bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of STAT3 activity by DARPP-32 in gastric cancer.
Authors: Chen Zheng , Zhu Shoumin , Soutto Mohammed , Hong Jun , Belkhiri Abbes , Zaika Alexander , El-Rifai Wael 
Published: February 2017

47 Background: Dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) and its truncated form (t-DARPP) are overexpressed in two-thirds of gastric adenocarcinomas. STAT3 is a member of STAT family. It mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects. The relationship and interaction between DARPP-32 and STAT3 remain unknown. Methods: DARPP-32 was stable or transient overexpressed in gastric cancer cell lines. STAT3 expression and transcriptional activity were investigated by immunofluorescence and STAT3 luciferase reporter assay. DARPP-32 mRNA level was detected in 63 gastric cancer samples. Results: Using stable and transient expression of DARPP-32 and t-DARPP in AGS gastric cancer cell line, lacking endogenous DARPP-32, led to a significant increase of the phosphorylation of STAT3 as compared to empty vector control. Consistent with these findings, immunofluorescence assay also showed the up-regulation of nuclear p-STAT3 in AGS cells following transient expression of DARPP-32, as compared to empty vector control. Using the STAT3 luciferase reporter assay, AGS cells with stable overexpression of DARPP-32 showed higher luciferase activity than empty vector stable cells with and without IL-6 stimulate (p<0.01). Using qPCR in 63 gastric cancers, we found that DARPP-32 is frequently overexpressed in gastric cancer samples (p=0.018). We have also shown that DARPP-32 has a progressive increase in expression from normal to metaplasia, dysplasia, and adenocarcinoma (p<0.001). The relationship between DARPP-32 and STAT3 in these tissues will be examined. Conclusions: Our results suggest that DARPP-32 overexpression may participate in regulating the STAT3 phosphorylation and activating STAT3 signaling pathway in gastric cancer. The precise signaling mechanisms that mediate this activation and its functional impact on gastric tumorigenesis are under investigation.
BRAF and KRAS mutations in liver-resected metastatic colorectal cancer (mCRC) patients (pts).
Authors: Bergamo Francesca , Schirripa Marta , Loupakis Fotios , Cremolini Chiara , Casagrande Mariaelena , Lonardi Sara , Aprile Giuseppe , Marmorino Federica , Salvatore Lisa , Antoniotti Carlotta , Sensi Elisa , Lupi Cristiana , De Maglio Giovanna , Bertorelle Roberta , Galiano Antonella , Griguolo Gaia , Balistreri Mariangela , Fontanini Gabriella , Zagonel Vittorina , Falcone Alfredo 
Published: February 2017

476 Background: Up today there are no molecular markers to identify mCRC pts candidate to curative liver surgery at high risk of relapse. There are conflicting results about the prognostic role of KRAS mutation in mCRC pts, while BRAF mutation is a well-known negative prognostic factor characterizing a subgroup of mCRCs with a distinct metastatic spread. We analyzed the impact of BRAF and KRAS mutations on relapse free-survival (RFS) and overall survival (OS) in pts undergoing liver resection with curative intent. Methods: Medical records of pts referred to 3 Italian institutions between 1995 and 2012 were reviewed. 3024 mCRC pts were identified. 401 pts (13.3%) underwent liver resection with curative intent and had adequate follow-up. Mutational status was assessable on 360 samples from primary tumors (n=63), metastases (mts) (n=59) or both (n=238). Primary objective was to evaluate the impact of BRAF mutation on RFS in mCRC pts candidate to liver resection. Secondary objectives were to evaluate the prognostic role of BRAF status on OS, and of KRAS status on RFS and OS in this population. Results: BRAF and KRAS were mutated in 11 (3%) and 116 (32%) out of 360 cases respectively. In 238 cases in which paired samples from primary and metastases were available, no discordance was found in BRAF status while 18 cases (7.6%) showed a discrepancy in KRAS status and were thus excluded from analysis. Pts with BRAF mutation had significantly shorter median RFS compared to pts with BRAF wt tumor (5.7 mos vs 11.7 mos, HR=4.25; 95%CI: 1.52-11.88, p=0.005). OS was significantly reduced in pts with BRAF mutated tumors vs wt (HR=5.39; 95%CI: 1.59-18.27, p=0.007). Mutated KRAS was not prognostic for RFS (HR=1.14; 95%CI: 0.87-1.49, p=0.34), while demonstrated a weak prognostic impact on OS (HR=1.52; 95%CI: 1.05-2.21, p=0.03). In this cohort high-risk Fong score were significantly associated with shorter RFS (p<0.0001) and OS (p<0.0001). Conclusions: BRAF mutation is associated with higher probability of relapse and worse outcome in liver resected mCRC. KRAS mutation was not associated with RFS after liver resection. BRAF mutational status may become a new prognostic marker when planning liver resection in mCRC pts.
Safety and antitumor activity of selinexor (KPT-330), a first-in-class, oral XPO1 selective inhibitor of nuclear export: A phase I study expanded with colon cancer cohort.
Authors: Mau-Soerensen Morten , Razak Albiruni R. A. , Mahipal Amit , Mahaseth Hemchandra , Gerecitano John F. , Shacham Sharon , Yau Cindy Y. F. , Lassen Ulrik , Shields Anthony Frank , McCauley Dilara , Cooksey Jennifer , Tan David Shao Peng , Rashal Tami , Shacham Eran , Landesman Yosef , Pond Gregory , Oza Amit M. , Kauffman Michael , Siu Lillian , Mirza Mansoor Raza 
Published: February 2017

