bluuebunny/crossref_metadata_2025 huggingface dataset:
The antiviral effect of poly-gamma-glutamic acid (γ-PGA) in HPV-positive patients.
Authors: Lee Jae Kwan , Cho Hyun Woong , Kim Seunghoon , Park Min Young , Sung Moon Hee
Published: September 2018

e14623

Background: Poly-gamma-glutamic acid (γ-PGA), as a signaling regulator of Toll-like receptor 4 (TLR4), has been shown to induce innate immune responses. In previous non-clinical study, we showed that γ-PGA induces signaling pathway of Type 1 interferon, which consequently eliminates various viruses such as SARS, hepatitis C virus, influenza virus, etc. To evaluate the clinical efficacy of γ-PGA, we’ve investigated the antiviral effect of γ-PGA on human. In retrospective study to evaluate, the clinical significance of g-PGA treatment for vaginal intraepithelial neoplasia (VAIN), γ-PGA may be helpful for the cytological regression and reduction of viral load in patients with high-risk HPV-positive VAIN. Since previous human studies showed the possibility of a drug, we have completed a phase I dose escalation study to determine the safety, tolerance and pharmacokinetics of γ-PGA in healthy adult male subjects. Methods: In the current study, we designed a human study of γ-PGA orally treated daily (75 mL) for 24 weeks to demonstrate the antiviral effect of γ-PGA in female HPV-positive patients. HPV viral load and cell-mediated immune responses were measured during 24 weeks to compare HPV clearance rates between the γ-PGA-treated group and the placebo-controlled group and to evaluate immunological parameters, respectively. Results: . In phase IIb clinical trial to evaluate the efficacy and safety of γ-PGA for the fertile women with cervical intraepithelial neoplasia grade 1 (CIN1) patients, regression rate by the treatment of γ-PGA was 45.65%, whereas the placebo controls were 30.23% in ITT group with statistically significance ( p= 0.0247). Conclusions: γ-PGA may be helpful for the cytological regression and reduction of viral load in patients with high-risk HPV-positive CIN I.
Safety of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection: A randomized, multicenter, prospective, phase III IOCCRC trial (IOCCRC).
Authors: Zhang Rong-xin , Lin Jun-zhong , Chen Gong , LI Li-ren , LU Zhen-hai , Ding Pei-Rong , Wu Xiao Jun , Wan Desen , Pan Zhi-zhong
Published: September 2018

e15002

Background: The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. Patients and Methods: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative plus surgery group to receive intraoperative chemotherapy (portal vein, intraluminal, and intraperitoneal chemotherapy plus surgical resection), whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. Surgical complications and side effects of intraoperative chemotherapy were compared between the two groups. Results: Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. There were no significant differences in the length of hospital stay (8.31 vs. 7.98 days, P = 0.138), length of surgery (170.4 vs. 167.0 min, P = 0.526), length of antibiotic use (2.28 vs. 2.15 days, P = 0.322), or length of drain usage (6.37 vs. 6.16 days, P = 0.387) between the intraoperative chemotherapy and control groups. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2% vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group (0% vs. 0.3%, P = 0.99). Intraoperative chemotherapy did not decrease the rate of patients who received postoperative adjuvant chemotherapy between the intraoperative group and control group (29.3% vs. 30.2%, P = 0.795). Conclusions: Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. Register Number: NCT01465451. Clinical trial information: NCT01465451.
A pilot study of Irinotecan plus raltitrexed as second-line treatment for advanced colorectal cancer.
Authors: Qu Xiujuan , Wu Zhenhai , Wang Shuo , Qu Jinglei , Zhang Lingyun , Liu Jing , Shi Jing , Zhang Jingdong , Liu Yunpeng
Published: September 2018

e15024

Background: This pilot study is aimed to evaluated the efficacy and safety of irinotecan plus raltitrexed as second-line treatment for advanced colorectal cancer patients. Methods: A pilot study was made among patients with advanced, previously treated colorectal cancer from June 2013 to April 2016 in the First Hospital, China Medical University,. A total of 13 patients eligible were enrolled to receive irinotecan at a dose of 180mg/m2 d1, plus raltitrexed at a dose of 3mg/m2 d1, every 3 weeks, until disease progression or un-tolerable adverse events. All statistical analyses were performed using the SPSS (21.0) software program. Kaplan–Meier analysis and Log-rank test were used for survival analysis. P < 0.05 was considered as statistically significant. The primary end point was time to progression (TTP) and objective response rate (ORR), the secondary end point was safety. Results:The median follow-up time was 10.1 months at data cut-off on Dec1, 2016. 11 patients were defined progression of disease (PD) based on the criteria of RECIST 1.1 and 6 patients died. The median TTP of second-line was 4.0 months. The rate of disease control rate (DCR) was 46.2% (6patients stable disease). In univariate analysis, sex (3.2months of 12male patients versus 4.6months of 1female patient, P = 0.926), body mass index (BMI) (3.2months of 5 patients BMI < = 24 versus 4.0months of 8 patients BMI > 24, P = 0.311), site of tumor (4.0months of left versus 3.2months of right, P = 0.555) were not associated with TTP. Safety was assessed within 10 patients including nausea (70%), vomiting (30%), diarrhea (60%), constipation (10%), fatigue (90%), fever (20%), hand foot syndrome (20%), rash (40%), alopecia (40%), palpitations (20%), oral mucositis (10%), neurotoxicity (50%). 2 of 9 patients (22.2%) had hematologic toxic. Liver injury occurred in 3 of 8 patients (37.5%) and no kidney injury was reported. Conclusions: In advanced colorectal cancer patients, irinotecan plus raltitrexed as second-line treatment showed encouraging clinical activity and a tolerable safety profile.
Treatment monitoring of metastatic colorectal cancer by quantification and genotyping of mutated KRAS in circulating cell-free DNA.
Authors: Seufferlein Thomas , Schwerdel Daniel , Welz Hanna , Marienfeld Ralf , Schmidt Stefan A. , Kleger Alexander , Ettrich Thomas Jens , Berger Andreas W.
Published: September 2018

