bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of CDX2 on proliferation and glucose metabolism reprogram by targeting PGAM1 in colorectal cancer.
Authors: Li Qingguo , Mo Shaobo , Li Xinxiang , Cai SanJun 
Published: January 2019

561 Background: The CDX2 expression is significantly decreased in colorectal cancer (CRC) tissues and lost its expression is associated with poor survival. However, the underline of this activity of CDX2 is not well understood. In the present study, we sought to determine the role of CDX2 in tumorigenesis, and elucidate the possible mechanism. Methods: The effect of CDX2 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Human CRC tissues were also used to verify the relationship between CDX2 expression and glycolysis. Results: Forced CDX2 expression in CRC cells inhibited their proliferation and colony formation. In contrast, silencing CDX2 expression had the opposite effect, suggesting that CDX2 is a negative regulator of oncogenesis in CRC. Mechanistically, CDX2 negatively regulated the aerobic glycolysis, a process that contributed to tumor progression by providing energy source and building blocks for macromolecule synthesis. Consistent with this observation, an in vivo subcutaneous xenograft mouse model and in a series of patients (n=71) received PET/CT initial after diagnosed also confirmed the hypothesis that CDX2 is a negative regulator of glycolysis as reflected by the decreased 18FDG uptake in PET/CT system. Furthermore, increased expression of CDX2 downregulated that of a glycolytic enzyme, phosphoglycerate mutase 1(PGAM1) in vitro. Moreover, there was a negative relationship between CDX2 and PGAM1 expression in human CRC tissues as determined by both RT-PCR and Immunohistochemistry. Luciferase analysis further indicated that CDX2 could inhibited PGAM1 promoter activity at dose dependent. Conclusions: The CDX2 inhibits cell proliferation, reprograms glucose metabolism by targeting PGAM1 expression in CRC, and the CDX2/PGAM1 axis constitutes potential prognostic predictors and therapeutic targets for CRC.
A phase II study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair–proficient (MMR-p) advanced colorectal cancer.
Authors: Yarchoan Mark , Ferguson Anna K. , Durham Jennifer N. , Rozich Noah , Rodriguez Christina , Huang Chiung-Yu , Browner Ilene S. , De Jesus-Acosta Ana , Le Dung T. , Laheru Dan , Donehower Ross C. , Jaffee Elizabeth M. , Zheng Lei , Azad Nilofer Saba 
Published: January 2019

563 Background: Mismatch repair proficient (MMRp) colorectal cancer (CRC) is refractory to single-agent programmed cell death protein 1 (PD1) inhibitors. Cancer vaccines may prime the tumor microenvironment for anti-PD1 therapy. Colon GVAX is an allogeneic, whole-cell, GM-CSF-secreting vaccine that induces T-cell immunity against tumor-associated antigens. GVAX has previously been studied in combination with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. Methods: We conducted an open label, single-arm, phase 2 study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with MMRp CRC who had received at least two prior lines of therapy in the metastatic setting. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21 day cycle through 4 cycles, and were then continued on a maintenance regimen of pembolizumab every 3 weeks with cy/GVAX given every 12 weeks. Results: Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST and 29% by irRC. The median progression free survival was 2.7 months and the median overall survival was 7.0 months. Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Two patients (12%) had grade 3/4 adverse events that were attributed to study therapy. To test the hypothesis that the induction of a humoral response against CEA protein had resulted in the observed biochemical responses, we measured patient titers of anti-CEA antibodies. Anti-CEA antibody titers increased 13 of 13 patients (100%) with available paired pre- and on-treatment research blood samples, but the change in anti-CEA antibody titers were similar among CEA responders and non-responders. Multiplex immunohistochemistry performed on pre- and post- biopsy specimens will be reported at the conference. Conclusions: GVAX/Cy plus pembrolizumab is well tolerated in advanced MMRp CRC and resulted in CEA responses but not radiographic responses. PFS and OS compare favorably to historical controls in this small cohort. CEA responses were not observed with PD1 monotherapy in MMRp CRC, suggesting GVAX can modulate the antitumor immune response. Clinical trial information: NCT02981524.
MACC1 expression as a candidate prognostic biomarker in colorectal cancer patients receiving adjuvant oxaliplatin-based therapy.
Authors: Symonds Lynn Katherine , Baker Kelsey K. , Redman Mary Weber , Koch Lisa , Carter Kelly , Yu Ming , Wirtz Ralph , Poulios Christos , Pentheroudakis George E. , Papaxoinis George , Pectasides Dimitrios G. , Kalogeras Konstantine T. , Fountzilas George , Grady William M. , Cohen Stacey 
Published: January 2019

