bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiogenesis inhibitor bevacizumab and symptomatic anal ulcers in metastatic colorectal cancer patients: A single center experience.
Authors: Battaglin Francesca , Bergamo Francesca , Salmaso Beatrice , Murgioni Sabina , Intini Rossana , Saadeh Luca , Cavallin Francesco , Manai Chiara , Urbano Federica , Lonardi Sara , Lacognata Carmelo , Aliberti Camillo , Zagonel Vittorina , Castoro Carlo , Scarpa Marco
Published: September 2018

e15042

Background: Chemotherapy (CT) associated with angiogenesis inhibitor bevacizumab (bev) is a standard first line treatment in metastatic colorectal cancer (mCRC). Among adverse events related to bev, anal canal ulcers have never been extensively described. The aim of our study was to evaluate symptomatic anal ulcers development and its impact on clinical practice and proctologic management. Methods: We retrospectively reviewed clinical records of 601 consecutive mCRC patients (pts) undergoing first line CT from January 2010 to December 2015 at our Institute. Pts’ characteristics, treatments and proctology reports were analyzed. Anal pain was graded in a semi-quantitative scale. Vascularization of the anal canal was compared with contrast MRI in 5 pts treated with bev and 5 healthy controls. Non parametric statistics was performed. Results: Fifty out of 601 pts reported perianal complaints during treatment and underwent proctologic evaluation. Among those, 16 were found to have an anal ulcer. Symptomatic anal ulcers occurred only in pts receiving CT plus bev (16 out of 384, 4.2%) while none was observed in 217 pts treated with other regimens (p = 0.009). The peak incidence was 4-8 weeks after treatment start. Vascularization of anal canal was significantly lower in pts treated with bev (p = 0.03). Hypertension and hemorrhoids were associated with a lower risk of anal ulcer occurrence (p = 0.009 and p = 0.036) while a previous neoadjuvant pelvic CT-RT was not associated with a higher risk. Pain intensity was severe. All attempts at symptomatic treatment with topical and sistemic drugs only led to transient benefit. Pts with symptomatic anal ulcers suspended their first line therapy significantly earlier than other pts (HR = 0.30, 95%CI 0.07-0.80). Conclusions: Symptomatic anal ulcer in mCRC pts treated with CT plus bev is a common adverse event in our series. It can compromise oncologic treatment and pts’ quality of life. We recommend an early proctologic evaluation in case of anal symptoms with the aim to prevent and timely manage such complication in pts treated with bev. A more extensive analysis is ongoing considering subsequent treatment lines and other angiogenesis inhibitors.
Phase II trial of modified FOLIRI plus Panitumumab as first-line treatment in elderly patients with RAS wild-type metastatic colorectal cancer.
Authors: Karampeazis Athanasios , Vamvakas Lampros , Kentepozidis Nikolaos K. , Kotsakis Athanasios , Kalbakis Kostas , Xynogalos Spyros , Sougklakos Ioannis , Emmanouilides Christos E. , Voutsina Alexandra , Hatzidaki Dora , Georgoulias Vassilis
Published: September 2018

e15053

Background:The role of combination chemotherapy plus anti-EGFR treatment in older patients with metastatic colorectal cancer (mCRC) is unclear. We conducted an open label phase II trial in order to evaluate the safety and efficacy of modified FOLFIRI plus panitumumab as first-line treatment in elderly patients with RAS wild-type mCRC. Methods: Patients ≥70 years old with unresectable all-RAS wild-type mCRC were treated with Panitumumab 6mg/kg as 60min iv infusion followed by Irinotecan 130mg/m2 as 90min iv infusion, Leucovorin 400mg/m2 as 2h iv infusion and 5-Fluorouracil 400mg/m2 as bolus iv infusion on day 1 and 5-Fluorouracil 1.200 mg/m2 as continuous iv infusion for 46h, every 2 weeks. Sample size calculation was based on the minimax Simon two-step design: The null hypothesis was that the overall response rate (ORR) is ≤ 30% versus the alternative hypothesis of ORR ≥ 50% (α = 0.05, power 80%). Results: Forty-six patients were enrolled in the study. Two patients did not receive treatment because they were RAS mutant. Median age for the 44 treated patients was 76 years (range 70-88). Males were 32 and the PS was 0, 1 and 2 in 25%, 70.5% and 4.5% of patients, respectively. Rectal cancer accounted for 25% while 15.9% of patients had the primary tumour in situ. Twenty-one partial responses were observed for an ORR of 47.7% (95%CI: 32.9%-62.5%) while seven patients (15.9%) had stable disease. After a median follow-up of 36.0 months, the median progression-free survival was 6.1 months (95%CI: 3.6-8.7) and the median overall survival was 20.9 months (95%CI: 11.7-30.1). Grade 3-4 neutropenia was recorded in 4 (9%) and grade 3-4 diarrhea in 9 (20.4%) patients while one patient had a grade 4 bowel perforation. One patient experienced grade 3 mucositis, two patients grade 3 skin toxicity and two patients grade 3 fatigue. There were no toxic deaths while one patient died due to bowel obstruction and one due to postoperative complications after removal of the primary tumor. Conclusions: The modified FOLFIRI plus panitumumab combination presented significant efficacy with manageable toxicity in elderly patients with mCRC.
The risk of malnutrition in patients with rectal carcinoma: An analysis of 9789 patients.
Authors: Meissner Carl , Fahlke Joerg , Otto Ronny , Kahl Christoph , Ptok Henry , Asperger Walter , Lippert Hans , Ridwelski Karsten
Published: September 2018

