule of the SOCS family, was initially defined as a suppressor of cytokine signaling. The molecular mechanisms of SOCS1-mediated functions have been subsequently identified by studies using gene knockout mice and gene silencing technology. As part of a negative feedback regulation, SOCS1 downregulates cytokine signaling through direct inhibition of the JAK tyrosine kinase and the signaling cascade of activated cytokine receptors, thereby attenuating cytokine-initiated signal transduction. Moreover, other studies have demonstrated that SOCS1 also downregulates TLR signaling through direct and indirect mechanisms. Both cytokine receptor and TLR signaling pathways mediate important functions in survival, maturation and differentiation of various types of cells and in the regulation of immune function. Abnormal expression of SOCS1 in tumor cells has been detected in various human cancers, where it is associated with dysregulation of cytokine receptor and TLR signaling to promote cell transformation. Recent studies on the function of SOCS1 in tumor cells have revealed its novel role in carcinogenesis. In this review, we will focus on the mechanism of action of SOCS1 in both tumor cells and antigen-presenting cells in the tumor microenvironment. The potential of using SOCS1 as a diagnostic marker and therapeutic target in tumor diagnosis, prognosis and treatment is discussed.

How do tumor stem cells actively escape from host immunosurveillance?

Tumor stem cells (TSCs) are considered as the "seeds" in tumor development, metastasis and recurrence. Despite the various immunosurveillance mechanisms in the host, TSCs may possess the phenotypic and functional properties to evade host immunosurveillance and immune-mediated rejection in immunologically intact individuals. The mechanisms of TSC recognition and their consequent destruction are actively disturbed by various processes, including altered immunogenicity of TSCs, production of TSC-derived regulatory molecules, and interaction of TSCs with tumor-infiltrating immune cells. In addition to these TSC-mediated mechanisms, the diverse mesenchymal cells and cytokines in the tumor microenvironment are contribute to TSC immune escape. Recent mechanistic studies provide a more comprehensive understanding of TSCs in the biology, prevention, and therapy of solid tumors. This review will focus on the latest findings for mechanisms underlying TSCs' escape from the attack of immune system.

[Expression of indoleamine 2, 3-dioxygenase and its correlation with prognosis in breast cancer patients].

OBJECTIVE: To investigate the expression of indoleamine 2, 3-dioxygenase (IDO) in breast cancer and its correlation with clinicopathologic factors and prognosis. METHODS: The expression of IDO, CD31, CD105 proteins in 40 specimens of breast cancer were assessed by immunohistochemistry. RESULTS: The overexpression rate of IDO in breast cancer was 67.5% (27/40), and expression of IDO was closely associated with clinical stage and lymph nodes metastasis. The disease-free survival rate in patients with IDO overexpression was not significantly lower than that in patients with negative or low expression of IDO (P > 0.05). Moreover, the expression of IDO was positively correlated with CD105-labeled microvessel density (r = 0.659, P < 0.05). CONCLUSIONS: Expression of IDO is associated with clinical stage and lymph nodes metastasis, and microvessel densitty. IDO expression may promote the growth and metastasis of breast cancer, probably via the increased agiogenesis. A larger sample study is needed to verify whether the prognosis of beast cancer is significantly correlated with IDO expression.

Different sites and prognoses of gastrointestinal stromal tumors of the stomach: report of 187 cases.

BACKGROUND: The stomach is the most common site of gastrointestinal stromal tumors (GISTs), but the clinical behavior of gastric GISTs at different sites is unclear. This study was designed to evaluate the clinicopathological (CP) parameters and influence of different gastric sites on outcome in patients with GIST. METHODS: The CP and follow-up records of 187 patients with GIST who were treated at TianJin Medical University Cancer Institute & Hospital between January 1985 and December 2006 were reviewed. There were 97 men and 90 women (aged 17-88 (median, 56.5) years). CP factors were assessed for overall survival (OS) by using univariate and multivariate analysis. RESULTS: The numbers of cases of upper, middle, and lower third gastric GISTs were 69 (36.9%), 103 (55.1%), and 15 (8%), respectively. Sites of GISTs in the middle or upper stomach, tumor size, intermediate- or high-risk groups, high mitotic count, and low resection status were associated with poor OS (p = 0.041, 0.046, 0.006, 0.000, 0.000, respectively) in a univariate analysis. In a multivariate analysis, tumor location in the upper and middle third of the stomach (p = 0.035), an intermediate or high risk (p = 0.01), and incomplete resection status (p = 0.006) were predictive of poor OS. CONCLUSIONS: Patients in intermediate- and high-risk groups had an unfavorable outcome. A complete resection is the most important treatment for survival. The location of GIST in the lower third of the stomach may be a favorable factor, and the significance of different tumor sites for prognosis of gastric GISTs needs to be further clarified.