e15037

Background: Treatment of stage IV colorectal cancer (mCRC) has made substantial progress over the last years but therapy monitoring still is in its early stage. A facile, non-invasive, repeatable assessment of the mutational state of a given tumor even during treatment could constitute a desirable biomarker for therapy stratification and disease monitoring. "Liquid biopsies" analyzing circulating free and circulating tumor DNA (cfDNA/ctDNA) from patients’ blood have been proposed as a a simple, non-invasive method that could fulfil this requirement. Methods: 27 patients with histologically confirmed mCRC were enrolled into a treatment surveillance cohort. For the analysis of concordance between tumor tissue DNA and cfDNA we analyzed 40 tissue and blood pairs from therapy naïve patients regarding their KRAS mutation status. The course of cfDNA values combined with targeted genotyping of KRAS mutations were assessed during several palliative chemotherapeutic regimens. cfDNA data were correlated with clinical parameters to establish its prognostic and predictive value. Results: Baseline cfDNA levels allow to significantly differentiate mCRC from healthy controls (14.23 ± 6.33 ng/ml vs. 2.60 ± 1.59 ng/ml; p < 0.0001). cfDNA values at baseline in therapy naïve patients correlate well with tumor burden (p < 0.05) and CEA levels (p < 0.05). cfDNA values significantly increased upon disease progression during 1st (p < 0.01) and 2nd line (p < 0.05) treatment, enabling a non-invasive disease monitoring approach. Moreover, there was a significant correlation between the cfDNA levels upon treatment and progression-free survival (p < 0.05). In addition, our data show that KRAS genotyping of cfDNA under therapy is feasible (80% blood-tissue concordance) and might benefit the patient due to early detection of therapy resistance. Conclusions: Repetitive quantitative and mutational analysis of cfDNA is likely to complement current diagnostic standards in stage IV CRC over the whole continuum of treatment.
18F-FDG PET/CT evaluation of tumor response to the implantation of RENCA macrobeads (RMB) in phase I and II clinical trials [INDBB 10091] in advanced, treatment-resistant metastatic colorectal cancer (mCRC).
Authors: Nazarian Angelica , Sureshbabu Sudipta , Andrada Zoe Padua , Thomas Joanne , Arreglado Anna , Berman Nathaniel , Wolf David J. , Gazda Lawrence S. , Fahey Thomas J. , Ocean Allyson J. , Smith Barry H.
Published: September 2018

e15046

Background: RMB, a cytostatic, biological system form of anti cancer therapy have been used in Ph I & II clinical trials in mCRC w/ evidence of improved survival benefit & QOL. Evaluation of metastatic tumor response by standard CT RECIST criteria however has been unsatisfactory. We hypothesized that using 18F FDG PET/CT scan to evaluate tumor anatomy & metabolism could provide a more accurate picture of tumor response to RMB Methods: 48 mCRC pts (14, Ph 1; 34, Ph 2a) who failed available treatments were implanted intraperitoneally w/ RMB (8mb/kg). Physicals, biomarkers & lab evaluation were obtained at baseline & days 14-90, with PET CT imaging at baseline & day 90. PET scan was acquired 1 hour after FDG injection of 9.4 mCi. CT was used for attenuation correction. Correlation between 18F FDG PET SUVmax findings & CEA & or CA19-9 responses was assessed. Positive response was defined as ≥20% decrease post implant in CEA, CA19-9 & SUV. Only tumors w/ SUVmax ≥ 2.5 were evaluated. SUV measurements were made by 1 radiologist experienced in PET-CT scanning & SUV determination Results: 123 FDG positive mCRC lesions (39, Ph 1; 84 Ph 2a) were detected in 37 evaluable pts (14 m, 23 f; mean age 58.2; SUVmax 2.5-17.5). Of the 37 pts, 28 (76%) showed stabilization & or decreased FDG uptake (4 w/ frank necrosis) as well as stable/decreased CT tumor measurements. Pts w/ pulmonary lesions showed greater responses than those w/ hepatic lesions. 9 (24%) of 37 pts showed increased SUVs. 23 pts (62%) showed decrease in CEA & or CA 19-9 ≥ 20%. 17 pts (74%; 13 decrease, 4 central & peripheral necrosis) had correlation between decreased SUVs/necrosis & biomarkers decrease Conclusions: We conclude SUVs are useful in monitoring mCRC lesions response to RMB therapy. Changes in SUVs correlate w/ CEA & CA 19-9 changes. Taken together the combined data indicate anti tumor effect in these Ph 1/2a trials & offer preliminary support for our hypothesis that 18FDG can be useful in evaluating cell system therapies. Issues of SUVmax standardization & effects of intra tumor heterogeneity however must be considered. Further studies are merited & ongoing, including a planned Ph 3 trial Clinical trial information: NCT01053013; NCT00283075.
Chemotherapy efficacy in metastatic colorectal cancer (mCRC) patients treated with adjuvant or first-line FOLFOX-based chemotherapy.
Authors: Samalin Emmanuelle , Nguyen Tien Tuan , Thezenas Simon , Portales Fabienne , Mazard Thibault , Gourgou Sophie , Assenat Eric , Ychou Marc
Published: September 2018

