bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of standard chemotherapy on peripheral blood immune cell subsets in metastatic colorectal cancer.
Authors: Heery Christopher Ryan , Jochems Caroline , O'Sullivan Coyne Geraldine Helen , Madan Ravi Amrit , Singh Harpreet , Gulley James L. , Schlom Jeffrey , Marshall John 
Published: February 2017

597 Background: To date, there has been minimal impact with immunotherapy in patients with metastatic colorectal cancer. We have hypothesized that the lack of effect seen may be due to the refractory nature of the disease after multiple lines of standard chemotherapy. We hope to evaluate immunotherapeutic agents in combination with standard chemotherapy agents for evidence of additional clinical benefit. To our knowledge, there has never been an effort to evaluate the effects of standard chemotherapy agents for metastatic colorectal cancer on the immune system and its ability to respond to immunotherapeutic agents. Methods: We enrolled 8 patients with previously untreated metastatic colorectal cancer starting 5-FU based therapy and collected peripheral blood mononuclear cell (PBMC) samples prior to treatment, on day 8, and on day 15. PBMC were analyzed by a flow-cytometry based analysis using a panel of 26 markers to identify 40+ predefined immune cell subsets. Comparisons from baseline, day 8, and day 15 were made using the Friedman test and Dunn’s Multiple Comparison test to evaluate whether standard chemotherapy significantly altered the frequency of immune cells in any subset. Results: No significant differences were observed post treatment with this regimen in the frequency of any immune subset analyzed. Conclusions: Our preliminary findings indicate that 5-FU- based chemotherapy does not significantly affect the frequency of any of 40 analyzed peripheral blood immune cell subsets in patients with previously untreated metastatic colorectal cancer. Based on findings from other groups indicating potential tumor microenvironmental benefits of active chemotherapy on the immune response, we conclude that there should be no concern of detrimental effects of standard chemotherapy for use in combination with immunotherapy in the first line metastatic disease setting for colorectal cancer. We plan to enroll more patients for further analysis, which will be presented at the time of the meeting.
Routine multiplexed mutational analysis of colorectal cancers (CRCs): A single-institution experience.
Authors: Chan Emily , Goff Laura Williams , Cardin Dana Backlund , Berlin Jordan , Levy Mia Alyce , Vnencak-Jones Cindy L , Pao William 
Published: February 2017

599 Background: Colorectal tumors harbor mutations in genes that play key roles in CRC carcinogenesis and that may enable prioritization of appropriate anti-cancer therapy. KRAS testing is part of standard of care testing prior to initiation of anti-epidermal growth factor receptor antibodies. Other mutations are emerging as significant drivers, but they are not yet part of routine screening. Methods: As part of Vanderbilt-Ingram Cancer Center’s Personalized Cancer Medicine Initiative, we developed a clinical algorithm to genotype patient’s colorectal tumors using a SNaPshot-based assay (multiplexed PCR, primer extension, and capillary electrophoresis) designed to detect 65 somatic mutations in 7 genes (KRAS, BRAF, AKT1, PIK3CA, SMAD4, PTEN, and NRAS) important in CRC carcinogenesis. Adult patients with metastatic CRC were consented for genotyping of tumor tissue. Mutational profiling was performed in Vanderbilt’s CLIA-certified Molecular Diagnostics Laboratory. Results were reported in the electronic medical record for clinical use. Results: Study enrolled from May 2012 to February 2014. SNaPshot results were available from 126 patients. 49 tumors (38.9%) were wildtype for all mutations tested. 58 (46.0%) tumors had a KRAS mutation, including one with two KRAS mutations; the most common was G12D (n=23), but two had a Q61H mutation and two had a K117N mutation, which are not included in some commercial KRAS tests. Ten (8.9%) tumors carried the V600E BRAF mutation. Nine (7.1%) tumors harbored a PIK3CA mutation. Three (2.4%) tumors had mutations in SMAD4. Four (3.2%) tumors had a NRAS mutation. One (0.8%) tumor had a PTEN mutation. Nine (7.1%) tumors harbored double mutations, the most common being KRAS and PIK3CA double mutations (N=6). 24 (19%) subjects subsequently were treated on clinical trial therapy, including 6 subjects on therapy based on the SNaPshot results. Not surprisingly, RAS results impacted use of anti-EGFR therapy. Conclusions: 61% of the tumors carried at least one mutation in the seven genes tested, suggesting that trials of tumor genotyping-based treatment assignment are feasible. Study was supported by Vanderbilt University Medical Center.
Prognostic significance of ADAM17 expression in patients with gastric cancer who underwent curative gastrectomy.
Authors: Bilici Ahmet , Aydin Dincer , Yavuzer Dilek , Odabas Hatice , Ercelep Ozlem , Yuksel Sinemis , Guven Mert Aslihan , Ozcelik Melike , Aliustaoglu Mehmet 
Published: February 2017

