bluuebunny/crossref_metadata_2025 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.
The association of human epidermal growth factor receptor-2 (HER-2) expression with clinicopathologic findings in patients with colorectal cancer receiving adjuvant therapy.
Authors: Karaca Halit , Berk Veli , Inanc Mevlude , Deniz Kemal , Ozkan Metin
Published: March 2020

e14089

Background: Colorectal cancers (CRC) are the third frequent cancer worldwide. Like in other cancers; factors which might be associated with prognosis and treatment of the disease are investigated in molecular basis. In this study, it was aimed to determine the levels of HER-2 expression and it’s association with clinicopathological findings in patients with CRC receiving adjuvant therapy. Methods: A total of 80 patients (48 female, 32 male) whom were diagnosed with CRC and received adjuvant FOLFOX-4 from March 2006 to September 2010 were included in the study. The parameters; age, gender, histopathological diagnosis, tumor localization, presence of obsruction-perforation-bleeding history, grades, presence of perineural-lymphovascular invasion, pathological TNM staging at time of diagnosis, findings of relapse-metastasis, history of surgery and radiotherapy, the chemotherapy regimens received in adjuvant and metastatic stages, follow up intervals and survival data were analyzed. HER-2 receptors were stained immunohistochemically. FISH was performed for samples which were stained (++) or (+++). Statistical analysis was performed for the data. Results: Median follow up was found 24 months (min-max: 1-67) and median age was 59 (min-max: 33-84). Thirteen patients (16%) died and 17 patients relapsed (21%) during follow-up. The median disease-free survival was found 55 months (95% CI: 42.84-55.95). Themedian overall survival was not reached yet.In immunohistochemical stainings; (+++) staining was found in 2 patients (2.5%) while (++) was in 13 (16%) patients. All of 15 patients were performed FISH for HER-2; samples which were (+++) showed positivity but the ones with (++) were negative for FISH. No significant correlation was found between HER-2 expression and clinicopathological findings (p>0.05). Also, no statistical significance was found between HER-2 expression and survival (p>0.05). Conclusions: To current data; prognostic and predictive value of HER-2 overexpression for CRC seems to be poor. Larger, prospective and long-lasting studies are required to clarify this controversial topic.
KRAS mutation profile in Puerto Rican patients with colorectal cancer: Trends in expression of KRAS mutation in PR between April 2009 to January 2011.
Authors: Ruiz Yelitza , Miranda Christine , Hunter Robert F.
Published: March 2020

e14102

Background: The prevalence of a mutated KRAS gene in colorectal cancer shows ethnic variation with a range between 30-48% among the Caucasian, Asian, and European populations. The purpose of this study was to define the profile of KRAS mutation in colorectal cancer patients in Puerto Rico. Methods: Between April 2009 and January 2011, we collected the expression of KRAS gene among colorectal cancer patients in Puerto Rico. The assay was performed by a central laboratory which began to offer the test in the island in April 2009 (GENOPTIX). Data for the presence and type of mutation, age, sex, cancer histology, site of tumor, and cancer stage were collected. The site of the mutation in codon 12 and 13 were identified by the real time polymerase chain reaction (PCR). The study was approved by IRB. A total of 501 cases were available for study. SPPS version 14 was used for statistical analysis. Results: A mutated KRAS was present in 39% (n=195) of the cohort, more commonly in the 51-69 age group (55.4%; p=0.004), in females (55.4%; p=0.095), in the proximal area of colon (43.8%; p=0.017), in the codon 12 (91.2%), and 8.8% in the codon 13. The majority of mutated genes were in codon 12 (91.2%) with 12 ASP (39.5%) and 12 VAL (25.4%) most often seen. Mucinous histology was associated with 46.7% mutated KRAS, poorly differentiated tumor with 40.0% of KRAS mutation. The mutant expression of KRAS in cases with rectum carcinoma was 39.5%, where the most common mutation was 12 VAL. Conclusions: The prevalence of KRAS mutation in Puerto Rican population is similar to other reported studies. A higher prevalence of 12 VAL mutation in rectal carcinoma and a trend towards a higher mutation rate in females are different in this cohort as compared with published studies. This study was supported by NIH grant numbers G12RR-03035 & 8U54MD007587-03.
Midcourse neoadjuvant chemoradiation for locally advanced rectal cancer.
Authors: Ko Sanghwa , Oh Nahmgun
Published: March 2020

