Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study).

PURPOSE: Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide. METHODS: Included patients were randomly assigned to a control group [placebo plus low-dose temozolomide (50 mg/m2, daily)] or an experimental group [metformin (1000 mg, 1500 mg, and 2000 mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose temozolomide]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety. RESULTS: Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI 12.19-21.68 months) in the experimental group and 7.69 months (95% CI 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR: 0.78; 95% CI 0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.4% in the experimental group, respectively. CONCLUSIONS: Although the metformin plus temozolomide regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM. Trial registration NCT03243851, registered August 4, 2017.

Clinical Outcomes of Neoadjuvant Chemotherapy in Colorectal Cancer Patients With Synchronous Resectable Liver Metastasis: A Propensity Score Matching Analysis.

PURPOSE: The survival benefit of neoadjuvant chemotherapy (NAC) prior to surgical resection in colorectal cancer with liver metastases (CRCLM) patients remains controversial. The aim of this study was to compare overall outcome of CRCLM patients who underwent NAC followed by surgical resection versus surgical treatment first. METHODS: We retrospectively analyzed 429 patients with stage IV colorectal cancer with synchronous liver metastases who underwent simultaneous liver resection between January 2008 and December 2016. Using propensity score matching, overall outcome between 60 patients who underwent NAC before surgical treatment and 60 patients who underwent surgical treatment first was compared. RESULTS: Before propensity score matching, metastatic cancer tended to involve a larger number of liver segments and the primary tumor size was bigger in the NAC group than in the primary resection group, so that a larger percentage of patients in the NAC group underwent major hepatectomy (P<0.001). After propensity score matching, demographic features and pathologic outcomes showed no significant differences between the 2 groups. In addition, there was no significant difference in short-term recovery outcomes such as postoperative morbidity (P=0.603) and oncologic outcome, including 3-year overall survival rate (P=0.285) and disease-free survival rate (P=0.730), between the 2 groups. CONCLUSION: NAC prior to surgical treatment in CRCLM is considered a safe treatment that does not increase postoperative morbidity, and its impact on oncologic outcome was not inferior.

Procarbazine and CCNU Chemotherapy for Recurrent Glioblastoma with MGMT Promoter Methylation.

BACKGROUND: While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS: Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2-6). RESULTS: One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5-73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7-12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION: The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM. Trial registry at ClinicalTrials.gov, NCT017337346.

High expression of epidermal growth factor-like domain 7 is correlated with poor differentiation and poor prognosis in patients with epithelial ovarian cancer.

OBJECTIVE: The purpose of this study was to evaluate the expression of epidermal growth factor-like domain 7 (EGFL7) in epithelial ovarian cancer, and to assess its relevance to clinicopathological characteristics and patients' survival. METHODS: A total of 177 patients with epithelial ovarian cancer were enrolled in the current study. For each patient, a retrospective review of medical records was conducted. Immunohistochemical staining for EGFL7 was performed using tissue microarrays made with paraffin-embedded tissue block. EGFL7 expression levels were graded on a grade of 0 to 3 based on the percentage of positive cancer cells. We analyzed the correlations between the expression of EGFL7 and various clinical parameters, and also analyzed the survival outcome according to the EGFL7 expression. RESULTS: The expression of EGFL7 in ovarian cancer tissues was observed in 98 patients (55.4%). High expression of EGFL7 (grade 2 or 3) was significantly correlated with pathologic type, differentiation, stage, residual tumor after debulking surgery, lymphovascular space involvement, lymph node metastasis, high cancer antigen 125, peritoneal cytology, and ascites. Among these clinicopathologic factors, differentiation was significantly correlated with EGFL7 expression in multivariate analysis (p<0.05). Survival analysis showed that the patients with high EGFL7 expression had a poorer disease free survival than those with low EGFL7 expression (p=0.002). CONCLUSION: Our data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of epithelial ovarian cancer, and may constitute a therapeutic target for antiangiogenesis therapy in patients with epithelial ovarian cancer.

