L. Xie

Induction chemotherapy with cetuximab, vinorelbine–cisplatin followed by thoracic radiotherapy and concurrent cetuximab, vinorelbine–cisplatin in patients with unresectable stage III non-small cell lung cancer

OBJECTIVES The modest benefits from concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC) warrant a more effective treatment regimen. We herein report mature data of a phase I/II study testing the addition of cetuximab to induction vinorelbine/cisplatin (NP) followed by concurrent cetuximab NP and thoracic radiation in patients with unresectable stage III NSCLC. MATERIALS AND METHODS Eligible patients were treated with weekly cetuximab (initial dose 400 mg/m2, day 1, week 1; maintenance dose 250 mg/m2 from week 2 to the end of CCRT) and induction vinorelbine (25 mg/m2, days 1 and 8) and cisplatin (75 mg/m2, day 1) every 3 weeks for 2 cycles from week 2. Concomitant thoracic radiation (60-66 Gy/2 Gy) and two cycles of NP (vinorelbine 12.5 mg/m2, days 1 and 8; cisplatin 25mg/m2, days 1 to 3, every 3 weeks) were started from week 7. The primary endpoints were toxicities; the secondary endpoints encompassed response rate and survival. RESULTS In total, 27 patients were enrolled, and 24 completed the full regimen. No treatment-related death occurred. Severe (CTCAE Grade 3 or high) adverse events were experienced by 81% patients (22/27), mostly haematologic. Severe non-haematologic toxicities including nausea/vomiting, intestinal obstruction, pulmonary infection and esophagitis, each of which was detected in <7% of patients. With a median follow-up of 26.7 months, the median survival was 26.7 months, with 1- and 2-year survival rates of 88.9% and 51.9%, respectively. Six patients remained progression-free to date, and the median progression-free survival was 13.5 months. The overall response rate was 63% and 77.8% after the induction and CCRT phases, respectively. CONCLUSION Weekly cetuximab with induction vinorelbine/cisplatin followed by concurrent cetuximab vinorelbine/cisplatin thoracic radiation is feasible with a manageable toxicity profile and clinically active.

Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication

Background Previous studies have shown that industry funded trials are associated with pro-industry conclusions and publication bias. Less is known about the role of industry funders and their influence on trial conclusions and time to publication. Methods We identified all industry funded RCTs published in six high-impact clinical journals between 2014 and 2016 to estimate the prevalence of the role of industry funders in trial design, data collection, data analyses, data interpretation and manuscript writing. Ordinal logistic regression was used to assess the association between the role of industry funders and trial conclusions, which was classified on a five-point scale. Cox proportional-hazards were used to examine the effect of role of funder on time to publication. Results Of the 255 eligible RCTs, industry funders had a role in trial design in 179 (70.2%) trials, data collection in 160 (62.7%) trials, data analyses in 173 (67.8%) trials, data interpretation in 135 (52.9%) trials and manuscript writing in 168 (65.9%) trials. Trials with any role of industry funders had 3.6 times (95% CI 2.0-6.6) higher odds of having positive conclusions compared with those without role of industry funders. In trials with any role of industry funders, positive trials were published more rapidly than negative trials (hazard ratio = 4.3; 95% CI 2.7-6.7, P < 0.001), while for trials without role of industry funders, there was no association (hazard ratio = 1.07; 95% CI 0.57-1.99, P = 0.84). Conclusion The involvement of industry funders is common in all stages of clinical trials and was associated with more positive conclusions and more rapid publication of RCTs with positive results.

Integrated Genome-Wide Analysis of Gene Expression and DNA Copy Number Variations Highlights Stem Cell-Related Pathways in Small Cell Esophageal Carcinoma