e15059

Background: The problem of under-nutrition and lack of nutrition is increasingly placed in the focus of operational discipline. Many of them are deficient in malnutrition before being hospitalized. In surgical therapy, the prevention of postoperative complications is of utmost importance. Due to a preoperative condition of malnutrition, the complication rate may increase and thus the associated increased treatment therapy costs per patient. The consequence, of course, is also a diminished postoperative treatment quality of the treating clinic. Methods: Prospective Multicentre Observational Study: "Quality Assurance Study of Rectal Cancer from 2010-2014 of the" An-Institute for Quality Assurance in Operative Medicine "at the Otto-von-Guericke-University Magdeburg, was screened for Nutritional Risk Screening (NRS 2002) Kondrup J et al Results: 9789 primary data records from 2010 to 2014 were included. With the help of the NRS screening, a total score in the form of a scoring system is possible. The sum of 3 points or more identifies a patient with a food-related risk and should be a cause for further diagnosis and therapy. The median of all rectal carcinoma patients was NRS = 3. 53.9% of the patients had an NRS score of > = 3. In morbidity, the complications in colorectal cancer patients with NRS > = 3 points are significantly increased. Also in the case of general complications (such as pneumonia, urinary tract infection, etc.) the rate increases with a larger NRS score. Conclusions: If the risk of malnutrition is small in patients with a colon carcinoma, the morbidity is low.
Outcomes of concurrent chemoradiotherapy for anal cancer in Brazil.
Authors: Azeredo Andressa Cardoso , Silva Bruna Castilhos
Published: September 2018

e15073

Background: The incidence of anal cancer has increased in the last 30 years and concurrent chemoradiotherapy has been the standard treatment for anal cancer for many decades, since it is a curative treatment in most cases. Although, data from real life outcomes in brazilian patients is lacking. Methods: From October 2001 to November 2016, all the pacientes who were treated with concomitant 5-FU and mitomycin or more recently cisplatin plus radiation at Hospital de Clínicas de Porto Alegre, an academic hospital from South Brazil were identified by electronic database. Medical records were reviewed and demographic data, tumor and treatment characteristics were collected. OS and PFS were estimated by Kaplan-Meier curves. Statistical analysis was performed with SPSS 22. Results: Fifty one patients were analysed for this review. Patient characteristics revealed a mean age of 53 ± 9.03 years, 69% female, with predominantly histology being squamous cell carcinoma (90%). 92% (47) received chemoradiotherapy as a definitive treatment. The chemoterapy regimen used was 5-FU and mitomycin in 69% (35) of the patients and 5-FU plus cisplatin was used in 16 patients (31%). The standard chemoterapy regimen was changed because of lack of supply of mitomycin in our country. Approximately 66% of the patients achieved a complete response while 4 patients (7%) had persistent disease after treatment and 7% had disease progression during treatment. On multivariable analysis, the lymph node status and the size of the tumor were independently associated with worst results. The estimated median PFS was 78 months and the median OS was 92 months. Conclusions: To our knowledge, this is the first report of patients from Brazil treated with concurrent chemoradiation for anal canal cancer. Although we have a delay in the diagnosis and many patients present with locally advanced disease, the CR rate and prognosis are consistent with data from previous studies. We need a longer follow-up to confirm these data and also verify if there will be different outcomes because of the change in the chemoterapy regimen.
Study of circulating tumor DNA (ctDNA) of RAS-wild metastatic colorectal cancer (mCRC) as a tool for on-site mutation screening: A prospective study.
Authors: Sawada Takeshi , Nakamura Keishi , Takahashi Naoki , Kubota Eiji , Sugiyama Manabu , Nakano Shunsuke , Ichijo Toshimitsu , Sakai Rie , Numai Daisuke , Nakanishi Hiroyoshi , Inagaki Satoko , Wakita Shigenori , Ota Ryosuke , Hasatani Kenkei , Tsuji Kunihiro , Doyama Hisashi , Izawa Naoki , Tsuyada Akihiro
Published: September 2018

e15077

Background: Clinical use of ctDNA has been become an important criterion for patient care. The transfer of this knowledge and technology from top clinical labs to local hospitals is still distant. With the goal of a robust, precise, simple and cost-effective genomic test, we designed a prospective study featuring high-sensitive mutation screening of ctDNA from RAS-wild mCRC with digital PCR (dPCR) technology. This approach allows detection of 85 hotspot mutations of KRAS, NRAS, BRAF and PIK3CA, which are present in approximately 60% of CRC, and is clinically important information for anti-EGFR treatment. Methods: 18 “ RAS-wildtype” mCRC patients, initially diagnosed with PCR-rSSO (RASKET) using CRC FFPE samples, were recruited. After extracting ctDNA from patient plasma, dPCR analysis was conducted with LBx Probes. Results: Mutations in KRAS, NRAS, BRAF and PIK3CA, were detected in 5 samples ( KRAS in 3 samples, NRAS in 1 sample, BRAF in 1 sample, and PIK3CA in 2 samples). In a patient undergoing treatment with panitumumab, two different KRAS clones were detected, indicating possible clonal evolution under drug pressure. Interestingly, we also encountered another patient who had never received anti-EGFR antibodies, but who tested RAS mutation-positive at a level below the detection sensitivity of PCR-rSSO. Conclusions: Our dPCR screening with ctDNA was able to identify mutations successfully in a previously-diagnosed “ RAS-wild” mCRC group. Based on these results, we designed the following test, which with <0.1% mutation sensitivity, would be useful for 1) predicting the efficacy of anti-EGFR antibodies prior to treatment; 2) predicting early emergence of acquired resistance to EGFR blockade; and 3) monitoring disease progression during treatment. [Table: see text]
Dietary fiber intake and risks of proximal and distal colon cancers: A systematic review and meta-analysis.
Authors: Ma Yu , Huang Peilin , Hu Mingyue , Ling Sunkai , Li Yuan , Chen Baoan , Xu Yueshuang
Published: September 2018

