bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of LASEP3 as a new serological and prognostic biomarker for lung and various type of cancer.
Authors: Takano Atsushi , Nakamura Yusuke , Daigo Yataro 
Published: March 2020

e13565 Background: Identification of early cancer detection and prognostic biomarkers is urgently required to improve clinical outcome. Methods: We have screened cancer biomarkers using a strategy as follows; i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray representing 27,648 genes and 120 lung cancers, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot analysis, iii)To validate clinicopathological significance of their protein expression by tissue microarray consisting of 259 lung cancers, iv) To verify whether they are essential for the growth of cancer cells by siRNA assay, and v) To measure their serum protein levels by ELISA in patients with various type of cancers. Results: We identified LASEP3 (Lung cancer Associated Serum Protein 3) encoding secreted protein as a candidate. Immunohistochemical analysis showed that LASEP3 was frequently over-expressed in various histological types of lung cancers; positive staining of LASEP3 was observed in 198 (54.8%) of 361 NSCLCs. In addition, a high level of LASEP3 expression was associated with poor prognosis of patients with NSCLC (p=0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs; 131 (63.6%) of 206 ADCs and 29 (54.7%) of 53 SCCs, while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Serum LASEP3 levels were significantly higher in breast and colon cancer patients than in healthy volunteers, and tissue LASEP3 protein was overexpressed in breast and colon cancer tissues. Furthermore, treatment of lung cancer cells with siRNAs against LASEP3 suppressed its expression and resulted in growth suppression of cancer cells. Induction of exogenous expression of LASEP3 promoted cell mobility in vitro. We found a 50-kDa receptor (LASEPR) which interacts with LASEP3 on cancer cell surface, suggesting that LASEP3 is an autocrine/paracrine growth factor. Conclusions: LASEP3 is a potential target for the development of diagnostic and prognostic biomarkers for lung and various types of cancers
Therapeutic targeting of microRNA-31 in lung cancer.
Authors: Roengvoraphoj Monic , Guo Yongli , Ma Tian , Stan Radu V. , Obad Susanna , Kauppinen Sakari , Dmitrovsky Ethan , Freemantle Sarah J. 
Published: March 2020

e13567 Background: MicroRNAs (miRs) have emerged as powerful regulators of cellular processes and are frequently deregulated in cancer. Our previous work showed that miR-31 was overexpressed in human and murine lung cancers and repression of miR-31 inhibits lung cancer proliferation and tumorigenesis. Novel miR-31-targeting compounds were developed using a locked nucleic acid (LNA) drug platform. Compounds were tested in cell-based assays to assess levels of miR-31, miR-31-target genes and cell proliferation. A lead compound was chosen and we are currently examining its in vivo activity in human lung cancer cells and in murine transgenic lung tumor models. Methods: We previously developed a murine model of lung cancer by specifically overexpressing human cyclin E in the lung (CEO mice). The ED1 cell line was derived from a CEO mouse lung tumor. ED1 cells were transfected with the miR-31-LNA-targeting compounds and miR-31 levels and target genes quantified versus controls using RT-PCR assays. Cell proliferation was assessed using the CellTiter-Glo assay. Microarray analysis was performed to further investigate novel miR-31 target genes that were validated using independent RT-PCR assays. A pharmacodynamic study (5 daily tail vein injections) was performed in CEO mice that develop lung tumors spontaneously. Lung tissues were harvested 24 hours after the final dose and analyzed for immunohistochemical biomarkers of drug response (Ki67 and cyclin E). Results: Novel LNA anti-miR-31 compounds decreased miR-31 levels and proliferation rates in murine and human lung cancer cells. The compound, as expected, augmented expression of a known miR-31 target, LATS2. The microarray analysis identified over 100 genes with 2-fold elevated expression in anti-miR-31 treated cells. Validated novel miR-31 targets include GADD45a, Trp53inp1, Txnip and Slc40a1. Preclinical studies in mouse models are ongoing. Conclusions: Targeting miR-31 using LNA–based therapy inhibits cell growth in lung cancer cells and is a promising therapeutic approach for the treatment of lung cancer. Successful preclinical activity of these compounds will warrant translation into the clinic in proof of principle trials to assess pharmacodynamic and pharmacokinetic outcomes.
Effect of auranofin on oxidative and endoplasmic reticulum stress as well as anti-CLL activity with proteasome inhibitor.
Authors: Kambhampati Suman , Maddocks Kami J. , Rao Rekha , Chauhan Lata , Das Gupta Soumyasri , Ganguly Siddhartha , Reyes Ruben , Aljitawi Omar Salah , Schorno Kevin , Ford Kendra , Dickman Eileen D. , Byrd John C. , Bhalla Kapil N. 
Published: March 2020

