bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of Wnt9A induced by lithium chloride on β-catenin and colorectal cancer cell proliferation.
Authors: Braun Donald Peter , Ali Irshad 
Published: February 2017

631 Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation which often results from dysregulated Wnt signaling. β-catenin, a second messenger upregulated in neoplastic tissues is utilized by the canonical Wnt pathway (CWP) to promote cellular proliferation. In healthy tissues CWP is stringently controlled by components of the non-canonical Wnt pathway (NCWP). The NCWP, which does not utilize β-catenin for its activity, acts in concert with the CWP to maintain homeostasis in healthy tissues. Our recent studies in CRC cells indicate that LiCl increases expression of the NCWP ligand, Wnt9A leading to activation of the NCWP. Suppressing Wnt9A significantly attenuates LiCl-mediated inhibition of CRC cell proliferation. The present study investigated the capacity of Wnt9A to directly modulate expression of β-catenin mRNA and/or protein levels in CRC cells, and the effects on proliferation and apoptosis. Methods: Primary CRC lines established from resected tumors of 5 patients with metastatic disease were treated with LiCl and Wnt9A protein. Cellular proliferation and apoptosis were determined by MTS and caspase 3 assays. Total and activated β-catenin protein were determined by ELISA and Wnt pathway genes and β-catenin mRNA were determined with PCR arrays. Results: LiCl inhibited CRC proliferation (p<0.001) and increased apoptosis (p<0.01) which coincided with a 23-fold (p<0.025) increase of the NCWP ligand Wnt9A. LiCl decreased β-catenin mRNA (p<0.03) and suppressed protein levels of the total (p<0.025) and the activated form of β-catenin. Recombinant Wnt9A protein emulated LiCl effects by inhibiting proliferation (p<0.001), increasing apoptosis (p<0.03) and suppressing activated β-catenin protein (p<0.001) in CRC cells. Conclusions: This study demonstrates a novel mechanism for inhibiting CRC cell proliferation through suppression of activated β-catenin levels by the non-canonical Wnt ligand, Wnt9A. These results suggest that in CRC tumors that are driven by β-catenin, activation of the non-canonical pathway and/or direct induction of or treatment with Wnt9A protein may be therapeutically beneficial.
Cost-effectiveness analysis of radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) in patients with isolated hepatic metastases from colorectal cancer (CRC).
Authors: Kirichenko Vladimir , Thai Ngoc , Morris William , Heenan Amy , Parda David S. 
Published: February 2017

639 Background: Systemic therapy combined with surgery may prolong survival of patients with isolated hepatic metastases from CRC, however, only 10-25% are resectable. We applied a Markov model to estimate and compare cost effectiveness for the two competing treatments of SBRT and RFA in management of unresectable isolated hepatic metastases. Methods: We developed a multistate Markov decision model with probabilistic sensitivity analysis to simulate a randomized controlled trial for SBRT and RFA and compare respective cost effectiveness (in dollars per quality adjusted life years, or QALY). Model assumptions were based on extensive literature search of utilities and recurrence risks, including published data from our institution. Costs were taken from the 2013 Medicare reimbursement tables. In order to reflect reported patient selection variability across literature, two mortality rates due to hepatic metastases were considered for both treatment modalities: 50% probability of death in 1.5 years and 60% in 5 years. Sensitivity analysis was performed to model uncertainty in these parameters. Results: For patients with 5-year life expectancy, Markov cohort analysis demonstrated QALY-adjusted survival advantage of SBRT over RFA with QALY 4.35 vs. 3.89 respectively. This difference was marginal for patients with 1.5-year life expectancy. Physician-hour involvement was less in SBRT group. The incremental cost adjusted effectiveness (Cost/QALY) for SBRT over RFA was $2,379 in the 5-year life expectancy cohort, and $2,216 for SBRT over RFA in the 1.5-year cohort. Sensitivity analysis demonstated robustness of these results across a range of utility values, costs, recurrence rates, and procedure-related morbidity. Conclusions: In comparison to RFA, SBRT was more cost-effective modality for unresectable or potentially resectable hepatic metastases over a wide range of treatment and disease assumptions, including recurrence rates, and procedure-related morbidity. Additionally, SBRT is a relatively fast outpatient procedure requiring less physician-hour involvement.
Prognostic value of isolated peritoneal versus other metastatic sites in colorectal cancer (CRC) patients treated by systemic chemotherapy: Findings from 9,265 pts in the ARCAD database.
Authors: Franko Jan , Shi Qian , Meyers Jeffrey P. , Heinemann Volker , Falcone Alfredo , Tebbutt Niall C. , Maughan Tim , Seymour Matthew , Saltz Leonard , Tournigand Christophe , Diaz-Rubio Eduardo , Sougklakos Ioannis , Chibaudel Benoist , Moen Joseph , De Gramont Aimery , Adams Richard A. , Sargent Daniel J. , Grothey Axel 
Published: February 2017

