bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of TLR9 polymorphism with overall survival in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab enrolled in FIRE3.
Authors: Okazaki Satoshi , Stintzing Sebastian , Heinemann Volker , Cao Shu , Zhang Wu , Yang Dongyun , Ning Yan , Matsusaka Satoshi , Berger Martin D. , West Jordan D. , Miyamoto Yuji , Suenaga Mitsukuni , Lenz Heinz-Josef 
Published: February 2017

498 Background: Toll-like receptors (TLRs) play crucial roles in carcinogenesis and evolution of the tumor microenvironment. TLR9 dependent stimulation is known to cause antitumor activity not only by activating anti-tumor immunity but also by interfering with angiogenesis. We tested the hypothesis that genetic variations in TLR9 will be associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with bevacizumab based chemotherapy. Methods: Genomic DNA was isolated from tissue samples from 301 mCRC patients enrolled in the FIRE3 trial and treated in first-line with FOLFIRI plus bevacizumab. Three single nucleotide polymorphisms (SNPs) in the TLR9 gene, rs187084 A/G, rs352140 C/T, and rs5743836 T/C, were analyzed by PCR-based direct sequencing. These SNPs were tested for the association with tumor response, progression free survival (PFS), and overall survival (OS). Subgroup analyses by gender, tumor location, and Kras status were also analyzed. Results: The patients carrying variant genotype (T/C or C/C) for rs5743836 showed a strong trend toward shorter OS compared to those with a wild-type T/T genotype (median: 21.2 vs. 24.8 months, HR: 1.35, P = 0.069). This difference remained statistically significant in the multivariate analysis (HR: 1.53, 95%CI: 1.09-2.15, P = 0.014). In the subgroup of Kras-mutant type, the variants (T/C and C/C) were significantly associated with worse PFS (8.1 vs. 11.3 months, HR 2.06, p = 0.043) and OS (16.4 vs. 25.1 months, HR: 2.44, p = 0.012), which retained statistical significance in the multivariate analysis. No association with clinical outcome was observed for rs187084 and rs352140. Conclusions: Our findings suggest that TLR9 polymorphism of rs5743836 is a prognostic marker of mCRC patients, especially of those with Kras-mutant type, who were treated with FOLFIRI plus bevacizumab.
TGF-β inhibitor LY2157299 (galunisertib) in combination with standard chemotherapy and inhibition of signaling to pSmad and EMT and suppression of tumor growth in gastric cancer.
Authors: Miyoshi Sawako , Kudo Masahisa , Shitara Kohei , Yamauchi Mayumi , Doi Toshihiko , Matsumura Yasuhiro 
Published: February 2017

50 Background: TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) of tumor cells, thus producing tumor progression, invasion, and metastasis. Therefore, this signaling has been expected to be a new target of cancer therapy. In this study, we evaluated the antitumor effect of LY2157299, a TGF-βR1 kinase inhibitor, alone and in combination with 5-fluorouracil (5-FU) or paclitaxel (PTX), key agents in the treatment of gastric cancer (GC). Methods: TGF-β inhibition impedes phosphorylation of Smad2 and induces the expression of vimentin, an EMT marker. Vimentin expression was examined +/- LY2157299 by western blot. The phenotypic change of human GC cell, 44As3-Luc after TGF-β and LY2157299 treatment was assessed by Matrigel migration/invasion assay. The in vitro cytocidal effect and in vivo antitumor effect of LY2157299 alone or with either 5-FU or PTX were evaluated by water soluble tetrazolium-1 (WST-1) assay and by xenograft mouse model, respectively. Results: The phosphorylation of Smad2, the expression of vimentin and the optical mesenchymal transformation in 44As3-Luc induced by TGF-β were successfully suppressed by LY2157299. Accordingly, the activity of migration and invasion evoked by TGF-β was suppressed significantly by co-administration of LY2157299 with TGF-β. Although LY2157299 monotherapy did not show a tumor suppressive effect and LY2157299 did not potentiate the cell toxicity of 5-FU and PTX in vitro, LY2157299 reduced tumor volume (TV) of 44As3-Luc xenografts by 64% of control (p < 0.05). 5-FU + LY2157299 treatment reduced TV of 5-FU alone by 52% (p < 0.05) and PTX + LY2157299 treatment also reduced TV of PTX alone by 52% (p < 0.05). These results suggest that LY2157299 suppresses tumor growth possibly through some effect of LY2157299 in tumor-stroma environment. Conclusions: LY2157299 inhibited migration and invasion of GC cell line. Moreover, the monotherapy of LY2157299 and the combination therapy of LY2157299 with 5-FU or PTX significantly suppressed tumor growth. These findings warrant clinical evaluation of LY2157299 in patients with GC.
The FAMKOL trial: Trans-sectoral screening in high-risk populations, comparing nurse-led counselling versus written information materials in first-degree relatives of patients with colorectal cancer.
Authors: Bauer Alexander , Seufferlein Thomas , Reinshagen Max , Hollerbach Stephan , Ritter-Herschbach Madeleine , Boese Stephanie , Riemann Juergen F. 
Published: February 2017

