bluuebunny/crossref_metadata_2025_split huggingface dataset:
TFAP2E methylation status in patients with metastatic colorectal cancer treated with FOLFIRI.
Authors: Park Seong Joon , Kim Seung-mi , Hong Yong Sang , Lee Jae-Lyun , Kim Jeong-Eun , Kim Kyu-Pyo , Jin Dong-Hoon , Kim Tae Won 
Published: February 2017

515 Background: Transcription factor AP-2ε, a member of the AP-2 family has been extensively studied in many cancers. Recently, it has been suggested that the gene encoding AP-2ε (TFAP2E) is involved in the development of colorectal cancer (CRC) and is also associated with clinical non-responsiveness to chemotherapy in CRCs. Therefore, we have investigated the clinical significance of TFAP2E methylation status in patients with metastatic CRCs who have received combination chemotherapy with fluoropyrimidine, leucovorin, and irinotecan (FOLFIRI) as first-line treatment. Methods: Eligible patients were those with metastatic CRC treated at Asan Medical center from Jan 2009 to June 2012, and treated with first-line FOLFIRI chemotherapy. The patients without available surgical tissue were excluded. A total of 94 patients were finally included in the study. Results: Forty patients (43%) showed TFAP2E hypermethylation (HM group), and 54 patients (57%) showed TFAP2E hypomethylation (LM group). There were no statistically significant differences in the baseline characteristics according to TFAF2E methylation status. Response rate to chemotherapy was not significantly different between 2 groups (response rate, 50% in HM vs. 36% in LM group, p=0.200; disease control rate, 87% in HM vs. 85% in LM group, p=0.819). After a median follow-up duration of 39.9 months, both progression-free survival (PFS) and overall survival (OS) were not significantly different between 2 groups (HM group vs. LM group; PFS, 5.93 months vs. 5.90 months, p=0.893; OS, 20.9 months vs. 19.8 months, p=0.966). Multivariate analysis showed that there was no significant factor associated with PFS. The patients with well or moderately differentiated tumors showed better OS compared to those with poorly differentiated or mucinous tumors (hazard ratio 0.27, 95% confidence interval 0.13-0.55, p<0.001). However, TFAP2E methylation status was not an independent factor affecting neither PFS nor OS. Conclusions: TFAP2E methylation status may not be a useful biomarker in predicting the clinical outcomes in patients with metastatic colorectal cancers who have received first-line FOLFIRI chemotherapy.
UGT1A1*28 polymorphism in advanced colorectal cancer: The story is not yet ended.
Authors: El Bastawisy Ahmed El Saied , El-Zeiny Amany , Farid Samar , Bahnasy Abeer 
Published: February 2017

516 Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, this study tried to investigate correlation with other toxicities like vomiting. Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, group 1—patients with no mutation, group 2—patients with homo or hetero mutation. All patients received standard IFL regimen. Primary endpoints were (1) comparison between the 2 groups as regard vomiting (2) assessement of the incidence of UGT1A1*28 polymorphism. Secondary endpoints were comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS), and overall survival (OS). Results: 46 cases of advanced colorectal cancer presenting to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%) of them 15% are homozygous. Grade (2-4) vomiting was found in 8.3 % of group 1 versus 52.5 % of group 2. (p = 0.01). Grade (2-4) neutropenia were found in 20.8 % of group 1 versus 64.7 % of group2. (p = 0.03). Grade (2-4) diarrhea was found in 37.5 % of patients of group 1 and 27.5% of patients with group 2. (p = 0.75). Treatment delay occurred in 29.16 % of group 1 versus 72.4 % of group 2. (p = 0.02). 25% of group 1 showed PD versus 25 % of group 2. (p = 0.8). 1 year PFS was 19% in group 1 versus 23 % in group 2. (p = 0.8) while there was a trend towards better OS in group 1 (47 % versus % 35). (p = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.
Traditional Japanese oral mucositis medicine hangeshashinto to upregulate antimicrobial peptides in human salivary gland cells.
Authors: Kono Toru , Kaneko Atsushi , Omiya Yuji , Miyano Kanako , Uezono Yasuhito 
Published: February 2017