656 Background: Patients (pts) with peritoneal metastases from CRC (pmCRC) have reduced OS compared to mCRC pts without peritoneal involvement. Here we further investigated the impact of number and location of metastases among pts receiving first-line systemic chemotherapy. Methods: Individual patient data were available on 9,265 pts (median age 64; 63% male; 93% ECOG PS 0-1; 68% colon primary tumor; brain metastases excluded) enrolled onto 12 first-line randomized trials (4 tested targeted regimens). Stratified multivariable Cox models were used to assess the associations with overall survival (OS); adjusted hazard ratios (HRadj) and 95% confidence intervals are reported (CI). Results: There were 7,963 (86%) pts with non-pmCRC (3,904 with one disease site; 4,059 with ≥2 disease sites), 191 (2%) pts with isolated pmCRC, and 1,111 (12%) non-isolated pmCRC. These groups were similar in age, race, and use of targeted chemotherapy. Compared to non-pmCRC, pts with pmCRC were more likely to be female (41% vs. 36%, p<.001), have colon primary tumors (85% vs. 67%, p<.0001), and have PS2 (10% vs. 6%, p<.0001). Compared to isolated pmCRC, pts with solitary non-peritoneal sites (both M1a) had significantly better OS (HRadj=0.78; CI, 0.64-0.94, p=.009) while pts with ≥2 non-peritoneal sites had similar OS (HRadj=1.06; CI 0.88-1.28, p=.535). OS of pts with pmCRC with a single other disease site (n=446) was similar to isolated pmCRC (HRadj=1.13; CI 0.91-1.40, p=.28), but those with pmCRC + ≥2 additional disease sites (n=665) had shortest survival (HRadj=1.44; CI 1.17-1.77, p<.001). A combination of peritoneal and liver metastases (n=821; HRadj=1.37, CI 1.12-1.67, p=.002) was associated with poorer survival compared with isolated pmCRC; but combination with extrahepatic sites (n=290; HRadj=1.15, CI 0.91-1.45, p=.25) was not. Conclusions: pmCRC pts have significantly worse survival than those with other solitary site mCRC. Among those with multiple disease sites, poorer survival is a function of increased number of metastatic sites and peritoneal involvement, which indicates prognostic heterogeneities among M1b pts.
Comprehensive genomic profiling (CGP) to assess mutational load in gastric and esophageal adenocarcinomas: Implications for immunotherapies.
Authors: Frampton Garrett Michael , Schrock Alexa Betzig , Chalmers Zachary Rockow , Sun James , Ennis Riley , Gowen Kyle , Beg Muhammad Shaalan , Rubinson Douglas Adam , Yelensky Roman , Stephens Philip J , Miller Vincent A. , Ross Jeffrey S. , Ali Siraj Mahamed , Klempner Samuel Jacob 
Published: February 2017