e15048

Background: Efficacy results of Folfox or Folfiri chemotherapies (CT) are not different as 1st line in mCRC patients, alone or with targeted therapies. No data reported on progression-free survival (PFS) of 1st line Folfiri after Folfox-based adjuvant CT and of 2nd line Folfiri-based CT after a Folfox-based 1st line. The objective was to evaluate the efficacy of a Folfiri-based CT after adjuvant or 1stline Folfox-based treatment. Methods: 210 of 568 pts from a mCRC database were retrospectively selected and divided in 2 cohorts: pts who received adjuvant Folfox then Folfiri as 1st line treatment (n = 76, AdjF) and those treated with Folfox as 1st line treatment then Folfiri 2nd line (n = 134, FFox). PFS1 was the time from beginning of Folfox to 1st progression and PFS2 the time from the Irinotecan-based CT to 2ndprogression. Results: Median age was 62 (22-80). 49.3% pts had synchronous liver (72%) metastases. Primary tumour was right and left colon in 22% and 70% patients. Primary tumour was resected in 91% pts (98.7% and 86.6% in the AdjF and FFox groups, p= 0.003). KRASand BRAF-mutated status were found in 21.8% and 4.7% pts. In the AdjF group, pts received Folfiri as 1st line combined with Bevacizumab (Beva) or anti-EGFR therapy (Cetuximab or Panitumumab) in 70% and 13% cases. In the FFox group, 1st line Folfox-based CT was associated with Beva and anti-EGFRs in 7 and 6% pts, and 2ndline Folfiri-based CT with Beva or Aflibercept in 51 and 4% pts, and with anti-EGFRs in 7.5%. Median duration of a therapeutic line was 5 months (0-29.8). Grade 3-4 toxicities were for the AdjF and FFox groups respectively, diarrhea 13/15%, neutropenia (febrile) 16(7)/37%(1%) and neuropathy 24/18%. Response rates were 55.3% and 68.7% in the AdjF and FFox groups. Median PFS1 were 14 (95%CI:10-16) and 10 (95%CI:8-11) months in the AdjF and FFox groups, and PFS2 10 (95%CI:8-11) and 7 (95%CI:6-9) months, respectively. Median overall survival was 43 (95%CI:39-50) and 33 months (95%CI:26-36) respectively. Conclusions: Results in terms of survival are in favor of the AdjFFox group. It would be interesting to identify a subgroup of pts rapidly progressing after adjuvant Folfox, who might show the same profile than pts in the FFox group.
Sidedness and prognostic factors of peritoneal metastatic colorectal cancer: A single center experience.
Authors: Ilhan Aysegul , Demirci Umut , Aksel Bulent , Aslan Ferit , Dogan Lutfi , Oksuzoglu Berna
Published: September 2018

e15050

Background: Peritoneal metastasis in colorectal cancer (pCRC) is associated with poor prognosis. This study aimed to present a single centre experience for patients with pCRC. Methods: Between 2012 and 2016, 60 patients diagnosed with pCRC included in this study. Demographic and clinico-pathologic characterictics of patients were retrospectively analysed using patient medical records. Results: A total of 60 patients (31 female) were included and the median age was 61. Fifty-five patients (91%) had peritoneal metastases at the initial diagnosis, 37 patients (61%) had the left-sided colon cancer and 33 patients (55%) had the visceral metastases. Peritoneal metastasis was detected in 7 patients during the primary surgery. 30 patients (50%) received biologic therapy; 25 patients (41.6%) received anti-VEGF (bev) and 5 patients (8.3%) received anti-EGFR (cet/ pan) as the first line therapy. Seven (11%) patients underwent cytoreductive surgery and HIPEC. Median PFS of the analyzed patients was 10 months (SE: 2; 95% CI 6-13.9) and mOS was 20 months (SE: 4.2; 95% CI 11.7-28.7). The mPFS and mOS were 16.6 months (SE: 4.9; 95% CI 6.9-26.4) and 28 months (SE:7.1; 95% CI 13.8-42.1) in the group received surgery and HIPEC, respectively. No statistically significant survival difference was detected in terms of primary tumor localization, the presence of visceral metastasis (Table 1). Conclusions: In our study, the prognosis of pCRC patients was observed to be worse regardless of localization and the presence of accompanying visceral disease. A statistically significant difference was observed in the survival of the patients that received biologics. [Table: see text]
The risk of malnutrition in patients with a colon carcinoma: An analysis of 13239 patients.
Authors: Meissner Carl , Fahlke Joerg , Otto Ronny , Kahl Christoph , Krueger Matthias , Asperger Walter , Ptok Henry , Lippert Hans , Ridwelski Karsten
Published: September 2018