Purpose/Objectives. Primary small cell esophageal carcinoma (SCEC) represents a rare and aggressive malignancy without any prospective clinical trial or established treatment strategy at present. Although previous studies have indicated similarities between SCEC and small cell lung cancer (SCLC) in terms of their clinical manifestations, pathology, and morphology, very little genetic information is available on this highly malignant tumor. At present, patients with SCEC are staged and treated according to the guidelines established for SCLC. However, early recurrence and distant metastasis are common, and long-time survivors are rare. Current options available for patients with relapsed SCEC are fairly unsatisfactory, and their prognosis is generally poor. Novel therapeutic approaches against SCEC are therefore urgently needed and require a deeper understanding of the underlying genetic mechanisms. The current investigation aims to characterize the gene expression profile and copy number variations (CNVs) in SCEC to clarify molecular markers and pathways that may possess clinical significance. Materials/Methods. De novo expression array was carried out on three matched sets of primary SCEC and adjacent normal tissue samples procured from the institutional tissue bank, utilizing the Affymetrix HG U133 Plus 2.0 Array. After individual tissue normalization, the statistical software GeneSpring GX 12.5 was used to determine differentially expressed genes (DEGs) in the tumors relative to their paired normal tissues. Gene enrichments in addition to functional annotation and gene interaction networks were performed using DAVID 6.8 and STRING 10.0, respectively. A gene alteration was determined to be recurrent if it was observed in at least 2 samples. Chromosomes X and Y were not included in calculations as gender differences are a known source of analysis bias. The DEGs of at least one SCEC sample could be mapped to the CNV regions (fold change (FC) ≥ 2 and false discovery rate (FDR) < 0.01) after gene expression profiling by RefSeq Transcript ID. These overlapped genes were subjected to the functional annotation using DAVID 6.8. In order to elucidate the effect of CNV on mRNA expression, we integrated the genome-wide copy number data and gene expression in 3 paired samples. CNV-associated gene expression aberration (CNV-FC) was calculated for the recurrent DEGs using previously published integrated microarray data as reference. Pearsons correlation coefficient was employed to determine if there was a statistical correlation between the gene expression log2 ratios and their copy numbers using the SPSS 19.0 software. Genes that possessed CNV-FC ≥ 2 and r ≥ 0.6 (p < 0.05) were determined to be genes potentially associated with cancer. Results. High-quality DNA and total RNA were first extracted from both SCEC and normal tissues. Microarray data showed significant upregulation in WNT gene sets and downregulation in the PTEN and notch gene sets in SCEC. Functional annotation showed that genes associated with DNA replication, mitosis, cell cycle, DNA repair, telomere maintenance, RB, and p53 pathways were significantly altered in SCEC compared to corresponding noncancerous tissues (Benjamini p < 0.05). Thirteen recurrent CNVs were found in all SCEC samples by array CGH. Chromosomal regions with gain were located in 14q11.2, and regions with loss were located in 4q22.3-23.3, 3q25.31-q29, 5p15.31-15.2, 8q21.11-24.3, and 9p23-13.1 in all samples. In two samples, the 14q11.2-32.33 region was amplified, whereas 3p26.3-25.3, 4p16.3-11, 4q11-22.3, 4q23-25, 8p23.3, and 16p13.3 were deleted. We further identified 306 genes that consistently differed in copy number and expression (194 upregulated and 112 downregulated) between the SCEC and noncancerous tissues in all three samples. These genes were significantly enriched with those involved in cell cycle, mitosis, DNA repair, P53 pathway, and RB pathway, according to their functional annotation. These 306 DEGs also included network genes of the above pathways such as NUF2, CCNE2, NFIB, ETV5, KLF5, ATAD2, NDC80, and ZWINT. In addition, 39 individual DEGs demonstrated a minimum 2-fold copy number-associated expression change (median: 5.35, 95% CI: 4.53–16.98) and Pearsons correlation coefficient ≥ 0.6 (p < 0.05), of which PTP4A3 showed the highest correlation (CNV-FC = 21362.13; Pearsons correlation coefficient = 0.9983; p = 0.037). Two distinct groups of genes belonging to each SCEC and nonmalignant tissues were observed upon unsupervised two-way (genes and samples) hierarchical clustering. Conclusions. The current investigation is the first to produce data regarding the genomic signature of SCEC at the transcription level and in relation to CNVs. Our preliminary data indicate possible key roles of WNT and notch signaling in SCEC and overexpressed PTP4A3 as a potential therapeutic target. Further validation of our findings is warranted.

1157PBIOINFORMATICS ANALYSES OF GENOME-WIDE EXPRESSION PROFILE AND COPY NUMBER VARIATIONS (CNVS) OF SMALL CELL ESOPHAGEAL CANCER (SCEC)

ABSTRACT Aim: SCEC is a rare, aggressive tumor treated with regimens derived from pivotal studies of small cell lung cancer (SCLC), without robust data demonstrating the similarities between these two neuroendocrine cancers. This study was designed to investigate the gene expression profile and CNVs of SCEC, and compare it with the known data of SCLC and adeno/squamous cancer of the esophagus (EAC/ESCC) by bioinformatics approach. Methods: De novo expression profile and array-based Comparative Genomic Hybridization(aCGH) was performed on 3 pairs of primary SCEC and corresponding normal samples. The expression data were complemented with public domain data sets from the GEO repository using the same working platforms. After normalization, primary tumors were submitted to statistical analysis for identifying differentially expressed genes(DEGs). Copy number associated aberration in gene expression (CNV-FC), Pearson correlation coefficients (r) between copy number and expression for the recurrent genes were computed. The genes with CNV-FC ≥ 2 and r ≥0.6 were selected as possibly cancer-associated genes. Results: SCEC shared more DEGs in common with SCLC than EC (829 vs. 450), leading to greater correlation between SCEC and SCLC (r = 0.60 for SCEC vs. SCLC, 0.51 or 0.45 for SCEC vs. ESCC or EAC, 0.73 for ESCC vs. EAC). Functional annotation showed that a higher proportion of biological processes and pathways were in common between SCEC and SCLC, associating with mitosis, DNA repair, P53 and RB pathway etc (Benjamini p Conclusions: This bioinformatics analyses revealed that SCEC and SCLC displayed notably similar patterns of gene expression and CNVs on multiple biological processes. NUF2 and PTP4A3 might play a key role in carcinogenesis and metastasis of SCEC. Disclosure: All authors have declared no conflicts of interest.