66 Background: Gastroesophageal cancer (GEC) present a management challenge, particularly when ERBB2 is not amplified and cytotoxic therapy has failed. Tumor mutational load is linked to predicted benefit from immune checkpoint inhibitors in advanced cancers. Using CGP we assessed the relationship between mutational burden and clinically relevant genomic alterations in GEC samples in the course of routine clinical care. Methods: DNA was extracted from 40 microns of FFPE sections from patients with GEC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of greater than 500x for 236 or 315 cancer-related genes. Mutational load was characterized as the number of somatic base substitutions and short indels per megabase. Samples were stratified by histologic subtype, and presence or absence of therapeutically relevant receptor tyrosine kinase (RTK) alterations. The majority of samples were from patients with advanced disease. Results: The genomic profiles from a total of 736 gastric and 862 esophageal carcinomas were assessed. Median patient age was 57 for gastric and 60 for esophageal cases. There was no significant difference in mutational load between gastric and esophageal samples. 10th, 25th, median, 75th, and 90th percentiles of mutation load were 1.3, 2.7, 6.3, 11.3, and 20.0 for gastric cancers and 1.8, 3.6, 6.4, 11.3, and 17.5 for esophageal cancers. 27 (3.7%) gastric and 20 (2.3%) esophageal cases had alterations in mismatch repair genes MLH1, MSH2, MSH6 which was associated with ~2.5 fold increased mutational load. Mutational load was not significantly associated with the presence of RTK alterations, which occurred in 155 (21%) gastric and 355 (41%) esophageal cases. Conclusions: CGP in the course of clinical care can be used to assess mutational load in GEC. Alterations in RTKs were not exclusive of the high mutation subgroup, contrary to some previous reports. Mutations in DNA mismatch repair genes were associated with higher mutation burden as expected. Incorporation of CGP into ongoing prospective immunotherapy trials and clinical practice is needed to refine these relationships.
Impact of 18F-fluorodeoxyglucose position emission tomography/computed tomography on radiotherapy treatment planning and outcomes in esophageal cancer.
Authors: Ng Sweet Ping , Tan Jennifer , Osbourne Glen , Williams Luke , Bressel Mathias , Hicks Rodney J , Lau Eddie , Chu Julie , Ngan Sam , Leong Trevor 
Published: February 2017

67 Background: Currently there is no universally accepted method to accurately delineate the gross tumor volume (GTV) of primary esophageal cancer in patients undergoing radiotherapy. This prospective study aims to determine the impact of PET/CT on radiotherapy planning and outcomes in patients with localized esophageal cancer. Methods: 54 patients were recruited between June 2003 - May 2008. All underwent PET/CT scanning in the radiotherapy treatment position and received treatment planned using the PET/CT dataset. Of these, 13 (24.1%) had metastatic disease detected on PET and 3 patients had no radical radiotherapy, while another 3 patients had missing planning PET/CT data (excluded from planning component analysis). GTV was defined separately on PET/CT (GTV-PET) and CT (GTV-CT) data sets. A corresponding planning target volume (PTV) was generated for each patient. Volumetric and spatial analysis quantified the proportion of FDG-avid disease not included in CT-based volumes. Clinical data was collected for 38 patients treated radically to determine locoregional control and overall survival rates. Results: Mean age was 67 years (range:32 - 88). Median follow up was 4 years (range:2.7 – 6.8). FDG-avid disease would have been excluded from GTV-CT in 29 patients (79%) with a mean volume of 17% (range:1-100%). In 5 patients, FDG-avid disease would have been completely excluded from the PTV-CT (median volume missed = 6%, range:2-92%). For 8 patients, less than 95% of PTV-PET would have received at least 95% of prescription dose based on the CT-based plan. GTV-CT underestimated the cranial and caudal extent of FDG-avid tumor in 14 (36%) and 10 (26%) patients respectively. There were no significant differences in radiation doses to the lungs and liver. 5-year overall survival and locoregional failure free survival were 24%, and 42% respectively. Conclusions: PET/CT prevented futile radiotherapy for 1 in 4 patients and avoided geographic misses without significant impact on normal tissues in apparently localized esophageal cancer. However, survival remains suboptimal and indicates the need for further improvement in planning and therapeutic paradigms.
A national survey on the management of liver metastases from colorectal cancer (CRC): Comparison of perspectives and expectations among medical oncologists and hepatobiliary surgeons across Canada.
Authors: Ho Maria Yi , Cleary Sean P. , Mazurek Matthew , Ghosh Sunita , Cheung Winson Y. 
Published: February 2017