517 Background: The cause of chemotherapy-induced oral mucositis (COM) is thought to be direct injury and indirect stomatotoxic effects that result from the release of inflammatory mediators, loss of protective salivary constituents, and therapy-induced neutropenia. We previously found that gargling with hangeshashinto (HST), a traditional Japanese medicine, was effective for treatment of COM. Focusing on the pain and inflammation of COM, we reported at ASCO-GI 2013 and DDW 2013 that HST exhibited ameliorating effects in a hamster model of COM and multi-targeted effects on prostaglandin E2 (PGE2) production, followed by identification of active ingredients by PGE2 culture systems and LC-MS/MS. Our aim in this study was to address whether HST affects protective oral constituents. Methods: Human oral keratinocytes (HOK) and human salivary gland (HSG) cells were used for cell culture assays. Expression levels of mRNAs for antimicrobial peptides, extracellular matrixes, keratinocyte growth factor, amylase, COX-1/COX-2, and cNOS/iNOS in cells with or without HST (10–300 μg/mL) treatment were measured by RT-PCR. Results: HST increased gene expressions of some antimicrobial peptides (defensin β1, adrenomedullin, cathelicidin antimicrobial peptide), and amylase 1A in HSG cells. Further, HST dramatically inhibited COX-2 and iNOS mRNAs in IL-1β treated HOK cells, while it exerted no or little effect on expressions of any protective oral constituents in non-treated HOK cells. A random test to identify the ingredients that increase defensin β1 revealed that isoquinoline alkaloids like berberine were active. Conclusions: HST is expected to maintain oral homeostasis through two paths: increased production of antimicrobial peptides and decreased oral damage induced by excessive prostanoids and nitric oxide. HST thus functions as a multitarget agent, indicating that it may be beneficial in COM treatment.
Association of metformin with reduced mortality in patients with colorectal cancer: A systematic review and meta-analysis of observational studies.
Authors: Singh Preet Paul , Singh Siddharth , Gonsalves Wilson I. , Grothey Axel 
Published: February 2017

522 Background: Metformin inhibits mTOR and downstream pathways involved in cell proliferation and survival by inducing AMPK activation. Although its use has been associated with decreased risk of colorectal cancer (CRC), the effect of metformin on cancer related mortality is unclear. We performed a meta-analysis of published observational studies evaluating metformin use in patients with CRC and its association with overall and CRC-specific survival. Methods: Through a systematic search of PubMed and conference presentations (cut-off: August 2013), we identified 8 observational studies (18,537 total patients with CRC; 6242 CRC patients with DM) reporting the association between metformin use and survival after diagnosis of CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, metformin use was associated with a 34% reduction in mortality in CRC patients as compared to non-use (adjusted HR, 0.66; 95% CI, 0.54-0.81), albeit with high heterogeneity (I2=66.9%). After exclusion of one study, which contributed to considerable heterogeneity, a 28% reduction in mortality was considered a more conservative, consistent effect estimate (adjusted HR, 0.72; 95% CI, 0.64-0.81), with minimal heterogeneity (I2=16.2%). On restricting analysis only to patients with DM, use of metformin (vs non-use) was associated with decreased all-cause mortality (6 studies; adjusted HR, 0.63; 95% CI, 0.49-0.81) and CRC-specific mortality (3 studies; adjusted HR, 0.66; 95% CI, 0.50-0.87). Conclusions: Based on meta-analysis of observational studies, the use of metformin in diabetic patients with CRC appears to be associated with reduced all-cause mortality and CRC-specific mortality. Further prospective investigation of metformin’s effect on outcome in CRC patients is warranted.
The relationship between tumor and host factors and survival in patients undergoing adjuvant chemotherapy for colorectal cancer.
Authors: Park James Hugh , Richards Colin H. , Mcmillan Donald C. , Horgan Paul G. , Roxburgh Campbell S. D. 
Published: February 2017