567 Background: MACC1, part of the HGF-MET pathway, drives proliferation and regulation of MET expression in vitro. In vivo, MACC1 is associated with tumor progression and studies suggest greater MACC1 expression is associated with resistance to platinum-based chemotherapy. We hypothesized that MACC1 may be a prognostic biomarker in colorectal cancer (CRC). Methods: MACC1 expression was evaluated by immunohistochemistry on tumor microarrays (N = 428). Patients were stage I-III CRC who received an oxaliplatin-based regimen (either with 5-FU (FOLFOX) or capecitabine (XELOX)) within the HeCOG 6C/08 observational study. MACC1 expression was assessed by a blinded GI pathologist using a scale ranging from 0 (no staining) to 3+ (strong expression). Each patient had at least 3 samples and the strongest result was used for the final score. MACC1 positivity was defined as ≥2+ expression and 0-1+ as MACC1-. Cox regression models were used to estimate hazard ratios (HR) for the association of MACC1 expression with patient characteristics, disease-free (DFS), and overall survival (OS). Results: 400/428 CRC tumors were evaluable: 322 (80.5%) were MACC1+ and 78 (19.5%) MACC1-. Mucinous features were less likely in MACC1+ patients (24% vs. 38%, p = 0.02). Other unfavorable features including grade, lymphovascular invasion, perineural invasion, and tumor mutational burden were not significantly different. There was no difference for stage, microsatellite instability, BRAF, KRAS, or NRASstatus between MACC1+/- cancers. There was a trend towards worse survival in MACC1+ patients regardless of treatment (DFS HR 1.55 [95% CI: 0.87, 2.76], OS HR 1.59 [95% CI 0.74, 3.4]). This difference was not statistically significant for OS (p = 0.26) or DFS (p = 0.08) even when stratified by clinicopathologic variables. Conclusions: Patients with MACC1+ CRC tumors who received adjuvant oxaliplatin-based therapy were less likely to have mucinous histology. They had a trend toward independently worse survival that was not significant when accounting for stage and clinicopathologic variables. Studies focused on the predictive role of MACC1 and oxaliplatin in stage III CRC are in progress.
Survival after secondary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (CELIM, FIRE-3).
Authors: Moehler Markus Hermann , Folprecht Gunnar , Heinemann Volker , Holch Julian , Maderer Annett , Kasper Stefan , Hegewisch-Becker Susanna , Schroeder Jan , Overkamp Friedrich , Kullmann Frank , Bechstein Wolf Otto , Vöhringer Matthias , Oellinger Robert , Lordick Florian , Geissler Michael , Schulz-Abelius Armin , Linz Bernhard , Bernhard Helga , Schmidtmann Irene , Schimanski Carl Christoph 
Published: January 2019