e13568 Background: The gold-containing compound auranofin (AF) (Ridaura), is a treatment of rheumatoid arthritis. Recently, AF was shown to inhibit thioredoxin reductase (TRR), increase reactive oxygen species (ROS) and induce apoptosis in cancer cells. Methods: We determined the ability of AF (250 to 1000 nM) to induce oxidative, proteotoxic and lethal endoplasmic reticulum (ER) stress in CD19+ primary CLL cells, including those with deletion of chromosome 17p. Results: Treatment with AF induced 20 to 40% increase in ROS levels, decreased TRR activity (mean of 45%), but not its protein expression, in CLL cells. AF-mediated oxidative stress induced NRF2 activity with increase in hemeoxygenase-1 (HO-1) and glutamate cysteine ligase modifier (GCLM) levels. AF induced ER stress, associated with increase in GRP78 and the pro-apoptotic transcription factor CHOP protein levels. AF also induced the pro-apoptotic BH3-only domain protein BIM. Exposure to AF increased the intracellular levels of misfolded polyubiquitylated proteins. This disrupted the binding of heat shock protein (hsp) 90 with histone deacetylase 6 (HDAC6), resulting in hyperacetylation and inhibition of the chaperone function of hsp90. This led to proteasomal degradation of CLL-relevant hsp90 client proteins, including ZAP70, c-Raf and AKT. Nuclear STAT3 levels also declined. Exposure to AF induced significantly more apoptosis (range 40 to 60%) in primary CLL cells, as compared to CD19+ normal B cells and CD34+ human cord blood and bone marrow progenitor cells (< 15% apoptosis) (p < 0.01). AF treatment also induced apoptosis in CD19+ cells from patients with poor prognosis CLL with deletion of 17p or with deletion of 13q. Co-treatment with AF and the proteasome inhibitor carfilzomib or the GCLM antagonist buthionine sulfoximine (BSO) synergistically induced apoptosis in primary CLL cells. A FDA IND-supported phase II clinical trial of AF (6 to 9 mg PO/day) with correlative biomarker analysis (as above) is underway and three patients are enrolled. Conclusions: These findings support the full evaluation of clinical activity and predictive biomarkers of response to the re-purposed AF in patients with CLL.
Bevacizumab and risk of hand-foot syndrome associated with chemotherapy.
Authors: Flores Ronald A. , Lacouture Mario E. , Wu Shenhong 
Published: March 2020

e13591 Background: Hand-foot syndrome (HFS) is a dose-limiting cutaneous side effect of many chemotherapeutic agents. Its pathogenesis and risk factors have not been well understood. In this study, we propose that the inhibition of angiogenesis may contribute to the development of HFS. We investigated the risk of chemotherapy-induced HFS in patients treated with bevacizumab, an angiogenesis inhibitor that is widely used for the treatment of various cancers with a systematic review and a meta-analysis of published randomized-controlled clinical trials (RCTs). Methods: Databases from PUBMED, Cochrane Database, and abstracts presented at the American Society of Clinical Oncology until December, 2011 were searched for the identification of relevant studies. Eligible studies included prospective RCTs in which the addition of bevacizumab to chemotherapy was compared directly to chemotherapy alone in cancer patients. Relative risk (RR), and 95% confidence interval (CI) were calculated using a fixed-or random-effects model based on the heterogeneity of the included studies. Results: A total of six RCTs including 5,043 patients (bevacizumab 2665, control 2378) with a variety of tumors were analyzed. The addition of bevacizumab to chemotherapy significantly increased the risk of developing HFS with an RR of 1.68 (95% CI: 1.17-2.40, p=0.005) in comparison to chemotherapy alone. The risk of HFS significantly increased in patients receiving bevacizumab at 2.5 mg/kg/week (RR of 1.88, 95% CI: 1.39-2.54, p<0.001) and at 5 mg/kg/week (RR of 1.19, 95% CI: 1.03-1.36, p=0.016); however, the increased risk of HFS did not vary significantly with bevacizumab dosage (p=0.72) and with tumor types (p=0.92). The increased risk of HFS varied with concurrent chemotherapeutic agents with a significant difference (p=0.034) between docetaxel (RR 6.94, 95% CI: 1.67-28.81) and 5-FU based agents, including capecitabine (RR 1.25, 95% CI: 1.10-1.42). Conclusions: The risk of HFS associated with chemotherapeutic agents significantly increased with the use of bevacizumab, suggesting an important role of angiogenesis in the development of HFS. Moreover, combination with docetaxel appears to confer a higher risk than 5-FU based agents.
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR, in combination with erlotinib in patients with advanced solid tumors.
Authors: O'Dwyer Peter J. , Papadopoulos Kyriakos P. , Tolcher Anthony W. , Teitelbaum Ursina R. , Harlacker Kathleen , Smith Lon S. , Sohal Davendra , Rasco Drew Warren , Beeram Muralidhar , Mehran Mariam , Tawashi Manal , Drouin Michel A. , Wang James , Fournel Marielle , Maroun Christiane R. , Karam Andre , Besterman Jeffrey M. , Patnaik Amita 
Published: March 2020