e15080

Background: Epidemiological studies have suggested that intake of dietary fiber is associated with decreased risk of colon cancer, however, these findings are inconsistent in that dietary fiber intake is differentially associated with risks of proximal colon and distal colon cancers. To address this, we conducted a systematic review and meta-analysis. Methods: Pubmed database were searched to identify relevant cohort studies up to December 2016 to examine the association between dietary fiber and risks of proximal colon and distal colon cancers, respectively. A random-effects model was used to compute summary risk estimates. Results: 11 prospective cohort studies were identified and included in the analysis. We observed that the risk of proximal colon cancer was 14% lower among the highest dietary fiber intake compared with the lowest intake (RR = 0.86, 95% confidence interval [CI] = 0.78 to 0.95). A similar result was also found for distal colon cancer (RR = 0.79, 95% CI = 0.71 to 0.87). Conclusions: In current analysis, we show that dietary fiber intake is associated inversely with risks of both proximal and distal colon cancers.
Serum microRNA expression during neoadjuvant chemoradiation for rectal cancer.
Authors: Lim Stephanie Hui-Su , Ip Emilia , Chua Wei , Ng Weng , Henderson Christopher , Shin J-S , Harris Benjamin Howell Lole , Barberis Alessandro , Cowley Mark , De Souza Paul L. , Spring Kevin
Published: September 2018

e15081

Background: Changes in microRNA (miRNA) expression during treatment for locally advanced rectal cancer (LARC) may provide insight into disease biology and potentially act as predictive biomarkers. We investigated 112 miRNAs in serum during neoadjuvant chemoradiation for LARC. Methods: Serum was collected at baseline, week 3 and at completion of chemoradiation from 40 prospectively recruited patients with LARC. Responders were classed as tumour regression grade (AJCC classification) 0 or 1 and non-responders as 2 or 3. Serum was also collected from 20 healthy controls. RNA extraction was performed using the Norgen total RNA purification kit. Reverse transcription and pre-amplification were performed according to Taqman OpenArray MicroRNA Panels manufacturer's instructions. QuantStudio12K platform was used for miRNA array qPCR. The delta-delta-Ct method was used to identifiy differentially expressed miRNAs, normalised against U6 snRNA. Analysis was performed in R using paired t-statistics and the Benjamini-Hochberg False Discovery Rate for multiple hypothesis testing adjustment, with q < 0.05 for significance. Enriched KEGG pathways were identified using DIANA, based on verified gene targets of each miRNA from Tarbase. Results: Four miRNAs (miR-125b-1, miR-1183, miR-130a, miR-375) were differentially expressed in baseline patient samples compared to controls. From baseline to completion of treatment, three of these - miR-125b-1, miR-1183, miR-130a were downregulated by more than 2-fold. Comparing responders and non-responders, miR-130a was significantly downregulated in the non-responders only. Conclusions: miR-125b-1, miR-1183 and miR-130a are significantly downregulated in patients with LARC during chemoradiation. These miRNAs are known to target key colorectal cancer genes such as ATM and CHEK1, which have been implicated in chemoradiation resistance. miR-130a warrants further investigation as a predictive biomarker, being downregulated in patients with a poor response to therapy. Work is ongoing, investigating these miRNA targets in the solid tissue in these patients. To our knowledge, this is the first study to profile potentially predictive miRNA changes during chemoradiation in LARC.
Emergency department presentation with colorectal cancer.
Authors: Zerhouni Yasmin A. , Melnitchouk Nelya , Schneider Eric , Singh Aparajita
Published: September 2018

e15094

Background: Despite screening protocols shown to reduce mortality, colorectal cancer (CRC) remains the 2nd leading cause of cancer death in the US. CRC patients who have emergent surgery have worse outcomes than those treated electively. We examined presentation and index hospital outcomes for emergency department (ED) patients with a primary diagnosis of CRC. Methods: The 2013 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample was queried and all patients with a primary ICD-9-CM diagnosis of CRC were identified. Descriptive analyses were weighted to the level of the US population. Results: Among 134,869,015 ED visits, approximately 44,717 patients received a primary diagnosis of CRC. Patients with CRC were older (68 vs. 40 years, p < 0.001) and more likely to be male (50.4% vs. 44.3%, p < 0.001) than those presenting for other reasons. Among CRC patients, 88.6% were older than 50 years with males younger than females (66 vs. 70y, p < 0.001) and 90.4% were insured. 88.6% were admitted of whom 44% underwent oncologic resection. Females were more likely to undergo resection (47% vs.42%, p = < 0.001) and to be older at time of surgery (71 vs. 68, p = < 0.001). Average length of stay was 12.5 days for surgical vs. 6.6 days for non-surgical patients (p < 0.001). After admission, 68.0% of those admitted vs. 64.7% of patients who had surgery were discharged home. 6.9% of admitted CRC patients and 4.7% of surgical patients died in-hospital. Average total charges were $124,846 for patients undergoing resection vs. $53,542 for inpatients who did not undergo surgery (p < 0.001). Conclusions: Most patients presenting to the ED for CRC are admitted and many require surgical intervention. Because nearly 90% were 50 or older and insured, further research is warranted to determine if increased screening among eligible patients might reduce the numbers of ED presentations and emergent surgical procedures for CRC.
Factors affecting survival in laparoscopic vs. open surgery among stage III colon cancer patients.
Authors: Zhang Yang , Walters Ryan W , Silberstein Peter T.
Published: September 2018