509 Background: Prevention of colorectal cancer (CRC) is a major health care issue. First-degree relatives (FDR) of patients with colorectal cancer have a 2-4-fold increased risk for colorectal cancer. Thus, in this population an adequate participation in the screening colonoscopy is of particular importance. However, appropriate strategies to increase the participation in screening colonoscopy are still lacking. Methods: Cluster-randomized, single blinded, controlled, multicenter trial. At 64 trial sites, 2,411 patients treated for CRC (index patients) were enrolled and n = 1,158 randomized to either paper-based information material only or additional barriers-focused counselling. Index patients were asked to forward trial materials to their FDR. FDR in the intervention group (IG) also received an additional individualized nurse-led counselling on barriers against colonoscopy and were assisted in making appointments to office-based gastroenterologists. Results: N = 313 FDR (IG n = 148; n = 165 controls) aged 28-85 years participated in the trial. A total of 197 FDR underwent preventive colonoscopy (IG n = 99 [66.9%] vs. n = 98 [59.3%]; p >.05). In these 197 patients, polypectomy was performed in n = 69 patients (IG n = 39 [39.4%] vs. n = 30 [30.6%]; p <.05]). Histological examination revealed n = 2 colorectal carcinoma in 197 patients. Conclusions: The FAMKOL trial confirmed the high effectiveness of an interdisciplinary and trans-sectoral invitation to the screening colonoscopy. FAMKOL also verified the significantly higher risk for adenomas and CRC in the targeted patient population. Hence, the permanent implementation of this invitation program may contribute to decrease CRC mortality. Clinical trial information: NCT01903395.
Prevalence of colorectal adenoma in patients with multiple gastric adenoma or cancers.
Authors: Choe Jung Wan , Kim Seung Young , Hyun Jong Jin , Jung Sung Woo , Koo Ja Seol , Park Jong-Jae , Chun Hoon Jai , Lee Sang Woo 
Published: February 2017

517 Background: It has been reported that patients with single gastric cancer or adenoma are at increased risk of colorectal cancer or adenoma. However, the incidence of colorectal adenoma in patients with multiple gastric neoplasms has not been discussed yet. Methods: We retrospectively analyzed the esophagogastroduodenoscopic and colonoscopic findings as well as the clinicopathologic features between October 2012 and July 2014. The aim of this study was to investigate whether the incidence of colorectal adenoma is higher or not in patients with multiple gastric neoplasms than those with a single gastric neoplasm. Results: A total of 164 patients with gastric neoplasm were divided into two groups whether the number of lesions was single or multiple. Among the 138 patients with single gastric neoplasm, 51 patients performed colonoscopy for surveillance study and 9 patients underwent colonoscopy among the 26 patients with multiple gastric neoplasms. Colorectal adenoma were detected in 58.8% (30/51) of the single gastric neoplasm group, and in 88.8% (8/9) of the multiple gastric neoplasms group (p < 0.001). The mean number of colorectal adenomas was significantly higher in the multiple gastric neoplasm group than in the single group. (4.78 vs. 1.94, p = 0.013). The age, sex, BMI, presence of underlying diseases and the degree of gastric dysplasia were not significantly different between the two groups. Conclusions: The prevalence and the number of colorectal adenoma were significantly higher in patients with multiple gastric neoplasms than in those with single gastric neoplasm. Clinical trial information: KUGH14308-001.
Evaluation of microsatellite instability (MSI) status in gastrointestinal (GI) tumor samples tested with comprehensive genomic profiling (CGP).
Authors: Hall Michael J. , Gowen Kyle , Sanford Eric M. , Ali Siraj Mahamed , Kaczmar John , Miller Vincent A. , Stephens Phil , Yelensky Roman , Daly Mary Beryl , Sun James 
Published: February 2017