60 Background: Tumor invasion and metastasis are complex processes, involving regulation at the molecular level of adhesive molecules, proteolitic enzymes, and cell growth and angiogenesis factors. A Disintegrin and Metalloproteinase (ADAM)17 has been indicated to be indispensable regulator of celular event from proliferation to migration.Although prognostic importance of ADAM17 expression has been investigated in several tumors, its clinical utility as a useful prognostic molecular marker remains unclearin gastric cancer.In the present study, we evaluated the expression of ADAM17 and its prognostic significance in gastric cancer patients after surgery. Methods: Prognostic significance of ADAM17 expression was analyzed by immunohistochemically in 158 patients with gastric cancer and the relationship between its expression and clinicopathological factors was also evaluated. Results: High expression of ADAM17 was detected in 81 patients(51%),while low expression was found in 77 cases (49%). There was significant correlation between gender, histology, lymph node metastasis, vascular invasion, the presence of recurrence and high ADAM17 expression. Recurrence in patients with high ADAM17 expression was significantly higher than that for patients with low ADAM17 expression(p=0.032). The median disease-free survival (DFS) time for patients with high ADAM17 expressed tumors were worse than those of patients with low ADAM17 expressed tumor (16.6 vs. 44.2 months, p=0.004).In addition, patients with low ADAM17 expression had a higher median overall survival (OS)interval than those of high ADAM17 expressed patients (49.6 vs. 26.9 months, p=0.019). Multivariate analysis indicated that the rate of ADAM17 expression was an independent prognostic factor for DFS, in addition to known important clinicopathological prognostic indicator for DFS. But its' prognostic importance could not be proved by multivariate analysis for OS. Conclusions: The potential value of ADAM17 expression as a useful molecular marker in gastric cancer progression should be evaluated comprehensively,it may predict recurrence and poor prognosis in patients with gastric cancer after curative resection.
Targeting colon cancer metabolism through a long noncoding RNA.
Authors: Hatziapostolou Maria , Koutsioumpa Marina , Kottakis Filippos , Iliopoulos Dimitrios , Polytarchou Christos 
Published: February 2017

604 Background: Long non-coding RNAs (lncRNAs) have gained massive attention in recent years as a potentially new and crucial layer of gene regulation. We studied the function of the lncRNA HOTAIR in colorectal cancer, one of the most common causes of cancer mortality worldwide. Methods: Molecular profiling was performed in colonic normal (40) and cancer (160) tissues. Gene expression was evaluated by qRT-PCR and gene expression arrays. LncRNA-protein interactions were investigated by RNA-immunoprecipitation, mass spectrometry and mutational analyses. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq) was employed for the histone acetylome analysis. Subcutaneous xenograft mouse models were used to evaluate tumor growth in vivo. Results: HOTAIR is significantly upregulated (>30 fold) in colon cancer and inversely correlates with patient survival. Molecular profiling revealed a gene signature downstream of HOTAIR that links metabolic pathways to colon cancer cell growth and invasiveness. RNA immunoprecipitation/mass spectrometry analysis revealed the interaction of HOTAIR with the histone acetyltransferase PCAF. Mutational analyses identified the domains of both the lincRNA and acetyltransferase responsible for their interaction and function. Histone acetylome analysis demonstrated that HOTAIR is required for the recruitment and activity of PCAF towards a set of genes involved in the mTOR/insulin receptor/PI3K-Akt pathways. In specific, 44 genes involved in these pathways are regulated by Lysine 27 histone H3 acetylation, catalyzed by PCAF only when recruited by HOTAIR. Genome-wide profiling of colon cancer and normal colonic tissues revealed that the expression of this gene set correlates positively with HOTAIR levels and inversely with patient survival. Knockdown of either HOTAIR or PCAF sensitized colon cancer cells to dietary restriction and inhibited tumor growth in subcutaneous xenograft mouse models. Conclusions: Our results provide the mechanistic link between an lncRNA, a transcription activating chromatin mark and metabolic signaling in colorectal cancer. In conclusion, we identified a novel RNA-protein complex that affects growth factor/metabolic pathways essential for colon oncogenesis.
Next-generation sequencing of advanced, relapsed colorectal adenocarcinoma (CRC) to reveal mutations affecting Wnt, MAPK and PI3K pathway signaling: Emergence of novel combinatorial strategies.
Authors: Subbiah Ishwaria Mohan , Janku Filip , Tsimberidou Apostolia Maria , Naing Aung , Subbiah Vivek , Wheler Jennifer J. , Zinner Ralph , Eng Cathy , Overman Michael J. , Kopetz Scott , Palmer Gary A. , Hong David S. 
Published: February 2017