525 Background: The tumor microenvironment and host inflammatory responses are important determinants of outcome in colorectal cancer (CRC), however their impact on survival in patients receiving adjuvant chemotherapy remains unclear. The aim of the present study was to examine the relationship between these factors, clinicopathological characteristics and survival in patients receiving adjuvant chemotherapy for CRC. Methods: 365 patients who had undergone CRC resection at a single institution between 1997-2008 were included; 88 patients subsequently received chemotherapy. Tumor stroma percentage (TSP) and necrosis were assessed on H and E sections and graded as low or high. Local inflammatory response was assessed using the Klintrup-Mäkinen (K-M), Galon and revised Immunoscore (CD45RO+ /CD8+, and CD3+/CD8+at the invasive margin and tumor center, respectively). Systemic inflammation was assessed using modified Glasgow Prognostic Score (mGPS). Results: Patients receiving adjuvant chemotherapy were younger with a lower ASA (both P<0.05), had advanced T- and N-stage (P<0.05 and P<0.001, respectively), poor tumor differentiation (P<0.05), venous invasion (VI) (P<0.01), margin involvement, infiltrative invasive margin (both P<0.05) and high TSP (P<0.01). In those patients who received adjuvant chemotherapy, on multivariate analysis of clinicopathological factors, VI (HR 3.00, 95%CI 1.22-7.37, P=0.017), TSP (HR 3.00, 95%CI 1.26-7.12, P=0.013), K-M score (HR 5.24, 95%CI 1.21-22.68, P=0.027) and mGPS (HR 3.10 95%CI 1.47-6.55, P=0.003) were independently associated with cancer-specific survival. When the interrelationships between factors independently associated with cancer survival were examined, VI, mGPS, K-M score and TSP were independent of each other (all P>0.05). Conclusions: Compared to standard CRC pathological staging, the present results suggest that assessment of both tumor microenvironment and host inflammatory responses may have superior prognostic value compared with TNM in patients receiving adjuvant chemotherapy.
Rectal cancer treatment without neoadjuvant chemoradiation based on preoperative magnetic resonance imaging: Determinants of surgical quality in the German OCUM study.
Authors: Kreis Martin Ernst , Strassburg Joachim , Ruppert Reinhard , Ptok Henry , Junginger Theodor , Merkel Susanne , Hermanek Paul 
Published: February 2017

526 Background: Preoperative chemoradiation adds functional impairment to patients undergoing total mesorectal excision (TME). Surgical quality is of paramount importance to achieve low local recurrence rates in patients operated without preoperative chemoradiation when a negative circumferential margin was shown by preoperative magnetic resonance imaging (MRI). We aimed to determine surgical quality in a prospective multicenter cohort study (OCUM) in patients selected by MRI for surgery without neoadjuvant chemoradiation. Methods: Quality of TME was assessed in three categories for 282 patients from 12 hospitals enrolled for surgery without preoperative chemoradiation (Nagtegaal et al. 2005, Quirke and Morris 2007). Tumor perforation, local tumor cell dissemination and number of lymph nodes were assessed. Further, negative predictive value of MRI for histopathological involvement of the circumferential margin was determined. Results: In patients undergoing TME the muscularis propria plane (category III) was reached in 1/282 patients (0,4 %). Intraoperative tumor cell dissemination was observed in 3/282 patients (1,1 %). Total number of lymph nodes was 25 (median, range 10-79) and 79/282 patients had positive lymph nodes (28 %). The number of 12 lymph nodes recommended by UICC was not reached in one patient. Preoperative MRI correctly predicted a negative circumferential margin involvement as determined by histopathological workup in 98,9 % of patients. Conclusions: Excellent results in terms of surgical quality are possible justifying surgery without pretreatment in patients with MRI-negative circumferental margin tumors. This concept avoids additional functional impairment and reduced quality of life following preoperative chemoradiation in selected patients. Clinical trial information: NCT01325649.
The prognostic significance of MET overexpression in Chinese patients with gastric adenocarcinoma.
Authors: Li Jin , Wang Chenchen , Su Qin , Wang Yanong , Shi Yingqiang , Sun Menghong , Liu Lian , Sun Zuojun , Liu Xin , Li Wenhua , Zhao Xiaoying , Ji Dongmei , Peng Wei , Yu Hui , Zhang Zhe , Zhang Xiaowei , Piao Yongzhe , Hsu Wanling , Bai Sally Yan , Wang Xiyuan 
Published: February 2017