528 Background: PD-1 inhibitor therapy (pembrolizumab) has demonstrated promising activity in MSI-H (MSI-High) colorectal cancer (CRC) and MSI-H non-CRC compared to MSS tumors, supporting MSI as predictive of anti-PD-1/L1 therapy independent of tumor histology. We developed and validated a novel computational method to assess MSI status using next generation sequencing (NGS) data generated from CGP of clinical cases. We then sought to determine the frequency of MSI in a diverse sample of clinical cases of GI tumors previously assayed with CGP (FoundationOne). Methods: To determine MSI status, 114 intronic homopolymer repeat loci (10-20bp long in the human reference genome) with adequate coverage on the CGP panel were analyzed for length variability and compiled into an overall MSI score via principal components analysis. Translation of the MSI score to MSI-H or MSS (MSI-Stable) was established using a training data set. Results: Our methodology was validated in 69 samples with MSI status (20 MSI-H, 49 MSS) previously determined by standard clinical testing, either PCR or immunohistochemistry staining. Our concordance was 97% (65/67). We then applied our method to 2545 GI cancers assayed with CGP in the course of clinical care, with small bowel carcinoma having the highest rate of MSI-H (Table). The 3.5% frequency of MSI-H in CRC is lower than expected, possibly attributed to sampling bias against MSI-H CRC in the cohort. In CRC, we discovered significant differences in mutational profile: histone methyltransferase MLL2/3 mutations were enriched in MSI-H CRC (P<0.0001, Fisher’s Exact test), while TP53mutations were enriched in MSS CRC (P<0.0001, Fisher’s). Conclusions: CGP can be used to detect MSI with high accuracy. In addition, application of this approach to the 2545 GI cancers demonstrates the use of CGP to identify differences in mutational profiles between MSI-H and MSS cancers. Broadened application of these methods to more tumor types may provide target enrichment for emerging immunotherapies. [Table: see text]
Clinical outcomes of three-dimensional versus two-dimensional laparoscopic surgery for gastric cancer: A single center, prospective, randomized trial—An interim report.
Authors: Lin Jian-Xian , Huang Changming , Zheng Chaohui , Li Ping , Xie Jianwei , Wang Jiabin , Lu Jun , Chen Qiyue , Cao Longlong , Lin Mi 
Published: February 2017

53 Background: Laparoscopic surgery is more challenging compared with open surgery, in part because surgeons must operate in three-dimensional (3D) space through a two-dimensional (2D) projection on a monitor, which results in loss of depth perception. To counter this problem, 3D imaging for laparoscopic was developed. However, there is limited evidence regarding its efficacy and safety. We therefore conducted a phase III, single center, prospective, randomized study to validate the efficacy and safety of 3D laparoscopic gastrectomy for gastric cancer compared with 2D laparoscopic surgery. Methods: The eligible criteria were pathologically-proven adenocarcinoma, 18 to 75 years of age, no history of other malignant tumor, chemotherapy, or radiotherapy, and clinical stage T1-4aN0-3M0 with R0 resection. The primary end point was to determine whether there is a difference in operation time between the two groups. The morbidity and mortality were compared to evaluate the safety of this trial. Results: A total of 196 patients were randomized (97 cases in 3D Group; 99 cases in 2D Group) between January 1, 2015 and August 31, 2015. There were no significant differences between the two groups in clinicopathological characteristics. The mean number of retrieved lymph nodes was similar in the 3D and 2D groups (35.6±14.1 vs. 36.1±13.5 per case). The operation time was similar in 3D and 2D groups (183.6±34.1 vs. 180.0±37.2 min). The blood loss in 3D Group was 59.6±45.6 ml, which was less than that in 2D Group (69.9±62.4 ml) without statistically different. There were no significant differences in times to resumption of activities, first flatus, resumption of soft diet, and post-operative stay between the two groups (P > 0.05, respectively). The morbidity of the 3D and 2D groups were 21.6% (21/97) and 17.1% (17/99), respectively (P = 0.428). There was no patient died during the postoperative stay in both groups. Conclusions: 3D laparoscopic gastrectomy is a safe and feasible procedure for gastric cancer. However, compared with 2D group, there was no so much benefit from 3D laparoscopic gastrectomy for gastric cancer. Clinical trial information: NCT02327481.
Thrombocytosis as a predictor of poor prognosis in colorectal cancer patients.
Authors: Ramjeesingh Ravi , Jones Amie , Orr Christine , Bricks Corey Sean , Hopman Wilma M , Hammad Nazik 
Published: February 2017