605 Background: Advanced relapsed colorectal adenocarcinoma (CRC) is emerging as a cancer not with a singular phenotype but rather as a multitude of ‘diseases’ subdivided based on its molecular genotype. Given the heterogeneity in outcomes of CRC patients on targeted therapy clinical trials, we sought to identify a unique molecular subset within this disease. Methods: To that end, we identified advanced CRC patients in our Phase I clinic on whom adequate tissue was available for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: We identified 51 patients with advanced relapsed CRC (26 male, 25 female; median age 54 years; 49 colonic primary lesion, 4 rectum primary). Overall, 44 (86%) harbored a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 40 pts, 78%). Of these 44 patients, half (n=22, 50%) had ≥1 concurrent mutation affecting the PI3K/AKT/MTOR pathway, most commonly PIK3CA in 11 patients (4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K). Furthermore, 20 of these 22 pts with both Wnt and PI3K pathway mutations also demonstrated a concomitant MAPK pathway abnormality, most commonly KRAS (n=16) and 3 BRAF (V600E, G466R, D594G). Overall 20 of 51 (39%) patients had coexisting mutations implicated in all three signaling pathways (Wnt, PI3K, and MAPK). Conclusions: Three prominent pathways linked to the continuum of development and progression of cancer (Wnt, MAPK, PI3K) occur frequently in concurrence in patients with advanced CRC, thereby highlighting the role for an innovative therapeutic combination targeting all three pathways.
Mutational analysis of clinically relevant cancer related genes in colorectal cancer.
Authors: O'Reilly Aine , Barr Colin , Carr Aoife , Kay Elaine , Kennedy Susan , McDermott Ray , Grogan William , Fennelly David William , Breathnach Oscar S. , Winter Des C , McNamara Deborah A , Kelleher Fergal C , Crown John , Hennessy Bryan , Toomey Sinead 
Published: February 2017

615 Background: Whole genome sequencing of colorectal cancer (CRC) has identified common mutations that have been implicated in tumorigenesis. We investigated the association between genetic mutations in known cancer related signaling pathways, and clinicopathological variables in patients with CRC. Methods: DNA samples of patients with CRC were genotyped for Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations using the Sequenom platform. Results: Tissue from 68 patients was genotyped. 163 mutations were identified in 21 cancer related genes. 45% of patients had stage III CRC & 10% had stage IV CRC at diagnosis. 17 patients developed metastatic CRC. 59 patients had at least 1 mutation. Mutations occurring in at least 5% of patients included KRAS(35%), PIK3R1(34%), TP53(32%), PHLPP2(32%), BRAF(16%), PIK3CA(13%), APC(13%), IDH1(12%), FBXW(7%) & MET(6%). Less frequent mutations (<5%) included GNAS, PTPN, NRAS, STK11, TBX3, and EGFR. KRAS mutations were associated with mucinous histology (P=0.04). TP53 mutations were associated with nodal disease at diagnosis (p=0.03). There was no statistically significant difference in overall survival in patients with KRAS, PIK3, TP53 or BRAF mutations as compared to their wild type (WT) counterparts. No mutation was predictive of disease progression. In patients with mCRC and TP53 mutations, DFS was significantly shorter when mutations in APC, FBXW7, IDH1, MET and NRAS were present (10 months verses 15.5 months p=0.01). Mutations in APC, FBXW7, IDH1, MET and NRAS only occurred in the presence of other mutations. A trend towards reduced DFS was seen in KRAS WT patients with mCRC when mutations in APC, FBXW7, IDH1, MET and NRAS were present (9 months vs. 22 months, p=0.2). A trend towards reduced DFS was seen in patients with mCRC & 3 or more distinct mutations (10 months vs. 18 months p=0.2). Conclusions: These results suggest that mutations in known cancer related signaling pathways occur frequently in patients with CRC. Mutations in APC, FBXW7, IDH1, MET and NRAS conferred a shorter DFS in patients with mCRC &, TP53 mutations, KRAS wild type patients and patients with multiple distinct mutations
Proteomic features of colorectal cancer independently predict relapse-free survival.
Authors: Clarke Callisia , Lee Michael Sangmin , Manyam Ganiraju C. , Jiang Zhi-Qin , Tian Feng , Lu Yiling , Morris Jeffrey , Broom Bradley McIntosh , Menter David , Vilar Sanchez Eduardo , Raghav Kanwal Pratap Singh , Eng Cathy , Chang George J. , Overman Michael J. , Maru Dipen M. , Kopetz Scott 
Published: February 2017