Popliteal artery pseudoaneurysm after anterior cruciate ligament re-revision using a rigidfix cross pin.

Popliteal artery injury is a very rare complication of anterior cruciate ligament (ACL) reconstruction. The authors experienced a case of popliteal arterial pseudoaneurysm after re-revision of ACL reconstruction using Rigidfix for femoral tunnel fixation. Pseudoaneurysm was detected in knee magnetic resonance imaging, which caused pain, limit of motion, common peroneal nerve palsy, leg swelling and symptoms similar to compartment syndrome. After excision and re-anastomosis of the popliteal artery using a greater saphenous vein graft, all symptoms were resolved within 3 months except for common peroneal nerve palsy. So we report on this case with a review of the literature.

Acute simultaneous ruptures of the anterior cruciate ligament and patellar tendon.

Acute simultaneous rupture of the anterior cruciate ligament (ACL) and patellar tendon is a rare injury. We present a case report of a 32-year-old male patient with ruptured ACL and ipsilateral patellar tendon rupture sustained while playing baseball. Surgery was performed on the patellar tendon and the ACL simultaneously. The clinical and radiological outcomes of the treatment were successful. We present this case with a review of the literatures.

Overexpression of CD73 in epithelial ovarian carcinoma is associated with better prognosis, lower stage, better differentiation and lower regulatory T cell infiltration.

OBJECTIVE: The purpose of the current study was to evaluate survival outcome according to the expression status of CD73 in patients with epithelial ovarian cancer. METHODS: A total of 167 patients with epithelial ovarian cancer were enrolled in the current study. For each patient, a retrospective review of medical records was conducted. Immunohistochemical staining for CD73, CD8, FoxP3, and CD68 was performed using tissue microarray made with paraffin embedded tissue block. RESULTS: Among the enrolled patients, 29.9% of patients (n=50) showed negative expression for CD73, whereas 70.1% of patients (n=117) showed positive expression for CD73. The CD73 positive group showed better prognosis compared to the CD73 negative group (5-year overall survival of CD73 positive group, 73.0%; that of CD73 negative group, 50.1%; p=0.023). CD73 was more frequently expressed in mucinous adenocarcinoma and clear cell carcinoma compared to serous or endometrioid adenocarcinoma. In addition, CD73 overexpressions were more frequently detected in patients with known good prognostic factors, i.e., low stage, well/moderate differentiation, negative peritoneal cytology, no lymphovascular involvement, and no macroscopic residual tumor after debulking surgery. There was significantly more infiltration of regulatory T cells in the CD73 negative group compared to the CD73 positive group. CONCLUSION: Good prognosis in patients with overexpression of CD73 may be due to that overexpression of CD73 was more frequently observed in epithelial ovarian cancer patients with known good prognostic factors. Therefore, this result means that favorable differentiation and stage have more influence on survival outcome than adverse effect of CD73 per se.

Facile fabrication of aligned doubly open-ended TiO2 nanotubes, via a selective etching process, for use in front-illuminated dye sensitized solar cells.

A simple selective etching process easily removed a 2nd anodized TiO(2) nanotubes (TNTs) layer from a physically stable 1st anodized TNTs layer to produce noncurling, freestanding, large-area aligned doubly open-ended TNTs. These TNTs were easily transferred to a conducting glass for use in fabricating front-illuminated dye sensitized solar cells.

Inhibitory effects of Ginkgo biloba extract on inflammatory mediator production by Porphyromonas gingivalis lipopolysaccharide in murine macrophages via Nrf-2 mediated heme oxygenase-1 signaling pathways.