e13602 Background: MGCD265 is a multi-target oral tyrosine kinase receptor inhibitor that targets Met (wild type and clinically-relevant Met mutants), VEGFRs 1, 2, 3, Tie and Ron. Combining Met and EGFR inhibitors has been shown to be synergistic and can overcome resistance to EGFR inhibitors. MGCD265 in combination with erlotinib is being evaluated clinically for safety and efficacy. Methods: This is a phase I dose escalation trial of patients (pts) with advanced solid tumors, using the classic 3+3 design. MGCD265 and erlotinib were administered every day over a 21-day cycle. Safety evaluation included determination of dose limiting toxicities (DLTs) and the maximum tolerated dose of the combination. The pharmacokinetic (PK), pharmacodynamic (PD) profiles as well as anti-tumor activity, using RECIST 1.1, were also evaluated. Results: As ofJanuary 11, 2012, 45 pts were enrolled (median age: 58 years old; M/F: 27/18; ECOG 0/1: 20/25). MGCD265 was dose escalated from 96 mg/m2 QD to 162 mg/m2 BID, in combination with erlotinib (initially at 100 mg then at 150 mg QD). Diarrhea (n=6) was the only treatment-related ≥ grade 3 adverse event observed in ≥ 2 pts. The observed DLTs (all grade 3) were (n=1): diarrhea (96 mg/m2 QD MGCD265+100 mg erlotinib), rash and fatigue (144 mg/m2 QD MGCD265+150 mg erlotinib) and rhabdomyolysis (162 mg/m2 BID MGCD265+150 mg erlotinib). One out of 3 pts with NSCLC, who was positive for activating EGFR mutation, experienced a partial response (duration of response of 8 cycles). Seven pts with a variety of tumors experienced stable disease for 6 cycles or more. Three out of 8 pts with gastroesophageal cancer remained on study for ~12-26 cycles. The PD profile indicated a decrease in the plasma level of HGF at Cycle 1 Day 8 compared to baseline in some patients. Conclusions: MGCD265, at the doses tested, was well tolerated in combination with full-dose erlotinib. The activity of MGCD265 combined with erlotinib supports phase II development of the combination.
Outcome of patients with colorectal liver metastasis: Analysis of 1,613 consecutive cases.
Authors: Xu Jianmin , Zhu Dexiang , Ren Li , Wei Ye , Zhong Yunshi 
Published: March 2020

e14000 Background: To evaluate the long-time outcome of patients with colorectal liver metastasis (CRLM) undergoing different types of therapy and identify factors associated with prognosis. Methods: From 2000 to 2010, a total of 1,613 patients with CRLM were identified in Zhongshan Hospital. Clinicopathological and outcome data were collected and analyzed by univariate and multivariate analyses. Results: Of 1,613 patients the median survival was 23.1 months and the five-year survival rate was 23%. Synchronous liver metastasis (SLM), female, grade III-IV, T4 and N + of primary tumor, bilobar disease, number of liver metastases ≥ 4, size of largest liver metastases ≥ 5 cm, CEA ≥5 ng/ml and CA19-9 ≥ 37u/ml were the predictors of adverse outcome using univariate analysis. The median survival and five-year survival rate for patients after resection of liver metastases was 49.8 months and 47%, compared with 22.2 months and 19% for those after systemic chemotherapy alone, 19.0 months and 13% for those after hepatic arterial chemotherapy alone, 22.8 months and 10% for those after systemic chemotherapy combined with hepatic arterial chemotherapy, and 28.5 months and 6% for those after local regional treatment alone (p< 0.010). In addition, patients without treatment had the poorest survival rate (9.6 months and 0%). 64 initially unresectable patients underwent surgery after convertible therapy and had a median survival of 36.9 months and a five-year survival of 30%, which was better than that of unresectable patients who did not undergo surgery (18.2 months and 10%). By multivariate analysis, SLM, poorly differentiated primary tumor, number of liver metastases ≥ 4, size of largest liver metastases ≥ 5 cm, and no surgical treatment of liver metastases were found to be independent predictors of poor survival. Conclusions: Patients with CRLM could get long-term survival benefit from different types of therapy, and resection of resectable and initially unresectable liver metastases was the optimal strategy. The disease-free interval from primary to liver metastases, the differentiation of the primary tumor, the number and size of liver metastases and the types of therapy used to treat liver metastases were independent prognostic factors.
Effect of young age (<50) on clinical, pathologic features and survival of patients with colorectal cancer.
Authors: Zidan Jamal , Abu Salah Jehad , Sharabi-Nov Adi 
Published: March 2020