571 Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term overall survival (OS) and potential cure after complete hepatic metastasectomy. The appropriate postoperative treatment strategy is still controversial. L-BLP25 as antigen-specific cancer vaccine targeting mucin 1 (MUC1) was recently evaluated as adjuvant therapy in mCRC pts after R0/R1 LLD resection (LICC trial, NCT01462513). Here we compared the LICC surveillance program and efficacy results for secondarily resected LLD pts versus historical controls, i.e. the CELIM trial (Folprecht et al, Ann Oncol 2014) of potentially resectable LLD mCRC pts and a FIRE-3-LLD subgroup (Holch et al, Int J Cancer 2018). Methods: LICC, CELIM and FIRE-3-LLD subgroup pts with stage IV mCRC limited to liver metastases who underwent hepatic resection (R0 or R1) were compared regarding pts characteristics, surveillance and efficacy outcome. LICC pts received adjuvant L-BLP25 or placebo after secondary LLD resection as 8 weekly doses, followed by 6 week maintenance intervals and tight surveillance until recurrence or a maximum of 2 years. Results: In LICC, 41/121 pts (33.9%) were secondarily resected, and R0 resection was achieved in 31 pts (75.6%). In CELIM, 36/106 pts (34%) with primary unresectable LLD were secondarily R0 resected. In FIRE-3-LLD, secondary resection was feasible for 29/133 pts (21.8%). After R0 resection, median recurrence free survival (mRFS) was 8.9 months in LICC, 9.9 months in CELIM and 11.5/12.4 months in FIRE-3-LLD in either treatment arm. In the LICC trial, median overall survival (mOS) in secondarily resected pts was 65.1 months, with 38.3 months for the R1 and is not yet reached for the R0 subgroup. In CELIM, mOS was 53.9 months for R0 resected pts. In FIRE-3-LLD, after secondary resection mOS was 56.2 months. Median age was about 5 years less in LICC. Further details will be presented. Conclusions: Secondary resected pts of LICC, CELIM and FIRE-3 showed impressive median OS with better OS for LICC and a younger patient cohort. The established tight LICC surveillance program after surgery might have had a positive impact on survival. Clinical trial information: LICC: NCT01462513; FIRE-3: NCT00433927; CELIM: NCT00153998.
Integrated profiling the patterns of pathologic response to neoadjuvant chemoradiation and the genomic-based radiation sensitivity in rectal cancer.
Authors: Yuan Zhigang , Ahmed Kamran A. , Naqvi Syeda Mahrukh Hussnain , Schell Michael J. , Felder Seth , Sanchez Julian , Dessureault Sophie , Imanirad Iman , Kim Richard D. , Torres-Roca Javier , Hoffe Sarah E. , Frakes Jessica 
Published: January 2019

573 Background: Given the lack of biomarkers to predict a pathologic complete response (pCR) after neoadjuvant chemoradiation (NACRT) for rectal cancer, selection for non-operative management (NOM) mandates complete clinical response. We have previously developed/validated a model to assess genomic-based tumor radiosensitivity: the radiosensitivity index (RSI), which formulates a clinically actionable model to calculate genomic-adjusted radiation dose (GARD). We determined the profiles of RSI and GARD for rectal cancer and correlated these findings with the pathologic response patterns. Methods: One hundred seventeen rectal cancer patients treated from 2009 to 2018 with NACRT were assessed for the tumor regression grade (TRG) (0 = pCR; 1 = moderate response; 2 = partial response; 3 = poor response). RSI was analyzed in an independent tissue cohort of 113 resected rectal cancer samples. GARD was derived as described before, which shows a high GARD value indicated a superior therapeutic effect of radiation. Results: Median follow-up from completion of NACRT was 26 months. The primary tumor stages were 7% T2, 84% T3, and 9% T4. The majority of patients (82%) received concurrent 5-FU or Capecitabine and (83%) received RT dose of 50.4 Gy (range 45-56 Gy). Median time from end of NACRT to surgery was 61 days (range 36-105 days). The patterns of pathological response were TRG 0 (n = 24; 21%), 1 (n = 62; 53%), 2 (n = 25; 21%), and 3 (n = 6; 5%), suggesting heterogeneous sensitivity to treatment with similar tumor stage and treatment regimens. The median RSI for the tissue cohort was 0.46 (range 0.19-0.81) with 37% of the samples considered radiosensitive based on prior data. GARD values ranged from 5.17 to 41.79 (median 19.24), suggesting heterogeneous RT therapeutic effects. Conclusions: The findings from the clinical cohort were consistent with the tissue cohort showing significant heterogeneity in the individual tumor radiosensitivity and GARD-based RT therapeutic effects. With the development of GARD-based prospective trials, we anticipate more biology-based customized RT dosing which could optimize patient selection for NOM and individualize the most appropriate dose for each patient.
Oncogenic alterations detected by droplet digital PCR in patients with metastatic colorectal cancer resistant to cetuximab.
Authors: Liu Rujiao , Chen Zhi-Yu , Guo Weijian , Zhu Xiaodong , Huang Mingzhu , Zhang Wen , Zhao Xiaoying , Qiu Lixin , Zhang Xiaowei , Zhang Zhe , Wang Chenchen , Li Wenhua 
Published: January 2019