616 Background: Proteomic analysis continues to provide major insight into the pathophysiology of colorectal cancer (CRC). Recently, the Cancer Genome Atlas Project and others have utilized reverse-phase protein arrays (RPPAs) to identify critical protein markers and signaling pathways in a variety of tumor types. However, the prognostic relevance of many of these proteins remains unclear. We utilized RPPA to analyze stage 2 and 3 CRC to investigate the prognostic implications of the functional proteome. Methods: Protein extraction was performed on 232 snap frozen stage 2/3 samples from the MD Anderson Cancer Center with a median 5 year follow up. 163 validated proteins and phospho-proteins were analyzed by RPPA (with dichotomization by the median value), and used to identify protein predictors of tumor recurrence. Cox regression was used for univariate analysis with bootstrap validation, followed by inclusion of proteins with corrected p≤ 0.05 into multivariate model with clinical and pathologic variables, including stage, grade, and microsatellite status. Results: 12 proteins were found to be significant predictors of tumor recurrence on univariate analysis after bootstrap validation, which are notable for components of the energy balance/MTOR signaling pathway including AMPK, mTOR, PI3 Kinase p85, FoxO3a. On multivariate analysis, inclusive of known prognostic clinical and pathology variables, phospho-Bad (Ser112), FoxO3a, HER3, and phospho-S6 (Ser240-244) remained significant. Conclusions: Functional proteomic analysis has identified key proteomic features with prognostic importance independent of known clinical/pathological variables. Confirmation studies are ongoing to explore regulators of energy balance and apoptosis in colorectal cancer. [Table: see text]
Prognostic role of serum concentrations of high-sensitivity C-reactive protein in patients with metastatic colon rectal cancer: Results from the ITACa trial.
Authors: Casadei Gardini Andrea , Carloni Silvia , Scarpi Emanuela , Maltoni Paolo , Dorizzi Romolo , Passardi Alessandro , Frassineti Giovanni Luca , Ulivi Paola , Marisi Giorgia , Amadori Dino , Lucchesi Alessandro 
Published: February 2017

617 Background: Serum levels of interleukine-6 and C-reactive protein are significatively higher in patients with neoplastic conditions. Therefore, the determination of high-sensitivity C-reactive protein (hs-PCR) has been widely used as a surrogate marker for chronic elevation of circulating cytokines. Increased hs-CRP concentrations have been reported in many conditions, in particular in patients with cardiovascular diseases, obesity, diabetes, autoimmunity, inflammatory bowel diseases and cancer risk. Some authors, on the basis of these findings, have encouraged further studies to clarify the etiologic and prognostic role of the aforementioned test. Our study has been conducted in patients enrolled in the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa),” in order to assess hs-CRP levels at diagnosis and their significance with respect to overall survival (OS) and progresion free survival. Methods: Peripheral blood samples from 133 consecutive patients were collected into EDTA tubes. The collection was obtained before the beginning of first line chemotherapy. The supernatant was immediately transfer into a cryovial and stored at –80°C. Samples were thawed and hs-CRP has been measured with Cobas c501 analyzer. Results: Levels of hs-CRP >13.1 mg/L were associated with a worse median PFS, 8.9 months (95% CI 6.8-9.6) vs. 12.1 months (95% CI 9.3-14.9) in patients with levels <13.1 mg/L (p<0.0001). Similarly, levels >13.1 mg/L were associated with worse median OS, 14.4 (95% CI 11.5-17.1) vs. 28.8 (95% CI 24.3-36.6) in patients with a concentration <13.1 mg/L (p<0.0001). In multivariate analysis, hs-PCR adjusted for baseline factors including age (<70, ≥70 years), gender, ECOG perfomance status (0,1-2), tumor localization (rectum, colon), stage at diagnosis (I-III, IV), CT regimen (Folfiri, Folfox), KRAS status (wild type, mutant), site of metastases (liver, other metastases), was found to be independently associated with PFS and OS. Conclusions: Our study demonstrates the prognostic value of hs-CRP in patients with metastatic carcinoma of the colon and rectum.
Siginificance of platinum concentration in blood and red blood cell in patients with oxaliplatin-based chemotherapy [UMIN000009128].
Authors: Higashijima Jun , Shimada Mitsuo , Iwata Takashi , Yoshikawa Kozo , Nakao Toshihiro , Nishi Masaaki , Takasu Chie , Eto Shohei 
Published: February 2017