482 Background: Tumor suppressor proteins (TSPs) are inactivated by their export from the nucleus by Exportin1 (XPO1/CRM1). The oral selective inhibitor of nuclear export selinexor (KPT-330)restores the nuclear localization and function of TSPs and shows a broad anti-tumor activity in animal models. Here we report on the treatment of a subset of patients (pts) with metastatic colorectal cancer (CRC) in a phase I trial of selinexor. Methods: Objectives were to determine the recommended phase 2 dose, evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and tumor response (RECIST 1.1) of selinexor administered in two different schedules with 8 or 10 doses in a 28-day cycle. An expansion cohort of 15 pts with CRC was planned. Results: Twenty-seven pts with CRC were treated across eight doses (3-40 mg/m2) including 15 pts in the expansion cohort (30-35 mg/m2). Median age was 61 yrs and median number of prior regimens was 4. MTD of the 10-dose schedule was 30 mg/m2. MTD for the 8-dose schedule has not been reached. Thirteen pts experienced drug related gr 3-4 adverse events (AEs) including fatigue (n = 6), hyponatremia (n = 5), thrombocytopenia (n = 3), anorexia (n = 3), dehydration (n = 2), anemia (n = 2), hyperglycemia (n = 1), pulmonary embolism (n = 1), and hypotension (n = 1). The most common gr 1-2 drug related AEs were nausea (74 %), anorexia (67 %), fatigue (67 %), vomiting (59 %), dysgeusia (52 %), and weight loss (48 %). Cmax increased with dose to ≈ 1.4 µM with T½ of 4.0 – 7.4 hrs. Significant increases (2-20x) in PD marker XPO1 mRNA in circulating leukocytes were observed at all doses. Analysis of tumor biopsies confirmed nuclear localization of TSPs and induction of apoptosis following selinexor. CEA decreased in 4 of 12 pts. One pt had a partial response at 23 mg/m2, 6 patients had stable disease ≥8 weeks, and 3 patients had stable disease ≥24 weeks in 25 evaluable pts Conclusions: Preliminary signals of antitumor activity in CRC pts were observed. Selinexor is generally well tolerated and prolonged drug exposure is feasible. Selinexor induces Exportin in leucocytes and apoptosis in tumor biopsies with restoration of the nuclear location of TSPs. Clinical trial information: NCT01607905.
Effect of nintedanib, a triple angiokinase inhibitor, on EGFR and HER2 in colorectal cancer (CRC) models, and rational for its combinations with the ErbB family blocker afatinib.
Authors: Larsen Annette K. , de Gramont Aimery , Batistella Aude , Afchain Arnaud , Mésange Paul , Poindessous Virginie 
Published: February 2017