e14121

Background: Neoadjuvant chemoradiotherapy is considered a standard approach for locally advanced rectal cancer. Many studies have showed that short-course radiation (25Gy in 5 fractions) and long-course chemoradiotherapy (50.4-55Gy/25 fractions over 5 weeks with oral capecitabine 825 mg/m2 twice daily on radiotherapy days) have similar long-term survival, local recurrence, and late morbidity. The aim of this study is to show the efficacy and safety of a newly modulated mid-course chemoradiotherapy with capecitabine in locally advanced rectal cancer. Methods: 252 patients with low lying (within 7cm from anal verge) locally advanced rectal cancer were recruited. All patients received a total irradiation dose of 30 Gy with conventional fractions for 3 weeks (2 Gy on weekdays). Capecitabine was administered 1000mg/m2 twice a day on 21 days during radiotherapy, followed total mesorectal excision surgery in a week without resting period. Results: The mean patients age was 60.2 years, and 57.9% (146/252) were men. The mean location of cancer was at 4.7cm from anal verge (1-7cm). There were 8 patients (3.2%) with pathologic complete response. 32 patients (12.7%) underwent abdominoperineal resection or Hartmann's operation. Among other 220 patients, 163 patients (74.1%) concomittent diverting ileostomy. Anastomotic leakage was confirmed in 32 patients (14.5%) in the patients with sphincter-saving surgery. There was one case of septicemia, which was recovered. The postoperative mortality was none. Eight patients (3.2%) experienced locoregional recurrence of pelvic cavity. 3-year overall survival rate was 84.1%. Conclusions: Preoperative mid-course chemoradiotherapy using oral capecitabine 2,000 mg/m2/day on 21 days during 2 Gy radiation of each 15 weekdays is seemed to be a tolerable and effective modality, in patients with low lying, locally advanced rectal cancer.
Correlation of VEGFR activation within the tumor-associated stroma with an aggressive colon cancer phenotype.
Authors: Huijbers Anouck , Pin Elisa , Pierobon Mariaelena , Pelt Gabi W. van , Belluco Claudio , Silvestri Alessandra , Liotta Lance A. , Tollenaar Rob A , Petricoin Emanuel , Mesker Wilma E
Published: March 2020

e14151

Background: The tumour microenvironment, and especially the stroma surrounding the tumor cells, is an important target for cancer therapy. Previous results published by our group showed that colon cancer (CC) patients with a high (>50%) intra-tumor stroma ratio had poor prognosis compared to patients with low intra-tumor stroma ratios. In order to evaluate the contribution of the underpinning signalling and molecular architecture of the tumor associated stroma (TAS) to this aggressive phenotype, we utilized laser capture microdissection (LCM) coupled to broad-scale protein pathway activation mapping using reverse phase protein microarrays (RPMA). Such analysis could identify new stromal-based targeted treatment options through the identification of activated pathways within the TAS of patients with aggressive CC. Methods: CC stage II and III tissue specimens were scored for the amount of stroma and a stroma-high and a stroma-low group were defined. Correspondent frozen tumor specimens were selected for a pilot study (n=30; 15 high and 15 low TAS) and subjected to LCM to enrich for TAS cells. RPMA was performed on the resultant lysates whereby an initial set of 30 total and phospho-proteins, known to be involved in stroma proliferation and activation, were analyzed. Results: Unsupervised hierarchical clustering analysis showed partial grouping of stroma high and stroma low samples with phosphorylation of VEGFR-2 being significantly higher in the stroma high group compared to the stroma low (p=0.030). Conclusions: These preliminary results reveal the potential presence of biochemical derangements in the TAS of tumors from patients with aggressive CC with increased activation of VEGFR-2. Considering the central role this protein plays in angiogenesis and cell migration, these results suggest that anti-VEGFR targeted therapy could be considered for a pre-stratified group of patients with aggressive tumors with high recurrence rates. Ongoing expanded pathway analysis with additional signalling proteins including downstream signalling components of VEGFR are being conducted in order to validate this pilot finding and identify new TAS related signalling derangements.
A phase II-III clinical study with the immunomodulator MGN1703 in patients with advanced colorectal carcinoma: The IMPACT study.
Authors: Tschaika Marina , Schmoll Hans-Joachim , Riera-Knorrenschild Jorge , Kröning Hendrik , Mayer Frank , Weith Ekaterina , Schroff Matthias , Krikov Maxim , Schmidt Manuel , Wittig Burghardt
Published: March 2020