620 Background: Oxaliplatin(Ox) based regimen is widely used in colorectal cancer patients.One of the major adverse effects of Ox is a neuropathy. There is no useful biomarker predicting such adverse effect. The aim of this study is to evaluate platinum concentration as a biomarker predicting the adverse effect. Methods: Ten patients who underwent curative colectomy were included in this study. Final stage of all patients was UICC stage III. All patients underwent adjuvant chemotherapy by CapeOX regimen for eight cycles (or six months). Blood samples were collected after fourth cycle and last cycle. Ox concentration was measured in red blood cells (RBC) and serum, and evaluated the kinetics of platinum (PL) in blood. In addition, we investigated relationship between Ox concentration and adverse effects. Results: 1) Kinetics of PL concentration: PL concentration in RBC tended to be correlated with the difference of RBC numbers between pre- and post-chemotherapy (R2=0.358, p=0.068). The PL concentration in RBC siginificantly correlated with the difference of mean corpuscular volume (MCV) between pre- and post-chemotherapy (R2=0.661, p=0.004). After four cycle, the platinum concentration in RBC siginificantly correlated with the hemoglobin and hematocrit (R2=0.447, p=0.004 and R2=0.425, p=0.041). There was no siginificant difference in PL concentration in both RBC and serum between the points after four cycle and last cycle points (RBC: 1380.5±495.2 ng/ml vs. 1107.0±699.2 ng/ml Aserum: 210.1±38.9 ng/ml vs. 221.2±99.2 ng/ml). 2) PL concentration and adverse effects: PL concentration did not elevate depending on cycle number. There was no siginificant correlations between PL concentrations in RBC or serum and the grade of neuropathy. Conclusions: The PL concentration was significantly related with the difference of RBC numbers and MCV between pre- and post-chemotherapy. However, there was no siginificant relationship between Ox concentration in blood and side effects including neuropathy. So Ox concentration in blood could not be a reliable biomarker for predicting the grade of neuropathy. Clinical trial information: 000009128.
Acquired mutations in MAPK signaling pathway following initial pharmacological response in BRAF-mutated metastatic colorectal cancer (mCRC).
Authors: Morris Van Karlyle , James Brian , Tian Feng , Jiang Zhi-Qin , Overman Michael J. , Maru Dipen M. , Menter David , Powis Garth , Kopetz Scott 
Published: February 2017

629 Background: BRAF V600 mutations are associated with inferior survival and limited responses to standard therapies. Blockade of BRAF by vemurafenib generates reflexive activation of EGFR, whose activity can be overcome by concomitant addition of cetuximab. Early-phase clinical trials have demonstrated objective responses with the combination of vemurafenib and cetuximab in patients with BRAFmutmCRC. Mechanisms of resistance following initial anti-tumor response have not yet been described. Methods: Patient-derived xenograft (PDX) models of BRAFmut mCRC have been established at our institution by subcutaneous implantation of tumor into NSG female mice. Here, two different models of BRAFmut mCRC, one with innate sensitivity to vemurafenib and another with innate resistance, were selected for further study. Mice were given vemurafenib chow (417 mg/kg) and/or intraperitoneal cetuximab (1 mg/kg twice a week). Tumor dimensions were serially measured. Tumor resistance developed after a median of 35 days. Tumor DNA was extracted, and whole exome sequencing was performed and compared to untreated controls. Results: In one model of BRAFmut mCRC, 8 mice treated with vemurafenib demonstrated an initial complete response but later developed resistance despite continued treatment. Exome sequencing of the resistant tumors from 6 of 8 mice revealed novel mutations in EGFR, KRAS, NRAS, and MEK not detected in untreated controls (Table). All mutations are predicted to be damaging in COSMIC. Expansion of tumors with acquired NRAS G13D mutation into another generation of mice showed cross-resistance with the combination of BRAF and EGFR inhibition in vivo. In contrast, another PDX model with innate resistance to vemurafenib did not acquire additional mutations in MAPK oncogenes. Conclusions: Acquired activating mutations in oncogenes critical to MAPK signaling have not been described in BRAFmut mCRC after initial pharmacological response. Such mutations, if present as low-frequency clones prior to treatment, may generate resistance following treatment with BRAF and EGFR inhibitors. [Table: see text]