575 Background: Anti-EGFR therapy is the standard of care for metastatic colorectal cancer (mCRC) patients with RAS and BRAF genes wild type (wt). Secondary alterations of several genes have been identified as possibly resistant mechanisms to EGFR blockade, these including mutations of KRAS, NRAS, BRAF, MEK and EGFR ectodomain, as well as amplifications of HER2 and c-MET. In this study, we investigated alterations of these targeted genes for mCRC patients with acquired resistance to cetuximab treatment by using non-invasive droplet digital PCR (ddPCR) method within circulating DNA. Methods: We enrolled 38 RAS and BRAF wt patients, who progressed after failure of cetuximab contained regimens between Jul 2015 and Jan 2018. Plasma samples from all 38 patients were collected and detected for seven candidates (mutation of KRAS, NRAS, EGFR, BRAF, MEK, amplification of HER2, c-MET) by using ddPCR at the time of baseline, each evaluation by interval of 2 months and documented progression. All clinical parameters were collected simultaneously. Results: A total of 23 secondary alterations were found in 17 (17/38,44.7%) cetuximab resistant patients. The targeted gene alterations were detected as follows: 9 (9/23,39%) RAS mutations, 5 (22%) HER2 amplifications, 5 (22%) EGFR mutations, 2 (9%) c-MET amplifications, 1 (4%) BRAF and 1 MEK mutation. Among 17 patients, 6 patients had multiple alterations, including 2 patients with KRAS+EGFR mutations, 2 patients with HER2+c-MET co-amplifications and 2 patients with KRAS gene exon 2 and 3 multiple mutations. Primary sites were 15 left sides and 2 right sides, descending colon (12 cases) was the most common origins. Eleven patients were synchronous disease. Twelve patients received cetuximab as first line therapy, whereas 5 patients in the ≥ 2nd line setting. All of these 17 patients, plasma levels of oncogenic alterations detected by ddPCR were showed dynamic changing and good agreement with tumor responding status. Conclusions: Oncogenic alterations detected by ddPCR were found in almost half mCRC patients resistant to cetuximab. Dynamic changes of specific alteration may facilitate making decisions for selection of anti-EGFR mAb during the treatment course.
Comparison of HER2 expression by immunohistochemistry and HER2 copy number by digital PCR in tumor tissue during treatment with trastuzumab in the prospective cohort of metastatic HER2-positive gastric cancer patients.
Authors: Takahashi Naoki , Iwasa Satoru , Matsushima Tomohiro , Miyazawa Shoichi , Kumekawa Yosuke , Shimizu Satoshi , Yoshii Takako , Asayama Masako , Hara Hiroki 
Published: January 2019

58 Background: Trastuzumab (Tmab) is an active molecular-targeted drug for HER2-positive gastric cancer (GC) patients. HER2 expression is known to change during the treatment of Tmab and HER2 amplification in blood is widely investigated as a new biomarker of the treatment candidate or the monitoring of HER2-target therapy. We evaluated the change of the HER2 expression by immunohistochemistory (IHC) and HER2 copy number by degital PCR during the treatment with Tmab in metastatic HER2-positive GC patients. Methods: Metastatic HER2-positive GC patients treated with Tmab were registered prospectively, and tissues were obtained by biopsy from primary lesions at the following points: (1) pre-treatment, (2) post-treatment, and (3) disease progression during chemotherapy with Tmab. Formalin-fixed paraffin-embedded tissue slides were prepared, and the expression of HER2 expression were scored by IHC and HER2 copy number were evaluated by digital-PCR. Results: Among 20 enrolled patients, HER2 expression was evaluated by IHC in all patients. HER2 copy number was evaluated by digital PCR in 15 patients. A patient was excluded because HER2 expression were not detected by re-evaluation. The median of HER2 copy number of 33 sampling points during the treatment was 6.37 (range: 2.12 - 85.8). The median of HER2 copy number of IHC 3+, IHC 2+, IHC 0-1 were 22.4 (3.37 – 85.8), 2.88 (2.65 – 3.6), 2.37 (2.12 – 3.85), respectively. High level of HER2 copy number was detected in tumor tissues of HER2 IHC 3+ compared with that of IHC≦2+. HER2 expression by IHC was disappeared after treatment of Tmab in 42% of HER2-positive patients. Among these patients, HER2 copy number at pre-treatment were relatively low (2.63 - 3.6). Conclusions: High copy number of HER2 was detected in tumor tissues with HER2 IHC3+ in HER2-positive GC patients during the treatment of Tmab. In addition, low copy number of HER2 in tumor tissues at pre-treatment may be associated with the loss of HER2 expression after treatment of Tmab. Further research by large number of patients to confirm our results is required.
KRAS mutation as a predictor for cause-specific survival in early- versus late-onset colorectal cancer: A United States population-based study.
Authors: Lin Albert Y. , Kahl Amanda R , Pan Jennifer Y. , Lo Joshua , Tung Winifred , Fisher George A. , Charlton Mary E. 
Published: January 2019