[Killing effect of interleukin-18-enhanced FasL-expressing colon cancer cells on human hepatocytes in vitro].

OBJECTIVE: To investigate the influence of mutual interactions between FasL expressed by colon carcinoma cells and endogenous cytokines interleukin-18 on liver metastasis and invasion of human colon cancer cells. METHODS: Using immunohistochemical streptavidin-biotin complex (SABC) method, the expressions of Fas receptor and Fas ligand in SW620 colon carcinoma cells and Chang liver cells were observed so as to provide morphological evidence for the functions of Fas receptor and Fas ligand. In an effort to examine the cytotoxicity of effector cells, CytoTox(96) Non-Radioactive Cytotoxicity Assay was adopted to measure the LDH releasing value after the SW620 cells were co-cultured with Chang liver cells. RESULTS: It was shown that the Fas ligand of colon carcinoma SW620 cells was positive and the positive substances were distributed in the cell membrane and cytoplasm, and the Fas receptor of colon carcinoma SW620 cells was negative. The Fas receptor of Chang liver cells turned out to be positive and the positive substances were distributed in the cell membrane, and the Fas ligand of Chang liver cells was negative. At 6 hours after co-culture of IFN-γ-stimulated Chang liver cells with interleukin-18-stimulated (for 36 h) SW620 cells or unstimulated SW620 cells, the cytotoxicity of SW620 cells to IFN-stimulated Chang liver cells at effector-to-target ratios of 10:1, 5:1, 2.5:1 and 1.25:1 was 68.3%, 49.8%, 21.1%, 9.7% (F = 76.87, P < 0.05) and 32.7%, 21.8%, 11.1%, 6.7% (F = 7.27, P < 0.05), respectively. The non-radioactive cytotoxicity assay showed that the apoptotic rate of Chang liver cells was remarkably increased with the increase of planting concentration of SW620 after the SW620 cells were co-cultured with Chang liver cells. The cytotoxicity was significantly enhanced by interleukin-18. CONCLUSION: The FasL expression of human colon cancer cells may be regulated by endogenous interleukin-18 in the host microenvironment and enhance the liver colonization competence of colon cancer cells through induction of apoptosis in the Fas-expressing hepatocytes.

Radiosensitizing effects of gefitinib at different administration times in vitro.

The optimal administration time for applying epidermal growth factor receptor inhibitors combined with radiotherapy has been unclear. We investigated the efficacy of combining gefitinib with radiation in different treatment schedules. We demonstrated that gefitinib was administered to A549 lung cancer cells in three ways (administration before irradiation, administration upon irradiation, administration after irradiation) to establish the radiosensitizing effect. Cell-survival rates were evaluated by colony-forming assays. Cell apoptosis and cell-cycle distribution were investigated using flow cytometry; meanwhile, the expression of P21, Cdc25c, Bcl-2, Bax, Rad51 and phosphorylated DNA-PKcs (phospho-DNA-PK) after 6 Gy irradiation and/or gefitinib were determined by Western blot analysis. The sensitizer enhancement ratios of the gefitinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.23, 1.51 and 1.30, respectively. A higher apoptosis rate and G(2)/M phase arrest were observed in cells at 48 h after exposure to 6 Gy irradiation when gefitinib was administrated before irradiation. Increased cell apoptosis and cell cycle arrest were further supported by the expression changes of Bcl-2, Bax, P21, Cdc25c, Rad51 and phospho-DNA-PK at the same time. The best radiosensitizing effect was obtained when gefitinib was delivered before irradiation. Apoptosis might be an important way of cell killing and G(2)/M phase arrest might be an important mechanism of apoptosis. The expression proportion changes of P21/Cdc25c proteins may play an important role in G(2)/M cell cycle arrest. Moreover, the pro-apoptotic/antiapoptotic and DNA repair factors may be important modulators taking part in the molecular events of the radiosensitizing effect of gefitinib combined with irradiation.