e15095

Background: The role of laparoscopic surgery (LS) in the cure of advanced non-metastatic colon cancer is controversial. The study aims to define long-term survival of LS and open surgery (OS) of stage III colon cancer as well as to examine factors that influence the choice in surgical approaches. Methods: We abstracted 22,821 patients from the National Cancer Database who were diagnosed with stage III colon cancer from 2010 to 2012 who had undergone surgery of their primary site by either LS or OS; we only included patients who had also received adjuvant chemotherapy. The probability of undergoing a LS or OS was estimated using multivariable marginal logistic regression model, whereas the between-procedure survival difference was estimated with the Kaplan-Meier method with associated log-rank test and a multivariable marginal Cox regression model. Results: Holding the patient- and facility-level characteristics constant, significantly greater odds of receiving LS was associated with private insurance, patients living in areas with higher socio-economic status, patients receiving care at academic facilities, and patients living in the northeast United States. Kaplan-Meier results indicated that patients undergoing LS had significantly longer survival compared to patients undergoing OS (χ21 = 111.6, p < .001). Table 1 shows three-year survival estimates. After adjusting for the patient- and facility-level covariates, patients who underwent LS had 26.7% lower risk of death compared to those undergoing OS (95% CI: 21.7% to 31.4%, p < .001). In general, lower adjusted risk of death was observed in patients who were younger, female, as well as patients with fewer comorbid conditions and those with private insurance (all p< .05). Conclusions: In this largest, most recent analysis of surgical treatment of stage III colon cancer, our data suggest that long-term survival after LS is superior to conventional OS. Identification of associated demographic factors may prove useful for future allocation of treatment resources. [Table: see text]
Long-term followup of bi-shRNAfurin and GMCSF augmented autologous tumor cell immunotherapy treated colorectal cancer patients in phase I and IIa studies.
Authors: Barve Minal A. , Melnyk Anton M. , Manning Luisa , Wallraven Gladice , Birkhofer Martin , Nemunaitis John J.
Published: September 2018

e15100

Background: Vigil is an immuno-stimulatory autologous tumor cell therapy, which uses patient tumor cells transfected with a plasmid encoding genes to upregulate GM-CSF and down regulate TGFβ 1&2. It is administered monthly by intra-dermal injection. In Phase I and IIa trials patients with over 19 different tumor types were safely treated. Rapid and durable systemic immune activation was demonstrated using an IFNγ ELISPOT assay. Methods: Data are summarized for a group of 9 patients with advanced colorectal cancer followed for up to 3.5 years. Results: Six women and 3 men with Stage III or IV colorectal cancer were treated between March, 2010 and September, 2013. Six patients received Vigil as a monotherapy and 3 in combination with FOLFOX chemotherapy. Results: Demographics and treatment details are displayed below. Two patients with Stage III disease received combination therapy after complete surgical resection, and remain disease free over 3 years from surgery. The patients received 9 and 12 Vigil injections with a brisk and durable ELISPOT reactions. Conclusions: Preliminary results suggest that Vigil can be combined safely with FOLOX chemotherapy and still elicit a systemic immune response. Long term disease free survival has been observed in several patients justifying further exploration of this combination. More detailed molecular characterization and neoantigen identification of patient tumor will be undertaken in future studies. A combination with immune checkpoint inhibitors may also be explored. [Table: see text]
Serum chitinase activity to predict survival and metastasis of colorectal cancer.
Authors: Song Zhangfa
Published: September 2018

e15105

Background: In this study we evaluated the role of the chitinase activity (one of the biomarkers) in predicting the liver metastases of colorectal cancer in blood. Methods: The level of chitinase activity were examined in 400 colorectal cancer patients, including 53 synchronous liver metastases in peripheral blood 0.347 colorectal cancer patients peripheral blood was measured before resection of the cancer. The clinical parameters were collected, and the patient were prospectively followed up. Results: The chitinase activity was significantly over-expressed in synchronous liver metastases than colorectal cancer who has no metastases. During the follow up in 347 colorectal cancer patient, higher expression of chitinase activity, higher risk of liver metastases, bothunivariate cox analysis (HR6.0) and multivariate Cox analysis (HR 5.3) show chitinase has high value of predictive the liver metastases after resection of the primary colorectal cancer. Kaplan-Meier analysis shows the chitinase activity has significant correlation to survival in colorectal cancer patients. Moreover, the in vitro study shows the chitinase play important role in cell migration. The metastasis ratio between two groups in non-synchronic colorectal metastasis patients. Conclusions: This study provide experimental evidence that chitinase activity has the potential biomarker for predictive the liver metastases in colorectal cancer. [Table: see text]
Pharmacokinetics of cetuximab and tumor uptake of 89Zr-cetuximab as potential predictive biomarkers for benefit of cetuximab in patients with advanced colorectal cancer.
Authors: Van Helden Erik Jacobus , Menke Catharina Wilhelmina , Boon Eline , van Es Suzanne , Huisman Marc C. , Dongen G.a.M.S. van , Vugts Danielle J. , De Groot Derk Jan , Van Herpen Carla M.L.- , De Vries Elisabeth , Hoekstra Otto S. , Verheul Henk M.W.
Published: September 2018