540 Background: Thrombocytosis has been identified as a prognostic factor in many cancer types including ovarian, breast, and lung cancers. In colorectal cancer (CRC), the literature is divided. Several smaller case studies suggest a negative prognosis in CRC patients with pre-operative thrombocytosis, a larger population study contradicts this. Methods: We performed a retrospective chart review of CRC patients treated at the Cancer Center of Southeastern Ontario diagnosed from January 2005 to December 2011. 1304 confirmed CRC patient charts were identified and patient, tumor, blood work and treatment variables were extracted. Results: 1,096 patients had platelet count available at the time of oncology consult. 222 (20.3%) were characterized as having thrombocytosis (>400x109/L). No difference was identified between those with normal and with thrombocytosis with regards to age, sex, comorbidities, and BMI. However, a statistically significant difference was identified when looking at several pathological characteristics. Significantly more patients with thrombocytosis presented with stage 4 disease (p<0.0001). Additionally less early T-stage (T1: p<0.05, T2: p<0.001), lymph node positivity (p<0.05) and LVI (p<0.05) was identified. Univariate analysis identified a significant difference in survival (1yr: 71.6% vs 88.1%, p<0.0001; 2 yr: 58.1% vs 78.1%, p<0.0001; 5yr: 48.2% vs 64.7%, p<0.0001). Multivariate Cox regression analysis, identified a statistically significant effect of thrombocytosis on risk of dying (HR=1.434, C.I 1.153-1.784, p=0.001). A survival difference was primarily identified in the Stage 4 population (1yr: 55.8% with thrombocytosis vs 72.9% with normal platelet count, p=0.0058; 2 yr: 36.0% vs 50.2%, p=0.0388; 5yr: 26.7% vs 32.0%, p=0.4042). There were no differences in the number of metastatic sites or the number of days on chemotherapy to account for the survival difference. Conclusions: Thrombocytosis, at the time of oncology consultation appears to predict a lower chance of survival in CRC patients, especially in the stage 4 population. Further work is required to elucidate the mechanism of action between elevated platelet counts and survival.
Treatment patterns and outcomes in patients with KRAS wild type (WT) metastatic colorectal cancer (mCRC) treated in first line with bevacizumab (B) or cetuximab (C) containing regimens.
Authors: Houts Arthur C. , Ogale Sarika , Sommer Nicolas , Walker Mark Stephen 
Published: February 2017

550 Background: Patients with KRAS WT mCRC treated with B or C plus standard chemotherapy backbones had comparable outcomes in the Phase III CALGB 80405 trial; comparative effectiveness in a real-world community setting remains unknown. Methods: This retrospective study examined PFS and OS in a US community sample of adult, KRAS WT, mCRC patients treated 1st line with B or C containing regimens. Medical records from the Vector Oncology and Affiliate Data Warehouse were used. Disease progression was determined from patient charts. OS was measured from start of 1st line treatment until death; patients were censored at the last observed office visit. Results: B and C samples were comparable on patient characteristics (Table). Oxaliplatin-based and Irinotecan-based backbones were used more frequently with B and C, respectively. Median PFS and OS did not differ significantly between B and C, and were of similar magnitude as in CALGB 80405. In Cox models, number of metastatic sites was a significant predictor of PFS and OS, p < 0.01. Outcomes did not differ significantly with different chemotherapy backbones. Conclusions: Consistent with CALGB 80405, 1st line PFS and OS for KRAS WT mCRC patients treated with B or C were comparable in this real-world analysis. Further analyses will focus on treatment sequences. [Table: see text]
A pilot study of AMP-224, a PD-L2 Fc fusion protein, in combination with stereotactic body radiation therapy (SBRT) in patients with metastatic colorectal cancer.
Authors: Duffy Austin G. , Makarova-Rusher Oxana V. , Pratt Drew , Kleiner David E , Fioravanti Suzanne , Walker Melissa , Carey Stephanie , Figg William Douglas , Steinberg Seth M. , Anderson Victoria , Levy Elliot , Krishnasamy Venkatesh , Wood Bradford J. , Jones Jennifer , Citrin Deborah E. , Greten Tim F. 
Published: February 2017