580 Background: While the overall incidence rates for colorectal cancer (CRC) —the third leading cancer diagnosis in the U.S.—have been decreasing over the last several decades, incidence rates for early-onset (EO, age 20-49 years) CRC have shown an upward trend. Multiple studies have documented mutations in KRAS proto-oncogene (KRAS) as a poor prognostic factor in sporadic CRC, but its impact on EO versus late-onset (LO, age > 49 years) CRC is unclear. Methods: Surveillance, Epidemiology, and End Results (SEER) Program data were queried to identify pathologically-confirmed CRC cases tested for KRAS and diagnosed between 2010 and 2015. Demographic, histologic, and KRAS data were compared between EO and LO using Chi-square tests. Kaplan-Meier and Cox proportional hazards models were used to estimate cause-specific survival (CSS) and examine factors associated with CSS. Results: Of 202,173 CRC cases, 3,842 EO and 17,819 LO CRC cases had KRAS testing with a KRAS mutation frequency of 40% and 41%, respectively. Compared with LO tumors harboring mutated KRAS, EO tumors with KRAS mutations were more frequently found in females (52% vs. 45%, P < 0.001), left-sided (LS) or rectal cancers (62% vs. 48%, P < 0.001), stage III/IV (89% vs. 81%, P < 0.001), and grade III/IV (21% vs. 18%, P = 0.038). Compared to CSS in EO with KRAS mutation, LO with KRAS mutation was associated with worse prognosis—with an overall hazard ratio (HR) of 1.21 (95% CI, 1.15-1.27, P < 0.0001). Results [HR (95% CI)] from Cox analyses on the effects of KRAS mutation on CSS, stratified by sidedness, are shown below. Conclusions: Despite EO CRC carrying worse prognostic factors than LO CRC, it confers better CSS than LO CRC. EO CRC is distinct from LO CRC in clinical and pathological features, in addition to its response to mutant KRAS. Mutated KRAS is an independent prognostic factor in LS colon and rectal cancers among the LO, but not in the EO population. [Table: see text]
Comparison of phosphoproteomic profiles in left- and right-sided colorectal cancers.
Authors: Buffart Tineke , Beekhof Robin , van den Oord Rosanne , de Haas Richard R. , Pham Thang V. , Dekker Henk , van Grieken Nicole C.T. , Piersma Sander R. , van den Brule Adriaan , Nooijen Peet , Pruijt Hans , Jiménez Connie R. , Verheul Henk M.W. 
Published: January 2019

582 Background: Left- and right-sided colorectal cancers (CRCs) are different in terms of prognosis, treatment response and underlying molecular mechanisms. The aim of this study was to unravel the phosphoproteomic profiles of left- and right-sided primary CRCs and to identify potential drug targets for both primary tumor sites. Methods: In total phosphoproteomic profiles of 69 fresh-frozen biopsies, including 34 left-sided and 35 right-sided primary CRCs, were obtained by LC-MS/MS after cell lysis, digestion and phosphopeptide enrichment using anti-phosphotyrosine antibodies. MS/MS spectra were searched against a UniProt human reference proteome FASTA file using MaxQuant software. Fold changes between normalized intensities were calculated. Group comparison was performed using the R package Limma. P values below 0.01 and fold changes > two were considered significant and biologically relevant. Results: In total 2,840 phosphopeptides were detected in at least 5% of the samples. Of these, 36 phosphopeptides were significantly upregulated and 14 were significantly downregulated in right-sided compared to left-sided CRCs using our stringent selection criteria. Since BRAF mutations and deficient DNA mismatch repair (dMMR) were more frequently observed in right-sided CRC (p < 0.01), group comparison was repeated with MMR proficient CRCs only, resulting in 21 phosphopeptides up- and one downregulated in left- versus right-sided CRC. The identified phosphoproteins from the phosphopeptides included three FDA approved drug targets. Conclusions: Differences in phosphoproteomic profiles were detected between left- and right-sided CRCs, besides molecular differences such as BRAF mutation and MMR status. These results indicate that the molecular biology of left-and right-sided CRCs may explain their differences in clinical behavior and response to treatment.