Periodontitis is an oral chronic inflammatory disease that influences systemic diseases. Heme oxygenase-1 has several beneficial abilities through Nrf-2 regulation. Ginkgo biloba has been reported to have anti-inflammatory effects associated with heme oxygenase-1 (HO-1) expression. In this study, we investigated whether the anti-inflammatory effects of G. biloba were involved with Nrf-2-mediated HO-1 expression in Porphyromonas gingivalis LPS-stimulated RAW264.7 macrophage cells. G. biloba was extracted with ethyl acetate (EGB). EGB exhibited anti-inflammatory activities, which suppressed the production of pro-inflammatory mediators, the activation of mitogen-activated protein kinases, and nuclear translocation of transcription factors. EGB also up-regulated the HO-1 expression, and the Nrf-2 level in the nucleus and its transactivity. Furthermore, reduced pro-inflammatory mediator levels by EGB were inverted in the presence of SnPP. The collective results suggest that the anti-inflammatory effects of EGB are due to the HO-1 expression via up-regulation of Nrf-2 in RAW 264.7 cells stimulated by P. gingivalis LPS.

Thermodynamic control over the competitive anchoring of N719 dye on nanocrystalline TiO2 for improving photoinduced electron generation.

TiO(2) electrodes, sensitized with the N719 dye at high immersion temperatures during the sensitization process, were found to have large fractions of weakly bound N719 on the electrode surface, which resulted in dye aggregation and decreased device longevity. These disadvantages were ameliorated using a low-temperature stearic acid (SA)-assisted anchoring method described here. The activation energy (ΔE(NS)(++)) and relative fraction of strongly bound N719 were twice as large as the respective values obtained without the use of SA. Slowing of adsorption, both by thermal means and through SA-mediated processes, effectively controlled the binding mode of N719 on the surface of TiO(2). The resulting sensitized electrodes displayed enhanced device longevity and improved generation of photoinduced electrons.

A novel hole transport material for iodine-free solid state dye-sensitized solar cells.

A novel bis-EDOT-based monomer with ethylene glycol oligomers was synthesized and shown to exhibit strong ion solvation, good transport properties, and effective charge screening. These properties greatly improved J(SC) (4.2 to 7.0 mA cm(-2)) and η (1.6 to 2.9%) in an iodine-free solid state dye-sensitized solar cell (DSSC) employing a Z-907 sensitizer, compared with the corresponding values of DSSCs fabricated using the standard bis-EDOT.

Dye-sensitized solar cells using polymer electrolytes based on poly(vinylidene fluoride-hexafluoro propylene) nanofibers by electrospinning method.

The dye-sensitized solar cell (DSSC) devices using polymer electrolytes based on electrospun poly(vinylidene fluoride-hexafluoro propylene) (PVDF-HFP) nanofibers were fabricated and investigated the photovoltaic performances. The electrospun PVDF-HFP nanofibers were prepared by various parameters such as; polymer concentrations, applied voltages, and tip to collector distances (TCD) by the electrospinning method. The open circuit voltage (V(OC)), short circuit current (J(SC)), fill factor (FF), and overall power conversion efficiency (eta) of DSSC devices using electro-spun PVDF-HFP nanofibers were 0.7180-0.7420 V, 9.7200-10.8837 mA/cm2, 0.5610-0.6250, and 4.1700-5.0186%, respectively. When 15 wt% of polymer concentration, 14 kV of applied voltage, and 14 cm of TCD is applied to fabricate the PVDF-HFP nanofiber, the electrospun PVDF-HFP nanofiber should be the regular diameter of a nanofiber, the power conversion efficiency of the DSSC device reached 5.0186% as the best result.

N-linked oligosaccharide analysis of glycoprotein bands from isoelectric focusing gels.

Glycoproteins often display a complex isoelectric focusing profile because of the presence of negatively charged carbohydrates, such as sialic acid, phosphorylated mannose, and sulfated GalNAc. Until now, understanding the role of these charged carbohydrates in determining the isoelectric focusing profile has been limited to observing pattern shifts following complete removal of the sugars in question. We have developed a simple and sensitive method for analyzing N-linked oligosaccharides from the individual isoelectric focusing bands of a glycoprotein using recombinant human thyroid-stimulating hormone as a model system. N-linked oligosaccharides were released and profiled from individual bands following electroblotting of isoelectric focusing gels. As might be predicted, high-pH anion-exchange chromatography-pulsed amperometric detection and matrix-assisted laser desorption/ionization-time of flight analyses indicated that the bands that migrated closer to the positive electrode contained more sialylated N-linked oligosaccharides. The sialic acid content of these bands correlated with that predicted from the corresponding oligosaccharide analyses.