e15057

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 Multicentric Observational Study: "Quality Assurance Study Colorectal Cancer from 2010-2014 of the" An Institute for Quality Assurance in Operational Medicine "at the Otto-von-Guericke-University Magdeburg. The screening for lack of nutrition was carried out with the Nutritional Risk Screening (NRS 2002) Kondrup J et al .. Results: 13239 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 nutrition-related risk and should be a cause for further diagnosis and therapy. The median of all colorectal cancer patients was NRS = 3. 65.4% 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.
Role of chemotherapy in improving survival in stage IV colon cancer patients without surgery: An NCDB analysis.
Authors: Chintalacheruvu Lakshmi Manogna , Buddam Avanija , Diab Osama , Silberstein Peter T. , Walters Ryan W
Published: September 2018

e15058

Background: Approximately 20% of patients with colorectal cancer have metastases at the time of presentation. Use of systemic chemotherapy for stage IV colon cancer has greatly increased over past several years with newer advancements. With advancements in chemotherapy annual rate of Primary tumor resection dropped from 74.5 percent in 1988 to 57.4 percent in 2010 with improved survival rates. Methods: A total of 39,428 patients with stage IV colon cancer were analyzed from the national cancer data base (NCDB). Differences in demographic and clinical co-variates were compared using Fisher’s exact test, where as survival differences were estimated by the Kaplan-Meier method and associated log-rank test; p < 0.05 indicated statistical significance. Results: The log-rank tests indicated statistically significant difference in survival (p < 0.001), such that patients receiving chemotherapy survived significantly longer (median survival = 12.0 months, 95% CI = 11.8 to 12.2 months) compared to patients not receiving chemotherapy (median survival = 1.5 months, 95% CI = 1.5 to 1.5 months). Patients receiving chemotherapy were younger (63.2 +/- 13.2 vs 73.8 +/- 13.0 ) with lesser co morbidity when compared to people who did not receive chemotherapy. Conclusions: Patients receiving chemotherapy are considerably younger, with less co-morbidity, and they survive significantly longer. This study signifies the survival advantage with chemotherapy in Stage IV colon cancer patients who did not get any type of surgery. Further studies need to be establish to define the role of chemotherapy comparing to surgery in stage 4 colon cancer patients.
Positive effect on survival of epidural analgesia in patients undergoing cytoreductive surgery for peritoneal metastasis.
Authors: Eveno Clarisse , Gayat Etienne , Caballero Marie-Josee , Schiavone Roberto , Andre Thierry , Pocard Marc
Published: September 2018

e15064

Background: Potential benefits of regional analgesia in reduction of cancer recurrence have been reported for colon and ovarian cancer. The aim of this study was to evaluate the influence of regional analgesia with patient controlled epidural analgesia (PCEA) on disease-free survival (DFS) and overall survival (OS) in patients with peritoneal metastasis (PM) of various origins operated to achieve cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods: From 2006 to 2015, 734 patients were operate on curative purpose to undergone CRS and HIPEC for PM. Three hundred patients for which details on PCEA were available were included in the present study. Aiming to obtain two well-balanced cohorts for available variables influencing early outcome and survival, the PCEA group was matched 1:1 with the non PCEA group by using a propensity score-based method. Results: Matching criteria included demographic characteristics, ASA score, origin of PM, presence of liver metastasis, Peritoneal Carcinomatosis Index (PCI) and complete resection. The median duration of follow-up was 18 months. In the matched cohort (PCEA: 68, non-PCEA: 68), early outcomes were comparable between the two group in terms of blood lost (200 vs 200 ml), transfusion (15 vs 18%), length of surgery (440 vs 450 min) and of hospitalization (12 vs 13 days) and major morbidity (25 vs 22%). After PS-matching, the PCEA group had better OS comparing non-PCEA (Hazard ratio and 95% confidence interval at 0.41 [0.21 – 0.86]). Improvement of DFS rate in PCEA group was observed only in the original sample but not after PS-matching (HR 95%CI: 0.70 [0.45 – 1.07]). Conclusions: In our study, regional analgesia is associated with improved overall survival and transient effect on disease-free survival in patients with peritoneal metastasis of various origins.
Efficacy and safety of Qu Xie capsule in metastatic colorectal cancer: A double-blind, randomized, placebo-controlled trial.
Authors: Zhang Tong , Yang Yufei
Published: September 2018

e15069

Background:Qu Xie capsule was discovered by Li Zhongzi, a traditional Chinese Medicine doctor in the Ming Dynasty. Doctor Yang Yufei improved Qu Xie capsule and used it clinically for more than 10 years. In a previous study, we found that Qu Xie capsule reduces the risk of stage II–III colorectal cancer postoperative recurrence and metastasis and prolongs the survival of patients with metastatic colorectal cancer (mCRC). The present clinical trial was designed to verify the efficacy and safety of Qu Xie capsule in patients with mCRC. Methods: The present study was a randomized, double-blind, placebo-controlled trial. Sixty patients with mCRC were randomized into two groups at a 1:1 ratio. The treatment group received conventional therapy combined with Qu Xie capsule. The control group was treated with conventional therapy combined with placebo. Main outcome measures were overall survival (OS) and progression-free survival (PFS). Results: A total of 121 patients were enrolled and 60 patients were eligible; 54 patients were analyzed. The median OS was 23 months in the treatment group [95% confidence interval (CI) 15–not calculated] vs. 14 months in the control group (95% CI 11–22) (Kaplan–Meier, Log-rank p = 0.060). The OS of the treatment group tended to be longer than that of the control group, although the difference was not significant. This may have been related to the small sample size. In the subgroups of patients < 65 years old, left-sided colon, and ≥second-line therapy, the treatment group showed a significant survival benefit compared with the control group ( p = 0.006, 0.038, 0.013). There were no significant differences between the two groups in PFS. Safety analysis showed no severe hematological toxicity or liver and renal function injury in the treatment group. In the treatment group, one patient had 'abdominal pain' once, which may have been related to the Qu Xie capsule. No other related adverse events were reported. Conclusions:Qu Xie capsule showed good safety and efficacy, and can prolong the OS of patients with mCRC. Clinical trial information: ChiCTR-IOR-16009733.
Laparoscopic radical left hemicolectomy: Use of a bursa omentalis approach to ease splenic flexure mobilization.
Authors: Wang Wei , Wang Wei , Xiong Wenjun , Wan Jin
Published: September 2018