e15117

Background: One third of patients with RAS wild-type metastatic colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Thus, predictive biomarkers to identify patients with primary resistant mCRC are urgently needed. Methods: Patients with chemotherapy refractory mCRC received 500 mg/m2 cetuximab 2-weekly (NCT02117466 and NCT01691391). Patients underwent a 89Zr-cetuximab PET/CT 6 days post-injection after a therapeutic dose of cetuximab. In case of lack of tumor targeting on 89Zr-cetuximab PET, the cetuximab dose was escalated. Pharmacokinetic (PK) analyses included 89Zr-cetuximab plasma levels, EGFR saturation in skin, soluble EGFR (sEGFR), and tumor uptake and biodistribution on 89Zr-cetuximab PET. We defined treatment benefit as response or stable disease (according to RECIST v1.1) at 2 months. Results: Of the 44 patients, median age was 64 years, 25% had a right-sided primary tumor, 5 patients had a BRAF mutated (mt) tumor and 62% had treatment benefit. Cetuximab treatment dose was escalated to maximally 1250 mg/m2 in 8 patients. Visual and semiquantitative data of 89Zr-cetuximab uptake in the tumor, biodistribution and plasma activity 6 days post-injection were not correlated with treatment benefit. Although EGFR saturation in skin after 2 cycles cetuximab had a wide range (21 – 98%), saturation did not correlate with treatment benefit. On-treatment levels of sEGFR were higher than baseline (median 4.1 vs 2.0 ng/ml; p < 0.001), but levels and change of sEGFR did not correlate with PK or treatment efficacy. PFS and OS correlated with right-sided mCRC (p < 0.001 and p = 0.002 respectively) and the presence of a BRAF mt (p < 0.001 and p = 0.004 respectively). In a multivariate Cox-regression only BRAF mt remained correlated with PFS and OS (p = 0.003 and p = 0.027). Conclusions: Interpatient variances in PK and tumor uptake of 89Zr-cetuximab as performed in this setting do not predict treatment benefit of cetuximab in patients with mCRC. In contrast, BRAF status correlated with treatment benefit and warrants further research to confirm the predictive value. Clinical trial information: NCT02117466 and NCT01691391.
Evaluation of a fully automated extended RAS-BRAF test on prospectively collected plasma samples from patients with metastatic colorectal cancer.
Authors: Jacobs Bart , Claes Bart , Bachet Jean-Baptiste , Bouche Olivier , Sablon Erwin , Maertens Geert G. , Laurent-Puig Pierre
Published: September 2018

e15127

Background: Extended analysis of RAS genes in metastatic colorectal cancer (mCRC) is not available in many settings and the need for an easy plasma test is high. Methods: Pre-treatment plasma samples from 198 mCRC patients enrolled in the prospective multicenter RASANC study (NCT02502656) were retrospectively assessed for the presence of ctDNA mutations in KRAS, NRAS and BRAF by the fully automated Idylla platform.Proper informed consent and statistical analysis were included. The study is ongoing. We used Idylla platform which allows analysis of 21 KRAS, 18 NRAS and 4 BRAF ctDNA mutations from mCRC using 2 ml of plasma. The tests were performed using prototype versions of the Idylla ctKRAS and ctNRAS-BRAF-EGFR S492R Mutation Assays (RUO), which contain all reagents for integrated sample preparation and multiplex real time PCR detection. The tests each require 1 ml of plasma, less than 1 minute hands-on time, and have a turnaround time of less than 130 minutes.As a comparator test, NGS analysis with a sensitivity of 0.2% was performed on extracted plasma ctDNA according to Pécuchet et al. (2016). Results: The Idylla ctDNA assays identified 84 KRAS mutated (42.4%), 6 NRAS mutated (3%) and 13 BRAF mutated (6.6%) cases. The Idylla assays detected 62 KRAS codon 12 (31%), 16 codon 13 (6.5%), 3 codon 61 (1.5%), and 8 codon 146 (4%), and 1 NRAS codon 13 (0.5%) and 5 (2.5%) codon 61 mutated samples. All BRAF mutations detected were V600E. Overall agreement between Idylla and NGS for KRAS, NRAS, and BRAF was 96%, 100%, and 99.5% respectively. Overall RASconcordance with the NGS reference method was 96.5% with a positive agreement of 98% and a negative agreement of 95% (Table 1). Discordancy analysis by means of ddPCR on plasma and/or tissue will be presented. Conclusions: Plasma-based analysis of 41 extended RAS and BRAF mutations in ctDNA on the Idylla platform enables rapid and reliable genotyping in patients with advanced colorectal cancers. Clinical trial information: NCT02502656. [Table: see text]
Different small leucine-rich proteoglycans expression pattern by tumor location in colorectal cancer.
Authors: Solis Hernandez Maria Del Pilar , Fernandez-Vega Ivan , García-Suárez Olivia , Perez Lopez Natalia , Quirós Luis M , García Beatriz
Published: September 2018

e15138

Background: Colorectal cancer (CRC) is a heterogeneous disease defined by anatomic, functional and molecular differences depending on the primary tumor location (PTL). Several molecular phenotypes have been associated with aggressive behavior, and some of these markers are related with proteoglycans, which in turn show alterations in CRC. Small leucine-rich proteoglycans (SLRPs) are a family of molecules encoded by18 genes that may appear coupled to different glycosaminoglycan chains ––including chondroitin/dermatan or keratan sulphate–– or not, depending on the specific species. They are ubiquitously expressed in extracellular matrices, and it’s been described their role in organ size and shape regulation during embryonic development. This study aims to investigate the expression patterns of SLRPs in CRC depending on the PTL. Methods: A transcriptomic approach was carried out by using qPCR to analyze SLRP core protein transcriptions in 32 tumor specimens and their respective healthy tissue: 12 right-sided & 20 left-sided. When significant differences were detected, immunohistochemical techniques were used to enhance the test. Results: While right-sided (R) CRC displayed significant alterations in 2 genes (biglycan BGN overexpression p = 0.015, osteoglycin OGN underexpression p = 0.048), left-sided (L) showed differences in 5 genes (BGN overexpression p = 0.0019 and underexpression of OGN p = 0.0016, prolargin PRELP p = 0.0049, chondroadherin CHAD p = 0.0180 and podocan PODN p = 0.0061). In L tumors CHAD was the most affected gen underexpressed by 16 times, while in R it was present in only 50% of healthy tissue. Transcripts for opticin and nyctalopin were not detected in most patients regardless of PTL. Lumican, decorin, keratocan, asporin, ECM2, fibromodulin, tsukushi, osteoadherin, osteomodulin, epiphycan and PODN-like 1 were detected with no significant differences compared to healthy tissue. Conclusions: Normal mucosa of the large bowel expresses most SLRP. BGN and OGN seem to be dysregulated in both L and R CRC, but CHAD, PRELP and PODN appear to show differences only in L CRC. These alterations could be related to the interaction with different ligands and modulation of homeostasis.
Prevalence and mortality of colorectal cancer with iron deficiency anemia in the South.
Authors: Perimbeti Stuthi , Hou Kevin Ye , Lee William May , Correa Erika , Degen Kathleen , Hanson Shaun Bryan , Marconcini Luiz Antonio Liarte , Niphadkar Seema , Ward Kristine Marie , Jain Maneesh Rajiv , Nandi Neilanjan , Styler Michael
Published: September 2018