Dendritic cell-activated cytokine-induced killer cells enhance the anti-tumor effect of chemotherapy on non-small cell lung cancer in patients after surgery.

BACKGROUND AIMS: Cytokine-induced killer (CIK) cells have shown cytolytic activity against several tumor cells in vitro and in animal tumor models. Furthermore, CIK cells activated by dendritic cell (DC) stimulation show increased anti-tumor activity. This study aimed to evaluate the clinical efficacy of DC-activated CIK cell treatment following regular chemotherapy and the effects of this therapy on immune responses in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: A paired study, with 42 patients in each group with stage I-IIIa NSCLC after surgery, was performed. Patients received chemotherapy alone (CT) or chemotherapy and DC-activated CIK cell treatment (immuno-CT). Disease-free survival (DFS) and overall survival were evaluated. CIK cell cytotoxicity against tumor cells was detected using a lactate dehydrogenase-based method. Serum cytokine levels in the immuno-CT group were detected using cytokine antibody arrays. RESULTS: The cytotoxicity of CIK cells was significantly enhanced by DC activation. The 2-year overall survival rate in the immuno-CT group was significantly improved compared with the CT group (94.7 +/- 3.6% versus 78.8 +/- 7.0%, P < 0.05). The 2-year DFS of these two groups showed no significant difference. DC-activated CIK cell treatment increased production of cytokines that have known anti-tumor effects, including IFN-gamma, MIG, TNF-alpha and TNF-beta, in patients who had no progression, but they were not found in patients who developed recurrence/metastasis. CONCLUSIONS: This study suggests that the role of DC-activated CIK cells in improvement of chemotherapy for malignant tumor treatment is associated with up-regulation of the production of cytokines involved in the anti-tumor effect.

Synchronous infiltrating ductal carcinoma and primary extramedullary plasmacytoma of the breast.

BACKGROUND: Extramedullary plasmacytomas are seldom solitary and usually progress to diffuse myelomatosis. Plasmacytomas of the breast are rare, especially when not associated multiple myeloma. Synchronous infiltrating ductal carcinoma and primary extramedullary plasmacytoma of the breast have not previously reported. CASE PRESENTATION: A 27-years-old woman with an untreated upper outer quadrant breast mass for 1-year was referred to our cancer hospital for surgical evaluation of increasing breast pain. Postoperatively, microscopic examination revealed an infiltrating ductal carcinoma complicated by an extramedullary plasmacytoma divided by fibrous tissue in one section. Following surgery, the patient received chemotherapy for the carcinoma and radiotherapy for the plasmacytoma. CONCLUSION: In this case, careful histopathology examination was essential to make the correct diagnosis and therapy for these synchronous lesions. The patient finished chemotherapy and radiotherapy without significant adverse effects.

[A preliminary study on the effects of feto-maternal microchimerism in activated human leukocyte antigen haploidentical mobilized peripheral blood stem cells on treatment of solid tumors].

OBJECTIVE: To study the effect of feto-maternal microchimerism in the treatment of activated human leukocyte antigen (HLA) haploidentical mobilized peripheral blood cells against solid tumors. METHODS: Genomic DNA samples of 25 pairs of HLA haploidentical donors and recipients were extracted. The donor-derived HLA-DRB loci were detected with nested PCR-sequence specific primer (SSP) typing. The mixed lymphocyte proliferation action between the patients and respective donors, the engraftment of donor's cells and the serum levels of Th1/Th2 type of cytokines were measured with MTT, FISH and ELISA method respectively. The survival time of patients with or without feto-maternal microchimerism were compared as well. RESULTS: Using nested PCR-SSP typing, the positive rates of feto-maternal microchimerism in the 25 pairs of HLA haploidentical donors and recipients were 40% in the maternal/children pairs and 0 in the paternal/children pairs. The chimerism positive patients showed less proliferation activity when cocultured with respective donors as compared with unrelated ones (P = 0.03). Only one chimerism positive patient experienced the engraft of donor's cell 3 months after treatment as the donor derived XX chromosome was identified with FISH. When the data of chimerism positive patients were deleted, the serum levels of IFNgamma 1 month after treatment dropped dramatically from 171.4 (26.3 approximately 258.4) ng/L to 29.4 (1.2 approximately 39.9) ng/L. The survival time in chimerism positive patients of the maternal/children pairs was significantly longer than that in chimerism negative patients, which was (31.2 +/- 4.3) months and (11.1 +/- 3.3) months, respectively (P = 0.036). CONCLUSION: Feto-maternal microchimerism might induce anergy in the HLA haploidentical donors, favor the engraftment of donor's progenitors and maintenance of positive microenvironment and prolong the survival time.