e14152

Background: Based on promising data from a phase 1 study of MGN1703 in patients with metastatic solid tumors including those with CRC, a phase 2-3 study was initiated in patients with advanced CRC having disease control after first-line therapy. MGN1703 is a synthetic DNA-based immunomodulator which acts as an agonist of toll-like receptor 9. The objective of the study is to assess efficacy and safety of treatment with MGN1703 in comparison to placebo. Methods: The IMPACT study is designed as an international, multicentric, randomized double-blind placebo-controlled phase 2-3 study. It is conducted in patients with advanced CRC showing disease control after 1st-line therapy with standard chemotherapy regimen. The study treatment is administered s.c. twice weekly (60 mg MGN1703 or placebo; ratio 2:1). The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment is continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent. Results: Up to now, the patients received a maximum of 132 (mean: 32.1) treatment administrations, which equals 66 weeks. Drug-related adverse events (as assessed by the investigator) include mild fever, injection site itching, muscle aching, arthralgia, fatigue, paresthesia, rash, and moderate subfebril temperature and increased ANA in single patients. These represent only 16% of all adverse events reported in the study so far. Nine serious adverse events have been reported and only one was assessed as probably drug-related (“atypical pneumonia”). Local reactions reported in single patients include such symptoms as mild redness and swelling at injection site. Currently no laboratory or clinical signs of dose-limiting toxicities have been reported. Conclusions: The preliminary results of the ongoing clinical study in patients with advanced CRC show a good safety profile of the treatment with MGN1703 at the dosage of 60 mg. Most adverse events which were assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs.
Hepatic resection for colorectal cancer metastasis: A retrospective review of the Ottawa Hospital Cancer Centre over 7 years.
Authors: Boame Nana , Gresham Gillian , Martel Guillaume , Rekman Janelle , Jonker Derek J. , Alnajjar Abdulsalam , Mohammad Waleed , Balaa Fady , Asmis Timothy R.
Published: March 2020

e14154

Background: The timing of chemotherapy (adjuvant vs neoadjuvant) for patients undergoing potentially curative hepatic resection of metastasis from colorectal cancer origin is controversial. Methods: We performed a retrospective review of all patients at TOHCC who underwent successful surgical resection of hepatic metastasis from CRC between 2002-2009. Patients receiving intra-operative radiofrequency ablation (RFA) as part of their management were included. Factors associated with overall survival were evaluated. Results: 168 patients had median age 62 years (31-84), 57/43% male/female. Median pre-op CEA was 5.5 ng/ml (0.3 - 529.2). Primary tumor location included 40% left, 35% rectum, 20% right, 5% transverse. 61.5% patients were node positive. Following hepatectomy 10.2% had positive resection margins. Intra-operative RFA was used in 26 (15.4%) patients. Chemotherapy was administered in a neo-adjuvant (47.6%), adjuvant (58.4%) or “perioperative” (both neoadjuvant and adjuvant; 36.1% ) setting. Use of intraoperative RFA vs. no RFA was not associated with overall survival (HR: 0.94 [95%CI: 0.49-1.80],p=0.85). In both univariate and multivariate analysis, the only adverse factor found associated with survival was R1 status (HR 2.38 [95% CI 1.49-5.0], p=0.0198). Other baseline variables (age, gender, node status, histologic grade, primary tumour site, timing of metastatic diagnosis [metachronous vs. synchronous]) did not reach statistical significance. Conclusions: While statistical significance was not achieved, ability to demonstrate benefit of chemotherapy may have been limited by sample size. Hazard ratios suggest trend to greatest benefit with use of post-operative adjuvant chemotherapy. 3y and 5y survival data is encouraging. Use of RFA where required as an adjunct to hepatic resection appeared as effective as resection of all disease in this series. Recurrence and morbidity data will be presented. [Table: see text]
ERCC1, KRAS mutation, redox status, and oxaliplatin sensitivity in colorectal cancer: “Radical” change in an old model.
Authors: Orlandi Armando , Di Salvatore Mariantonietta , Basso Michele , Bagalà Cinzia , Strippoli Antonia , Plastino Francesca , Dadduzio Enzo , Di Lascio Simona , Cursio Elisabetta , Amoruso Alessia , Rodriquenz Mariagrazia , Cassano Alessandra , Astone Antonio , Barone Carlo
Published: March 2020