e15141

Background: The Centers for Disease Control and Prevention has published data on incidence rates of colorectal cancer (CRC) referenced from the U.S. Cancer Statistics Working Group. Using data on admissions from the National Inpatient Sample (NIS) from 1999-2014. Iron deficiency anemia (IDA) is a commonly encountered comorbidity of CRC, particularly in late stage disease and is associated with higher rates of complications. Methods: Adult admissions with a primary diagnosis of CRC and secondary diagnosis of IDA were extracted from the NIS database using ICD-9 codes from 1999-2014 (N = 5,130, weighted N = 25,594). The sample was weighted to approximate the full inpatient population of the U.S. to analyze differences in regional distribution (Northeast, Midwest, South, and West) we assumed a normal distribution of 25% per region and then performed a chi squared analysis. Results: There were more cases of CRC with IDA in the South (38.32%) compared to the Midwest (22.76%), West (20.45%) and Northeast (18.46%) (p = 0.001). In addition, there were higher rates of mortality from CRC with IDA in the South (29.32%) compared to the Midwest (22.87%), West (21.43%) and Northeast (16.37%) (p < 0.0001). Conclusions: Our data demonstrates a correspondence between the prevalence of IDA associated CRC with a greater prevalence and increased risk of mortality in the South relative to other regions in the U.S.Regional differences in prevalence also corresponded to regional differences in mortality. Future research should investigate the factors that explain these regional disparities.
A retrospective analysis on the impact of preoperative neutrophil to lymphocyte ratio in stage II colon cancer.
Authors: Jaiswal Deepna Deepak , Mantha Suparna , Seija Luis , Munoz Yolanda , Wong Lucas
Published: September 2018

e15146

Background: Inflammation has a critical role in tumor genesis and progression of cancer. The neutrophil to lymphocyte ratio (NLR) is an indication of balance between the immune systems pro and defense mechanism against cancer. Elevated NLR is of interest in many cancers, including colon cancer. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant chemotherapy for stage II colon cancer has remained debatable. We proposed to study the impact of the NLR in patients with stage II colon cancer and to identify high risk patients who would benefit from adjuvant chemotherapy. Methods: Three hundred and eighty patients diagnosed with Stage II colon cancer at our institution were included in this retrospective study. Kaplan-Meir curves and multivariate Cox-regression analyses were calculated for overall survival. Results: Univariate analysis showed NLR was not statistically significant as predictor of mortality (p-value = 0.0857). However, after adjusting for recurrence, chemotherapy, age, white blood cell count, the NLR was predictive for survival, with a hazard ratio of 1.05 and 95% confidence interval of (1.006 - 1.1). Recurrence and age were also significant predictors of survival (p-values of < 0.0001 for both), and HR of 3.1 (2.0 – 4.6) and 1.4 (1.2 – 1.5), respectively. Conclusions: The neutrophil to lymphocyte ratio might be an independent prognostic marker for overall survival in stage II colon cancer patients. Given the retrospective nature of our study, further studies are indicated to confirm our findings.
Pilot trial of KD018 with neo-adjuvant concurrent chemo-radiation therapy in patients with locally advanced rectal cancer.
Authors: Kann Benjamin H , Johung Kimberly , Cheng Yung-Chi , Lam Wing , Liu Shwu-Huey , Decker Roy H. , Higgins Susan A.
Published: September 2018

e15162

Background: Neo-adjuvant chemo-radiation (CRT) is commonly used for rectal cancer, though is associated with gastrointestinal (GI) toxicity. KD018 is a state-of-the-art adaptation of Huang-Qin-Tang, a traditional Chinese medicine used to treat GI ailments. KD018 is a standardized pharmaceutical product subjected to quality-control measures including chemical fingerprinting by liquid chromatography and mass spectroscopy, individual target bioassays, and genomic bioresponse profiling to ensure product consistency. Clinical studies showed the safety of KD018 when given with chemotherapy to reduce GI toxicity. Preclinical study showed that KD018 decreased GI toxicity of abdominal RT without compromising tumor control. Here, we present preliminary results of the first clinical trial to use KD018 in patients receiving RT (neo-adjuvant CRT for rectal cancer). Methods: We conducted a pilot phase I trial of KD018 in patients with biopsy proven rectal adenocarcinoma, clinical stage T3-T4, N0-N2, who received neo-adjuvant CRT. Patients received 3D-conformal pelvic RT to 45 Gy in 1.8 Gy fractions, followed by a 5.4 Gy tumor boost with capecitabine 825mg BID on days 1-5 of RT (weekly) and KD018 800mg PO BID on days 1-4 of RT (weekly). Accrual goal was 24 patients. Primary endpoint was grade 3-4 GI toxicity by CTCAE v4.0 assessed weekly during RT, and until at least 30 days after RT. Secondary endpoint was pathologic response. Results: Of 19 patients enrolled, 16 began treatment, and 14 completed the protocol. Of these, there were no treatment related grade 3-4 GI toxicities (Table 1). Of 11 patients who completed surgery thus far, all had pathologic partial responses. Conclusions: This is the first clinical study of KD018 with concomitant RT and demonstrates the safety and favorable toxicity profile of this regimen compared to historical controls. These preliminary results warrant further study of the efficacy of KD018 as an adjuvant to pelvic CRT or RT to reduce GI toxicity. See table. Clinical trial information: NCT02178644. [Table: see text]
Genomic profiling of young adults with colorectal cancer: A single-institution experience.
Authors: Koenig Kristin Lynn , Wu Christina Sing-Ying , Chen Wei , Frankel Wendy L , Jones Daniel , Zhao Weiqiang , Mikhail Sameh , Roychowdhury Sameek , Hays John L. , Noonan Anne M. , Goldberg Richard M. , Bekaii-Saab Tanios S. , Ciombor Kristen Keon
Published: September 2018