485 Background: We have recently shown that combinations of afatinib, a pan-HER/ErbB blocker, and nintedanib, a triple angiokinase (VEGFR, FGFR, PDGFR) inhibitor show synergistic activity in CRC models (Poindessous et al., Clin Cancer Res. 17:6522, 2011). However, the mechanistic basis for the synergistic effects of the combination is incompletely understood. EGFR is activated following exposure to a wide variety of therapeutic modalities including ionizing irradiation and irinotecan. We speculated that nintedanib exposure could also activate EGFR signaling which might explain the synergistic activity of the combination. Methods: Mice with human CRC xenografts were treated with nintedanib and afatinib alone or in combination and the influence on tumor growth, viability and the presence of phosphorylated HER family members was determined. Different scheduling regimens were explored to identify an administration schedule which combined optimal antitumor activity with minimal toxic side effects. Results: We here show that nintedanib treatment results in activation of EGFR and HER2 in multiple CRC xenograft models in a dose-dependent manner. Among the different regimens tested, continuous nintedanib with administration of afatinib every second week proved almost as efficient as continuous administration of the two agents together and was less toxic. Finally, nintedanib plus afatinib was superior to nintedanib alone in three different tumor xenografts with mutant KRAS. Conclusions: We here report that prolonged exposure to nintedanib, a small molecule angiogenesis inhibitor, is accompanied by activation of EGFR and HER2. Accordingly, afatinib, an ErbB family blocker, was synergistic with nintedanib. We subsequently identified a novel regimen for optimizing the antitumor effects of the combination with limited toxic side effects and showed that this regimen is active in four different CRC tumor models including three with mutant KRAS. These findings provide a rationale for clinical trials of the two small molecules, even in patients with mutant KRAS.
RAS mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).
Authors: Sclafani Francesco , Gonzalez David , Cunningham David , Hullki Wilson Sanna , Peckitt Clare , Tabernero Josep , Glimelius Bengt , Cervantes Andres , Wotherspoon Andrew , Brown Gina , Tait Diana M. , Oates Jacqueline Rose , Chau Ian 
Published: February 2017

489 Background: Studies indicate that RAS mutations beyond KRAS exons 2-3 may predict anti-EGFRs benefit. EXPERT-C was a randomized phase II trial of neoadjuvant CAPOX and CRT ± C in MRI-defined, high-risk RC. We have previously shown that adding C in KRAS (exons 2-3)/BRAF wild type (WT) patients did not improve complete response (CR) and was associated with a non-significant improvement in progression-free survival (PFS) (HR 0.62, p=0.23) and overall survival (OS) (HR 0.56, p=0.20). The aim of this study was to analyse the impact of RAS mutations on the outcome of C-treated patients in this trial. Methods: Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83). KRAS (exons 2-3) and NRAS (exon 3) mutations were prospectively analysed. Of 90 KRAS/NRAS WT patients, 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of C on CR, PFS, and OS in patients with RAS WT tumors was analyzed. PFS and OS were estimated with the Kaplan-Meier method and treatment arms compared using a log-rank analysis. Results: Eleven (13%) of 84 patients initially classified as KRAS/NRAS WT were found to have tumours harbouring a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, after this retrospective mutation analysis, 78/149 (52%) assessable patients were RAS WT (CAPOX, n=40; CAPOX-C, n=38). After a median follow-up of 63.8 months, in line with the initial analysis, the addition of C in the group of RAS WT patients, was associated with numerically higher, but not statistically significant, rates of CR (15.8% vs. 7.5%, p=0.31), 5-year PFS (78.4% vs. 67.5%, p=0.17) and 5-year OS (83.8% vs. 70%, p=0.20). Conclusions: Although the results of our analysis are potentially affected by the small numbers, in our locally advanced RC population the status of RAS did not appear to significantly improve the selection of patients who may benefit from the use of an anti-EGFR therapy.
Quantitative analysis of the impact of deepness of response on survival time following patients with metastatic colorectal cancer treated by chemotherapy and anti-EGFR monoclonal antibodies.
Authors: Osumi Hiroki , Matsusaka Satoshi , Suenaga Mitsukuni , Wakatsuki Takeru , Ogura Mariko , Ozaka Masato , Shinozaki Eiji , Chin Keisho , Mizunuma Nobuyuki 
Published: February 2017