e14156

Background: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxa in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1 and cellular Redox status. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8, HT-29) and two K-RAS mt (SW620, SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test and the ERCC1 levels before and after 24h exposure to Oxa by RT-PCR. We silenced K-RAS in a K-RAS mt cell lines to evaluate the impact on Oxa sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxa resistance factor. Cellular oxidative stress was determined by DCFDA. Results: The K-RAS mt cell lines were more sensitive to Oxa (p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24h exposure to Oxa, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (p<0.005). The silencing of K-RAS in K-RAS mt cell lines (SW620s) demonstrated to reduce sensitivity to Oxa associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxa. The levels of reactive oxygen species were higher in K-RAS mt cell lines. The Pearson correlation test showed a statistically significant relationship between basal levels of ROS and sensitivity to Oxa ("r" -0,988, p<0.01). The baseline levels of ROS were higher SW620 than the line SW620s. The administration of Oxa in these cell lines resulted in a statistically higher fluorescence index in SW620 versus SW620s (p<0.003). Conclusions: The K-RAS mutated cell lines were more sensitive to Oxa. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxa and to the synergism between K-RAS mutation and Oxa in increasing oxidative stress. K-RAS can thus be a predictor of response to Oxa in colorectal cancer.
Should patients with peritoneal carcinomatosis of colorectal origin with synchronous liver metastases be treated with curative intent? A case-control study.
Authors: Diane Goere , Maggiori Leon , Viana Benjamin , Dumont Frédéric , Honoré Charles , Malka David , Elias Dominique
Published: March 2020

e14158

Background: This aim of this case-control study was to assess the prognostic impact of the presence of liver metastases (LM) in patients operated on colorectal peritoneal carcinomatosis (PC) who underwent complete cytoreductive surgery (CRS) and LM resection followed by intraperitoneal chemotherapy. Methods: From a prospectively maintained database, all patients with colorectal PC and synchronous LM who underwent CRS followed by intraperitoneal chemotherapy, were manually matched to all identical patients with isolated PC, operated on over the same period, on the following matching criteria: age, peritoneal cancer index (PCI), site of the primary colorectal cancer (colon or rectum), lymph node involvement on the primary colorectal cancer specimen (pN), and postoperative chemotherapy. Results: From 1993 to 2009, 37 patients with PC and LM were matched to 61 patients with isolated PC. After a mean follow-up of 36 months, 3-year overall (OS) and disease free survival rates were significantly lower in patients with PC and LM, respectively 40% and 66% (p=0.04) and 6% and 27% (p=0.001). In Cox regression analysis, a PCI ≥ 12 (Odds-ratio (OR): 4.6), a pN+ status (OR: 3.3), no adjuvant chemotherapy (OR: 3.0) and presence of LM (OR: 2.0) were identified as independent factors of poor OS. Thus, 3 groups could be identified: 1) patients with a low PCI (<12) and no LM, with an associated a median OS of 76 months; 2) patients with a low PCI (<12) and 1 or 2 LM, with an associated OS of 40 months; and 3) patients with a high PCI (≥12) or patients with ≥ 3 LM, with an associated OS of 27 months. Conclusions: This first case-control study confirms that prolonged survival can be achieved in highly selected patients operated on limited carcinomatosis and liver metastases less than 3. When the peritoneal and the liver involvement are greater, the complete surgical treatment followed by intraperitoneal chemotherapy should be discussed according to criteria of aggressiveness of the tumor disease.
Prognostic factors for metastatic colorectal cancer with and without bevacizumab therapy.
Authors: Osuorji Ikenna , Dyson Greg , Yerasuri Durga , Philip Philip Agop , Shields Anthony Frank , Choi Minsig
Published: March 2020