e14025 Background: Colorectal cancer is one of the most common malignancies in both men and women in Israel. Most patients with colon cancer are older than 50 years of age. However young patients are not rare. There is no consensus in the literature regarding the behavior of this disease in young patients. Clinical and pathological characteristics of colon cancer patients treated at Oncology Institute in Ziv Medical Center were retrospectively analyzed. The aim of the present study is to compare clinical and pathological features of colon cancer between young and old patients. Methods: A total of 200 patients with colon cancer were treated at our institute during 8 years. Twenty five (12.5%) of them were <50 years age (young patients) at diagnosis. All clinical and pathological characteristics were taken retrospectively from the hospital files. In situations where the pathological findings were not noted in the chart, review of the stored tumor was requested from the pathology department. Acceptable statistical methods were used for statistical calculations. Results: Among the 200 patients 25 (12.5%) were <50 years age at diagnosis (mean age 41 years) and 175 were >50 years (mean age 70 years). Males were 56% of the young group and 60.1% of the old one. Arab patients were 52% of the young and only 12.6% of the old group although total number of Arabs was 35 of 200 patients. No significant difference was found in stage of tumor at diagnosis between the young group (YG) and the old group (OG). Twenty percent of YG had distant metastases compared to 26.5% in the OG. Histopathological grade 3 tumors were found in 33.3% of the YG versus 7.7% in the OG. Surgery and chemotherapy were done in 96% and 88% in YG versus 95.4% and 69.7% in the OG respectively. In a median follow up period of 96 months 35% of young patients died of their disease compared to 33.1% of the old patients. Conclusions: Young patients with colon cancer were diagnosed at the same stage of the disease as old patients. More tumors were high grade in YG. More patients were candidates for chemotherapy in the YG. Significantly more Arab patients were young at the time of diagnosis than Jewish patients. Further studies with higher number of patients are suggested to clarify our findings.
Long-term outcomes of stenting as a bridge to surgery for acute left-sided malignant colonic obstruction.
Authors: Quereshy Fayez A. , Poon Jensen T.C. , Law Wai Lun 
Published: March 2020

e14032 Background: Stenting as a bridge to surgery has been increasingly applied in cases of acute left-sided colonic obstruction. This study aims to evaluate both the short and long-term outcomes associated with colonic stenting as a bridge to surgery in patients with obstructing adenocarcinoma of the colon. Methods: Patients with potentially curable acute left-sided colonic obstruction treated with stenting as a bridge to surgery (28) or with emergency surgical resection (39) from January 1998 to December 2008 were identified using a prospectively maintained database. Short-term data on post-operative mortality, morbidity, necessity of intensive care, and length of hospital stay were compared. Disease-free and overall survival data were also analyzed. Results: Patients within the two study arms had similar demographic profiles. Patients receiving preoperative stenting had a higher likelihood of a laparoscopic resection (p<0.001). Further, the emergency surgery group had a higher rate of post-operative complications (p=0.024), rate of ICU admission (p=0.013), and longer total length of stay (9 vs. 12 days, p=0.001). With a median follow-up of 26.5 and 31.3 months for the stenting and surgical resection groups respectively, there was no difference in overall and disease-free survival (overall survival = 30 vs. 31 months, p=0.858; DFS = 13 vs. 12 months, p=0.989). As well, there was no difference in the rate of systemic recurrences (8 vs. 13, p=0.991). Conclusions: Stenting as a bridge to surgery is a safe treatment strategy in the management of patients with acute left-sided colonic obstruction with improved short-term outcomes and comparable long-term oncologic results.
Use of leucine-rich and immunoglobulin-like domains germ-line polymorphisms to predict clinical outcome in metastatic colorectal cancer.
Authors: Páez David , Labonte Melissa Janae , Paré Laia , Yang Dongyun , Bohanes Pierre Oliver , Gerger Armin , Zhang Wu , Benhaim Leonor , Ning Yan , Wakatsuki Takeru , Loupakis Fotios , Lenz Heinz-Josef 
Published: March 2020