53 Background: MET, receptor for hepatocyte growth factor (HGF), has been proposed as a therapeutic target in gastroesophageal cancer (GEC). The purpose of this study was to evaluate MET expression in Chinese patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma and to correlate expression with clinicopathologic parameters and prognosis. Methods: MET protein expression was assessed by immunohistochemistry (IHC) in paraffin-embedded tissues from resected tumor specimens. MET IHC was conducted using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems Inc., Tucson, AZ). Four MET IHC scores were defined: 3+ (≥50% of tumor cells staining with strong intensity); 2+ (≥50% of tumor cells with moderate or higher staining, but <50% with strong intensity); 1+ (≥50% of tumor cells with weak or higher staining, but <50% with moderate or higher intensity); or 0 (no staining, or <50% of tumor cells with any intensity) (Spigel et al, J Clin Oncol 2011;29:Suppl, Abst 7505). Kaplan-Meier was used to estimate OS and differences between MET subgroups were compared using the log-rank test. Univariate survival analysis was performed using the stratified Cox model. Results: 442 resected gastric adenocarcinoma samples were collected from patients who underwent surgery between Sept 2007 and Feb 2010. After excluding patients with missing survival, MET, tumor location, differentiation status and stage data, 362 samples were analyzed. Stage II and III accounted for 23% and 59%, respectively. MET prevalence by IHC was: 3+, 5.5%; 2+, 19.6%; 1+, 37.0%; 0, 37.9%. At the OS cut-off, 15 Apr 2012, median follow-up was 35.3 months (range 5.9–49.8 months). The group with MET IHC scores of 2+ or 3+ had significantly shorter OS compared to those with scores of 0 or 1+. The 2-year survival rate was 64% in the 2+/3+ group and 73% in the 0/1+ group (p=0.047). The HR for MET 2+/3+ versus 0/1+ was 1.65 (95% CI: 1.13–2.39, p=0.009), stratified by stage, tumor location and differentiation status. Conclusions: MET expression in resected tissue from Chinese patients with GEC was correlated with poor prognosis. This finding further supports the development of anti-MET agents in this patient population.
Randomized phase II trial of preoperative chemoradiotherapy with or without cetuximab in locally advanced rectal adenocarcinoma.
Authors: McCollum A. David , Kocs Darren M. , Chadha Punit , Monticelli Michael A. , Boyd Thomas E. , Fain Jerry Dean , Kasper Michael , Sanchez James , Simon Miklos , Singh Paramjeet , Thummala Anu , Vukelja Svetislava J. , Wang Yunfei , Asmar Lina , Richards Donald A. 
Published: February 2017

537 Background: Treatment for locally advanced rectal cancer (LARC) includes preoperative radiation concurrent with fluoropyrimidine chemotherapy (CRT). Local recurrence is a problem. Cetuximab is active in colorectal cancer and is effective with radiotherapy in other diseases. This study evaluated the pathologic response rate for LARC treated with preoperative chemoradiotherapy w/wo cetuximab. Methods: LARC (T3/4 or LN+, M0) pts were randomized to Arm1/Arm2. Arm 1 received standard pelvic radiotherapy (5040-5400cGy in daily fractions) with continuous infusional 5-FU (225mg/m2/day); Arm 2 received identical chemoradiotherapy + concurrent cetuximab (400mg/m2 initial dose) 1 week before pelvic radiotherapy, followed by 250mg/m2 weekly for the duration of chemoradiotherapy. After study treatment completion, pts were re-evaluated clinically and radiographically for clinical response. After 6-8 weeks, patients underwent surgical resection. The primary end point was pathologic CR (pCR), and secondary endpoints included ORR, RFS, OS, and local recurrence rates. Results: 139 pts were enrolled (Arm 1=69/Arm2=70); Arm1/Arm2 median age 61/55 yrs, and stage II and III 59%, 39%/40%, 60%. In 124 postsurgery pts, pCR occurred in 17 Arm 1 pts (28.3%, 95% CI 17.5-41.4) and 17 Arm 2 pts (26.6%, 95% CI 16.3-39.1); TRG postsurgery was similar between treatment arms (Table). Grade 3 and 4 toxicities were largely nonhematologic: diarrhea 16%/22%, rash 0%/12%, dehydration 5%/8%, mucositis 5%/6%. The 5-yr RFS for Arm1/Arm2 was 61%/65%, 5-yr OS was 66%/83%, local recurrence was 3%/4%. Conclusions: The addition of cetuximab to preoperative CRT for LARC was associated with increased but manageable toxicities. pCR rates were similar between treatment arms, as were survival statistics and local recurrence rates. No association was found between KRAS status and pCR. Clinical trial information: NCT00527111. [Table: see text]
Observational study of the first-line chemotherapy including cetuximab in patients with metastatic colorectal cancer: CORAL trial.
Authors: Muro Kei , Itabashi Michio , Hashida Hiroki , Masuishi Toshiki , Kotake Masanori , Denda Tadamichi , Ohashi Yasuo , Sugihara Kenichi 
Published: February 2017