e15168

Background: 2-8% of all colorectal cancer (CRC) cases are in younger adults (YAs), patients (pts) less than age 50. However, current understanding of CRC in YAs is inadequate, especially that of sporadic onset. We conducted a study to describe the landscape of genomic alterations in YA CRC pts presenting to a large academic practice. Methods: Adult pts with CRC presenting to The Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing (NGS) through a customized 22-gene Ion AmpliSeq Mutation Panel as part of clinical care. Commonly mutated areas of select genes (including AKT1, ALK, BRAF, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS/NRAS, MET, NOTCH1, PIK3CA, PTEN, TP53) were sequenced from tumor sections. Institutional review board approval was obtained to retrospectively analyze this NGS testing between 1/2013-3/2016. Results: 258 CRC pts underwent genomic profiling. 57 pts (22.1%) were YAs at diagnosis (range 22-49 years); 20 pts (7.8%) were 40 years old or younger. 31 YA pts (54.4%) had metastatic disease. Of the YAs with CRC, 18 pts (31.6%) were diagnosed with R-sided colon, 16 pts (28.1%) with L-sided colon, and 22 pts (38.6%) with rectal cancer. 110 genomic alterations were found in YA pts, with a mean of 1.9 mutations per tumor (range 0-6); 35 (31.8%) of these in 32 (56.1%) YA pts were actionable. Of these 110 alterations, 41.8% were in TP53, 28.2% in KRAS/NRAS, 10.0% in PIK3CA, 3.6% in BRAF, 3.6% in FBXW7, and 2.73% in PTEN. 6 YA pts (10.5%) had microsatellite instability (MSI-H). Only 1 pt had concomitant MSI-H and a BRAF mutation; 4 pts with BRAF mutations were microsatellite stable. Comparing our YA pts to a separate cohort of pts age > 50 who had testing done, no significant difference was seen in mutation incidence in KRAS/NRAS (p = 1.0), TP53 (p = 0.3), PIK3CA (p = 0.128), or BRAF (p = 1.0). Conclusions: Genomic profiling through a targeted NGS panel is feasible as part of routine clinical practice. There is disagreement in the literature on genetic mutations in YA compared to older age CRC pts. Knowledge of the genomic landscape in YAs with CRC will lead to improved understanding of the underlying biology of CRC in YAs as it differs from CRC in older pts, and could impact future care of this cohort.
The importance of red cell distribution width on gastric cancer.
Authors: Erdem Dilek , Erdem Emre , Turgut Kurt Yasemin , Topcu Turkan , Kacan Turgut , Gunaldi Meral , Yilmaz Bahiddin
Published: September 2018

e15502

Background: Red cell distribution width (RDW) is an elevated marker in several cancers like breast, colon, prostate and pancreatic cancer at the time of diagnosis. Gastric cancer (GC) is the fifth most common cancer and also third leading cause of cancer deaths.We aimed to determine whether RDW values differ between gastric cancer and healthy subjects, as well as to evaluate association between RDW and other factors. Also, we examined other two important inflammatory markers in GC patients: neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) Methods: This retrospective study included 68 gastric cancer patients and 42 age and sex matched healthy controls. The exclusion criteria involved cardiac disease, chronic obstructive lung disease, thromboembolism, chronic renal failure, hepatic disorders, hypertension, acute and chronic infections, stroke, hematologic disease and other accompanying cancer. Blood samples were retrospectively obtained from computerized patient database. Results: Among 110 subjects; RDW, NLR and PLR were significantly higher in GC patients when compared to healthy subjects (RDW: 44,9 vs 41,4 p < 0.0001, NLR: 3,40 vs 1,90 p < 0.0001, PLR: 245,9 vs 131,1 p = 0.007). There was no statistically significant association between these markers (RDW, NLR and PLR) and stage, histopathological subgroups and metastasis stage at the time of diagnosis. Conclusions: Elevated RDW is a simple, cheap and readily available marker and may be useful in gastric cancer at the time of diagnosis. Also, NLR and PLR can accompany RDW in the assessment of gastric cancer. Key words: gastric, red cell distribution width, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, cancer
A metabolomic signature for predicting chemosensitivity in gastric cancer.
Authors: García Verdejo Francisco José , Ortega Granados Ana Laura , Díaz Navarro Caridad , Luque Caro Natalia , Fernández Garay David , Álamo de la Gala Maria Carmen , Ruiz Sanjuan María , de la Torre Cabrera Capilla , Fernández Navarro Mónica , Dueñas García Rosario , Navarro Pérez Victor , Martínez Ortega Esther , Cárdenas Quesada Nuria , Jaén Morago Ana , Plata Fernández Yessica , Vicente Pérez Francisca , Genilloud Olga , Lozano Barriuso Ana María , Sanchez Rovira Pedro , Pérez del Palacio Jose
Published: September 2018