e14052 Background: Leucine-rich and immunoglobulin-like domains (LRIG) 1, 2, and 3 are integral membrane proteins recently discovered as regulators of the epidermal growth factor signalling. LRIG1 negatively regulates growth factor signaling and increasing evidence indicates that LRIG1 is a tumor suppressor in certain cancer types. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some colorectal tumors.We postulate that polymorphisms located in the LRIG1 gene could influence the EGFR signalling pathway and be related with the clinical outcome in metastatic colorectal cancer (mCRC). Methods: This study included 318 patients with mCRC treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Common and putatively functional polymorphisms in the LRIG genes were selected using public literature resources and databases (NCBI, PubMed, db SNP, Ensembl and GeneCards). Whole blood samples were analyzed for germline polymorphisms by direct DNA-sequencing. Overall survival (OS) was evaluated according to each genotype. Furthermore, polymorphisms with suggestive statistical significance were replicated in an independent validation cohort of 126 Spanish mCRC. Results: In a preliminary analysis, two non-synonymous (c3158A>C and c1843A>G) and two synonymous (c2221T>C and c1317C>T) polymorphisms in the LRIG1 gene were selected. There were significant interactions between LRIG1 c1317C>T polymorphisms and clinical outcome. OS was lower for patients harboring T/T genotype (median=11.9 months, 95% C.I (3.5-16 months) than for patients with the C/C or C/T genotypes (median=14.5 months; 95% C.I (12.2-18.3 months); p= 0.04, log-rank test) and the association was also significant in the validation cohort (p=0.01). Conclusions: In this study, we identified common germline variants in LRIG1 gene predicting clinical outcome in patients with mCRC. Although, no functionality has been documented for these SNPs to date, our clinical data suggest that these polymorphisms may affect the mRNA stability and/or translation efficiency of the gene.
Sequential chemotherapy of hepatic arterial infusion of FOLFOX and FOLFIRI with intravenous bevacizumab in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure.
Authors: Itano Osamu , Itano Satoshi , Nagamatsu Hiroaki , Jinno Hiromitsu , Kitagawa Yuko 
Published: March 2020

e14080 Background: At present, systemic chemotherapy is the only established treatment in patients with unresectable colorectal liver metastases (CRLM). The regimen combining irinotecan or oxaliplatin to 5-FU/LV is recommended as a first and second line treatment. However, after failure of oxaliplatin- or irinotecan-based combination chemotherapy, there is no effective regimenremained. This pilot clinical trial explored the feasibility, safety, and efficacy of sequential chemotherapy of hepatic arterial infusion of FOLFOX and FOLFIRI with Intravenous Bevacizumab in unresectable CRLM after systemic chemotherapy failure. Methods: Patients with unresectable CRLM and history of systemic chemotherapy failure were treated with HAI oxaliplatin (35 mg/m2 2 hours: HAI-FOLFOX) or irinotecan (50 mg/m2 2 hours: HAI-FOLFIRI) followed by 5FU (1500mg 46hours) combined with intravenous Bevacizumab (200mg 90min) and LV (200mg 2hours) every 2 weeks until disease progression. Basically, HAI-FOLFOX was applied first, and after disease progression or limiting toxicity, HAI-FOLFIRI followed when the patient was still able to receive treatment. Results: Fourteen consecutive patients (median age 65 years; mean therapeutic term of prior systemic chemotherapy regimens,533 ± 266 days) were included, of whom 11 (79%) had previously received oxaliplatin (n =5), irinotecan (n = 2), or both (n = 4). Patients received a median of 13 cycles of HAI-FOLFOX (range 4–32) and among those, 7 patients sequentially received a median of 22 cycles of HAI-FOLFIRI (range 2–42). There was no technical nonfeasibility to discontinue treatment. The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. The complete and partial response rate totaled 71.4% in this sequential therapy. Median survival time was 20.1 months. Conclusions: A sequential chemotherapy of hepatic arterial infusion of FOLFOX and FOLFIRI with intravenous bevacizumab is feasible, safe, and shows promising activity in unresectable CRLM after systemic chemotherapy failure.