493 Background: "Deepness of response" (DpR) is a new efficacy outcome measure that could explain the impact of tumor shrinkage on long-term survival outcome. In FIRE-3 trial, OS was significantly longer in patients (pts) treated with FOLFIR plus cetuximab compared with pts who received FOLFIRI plus bevacizumab. One reason was that first-line treatment with Cetximab have a DpR, so it takes a lot of time to grow tumors. The aim of the present analysis was to evaluate OS, PFS, pathological grade and DpR for pts with mCRC treated with anti EGFR antibody+FOLFOX or FOLFIRI. Methods: A total of 100 pts with histopathologically confirmed mCRC treated with first-line chemotherapy in combination with anti-EGFR antibody and second-line chemotherapy with cetximab were enrolled between October 2008 and June 2013. First, we compare DpR for pts with first-line chemotherapy+anti EGFR antibody and second-line chemotherapy+cetximab. Second, we analyzed DpR and pathological grade for 32 pts performed conversion surgery. Third, we compare OS, PFS and DpR for 43 pts treaded with second-line chemotherapy+Cetximab. Results: The 38 (26) pts treated with FOLFOX+cetximab (panitumumab) had a mean DpR of 44.9 (51.4)% (Interquartile range [IR]:36.6 (39.8)%, 60.97 (64.65)%), minimum DpR -45.2 (0)%. The 43 pts treated with second-line FOLFIRI + Cetximab had a mean DpR of 10% (IR:-7.8%, 30.9%) and a minimum DpR of -158%. The DpR wans’t different between first-line FOLFOX+cetximab and panitumumab. But the DpR was significantly different between first-line FOLFOX+cetximab and second-line FOLFIRI+cetximab. Tumor regression grades 0 after preoperative. FOLFOX+cetximab (panitumumab) had a mean DpR of 61.3 (0)%, grade 1 had a mean DpR of 50.83 (56.14)%, grade 2 had a mean DpR of 54.91 (40.5)% and grade 3 had a mean DpR of 58.5 (76)%. Individual DpR of the pts treated with FOLFIRI+cetximab is a significant prognostic factor for survival time (OS and PFS) in the Longest diameter-based models (PFS:p=0.006 OS:p=0.01). Conclusions: Our results emphasize the value of the variable DpR as a new efficacy outcome measure and the DpR was shown to be associated with its ability to prolong OS and PFS.
MSI versus MSS sporadic colorectal cancers: Morphology, inflammation, and angiogenesis revisited.
Authors: Sagaert Xavier , Van Cutsem Eric , Tejpar Sabine , Prenen Hans , De Hertogh Gert 
Published: February 2017

495 Background: MSI is a well-documented pathway in the pathogenesis of colorectal cancer. A specific cphenotype has been associated with MSI tumors, as they tend to be more right-sided, have a better prognosis, mostly display a poor histologic differentiation and are marked by extensive inflammation. However, the biological basis and of all these features is still largely unknown. We hypothesize that MSI results in an accumulation of intratumoral mutations. Consequencely, lots of aberrant proteins are formed, probably resulting in a poor histologic differentiation but also evoking a strong immune response that may have the ability to limit tumor expansion (hence explaining a better prognosis) and to stimulate angiogenesis. Methods: To sustain this hypothesis we compared 35 MSI and 35 MSS tumors (matching for TNM staging) with respect to their morphology, inflammation and vessel density. Morphology was analyzed on HE stains. Immunohistochemical stainings for CD 3, CD4, CD8, CD20 and CD68 were performed to document the number of T-lymphocytes, B-lymphocytes and macrophages in relation to tumor location (intraepithelial, intratumoral, peritumoral). CD 31 staining was performed to highlight vessel density in the tumor and assess angiogenesis. Conclusions: (1) In accordance with literature, MSI tumors occured at younger age, with preponderance of the right colon and with a smaller likelihood of metastasis. (2) The most striking observation was the higher number of intra-epithelial T-lymphocytes in MSI tumors (not present in their microsatellite stable counterparts). No difference was found between MSI and MSS tumors in terms of intra/peritumoral B-cells, macrophages, and/or T-cells. (3) Half of the MSI tumors and none of the MSS tumors displayed different histological subtypes/patterns within one tumor. As such, we suggest that in daily routine practice, presence of morphologic tumor heterogeneity should initiate analysis for microsatellite instability. (4) MSI tumors had a statistically much higher (micro)vessel density as compared to their MSS counterparts, hence hinting at a potential application of anti-VEGF therapy in this subgroup of colorectal cancers.
Molecular and clinical prognostic factors in metastatic colorectal cancer (CRC) patients (pts): A retrospective study.
Authors: Foltran Luisa , Ermacora Paola , Pella Nicoletta , Aprile Giuseppe , De Maglio Giovanna , Masiero Elena , Giangreco Manuela , Lutrino Stefania Eufemia , Ferrari Laura , Casagrande Mariaelena , Pizzolitto Stefano , Fasola Gianpiero 
Published: February 2017