690 Background: To compare the perspectives of medical oncologists versus hepatobiliary surgeons in the management of liver metastases from CRC. Methods: Medical oncologists and hepatobiliary surgeons across Canada were surveyed to evaluate for criteria used to determine resectability of liver metastases from CRC and availability of multidisciplinary clinics. Results: Of 220 experts surveyed, 145 (66%) responded. 137 (95%) had received specialized training in oncology. Only 37 (26%) respondents reported access to both multi-disciplinary tumor boards and clinics. 109 (75%) reported lack of institutional criteria. Oncologists and surgeons disagreed with regard to absolute contraindications for resection of hepatic metastases. More oncologists reported a higher percentage of liver parenchyma involvement (70% vs. 45%), proximity to major vessels and poor performance status as contraindications compared to surgeons (p < 0.05). All physicians deemed CT as the preferred first-line imaging study for evaluating CRC liver metastases with significantly more surgeons indicating the need for MRI of the liver (p < 0.05). Oncologists and surgeons also showed high discordances with respect to both clinical and radiographic findings in terms of their influence on surgical decision regarding resection of liver metastases (Table). Conclusions: Medical Oncologists and surgeons have discordant criteria with respect to resection of hepatic metastases and the roles they play in the management of these complex patients. Uncertainties and discordances can lead to deficiencies in care, supporting the need for a standardized clinical preoperative risk scoring system for resection of liver metastases from CRC. [Table: see text]
Evaluation of an interactive electronic patient-reported outcome (e-PRO) system in outpatient with oral chemotherapy.
Authors: Rasschaert Marika Anna , Papadimitriou Konstantinos , Peeters Marc , Van den Brande Jan 
Published: February 2017

696 Background: Health Information Technology (HIT) is increasingly integrated in clinical cancer care. Simultaneously routine assessment of patient reported outcomes (PROs) has been shown to reliably improve symptom management, identification of psychosocial problems and patient-provider communication. Methods: This study is a single center experience of a multicenter randomized study for the development and validation of an interactive e-PRO tool (RemeCoach). After obtaining informed consent, outpatients, using oral anti-cancer treatment, recorded their medication intake and 17 clinical parameters using this E-PRO tool. The device allowed real time data collection and communication with other care providers via a central platform. The registered data were processed by an algorithm, this algorithm stratifies the data into different grades according to international standards of care (CTCAE v4.0) and clinical importance. Patient clinical and demographic information is collected from medical records and analyzed using descriptive statistics. Results: 21 Patients were included, 62% male, mean age 59,2 (range 38-79). 38% Of patients used capecitabine, 52% regorafenib, 5% pazopanib and 5% sunitinib. Most common symptoms cited were fatigue (95%), myalgia and joint pain (75%) and cough (62%). Median pain score : 3 (Brief Pain Inventory(BPI)). Treatment compliance using the e-PRO was 75%. Conclusions: This study confirms the feasibility of the program, in an outpatient setting. This e-tool provides a means to register compliance, early symptoms of disease and toxicity of treatment.The compliance to the e-PRO tool will be confirmed, with further development of this program in a multicenter, randomized design. Evaluation of quality of life PRO-measurements and further exploration of the relationship between optimal pharmacovigilance and improvement of patient’s outcome will ensue.
Phase II trial of induction mFOLFOX6 plus bevacizumab followed by neoadjuvant S-1-based chemoradiation for MRI-defined poor-risk rectal cancer.
Authors: Konishi Tsuyoshi , Shinozaki Eiji , Murofushi Keiko , Ueno Masashi , Fukunaga Yosuke , Nagayama Satoshi , Fujimoto Yoshiya , Akiyoshi Takashi , Suenaga Mitsukuni , Matsusaka Satoshi , Chino Akiko , Kawachi Hiroshi , Yamamoto Noriko , Ishikawa Yuichi , Igarashi Masahiro , Oguchi Masahiko , Mizunuma Nobuyuki , Sano Takeshi , Yamaguchi Toshiharu 
Published: February 2017