560 Background: AMP-224, a PD-L2 Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not PD-1LO cells which represent the normal activated T cell population. Preclinical studies have documented an increase in antitumor immunity following radiation therapy (RT), but also tumor PD-L1 expression as an escape mechanism. The aim of the study is to evaluate whether inhibition of PD-1/PDL-1 axis could improve anti-tumor immunity effects of RT. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver were treated with SBRT to a site of liver metastasis at 8Gy in a single fraction (DL1) or 8Gy in 3 daily fractions (DL2). All patients received AMP-224 10mg/kg IV beginning Day 1 after SBRT preceded by cyclophosphamide 200mg/m2 (D0). Primary objective was to determine the safety and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Mandatory pre- and post-treatment biopsies were attempted on all patients. Results: N = 17 patients with refractory metastatic CRC were enrolled. N = 2 pts were unevaluable. 6pts were treated at DL1 (8Gy x 1fraction SBRT, AMP-224 10mg/kg q2-weekly) and 9pts were treated at DL2 (8Gy x 3fractions SBRT, AMP-224 10mg/kg q2-weekly) No DLT was encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. N = 3 patients experienced G2 infusion reaction which responded to standard interventions. 5/15 pts did not complete treatment due to rapid PD. No objective responses have been seen, although N = 6 pts remain on study. Pre- and post-tumor biopsies were performed on 7 of first 11 pts. Conclusions: AMP-224 in combination with SBRT to site of colorectal hepatic metastases is safe and feasible. Preliminarily no objective responses have been seen. Full clinical and correlative data including post-therapeutic radiated and non-radiated tumor biopsies will be presented. Clinical trial information: NCT02298946.
BRAF mutations in patients with large cell neuroendocrine carcinoma of the colon (LCNECC).
Authors: Ganesh Karuna , Raj Nitya Prabhakar , Yaeger Rona D. , Berger Michael F. , Shia Jinru , Reidy Diane Lauren 
Published: February 2017

567 Background: LCNECC is a rare, poorly differentiated neoplasm with a median survival of 13 months. The cell of origin, genetic mediators and optimal clinical management of LCNECC are unknown. Current guidelines recommend treatment with platinum and etoposide, but nearly all patients rapidly fail therapy. Identification of actionable genomic alterations in LCNECC may lead to improved outcomes. Methods: We identified 123 patients (1.1%) with LCNECC or non-small cell high-grade neuroendocrine carcinoma of the colon or rectum, out of 11134 colorectal cancers treated at MSKCC from 1991-2015. Genomic testing had been performed on 8 tumors: 5 using mass spectrometry based genotyping of 8 genes and 3 using hybridization exon capture of 341 cancer-associated genes (MSK IMPACT). Results: BRAF V600E mutations were identified in 5/8 (62.5%) LCNECCs. One patient each had KRAS Q61H and G12V mutations. Only 2/8 patients had TP53 mutations. All 5 patients with BRAF V600E mutations had non-regional lymphadenopathy, consistent with the metastatic pattern seen in BRAF-mutant colorectal adenocarcinoma (CRC). One patient, a 52-year old female with metastatic LCNECC, was first treated with cisplatin/irinotecan but progressed after 2 cycles. She was treated with FOLFOX, with dramatic clinical and radiological response lasting 7 months. BRAFV600E mutation was identified, and she was treated with dabrafenib+trametinib with radiologically stable disease at 2 months. In sum, 4/6 evaluable patients treated with first line FOLFOX, and 3/3 patients receiving second line FOLFOX after disease progression on cisplatin-based therapy achieved radiological responses. Conclusions: BRAF and KRAS hotspot mutations are near universal features of LCNECC, suggesting that LCNECC is an ERK driven tumor. BRAF inhibitor therapy was associated with clinical benefit in one LCNECC patient. Mutations in TP53, RB1 and PTEN, frequent in small cell cancer, are uncommon in LCNECC. Moreover, several patients responded to FOLFOX, a standard of care for CRC. Together, the mutation patterns and therapy responses suggest some similarities between LCNECC and CRC. MSK IMPACT analysis of further LCNECCs is underway and will be reported at the meeting.