e15071

Background: Laparoscopic splenic flexure mobilization was technically difficult for left colon cancer. This study was aimed to compare the safety and feasibility of laparoscopic radical left hemicolectomy using a bursa omentalis approach (BOA) versus medial-to-lateral approach (MtLA). Methods: BOA was entering the bursa omentalis prior to separating left Toldt’s fascia. We retrospectively analyzed data of 32 cases undergoing laparoscopic radical left hemicolectomy using BOA, matching with using MtLA from January 2013 and October 2016. The matching factors consisted of gender, age, ASA score, BMI, and TNM stage. Data of intraoperative and postoperative characteristics were reviewed. Splenic flexure mobilization time was defined as laparoscopic operation time minus left Toldt’s fascia separating time. Results: There was no significant difference in average time of ambulation, time to first flatus, hospital stay between two groups. The operative time was also similar between two groups (134.2±27.6 min vs 139.4±23.5 min. P = 0.42), but there are significantly shorter splenic flexure mobilization time in BOA group (25.9±12.3 min vs 35.5±22.5 min. P = 0.03). No entry to posterior pancreatic space was recorded in BOA group and 9.4% (3/32) were wrongly entering to posterior pancreatic space when separating left Toldt’s fascia in MtLA group. However, there was no significant difference in intra- or postoperative complication between groups. Conclusions: Our initial results suggest BOA for laparoscopic radical left hemicoletomy may be safe and feasible approach especially for unexperienced surgeons. The main advantages of present approach contain easy to identify pancreas and avoiding wrongly entering posterior pancreatic space when expanding the left Told’s fascia.
Clinical utility of Oncotype DX in early stage colon cancer.
Authors: Dawod Mohammed Adam Ibrahim , Sui Jane Sze Yin , Kelly Deirdre , McSorley Lynda M. , Brady Claire , Bambury Richard , O'Reilly Seamus , Andrews Emmet J , McCourt Morgan , O'Riordain Michael , Murray Kevin J. , Waldron Brian , Bennett Michael William , Feeley Ken , Power Derek Gerard
Published: September 2018

e15076

Background: With the advent of colon cancer screening, patients with early stage colon cancer will be more common in our clinics. The evidence supporting the absolute benefit of chemotherapy in resected Stage II and (to a lesser extent) Stage IIIA disease is poor. Not all patients benefit from chemotherapy and toxicity is a problem. There is a need for validated biomarkers to assess individual patient recurrence risk and discriminate absolute treatment benefit. Several studies have validated the role of the OncotypeDX testing in Stage II/IIIA disease. Our objective is to characterize whether this test impacted oncologists’ decisions in treating patients with Stage II/IIIA in the adjuvant setting. Methods: :The Onco typeDX assay is a multi-gene reverse-transcriptase-polymerase-chain-reaction test that analyses the expression of 12 genes involved in key biologic pathways in colon cancer. Stage II and Stage IIIA colon cancers were studied in affiliated hospitals of our region in southwest Ireland. All data collected is prospective and each colon cancer was assigned a recurrence risk score. Oncologists were blinded to this score and the decision to prescribe adjuvant chemotherapy was recorded. After un-blinding the score, a second decision was recorded and comparisons made. Results: :From August 2015 to September 2016, 70 patients have been recruited with M: F of 2:1. Median age at diagnosis was 65 years. Most patients (80%) had stage II disease, 11 of whom had mismatch repair loss on IHC. OncotypeDX testing has been carried out and reported for 59 patients (85%), MMR intact. Recurrence scores: < 30 in 46 patients (77.9%), 30-40 in 10 patients, and > 40 in 3 patients. The treatment plan was altered in 16 patients (27%), of whom 12 patients (20%) received none or less intense chemotherapy. Conclusions: We have shown that the decision to prescribe adjuvant chemotherapy was changed in 27% of patients. This test has helped to define patients with low scores, where chemotherapy-related toxicity is a concern especially in older patients. Absolute benefit of adjuvant chemotherapy versus the risk of toxicity should be discussed. . Hospital managers may be interested in cost savings due to a reduction in chemotherapy use.
Measuring the effects of radiotherapy on DNA methylation in colorectal cancer.
Authors: Maher Jedi , Young Graeme P , Pedersen Susanne Kartin , Symonds Erin L.
Published: September 2018