539 Background: The combination therapy of Cetuximab (Cmab) + chemotherapy is one option as the first-line chemotherapy for KRAS wild-type metastatic colorectal cancer (mCRC). The efficacy of Cmab+FOLFIRI has been shown by CRYSTAL trail. There has been little experience of Cmab as the first-line chemotherapy in Japan, the data on Cmab combined with other drugs are insufficient, and efficacy according to the ESMO guideline groups (groups 1, 2, 3) has not yet been reported. Methods: The subjects were mCRC patients with PS 0-2 who received the first-line chemotherapy including Cmab, either in combination with chemotherapy or as monotherapy. Treatment duration, reason of discontinuation of the first-line chemotherapy (PD, conversion to surgery, adverse events), the second-line treatment, time to treatment failure, progression-free survival, response rate (RR), changes in paraneoplastic symptoms, skin symptoms (incidence, degree, prevention), and incidence and degree of other adverse events were investigated. Results: The 578 patients from the 158 institutes between January 2012 and June 2013 were enrolled. There were PS0/1/2 at 409/144/25, male/female at 368/210, median age of 65 (31-88) and groups 1/2/3 at 172/231/175. KRAS was wild type/mutant type/undetermined in 95.5%/2.4%/2.1%. Chemotherapies combined with Cmab were oxaliplatin-based/irinotecan-based/others (377/176/25). In evaluable cases, RR in groups 1/2/3 were 68.3%/50.8%/41.7%. In the frequency of skin symptoms reported up to 8 weeks/16 weeks, acneform rash was observed in 70.1%/62.1% (all grades) and in 1.2%/5.7% (grade 3 or higher), while paronychia was in 32.1%/40.6% (all grades) and in 2.6%/9.4% (grade 3 or higher). Liver resection rate and survivals are to be examined in the future. Conclusions: This is the first report on the first-line chemotherapy using Cmab, with RR as efficacy and skin symptoms as safety. Efficacy of the patients with the first-line chemotherapy using Cmab is different among 3 groups. This study is sponsored by the Public Health Research Center Foundation CSPOR in Japan. Clinical trial information: UMIN000007275.
A comparison of biologics in first-line advanced colorectal cancer: A Bayesian network meta-analysis of EGFR inhibitors and bevacizumab.
Authors: Kumachev Alexander , Yan Marie , Berry Scott R. , Ko Yoo-Joung , Riesco Martinez Maria Carmen , Shah Keya , Chan Kelvin K. 
Published: February 2017

543 Background: Adding bevacizumab (B) or EGFR inhibitors (E) to chemotherapy have improved outcomes when compared to chemotherapy (chemo) alone in the first-line treatment of mCRC, however it is unclear which of these combinations is optimal. As the 2 RCTs presented to date were not powered to detect overall survival (OS) benefits and have shown conflicting OS results, a meta-analysis may be beneficial. Methods: We conducted a systematic review of RCTs comparing (1) E + chemo vs. B + chemo (2) E + chemo vs. chemo only, or (3) B + chemo vs. chemo only, using MEDLINE, Embase, Cochrane Central, and ASCO abstracts up to June 2013 with Cochrane methodology. Data on PFS and OS were extracted using the Parmar method. For RCTs involving E, only the K-ras WT data was included. The patient characteristics and outcomes of the reference arms of the RCTs were examined to assess for heterogeneity. Bayesian pairwise and network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios comparing E to B using WinBUGs. Results: Seventeen RCTs (8,048 patients) were identified; 15 of them contained extractable data for quantitative analysis. Direct pairwise meta-analyses (2 RCTs) comparing E vs. B showed that PFS HR=1.00 (95% credible regions (CR): 0.86-1.17) and OS HR=0.76 (95% CR: 0.63-0.92) in favour of E. Indirect comparisons of E vs. B (through the intermediate of chemo only: 5 RCTs comparing E + chemo vs. chemo only, 8 RCTs comparing B + chemo vs. chemo only) showed that PFS HR=1.31 (95% CR: 0.98-1.85) and OS HR=1.06 (95% CR: 0.93-1.22). Combining direct and indirect comparisons with NMA (15 RCTs) showed that the PFS HR=1.10 (95% CR: 1.00-1.21) (trend in favour of B) and OS HR=0.95 (95% CR: 0.85-1.06). Conclusions: The results of direct pairwise meta-analysis, dominated mostly by FIRE-3, suggested E improves OS without PFS benefits when compared to B. However, the results from indirect or combined NMA synthesizing all relevant data from the existing literature did not confirm those findings. The findings of FIRE-3 may be due to chance or trial specific reasons. The results of the upcoming CALGB 80405 will provide further direct evidence to help refine these estimates.