Markedly enhanced intratumoral spread and antitumor effect of oncolytic adenovirus expressing decorin

With the aim of improving viral distribution and tumor penetration, we have engineered decorin expressing replication-incompetent (dl-LacZ-DCNG) and -competent (Ad-[DELTA]E1B-DCNG) adenoviruses. In both tumor spheroids and established solid tumors in vivo, administration of dl-LacZ-DCNG resulted in greater transduction efficiency and viral spread throughout the tumor mass. Ad-[DELTA]E1B-DCNG also enhanced viral distribution and tumor spread, leading to an increased anti-tumor effect and survival advantage. Upon histological analysis, Ad-[DELTA]E1B-DCNG also elicited greater percentage of apoptotic cells and extensive necrosis compared to those from untreated or control virus-treated tumors. Furthermore, Ad-[DELTA]E1B-DCNG substantially decreased extracellular matrix components within the tumor tissue, while normal tissue adjacent to the tumor was not affected. Finally, intratumoral administration of Ad-[DELTA]E1B-DCNG did not enhance but inhibited the formation of pulmonary metastases of B16BL6 melanoma cells in mice. Taken together, these data demonstrate the utility of decorin as a dispersion agent and suggest its utility and potential in improving the efficacy of replicating adenovirus-mediated cancer gene therapy

Usefulness of Bone Metabolic Markers in the Diagnosis of Bone Metastasis from Lung Cancer

Bone metastasis is common in lung cancer patient and the diagnosis of bone metastasis is usually made by using imaging techniques, especially bone scintigraphy. However, the diagnostic yield from bone scintigraphy is limited. The aim of this study is to assess the clinical usefulness of urinary pyridinoline cross-linked N-telopeptides of Type I collagen (NTx), urinary deoxypyridinoline (DPD), and serum alkaline phosphatase (ALP) in the assessment of bone metastasis in patients with lung cancer. Urinary NTx, DPD, and serum ALP were measured in 151 lung cancer patients (33 with and 118 without bone metastasis). Lung cancer patients with bone metastasis had a higher urinary excretion of NTx and DPD, and a higher serum ALP than those without bone metastasis. NTx had a better receiver operating characteristic (ROC) curve than DPD and ALP, since the areas under the ROC curve were 0.82, 0.79, and 0.71, respectively. Although correlation coefficients among NTx, DPD and ALP were significantly positive (p < 0.005), the strongest relationship was appeared between NTx and DPD (R=0.616). In conclusion, our results showed the utility of the new bone markers in detecting bone metastasis and suggested that measurement of urinary NTx was valid diagnostic method of bone metastasis from lung cancer

The combination effect of sodium butyrate and 5-Aza-2'-deoxycytidine on radiosensitivity in RKO colorectal cancer and MCF-7 breast cancer cell lines

<p>Abstract</p> <p>Background</p> <p>The overall level of chromatin compaction is an important mechanism of radiosensitivity, and modification of DNA methylation and histone deacetylation may increase radiosensitivity by altering chromatin compaction. In this study, we investigated the effect of a demethylating agent, a histone deacetylase(HDAC) inhibitor, and the two agents combined on radiosensitivity in human colon and breast cancer cell lines.</p> <p>Methods</p> <p>In this study, we used RKO colorectal cancer cell line and MCF-7 breast cancer cell lines and normal colon cell lines. On each of the cell lines, we used three different agents: the HDAC inhibitor sodium butyrate(SB), the demethylating agent 5-Aza-2'-deoxycytidine(5-aza-DC), and radiation. We then estimated the percentage of the cell survival using the XTT method and experimented to determine if there was an augmentation in the therapeutic effect by using different combinations of the two or three of the treatment methods.</p> <p>Results</p> <p>After treatment of each cell lines with 5-aza-DC, SB and 6 grays of radiation, we observed that the survival fraction was lower after the treatment with 5-aza-DC or SB than with radiation alone in RKO and MCF-7 cell lines(p < 0.001). The survival fraction was lowest when the two agents, 5-aza-DC and SB were combined with radiation in both RKO and MCF-cell lines.</p> <p>Conclusion</p> <p>In conclusion, 5-aza-DC and SB can enhance radiosensitivity in both MCF-7 and RKO cell lines. The combination effect of a demethylating agent and an HDAC inhibitor is more effective than that of single agent treatment in both breast and colon cancer cell lines.</p