511 Background: Strong evidence is emerging about the usefulness of mutational profiling for CRC pts. This study aimed to evaluate the overall survival in three molecular groups, taking as reference the all-wild type category: (1) BRAF mutated; (2) KRAS mutated codons 12-13 only; (3) any of KRAS codons 61-146, PIK3CA exon 9-20 or NRAS cod 12-13-61 mutations. Also clinical variables were investigated as potential prognostic factors. Methods: Data of 194 consecutive pts treated for metastatic colorectal cancer (mCRC) at our University Hospital in Udine, Italy, between Jan 2004 and Jan 2013 were reviewed. Point mutations were detected by pyrosequencing platform PyroMark Q96 ID instrument for KRAS/NRAS codons 12, 13, 61, and 146, BRAF exon 15, and PIK3CA exons 9 and 20. Clinical and molecular prognostic factors were identified using the Cox proportional hazards model. Results: The all wild-type population consisted of 76 pts (39%). 62 cases (32%) harboured mutations in KRAS codons 12-13. BRAF V600E mutation was found in 10 (5.2%) samples. Mutations in KRAS 61-146, PIK3CA and NRAS codons were detected in 9 (4.6%), 32 (16.5%) and 6 (3.1%) pts, respectively. All factors significant in univariate analysis were subjected to multivariate analysis (see Table). The all-wild type category had the longest survival (27.7 months). Patients carrying BRAF mutations reported an overall survival of 7.6 months and those with KRAS 12-13 mutation 16.7 months. Conclusions: This study reinforces the prognostic value of a full mutational molecular profile and points out some prognostic clinical factors in CRC. The influence of clinical variables such as right colon cancer, primary tumour not resected, exposure to bevacizumab and lines of chemotherapy need further investigation. [Table: see text]
Serum levels of vascular endothelial growth factor in patients with gastrointestinal cancers and correlation with malnutrition, immunosuppression involving MDSC, and systemic inflammation.
Authors: Gonda Kenji , Shibata Masahiko , Suzuki Satoshi , Nakamura Izumi , Kumamoto Kensuke , Shimura Tatsuo , Takenoshita Seiichi 
Published: February 2017

514 Background: Vascular endothelial growth factor (VEGF) reportedly plays an important role in the progression of malignant neoplasms, and have been reported to induce myeloid-derived suppressor cells (MDSC) that appears in cancer and inflammation. Methods: Blood samples were collected from 57 patients, including 8 with esophageal cancer, 20 with gastric cancer, 29 with colorectal cancer, and from 18 healthy volunteers. We measured serum concentrations of VEGF and analyzed correlations with nutritional damage, immune suppression and systemic inflammation. As markers of immune function, IL-12 production of PBMC and MDSC (CD 11b+, CD14-, CD33+) were measured. Serum concentrations of albumin and rapid turnover protein were measured as a marker of nutritional status. Results: A significant increase in serum levels was seen in patients with esophageal, gastric, and colorectal cancers compared to healthy volunteers. Levels of VEGF were inversely correlated with serum concentrations of albumin, prealbumin and retinol-binding protein. Serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)-12 and correlated with MDSC. VEGF levels also correlated with neutrophil count and neutrophil/lymphocyte count, and correlated inversely with lymphocyte count. Serum VEGF levels were then divided about a cutoff of 500 pg/ml, with levels of prealbumin and retinol-binding protein significantly decreased in patients with higher VEGF levels. Stimulation index and IL-12 production were significantly decreased in the group with higher VEGF levels, and MDSC counts tended to be higher in this group. Conclusions: These results demonstrated that increased production of VEGF correlated with systemic inflammation, nutritional impairment and inhibition of cell-mediated immunity involving MDSCs. An inactivation of dendritic cells may be occurring by the activation of MDSC. Anti-VEGF therapy may be of importance in treating digestive system cancers.