A mutation causing a reduced level of expression of six beta4-galactosyltransferase genes is the basis of the Lec19 CHO glycosylation mutant.

To identify factors required for the synthesis of complex glycans, we have isolated Chinese hamster ovary (CHO) cell mutants resistant to plant lectins. We previously identified Lec19 CHO cells as resistant to the Gal-binding lectins ricin, abrin, and modeccin and hypersensitive to the toxicity of other lectins that bind Gal, including L-PHA and E-PHA. Here we show that Lec19 cell extracts have a decreased ability to transfer Gal to simple sugar, oligosaccharide, and glycopeptide acceptors, particularly to biantennary, GlcNAc-terminated acceptors. Ricin(II)-agarose lectin affinity chromatography, oligomapping, and monosaccharide analyses provided evidence that Lec19 N-glycans have fewer Gal residues than CHO N-glycans. MALDI-TOF mass spectra of N-glycans released from Lec19 cell glycoproteins by peptide N-glycanase F revealed species with the predicted masses of neutral N-glycans with few Gal residues. Such truncated species are essentially absent from CHO cell glycoproteins. However, the complement of fully galactosylated or sialylated bi-, tri-, and tetra-antennary N-glycans was largely equivalent in Lec19 and CHO cells. In addition, the coding region sequences of the beta4GalT-1, -T-2, -T-3, -T-4, -T-5, and -T-6 genes were identical in CHO and Lec19 cells. However, Northern analyses revealed an approximately 2-4-fold reduction in the level of transcripts of all six beta4GalT genes in Lec19 cells. Since the recessive Lec19 phenotype is the result of a loss-of-function mutation, the combined data predict the existence of a trans-acting regulator of the steady-state level of transcripts that derive from these six mammalian beta4GalT genes.

Antibodies that recognize bisected complex N-glycans on cell surface glycoproteins can be made in mice lacking N-acetylglucosaminyltransferase III.

The bisecting GlcNAc is transferred to complex or hybrid N-glycans by the action of N-acetylglucosaminyltransferase III (GlcNAc-TIII) encoded by the Mgat3 gene. CHO cells expressing mouse GlcNAc-TIII were shown by matrix-assisted laser desorption ionization (MALDI) mass spectrometry to produce mainly complex N-glycans with the predicted extra (bisecting) GlcNAc. In order to probe biological functions of the bisecting GlcNAc, antibodies that recognize this residue in the context of complex cell surface glycoconjugates were sought. The LEC10 gain-of-function Chinese hamster ovary (CHO) cell mutant that expresses GlcNAc-TIII and complex N-glycans with the bisecting GlcNAc was used to immunize Mgat3(+/+) and Mgat3(-/-) mice. ELISA of whole sera showed that polyclonal antibodies that bound specifically to LEC10 cells were obtained solely from Mgat3(-/-) mice. Fluorescence-activated cell cytometry of different CHO glycosylation mutants and western blotting after glycosidase treatments were used to show that anti-LEC10 cell antisera from Mgat3(-/-) mice recognize cellular glycoproteins with complex N-glycans containing both a bisecting GlcNAc and Gal residues. The polyclonal antibody specificity was similar to that of the lectin E-PHA. IgM-depleted serum containing IgG and IgA antibodies retained full binding activity. Therefore Mgat3(-/-) mice but not wild type mice can be used effectively to produce polyclonal antibodies that specifically recognize glycoproteins bearing complex N-glycans with a bisecting GlcNAc.