Microbial Ecology of Watery Kimchi

© 2015 Institute of Food Technologists®. This article has been contributed by US Government employees and their work is in the public domain in the USA. The biochemistry and microbial ecology of 2 similar types of watery (mul) kimchi, containing sliced and unsliced radish and vegetables (nabak and dongchimi, respectively), were investigated. Samples from kimchi were fermented at 4, 10, and 20 °C were analyzed by plating on differential and selective media, high-performance liquid chromatography, and high-throughput DNA sequencing of 16S rDNA. Nabak kimchi showed similar trends as dongchimi, with increasing lactic and acetic acids and decreasing pH for each temperature, but differences in microbiota were apparent. Interestingly, bacteria from the Proteobacterium phylum, including Enterobacteriaceae, decreased more rapidly during fermentation at 4 °C in nabak cabbage fermentations compared with dongchimi. Although changes for Proteobacterium and Enterobacteriaceae populations were similar during fermentation at 10 and 20 °C, the homolactic stage of fermentation did not develop for the 4 and 10 °C samples of both nabak and dongchimi during the experiment. These data show the differences in biochemistry and microbial ecology that can result from preparation method and fermentation conditions of the kimchi, which may impact safety (Enterobacteriaceae populations may include pathogenic bacteria) and quality (homolactic fermentation can be undesirable, if too much acid is produced) of the product. In addition, the data also illustrate the need for improved methods for identifying and differentiating closely related lactic acid bacteria species using high-throughput sequencing methods.This work was carried out as part of the international collaborative R&D program funded by the Agency for Korea Natl. Food Cluster (2013), and supported in part by a grant from Pickle Packers Intl. Inc., Washington, D.C., U.S.A. The authors thank the Spanish Government (MECD) for the postdoctoral fellowship support for Dr. E. Medina-Pradas.Peer Reviewe

Geriatric Nutritional Risk Index as a prognostic marker in patients with extensive-stage disease small cell lung cancer: Results from a randomized controlled trial

Background Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive-stage disease small cell lung cancer (ED-SCLC) have not previously been reported. Methods This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first-line therapy for ED-SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92-98, and <92 were grouped into no, low, and moderate/major risk groups, respectively. Results The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression-free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012-1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069-2.216; P = 0.020). Conclusions This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED-SCLC.Key points Significant findings of the study The lower GNRI group had a low response rate to chemotherapy for ED-SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92. What this study adds Low GNRI is associated with poor prognosis in ED-SCLC.

Tolerability and Outcomes of First-Line Pemetrexed-Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in Korean Patients with Advanced Nonsquamous Non-small Cell Lung Cancer: A Post Hoc Descriptive Subgroup Analysis of a Randomized, Phase 3 Trial

Purpose We recently reported on a randomized, open-label, phase 3 trial comparing pemetrexedcisplatin chemotherapy followed by gefitinib maintenance therapy (PC/G) with gefitinib monotherapy in patients with non-small cell lung cancer (NSCLC). Here, we report on a post hoc subgroup analysis of that study assessing the demographics and disposition of the Korean patient subgroup, and comparing the tolerability of PC/G and gefitinib monotherapy and the tumor response with respect to epidermal growth factor receptor (EGFR) status. Materials and Methods Patients, who were 18 years, chemonalve, Korean, light ex-smokers/never-smokers with advanced NSCLC, were randomly assigned (1:1) to PC/G or gefitinib monotherapy. Treatment-emergent adverse events (TEAEs) were graded, and tumor response was measured as change in lesion sum from baseline at best response. The study was registered with ClinicalTrials.gov, NCT01017874. Results Overall, 111 Korean patients were treated (PC/G, 51; gefitinib, 60). Between-arm characteristics were balanced and similar to those of the overall population. Treatment discontinuations due to adverse events were low (PC/G: 1, 2.0%; gefitinib: 7, 11.7%). Overall, 92 patients (82.9%) reported >= 1 TEAE (PC/G, 44; gefitinib, 48); few patients (PC/G, 16; gefitinib, 7) reported severe TEAEs; the most frequent was neutropenia (PC/G arm) and elevated alanine aminotransferase (gefitinib arm). The lesion sum was decreased by PC/G treatment in most patients, regardless of EGFR mutation status, while gefitinib monotherapy reduced the lesion sum in EGFR-positive patients but had no effect in EGFR-negative patients. Conclusion Our results confirm that both PC/G and gefitinib were well tolerated in Korean patients, regardless of EGFR status; however, patients with EGFR wild-type NSCLC may not benefit from gefitinib monotherapy.