e15089

Background: BCAT1 and IKZF1are methylated with high frequency in colorectal cancer (CRC). This study aimed to investigate the level of methylation in these two genes in tissue samples from CRC patients who had undergone radiotherapy. Methods: Tumor and adjacent non-tumor tissue was collected from 50 CRC patients, including 14 subjected to radiotherapy prior to surgical resection. DNA was extracted, bisulfite converted and the levels of methylated BCAT1 and IKZF1 DNA were expressed as the percentage of 5ng tissue DNA (normalized to ACTB levels). Results: In the 36 CRC patients who did not receive radiotherapy prior to resection, tumor tissues had high levels of methylated BCAT1 and IKZF1 compared with adjacent non-tumor tissues (p < 0.001, Table). The CRC tissues from the 14 patients who received radiotherapy pre-surgery had significantly lower levels of methylation compared to the levels in tumors from non-treated patients (p<0.01, Table). Radiotherapy did not appear to affect the methylated BCAT1/IKZF1DNA levels in adjacent non-cancer tissues (p > 0.05, Table). In this limited dataset, a correlation was observed with %methylation and response to radiotherapy measured based on tumor size relative to original size, with the lowest methylation in the tumors associated with the greatest downsizing. Conclusions: The high levels of methylated BCAT1 and IKZF1 in CRC tissue and the low levels in the surrounding non-cancer tissue suggest that the markers are tumor specific with no obvious field effect. In contrast, in the samples obtained from patients treated with radiotherapy prior to resection, the methylation levels in CRC tissues were similar to the levels measured in the adjacent non-tumor tissues. Further studies are necessary to determine the reason for this and whether it has implications for monitoring response to therapy based on blood levels of methylated BCAT1 and IKZF1. [Table: see text]
FBI-1 expression in relation to clinicopathological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy.
Authors: Wang Chao-Jie , Zhou Jian-Wei , Zhou Yun , Sun Xiao-Feng
Published: September 2018

e15102

Background:FBI-1 is a recently characterized proto-oncoprotein of the POZ domain Krüppel-like (POK) family of transcription factors. Although several studies provide the evidence that FBI-1 is an important gene regulator in CRC, no analysis of any correlation between FBI-1 expression and preoperative radiotherapy (RT) has been studied in rectal cancers. Methods: This study included the patients with rectal cancer that participated in a Swedish clinical trial of preoperative RT between 1987 and 1990. Patients were divided into preoperative RT (62) and non-RT (77) groups. Applying immunohistochemstry, we detected FBI-1 expression in 118 normal mucosa, 139 primary rectal cancers, and 45 lymph node metastases, and analyzed its relationship with clinicopathological features and RT response. Results: FBI-1 was detected both in the cytoplasm and nucleus, and the cytoplasmic staining was up-regulated compared with normal mucosa both in non-RT and RT groups (74.0% vs. 17.7%, p < 0.001; 69.4% vs. 41.1%, p = 0.002), however, the nuclear staining was down-regulated compared with normal mucosa both in non-RT and RT groups (22.1% vs. 75.8%, p < 0.001; 35.5% vs. 83.9% p < 0.001). Both cytoplasmic and nuclear staining were no difference between the non-RT and RT groups (74.0% vs. 69.4%, p = 0.542; 22.1% vs. 35.5%, p = 0.080, respectively). So we combined the non-RT and RT group together for further analysis. Nuclear staining of FBI-1 was positively with TNM stage and distance recurrence, it showed higher expression in III+ IV stage than that in I+II stage (41.0% vs. 17.9%, p = 0.003). The patients with distance recurrence showed higher FBI-1 expression than that with no distance recurrence (39.7% vs. 19.8%, p = 0.010). In stage I, II and III patients, higher nuclear FBI-1 in primary cancer showed worse disease free survival (HR: 1.934; 95%CI: 1.055-3.579, p = 0.033) and overall survival (HR: 2.174; 95%CI: 1.102-4.290; p = 0.025) independent of gender, age, growth pattern, differentiation and RT. Conclusions: Higher nuclear FBI-1 is related with later TNM stage, distance recurrence, and worse prognosis, it can be used as a potential diagnostic and prognostic biomarker in rectal cancer.
Tumor associated macrophages to predict the efficacy of bevacizumab plus chemotherapy in patients with advanced colorectal cancer.
Authors: Akbulut Hakan , Dost Gunay Fatma Sena , Kirmizi Bilge Ayca , Koksoy Elif Berna , Ensari Arzu , Icli Fikri
Published: September 2018