Diprophylline inhibits non-small cell lung cancer A549 cell proliferation and migration, and promotes apoptosis, by downregulating PI3K signaling pathway.

Diprophylline (DPL) is identified as a methylxanthine (MX) derivative. A number of MX derivatives are reported to have anti-tumor effects. However, it is not clear whether DPL has a therapeutic effect on non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the effects of DPL on NSCLC and to elucidate the potential underlying mechanism. A Cell Counting Kit-8 assay was used to evaluate the potential effect of DPL on A549 cell proliferation. Transwell invasion and migration assays were performed to assess the effect of DPL on A549 cell migration and invasion. Furthermore, the percentage of apoptotic cells was detected by flow cytometric analysis, and proteins associated with apoptosis, including apoptosis regulator Bcl-2, apoptosis regulator BAX and active caspase-3, were examined by western blotting. Finally, the expression levels of molecules relevant to phosphoinositide 3-kinase (PI3K) signaling were detected by western blot analysis. The present study demonstrated that DPL may significantly inhibit A549 cell proliferation, migration and invasion. Furthermore, treatment with DPL may significantly induce A549 cell apoptosis. Finally, the protein expression levels associated with the PI3K signaling pathway were significantly inhibited in A549 cells following treatment with DPL. In conclusion, DPL may inhibit the proliferation and migration of NSCLC by inactivating the PI3K signaling pathway, and DPL is a promising novel therapeutic drug for NSCLC.

Experimental study on the treatment of intracerebral glioma xenograft with human cytokine-induced killer cells.

Objective. To investigate the phenotype changes and proliferation activities of cytokine-induced killer cells (CIKs) and lymphokine-activated killer cells (LAKs) from healthy donor, and the cytotoxicities of CIKs and LAKs to human in vitro glioma cell lines U251 and U87. Therapy of CIK intratumoral injection was evaluated in nude mouse models. Methods. CIK cells were induced from peripheral blood mononuclear cells (PBMC) of healthy donors with multiple cytokines. Phenotype analysis of CIKs and LAKs was performed with flow cytometer (FCM). The specific cytotoxicities of CIKs and LAKs against cell line U251 and U87 were determined by LDH method. After intracerebral injection of CIKs, the distribution of CIKs and the inflammatory reaction of their surrounding brain tissue were observed through continuous pathological sections. In vivo anti-tumor activity of CIKs was evaluated in athymic nude mice with intracerebral xenotransplanted U251 glioma by MRI. Results. Amount of CIKs was increased (49.83+/-2.04) times and double positive cells, CD3(+)/CD56(+) cells, were increased from (3.36+/-1.85%) to (44.07+/-14.14%) with elevated absolute amount over 1000 times after 2 week culture. In vitro experiments demonstrated that compared with LAK, CIKs possessed more obvious cytotoxic activity to U251 and U87. In vivo experiments showed that there was no severe inflammatory reaction in brain tissue. CIKs can markedly inhibit intracranial xenotransplanted glioma growth by intracranial injection (P<0.01). Conclusion. CIKs are a kind of highly effective immune cells which have a strong suppressive effect on growth for in vitro and in vivo glioma. Local injection of CIKs does not produce severe damage to normal brain tissue and is likely to be used in clinical adoptive immunotherapy of intracerebral glioma.

MicroRNA-544 promotes colorectal cancer progression by targeting forkhead box O1.