Health-related quality of life in KEYNOTE-010 : a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01)

We aimed to evaluate the efficacy of dual inhibition of epidermal growth factor receptor (EGFR) with nimotuzumab (EGFR monoclonal antibody) plus gefitinib (EGFR-tyrosine kinase inhibitor) in advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. An open label, randomized, phase II trial was conducted at 6 centers; 160 patients were randomized (1:1) to either gefitinib alone or nimotuzumab (200 mg, i. v. weekly) plus gefitinib (250 mg p. o. daily) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 3 months. Of the total 160 enrolled patients, 155 (77: gefitinib, 78: nimotuzumab plus gefitinib) received at least one dose and could be evaluated for efficacy and toxicity. The majority had adenocarcinoma (65.2%) and ECOG performance status of 0 to 1 (83.5%). The median follow-up was 22.1 months, and the PFS rate at 3 months was 48.1% in gefitinib and 37.2% in nimotuzumab plus gefitinib (P = not significant, NS). The median PFS and OS were 2.8 and 13.2 months in gefitinib and 2.0 and 14.0 months in nimotuzumab plus gefitinib. Combined treatment was not associated with superior PFS to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=NS) or those with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=NS). Combined treatment did not increase EGFR inhibition-related adverse events with manageable toxicities. The dual inhibition of EGFR with nimotuzumab plus gefitinib was not associated with better outcomes than gefitinib alone as a second-line treatment of advanced NSCLC (NCT01498562).

Health-Related Quality of Life in Patients with Advanced Nonsquamous Non–Small-Cell Lung Cancer Receiving Bevacizumab or Bevacizumab-Plus-Pemetrexed Maintenance Therapy in AVAPERL (MO22089)

IntroductionIn the phase III AVAPERL trial, patients with advanced nonsquamous non–small-cell lung cancer receiving bevacizumab-plus-pemetrexed maintenance after first-line induction had a significant progression-free survival benefit relative to those treated with single-agent bevacizumab maintenance but with an increase in grade ≥3 adverse events. Here, we compare health-related quality of life (HRQOL) between AVAPERL maintenance arms.MethodsPatient-reported outcomes were collected at designated intervals from preinduction to final visits. HRQOL was assessed using the self-administered European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the Quality of Life Lung Cancer–Specific Module 13. Differences in scores of 10 points or more between arms were above the minimum important difference threshold and considered clinically meaningful.ResultsDuring induction, patient-reported coughing symptoms improved slightly, whereas fatigue and appetite loss scores worsened relative to preinduction baseline. During maintenance, changes in mean global health status and the majority of Quality of Life Questionnaire Core 30 and Quality of Life Lung Cancer–Specific Module 13 subscale scores did not differ between trial arms by the minimum important difference defining clinically meaningful (better or worse) patient-reported outcomes. Exceptions were patient-reported role functional status, fatigue symptoms and appetite loss symptoms (favoring bevacizumab), and pain in arm or shoulder symptoms (favoring bevacizumab-plus-pemetrexed maintenance), which differed by clinically meaningful amounts at more than one maintenance assessment.ConclusionsIn AVAPERL, HRQOL remained relatively stable throughout maintenance and was generally similar in both arms. Despite an increase in adverse event rates, the addition of pemetrexed to bevacizumab maintenance resulted in similar stabilization of disease symptoms with improved efficacy outcomes