e15504

Background: Perioperative chemotherapy (QT) with platinum and fluoropyrimidines with or without anthracyclines is recommended option in patients with resectable gastric cancer (GC) at least cT2 or nodal involvement. Another option is surgery followed by QT with radiotherapy (QT/RT) or QT without RT in patients with D2 lymphadenectomy. Unfortunately, a considerable percentage of patients progress during neoadjuvant-QT (neo-QT) and some cases become inoperable cancer. These patients could benefit from curative surgery after diagnosis without neo-QT. Currently, histological/molecular markers have not been established to predict which patients can benefit from neo-QT. As potent analysis method, study of blood metabolites of resectable GC patients to establish a profile to differentiate responder patients (R-P) or not-responder (NR-P) to neoadjuvant-QT is promising. To establish a metabolomic profile or metabolomic signature and correlate with chemosensitivity, defined as pathological and clinical response is our endpoint. Methods: To this end we performend an untargeted metabolomic analysis by LC-HRMS of serum samples from resectable GC patients before neo-QT (n = 20 vs n = 10 healthy controls). Chemosensitive tumors were defined as those with good pathological response (Mandard 1 or 2) and partial response by TAC and chemoresistance tumors, defined as those with poor pathological response (Mandard 5) or/and progression by TAC. Reverse phase and HILIC chromatographic modes were applied to deal with highly polar as well as hydrophobic as required for untargeted metabolomics. For identification of potential biomarkers, we used in combination 2 independent variable selection techniques: principal component analysis and Student t test. Results: 11 patients were R-P and 9 patients were NR-P. We observed differences in metabolic profile between patients with GC & healthy controls and R-P & NR-P to neo-QT. Seven identified metabolites contributed most to the differentiating between R-P and NR-P. Conclusions: There are different metabolomic phenotypes among patients R-P and NR-P to neo-QT. It is necessary to validate a metabolomic signature to allow effective chemosensitivity prediction in patients with resectable GC.
Antibody-nanoparticle conjugate constructed with trastuzumab and nab-paclitaxel for the targeted therapy of positive human epidermal growth factor receptor 2 gastric cancer.
Authors: Xiong Jian , Zhang Haijun
Published: September 2018

e15506

Background: Gastric cancer is the most lethal malignancies in the digestive system. This study was to investigate antibody-nanoparticle conjugate (ANC) constructed with Herceptin® and Abraxane® (Herceptin®/Abraxane®) as a novel strategy of targeted therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer. Methods: Firstly, we fabricated the ANC with Herceptin and Abraxane by a “one-step” synthesis using EDC/NHS. In vitro study, the cell viability, apoptosis and cell cycle of the positive HER2 gastric cancer NCI-N87 cells were measured and compared in four groups of PBS, paclitaxel (Taxol), nano- paclitaxel (Abraxane) and ANC (Herceptin/ Abraxane). In addition, we constructed gastric cancer xenograft model in nude mice to evaluate the targeted antitumor effect in vivo. Furthermore, we chose the NIR797 to locate on the ANC and use the NIR imaging to demonstrate that the ANC could more precise target and delayed release of paclitaxel. Results: ANC of Herceptin/Abraxane was spherical in shape and in a suitable size (289.18 nm±102.6 nm). In vitro, the half-maximal inhibitory concentration (IC50), defined as the concentration of Taxol equivalent needed to kill 50% of cells, was found to be 0.24, 0.13 and 0.048 μg/ml for Taxol , Abraxane and ANC of Herceptin/Abraxane respectively for NCI-N87 cells with an excellent dose-effect relationship. Compared with Taxol and Abraxane, ANC of Herceptin/Abraxane could induce significant G2/M arrest. In vivo, at 4 weeks after treatment, mice treated by ANC of Herceptin/Abraxane had a mean tumor volume of 233±24 mm3, Abraxane of 559±97 mm3, Taxol of 871±94 mm3 and PBS as control of 1576±190 mm3. Obviously, the ANC could surpasses Abraxane and Taxol in reducing tumor volume with lesser side effects. Furthermore, NIRF imaging indicated a better targeting and sustained release of paclitaxel with ANC than that with Abraxane and Taxol. Conclusions: Antibody-nanoparticle conjugate of Herceptin/Abraxane could mediate targeted therapy and enhance antitumor activity, which could represent a novel targeted therapeutic agent for positive HER2 gastric cancer.
Multimodality treatment for esophageal cancer in Turkey: A single center experience.
Authors: Demirci Umut , Bugdayci Basal Fatma , Aslan Ferit , Erdur Erkan , Demirci Ayse , Ozatli Tahsin , Oksuzoglu Berna
Published: September 2018

e15507

Background: Esophagus cancer is an important cause of cancer-related deaths in Turkey as well as in the world. In our study, clinicopathological features and survival results of patients treated for esophageal cancer were presented. Methods: This study retrospectively reviewed esophageal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) patients who were admitted to our center, between 2012 and 2016. Results: A total of 82 patients (56 males) with a median age of 56 years were evaluated. Seventy-one (87%) patients were diagnosed with SCC, 10 (12%) with ADC, 1 with adenosquamous carcinoma. All ADC patients were HER2 negative. The localization of tumors; lower third (55%), middle third (27%) and upper third (18%) of the esophagus. Prior to surgery, neoadjuvant chemoradiotherapy (CRT) was administered in 21 patients (26%); 10 of them receiving carboplatin and paclitaxel (CP), and 11 receiving cisplatin and 5-FU (CF). TNM classification of operated patients were as follows; Stage 1 (n = 5), stage 2 (n = 10), stage 3 (n = 8) and stage 4 (n = 1). Adjuvant chemotherapy (CF) was administered in the other 6 (7%) patients. Definitive CRT was given in 36 patients (44%), with CF being administered in 32 patients, and CP therapy in 4 patients. There were 19 patients (23%) with metastatic diagnosis and 13 of whom were treated with CF, and 4 with docetaxel-cisplatin-5FU combination. With median follow up of 21 months, median overall survival (OS) and time to progression (TTP) were 24 and 17 months, respectively. The median OS and TTP of patients with metastatic disease were 14 and th 9 months, respectively. The median OS and TTP of the patients who underwent surgery were 45 and 34 months, respectively. Conclusions: Our findings in this study regarding the rate of histology, the percentages of patients with metastatic vs. locally advanced disease, and survival rates were similar to the literature.