e15103

Background: The tumor-associated macrophage (TAM) is one of the major components of tumor microenvironment. Neuroendocrine differentiation (NED) of the tumor has been linked to poor prognosis. We aimed to investigate the role of TAM infiltration and NED in tumor tissue on the efficacy of bevacizumab plus chemotherapy in patients with advanced colorectal cancer. Methods: A total of 123 consecutive patients with advanced colorectal cancer treated with bevacizumab plus either irinotecan or oxaliplatin-based combination chemotherapy were included in the study. Along with clinicopathological parameters including age, tumor location (right versus left colon), pretreatment CEA level, KRAS mutation status, tumor grade, histologic subtype (mucinous vs non-mucinous), the presence of NED and the level of TAM infiltration were studied as covariates for survival analysis. The patients with at least 2% or more staining with either synaptophysin or chromogranin A were regarded as NED positive. The +2 or less staining with anti-CD68 was regarded as low for TAM infiltration and +3 or +4 staining as high. The overall (OS) and progression-free survival (PFS) times were calculated from the start of bevacizumab. Results: Thirty-five percent of the patients were given bevacizumab in the first line setting, the others mainly at the second line. The chemo backbone was FOLFIRI in 75% of the patients. The median OS was 15,1 and PFS 7,1 months. The ratio of NED negative and TAM infiltration low patients were 73,9% and 13,8 %, respectively. The univariate analysis yielded only the NED and higher TAM infiltration as the significant factors for PFS. However, only NED was significant for PFS in the multivariate analysis (HR:0.542). The left-sided tumors and the low levels of TAM infiltration were the favorable factors for OS in the univariate analysis. However, the TAM level was the only independent factor predicting the OS (26,7±8,8 vs 14,1±1,7 months, respectively; HR: 0,301). Conclusions: Our results suggest that the TAM infiltration in the tumor tissue could be used as a predictive marker of efficacy of bevacizumab plus combination chemotherapy in patients with advanced colorectal cancer.
Division of elderly patients in colorectal cancer: Korean national health insurance big data analysis.
Authors: Baek Sun Kyung , Lee Ji Sung , Lee Sang-Cheol , Bae Sang-Byung , Kim Jong Gwang , Kim Tae Won
Published: September 2018

e15104

Background: This nationwide study was conducted to demonstrate the difference of the treatment and the survival of elderly patients with colorectal cancer (CRC) by the analysis of big data using the Korean National Health insurance service (NHIS). Methods: We analyzed the NHIS database of CRC patients admitted hospitals which received its quality assessment between 2011 and 2014. According to age, we divided patients into three groups, non-elderly patients ( < 65 years old), borderline elderly patients (65-74 years old) and elderly patients (≥ 75 years old). Results: We included 70,701 CRC patients. Median follow-up duration was 3.2 years (range 0.003-5.5 years). Male patients were 60% and median age was 65 years old (range 18-102 years). Comparing with non-elderly patients, elderly patients more received emergency operation (p < 0.001) and less received adjuvant therapy in stage I-III or palliative chemotherapy in stage IV (p < 0.001). Survival probability at 3 year of borderline elderly patients and elderly patients showed worse survival rate than non-elderly patients [HR 1.55, 95% confidence interval (CI) 1.46 - 1.64, HR 3.19, 95% confidence interval (CI) 3.03 -3.37, respectively]. Conclusions: These results show the treatment and the poor survival of elderly patients with CRC according to age in Korea. More study to reveal the biology of them and to improve outcome is warranted. Our study was the first to describe these data for CRC at a nationwide level.
Prognostic impact of cytomegalovirus (CMV) detection in colorectal cancer (CRC).
Authors: Lee Michael Sangmin , Selitsky Sara R. , Parker Joel S.
Published: September 2018

e15120

Background: CMV is a widespread herpesvirus that lies latent in the majority of immunocompetent hosts but may reactivate and infect colon epithelium. Prior studies have identified CMV proteins in CRC tumors, where CMV superinfection may play an oncomodulatory role. CMV constitutively activates virally encoded chemokine receptors that may act as oncogenes via promotion of angiogenesis, proliferation, and migration. However, the clinical significance of CMV superinfection in CRC has not been clearly demonstrated. Methods: We obtained clinical and tumor characteristics from 355 CRC patients in The Cancer Genome Atlas (TCGA). TCGA RNA-seq was aligned to curated viral genomes from GenBank after first filtering out the reads that mapped to the human genome. Reads that mapped to CMV were quantified. Consensus Molecular Subtypes (CMS) by gene expression were obtained from www.synapse.org. Results: Among 355 CRC patients, 60 (16.9%) had CMV detected by RNA-seq. CMV+ was significantly associated with older median age (69.5 vs. 64 years, p = 0.016) and rectal rather than colon primary (odds ratio 3.76, 95% CI 1.87-7.57). CMV status was not significantly associated with stage, sex, race, microsatellite stability, BRAF/ KRAS/ NRAS mutation, or CMS subtype. On Cox univariate analysis, CMV+ was associated with inferior survival (HR 1.91, 95% CI 1.10-3.34), as were age (HR 1.03, 95% CI 1.01-1.05), stage (HR 2.00, 95% CI 1.54-2.59), and CMS4 subtype (HR 2.12, 95% CI 1.29-3.48). CMV+ remained significantly associated with inferior survival on multivariate Cox analysis when adjusting for age, stage, and CMS4 subtype. Conclusions: CMV+ as detected on RNA-seq is significantly associated with older age at diagnosis and rectal primary tumor and independently confers inferior prognosis. These findings warrant further investigation of the potential oncomodulatory role and prognostic value of CMV reactivation in CRC.
Quantitative MR imaging biomarkers of tumor heterogeneity predict prognosis in metastatic colorectal lesions.
Authors: Daye Dania , Kamran Sophia C. , Tabari Azadeh , Michalski Mark , Clark Jeffrey W. , Ryan David P. , Allen Jill N. , Murphy Janet E. , Hong Theodore S. , Gee Michael S.
Published: September 2018