e14163

Background: Metastatic colorectal disease is generally incurable and treatment is palliative with the intent to balance toxicity with quality of life. Coin 3 trial showed that pre-chemotherapy platelet counts > 400,000 per μL were associated with poor survival when intermittent chemotherapy was used, whereas patients with lower platelet counts did not have any significant difference between the intermittent and continuous chemotherapy arms. Methods: We reviewed retrospectively 775 stage IV colorectal cancer patients at Karmanos Cancer Center over a 10 year period to see if high platelet count was associated with a poor outcome irrespective of treatment. Our analysis included 480 patients with adenocarcinoma who had not received chemotherapy prior to referral, and where information on the baseline platelet count, race, and age was available. We also analyzed the impact of race, age and bevacizumab use. We used Cox regression model for analysis. Results: Among the patients 48.3% were African American (AA) and 51.7% were Caucasians (C). 34.4 % had had PLT > 400,000 per μL. For those with lower platelet counts the median survival was 26.2 months in the C and 14.1 months in the AA groups respectively. Patients with platelet above 400,000 had a median survival of 15.2 months for C and 12.6 months for AA. Cox regression analysis, showed hazard ratios for outcome of death were; 1.16(1.07-1.26) p<0.001 for age (per 10 yrs), 1.60(1.31-1.94) [AA versus C(ref)] p< 0.001 for race and 1.35(1.10-1.65)[>400 versus <] p<0.004 for platelet count. In subset analysis, 296(61.7%) patients who received chemotherapy had data regarding use of bevacizumab (B). Among the 31.7% who received B, the median survival was 25.6 months compared to14.1 months in the no B arm. A Cox regression model using B as a stratification variable showed that the impact of race {hazard ratio = 1.32 (1.02-1.69) p =0.03} and platelet count {hazard ratio = 1.27(0.97-1.65) p =0.08} were much less. Conclusions: Pre-chemotherapy Platelet count< 400,000, C race and younger age are associated with improved survival. Use of bevacizumab may mitigate the impact of these factors.
Optimizing the sequence of biological agents in advanced colorectal cancer: A decision analysis.
Authors: Riesco Martinez Maria C. , Berry Scott R. , Ko Yoo-Joung , Chan Kelvin
Published: March 2020

e14171

Background: Patients (pts) with wild-type (WT) K-ras metastatic colorectal cancer(mCRC) may benefit from the following five drugs/classes: fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (B) and EGFR inhibitors (EGFRI). However, pending the results of ongoing randomized trials, the optimal sequencing of these agents is unclear. Methods: A Markov model was constructed for a hypothetical cohort of pts with WT K-ras unresectable mCRC to examine the outcomes of 3 different treatment strategies over a time horizon of 5 years. Strategy A: 1st line B+FP+O/I, 2nd line FP+I/O, 3rd line EGFRI monotherapy. Strategy B: 1st line B+FP+O/I, 2nd line FP+I/O, 3rd line EGFRI + I. Strategy C: 1st line EGFRI+FP+O/I, 2nd line B+ FP+I/O, 3rd line best supportive care. Efficacy and probability data were obtained from published clinical trials identified through a systematic review using MEDLINE, EMBASE and the Cochrane Central registry of clinical trials. The primary endpoint was mean overall survival (OS). Results: The results are shown in the table below. One-way sensitivity analyses revealed that strategy C may be preferred to B when less than 30% of pts were eligible to receive 3rd line treatment (base case was 34%), or when the relative benefit of 3rd line EGFRI+I to EGFRI alone had a hazard ratio (HR) of more than 0.57 (base case HR = 0.54). First order micro-simulation (n=100,000) suggested that 77% and 82% of the simulations revealed the differences between strategies B and C to be less than 1 month and 3 months respectively. Only 6% of the simulations suggested strategy B was superior to others by more than 3 months, while only 12% suggested strategy C was superior to others by more than 3 months. Conclusions: All 3 strategies appeared to result in similar OS for pts with unresectable mCRC. Objective evidence regarding the proportion of patients eligible for 3rd line EGFRI treatment in clinical practice would be useful given the implications for a preferred strategy to maximize OS. [Table: see text]