Dysregulation of microRNAs has been confirmed to serve an important role in cancer development and progression. However, the role of microRNA (miR)-544 in colorectal cancer progression remains unknown. In the present study, it was observed that the expression level of miR-544 was increased in breast cancer cell lines and tissues using the quantitative polymerase chain reaction. Overexpression of miR-544 promoted cell proliferation and invasion in colorectal cancer, whereas inhibition of miR-544 suppressed colorectal cancer progression as determined using MTT, colony formation and Transwell assays. Furthermore, forkhead box O1 (FOXO1) was a direct target of miR-544. FOXO1 mediated miR-544-regulated colorectal cancer progression and cell cycle distribution. In conclusion, the results of the present study revealed that miR-544 serves an important role in promoting human colorectal cancer cell progression.

Vaccination with allogeneic GM-CSF gene-modified lung cancer cells: antitumor activity comparing with that induced by autologous vaccine.

OBJECTIVE: The aim of this study was to investigate the whole allogeneic (differing tissue-type) tumor cells as vaccine in the mouse lung cancer model. The immunogenic and antitumor activity of allogeneic vaccine was compared with that of autologous cancer cell vaccine. METHODS: C57/BL mice inoculated with Lewis lung cancer (LLC) cells were used as the animal model to test the effects of allogeneic vaccination. LA795 and LLC lung cancer cell lines, which were transfected with the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, were administered as allogeneic and autologous tumor vaccine, respectively. The irradiated tumor cells were administered as subcutaneous vaccines before the tumor challenge. The immunity of cancer vaccine was tested by mouse interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) lactate dehydrogenase (LDH) assays. The serum level of IFN-gamma and interleukin (IL)-4 was tested using the enzyme-linked immunosorbent assay method. RESULTS: Prophylactic vaccination with allogeneic LA795 cells protected against the LLC tumor challenge in C57/BL. The tumor growth was inhibited and the survival was accordingly prolonged. The cytotoxicity of the spleen cells or the purified CD(8)(+) T-cells against LLC cells in the mice immunized with either the autologous or allogeneic cancer cell vaccine was significantly increased, relative to that of the control, untreated group (p<0.05). ELISPOT IFN-gamma assays showed that spleen cells from mice immunized with LA795 cells could be activated after coculture with irradiated LLC cells. In addition, the serum level of Th1-king cytokine IFN-gamma significantly increased after vaccination; however, no statistically difference was found in Th2-kind cytokine IL-4. CONCLUSIONS: The allogeneic cancer vaccine could induce immune responses and protection against lung cancer, which had no significant difference with that of autologous vaccine.

Antitumor effect of large doses IL-2-activated HLA haploidentical peripheral blood stem cells on refractory metastatic solid tumor treatment.

OBJECTIVE: The traditional immunotherapy for patients with refractory metastatic solid tumors is limited because tumors induce immunosuppression. New treatment is, therefore, needed. The aim of this study was to evaluate the clinical efficacy of infusion of high-dose interleukin (IL)-2-activated allogeneic haploidentical peripheral blood stem cells (haplo-PBSCTs) on patients with an advanced stage of refractory solid tumors. METHODS: This study involved 11 patients with refractory metastatic tumors and haploidentical relatives as donors for haplo-PBSCs. The therapeutic outcome of the IL-2-activated haplo-PBSC infusion and patients' cytokine levels were evaluated. The cytotoxicity of IL-2-activated haplo-PBSCs for tumor cells was determined using in vitro cytotoxicity assays. RESULTS: A range from 2.5 to 5.6 x 10(10) of activated haplo-PBSCs were harvested after exposure to rhIL-2, along with a significant increase in the proportion of natural killer (NK) cells and activated lymphocytes (CD69+ and CD25+), and enhanced cytotoxicity of haplo-PBSCs for several tumor cell lines. Following treatment, 1 (1/11) patient achieved a partial response (PR), 1 (1/11) achieved a mild response (MR), 6 (6/11) achieved stable disease (SD), and 3 (3/11) achieved progressive disease (PD). For all of the 11 patients, the median progression-free survival (PFS) was 5 months (3-14 months). We also observed the phenomenon of Th2 shifted to Th1, which played a crucial role in cancer immunotherapy. CONCLUSIONS: The adoptive transfusion of IL-2-activated haplo-PBSCs has potent antitumor effects both in vitro and in vivo. This finding suggests that IL-2-activated haplo-PBSCs may serve as an alternative therapy for advanced-stage solid tumors, especially for those patients who are refractory or ineligible for chemo- or radiotherapy.