e15121

Background: Intra-tumor heterogeneity is an independent determinant of patient survival outcomes in several tumor subtypes. Spatial variations in tumor enhancement on MRI is a macroscopic imaging marker of tumor heterogeneity. The goal of this study is to evaluate the potential role of MRI-based enhancement heterogeneity measures as predictors of survival in patients with metastatic colorectal cancer. Methods: We retrospectively analyzed T1-weighted contrast-enhanced MRI images of metastatic hepatic lesions in 41 patients (mean age 57.2 ±14.2 years) who were diagnosed with stage IV colorectal cancer between 2007 and 2013. Tumor Kras mutation status and patient survival data for up to 95 months was available for all patients. The largest metastatic hepatic lesion was identified by a radiologist and manually segmented. 14 Haralick texture features were extracted from each lesion. Cox proportional hazards regression analysis was used to assess the association between the enhancement heterogeneity measures and patient survival, with adjustment for Kras mutation status as a potential confounder. Backward stepwise feature selection was performed using p > 0.1 (Wald test) to select for statistically significant features. Results:Mean survival time was 39±3.9 months for the study population (51±4.1 months for Kras-wildtype and 37±5.1 for Kras-mutants). 68% of the patients had left-sided colon cancer; 21% had concurrent pulmonary metastases and 0.5% had concurrent brain metastasis. 61%, 27% and 12% of patients were on Flofox, Folfiri or other chemotherapeutic regimen, respectively. Texture matrix homogeneity (HR > 10; p = 0.016), inverse difference moment (HR < 0.1; p = 0.020), entropy (HR < 0.1; p = 0.033) and standard deviation (HR > 10; p = 0.006) exhibited significant independent association with patient survival. With the exception of entropy, these features maintained significant contribution to survival prediction independent of Kras mutation status. Conclusions: MRI-based quantitativeintra-metastasis heterogeneity measures are associated with patient survival and may add information beyond genetic mutation status to optimize prognosis prediction in metastatic colon cancer.
The FOXC1/FBP1 signaling axispromotes tumorigenicity by enhancing the Warburg effect in colorectal cancer.
Authors: Li Dawei , Li Qingguo , Cai Sanjun , Xie Keping
Published: September 2018

e15123

Background: Aberrant expression of Forkhead Box transcription factors plays vital roles in the oncogenesis and metastasis of many types of cancer. The purpose of this study is to elucidate the function of Forkhead Box C1(FOXC1) in colorectal cancer (CRC)malignancy maintenance. Methods: FOXC1 expression in CRC specimens was analyzed in the TCGA database and validated by immunohistochemistry using a tissue microarray (TMA). The effect of FOXC1 expression on cancer proliferation and glycolysis was assessed in cells by altering the expression of FOXC1 in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: FOXC1 was found to be overexpressed in CRC specimens compared with that in the adjacent benign tissues. Univariate survival analyses of the TCGA and validated cohorts showed that high expression of FOXC1 was significantly correlated with shortened patient survival ( P< 0.05). Attenuation of FOXC1 expression inhibited proliferation, clone formation and decreased glucose consumption and lactate production. By contrast, overexpression of FOXC1 had the opposite effect. Furthermore, increased FOXC1 expression downregulated the expression of a key glycolytic enzyme,fructose-1, 6-Bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Aberrant FBP1 expression contributes to CRC tumorigenicity, and decreased FBP1 coupled with increased FOXC1 provided better prognostic information than FOXC1 did alone. Conclusions: The FOXC1/FBP1 axis induces cell proliferation, reprograms the metabolic process in CRC and provides potential prognostic predictors and therapeutic targets for patients with CRC.
Prognostic significance of VEGF-A/VEGF-R and EGF in liver metastasis from colorectal cancer.
Authors: Nikipelova Elena Alekseevna , Kit Oleg I. , Frantsiyants Elena Mikhaylovna , Bandovkina Valeria , Kaplieva Irina V. , Trepitaki Lidia K. , Tkalya Lyudmila Dmitriyevna , Kolesnikov Evgeniy N. , Snezhko Alexander V. , Averkin Michail , Kozhushko Mikhail Anatolievich , Sanamyanc Sergey Vladimirovich , Myagkov Roman E. , Kharin Leonid , Trifanov Vladimir
Published: September 2018

e15128

Background: Liver metastasis from colorectal cancer dramatically reduces the treatment effectiveness and affects survival. Early detection of metastasis allows increasing the median survival and improving the quality of life of patients. The purpose of the study was to reveal factors significant for the prognosis of liver metastasis from colorectal cancer. Methods: Levels of VEGF-A, VEGF-R and EGF were studied by ELISA in tumors and resection line tissues of 113 patients with colorectal cancer (rectal cancer n = 43, colon cancer n = 70). Results: VEGF-A and VEGF-R levels in all tumors were increased compared to the resection line. VEGF-A levels in 46.5% patients with rectal tumors and in 29% patients with colon tumors were 2.5 times higher than in other patients; the VEGF-A/VEGF-R ratio was 2.9 times higher as well. Besides, these patients showed an increase in EGF levels in tumors by 3.9 times (rectal cancer) and 4.2 times (colon cancer), compared to the resection line. The follow-up demonstrated that the patient cohort developed liver metastases during next 3 months. Conclusions: Neoangiogenesis is activated in rectal and sigmoid tumors, and increasing VEGF-А and EGF contribute to tumor progression and metastasis. The VEGF-A/VEGF-R ratio in tumor tissues in comparison with the resection line value can be a reliable factor for the prognosis of liver metastasis.