700 Background: Induction chemotherapy has been explored as a novel treatment option to improve oncological outcomes in poor-risk locally advanced rectal cancer (LARC). Although previous studies have suggested high pCR rate with a favorable toxicity profile in S-1-based neoadjuvant chemoradiation, no study has evaluated induction chemotherapy added with this regimen. The present study is designed to evaluate the safety and efficacy of induction chemotherapy with bevacizumab followed by neoadjuvant S-1 based chemoradiation in MRI-defined poor-risk LARC. Methods: This was a single-center phase II trial at a high-volume cancer center. Eligible patients had low rectal adenocarcinoma with MRI-defined poor-risk features. Patients received 12-week (6 course) mFOLFOX plus bevacizumab (5 mg/kg every 2 weeks) followed by concomitant oral S-1 (80mg/m2/day on days 1-5, 8-12, 22-27, and 29-33) plus radiotherapy (50.4Gy). Surgery was scheduled for 6-10 weeks after chemoradiation. Pathological complete response (pCR) was the primary endpoint. Results: A total of 43 eligible patients were enrolled. Forty-two patients (98%) completed induction chemotherapy. Forty-two patients (98%) completed planned radiation dose. One patient with cCR after completion of preoperative treatment declined surgery, but all the other 42 patients (98%) underwent R0 resection thorough a laparoscopic approach. A pCR was achieved in 16 patients (37%; 95% confidence interval 24.4%-52.1%). CTCAE grade 3 adverse events (AEs) occurred in 4 patients (9.3%) during induction chemotherapy and 5 patients (12%) during chemoradiation. There were no grade 4 AEs. Clavien-Dindo Classification grade III-IV surgical complications occurred in 6 patients (14%), including 1 grade IVa delirium, 1 grade IIIb anastomotic leakage, 1 grade IIIb bleeding, 2 grade IIIa pelvic abscess and 1 grade IIIa urethral fistula. There was no mortality. Conclusions: Induction FOLFOX plus bevacizumab followed by S-1-based chemoradiation achieved a high pCR rate with favorable toxicity and tolerable surgical complications in poor-risk LARC. Phase III trial is needed for further evaluation. Clinical trial information: UMIN000011457.
Gene expression profiling of Japanese gastric cancer patinets using Asian Cancer Research Group classification.
Authors: Terashima Masanori , Makuuchi Rie , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Hikage Makoto , Hatakeyama Keiichi , Oshima Keiichi , Ohnami Shunpei , Urakami Kennichi , Kusuhara Masatoshi , Yamaguchi Ken 
Published: February 2017

72 Background: Gastric cancer is well known as having heterogeneous features. Recently, the Asian Cancer Research Group (AGRG) had proposed a new classification scheme based on the gene expression profile of the tumor. However, the genomi/expression profiling of gastric cancer in Japanese patients is still unknown. We started a comprehensive molecular profiling study that analyzes genome and transcriptome of tumor obtained from cancer patients admitted to Shizuoka Cancer Center from 2014. We already had evaluated more than 1,500 samples from various type of cancer. Among them, 104 gastric cancer patients were analyzed. Methods: Fresh surgically resected tumor/normal samples and peripheral blood were obtained and whole-exome sequencing (Ion Proton, Life Technologies) and gene expression profiling (DNA microarray, Agilent Technologies) were performed. Patients were grouped based on the gene expression profile according to AGRG classification, and clinicopathological features were compared among the group. Results: Patients were classified into MSI in 14, MSS/EMT in 15, MSS/TP53+ in 38 and MSS/TP53- in 37, respectively. There was no significant difference of sex among the group. Age was significantly younger in MSS/EMT and MSS/TP53-. In MSI, tumor tended to be located at antrum, and differentiated type tumor was predominant. In MSS/EMT, advanced T stage (T4) and undifferentiated type of tumor was predominant. In MSS/TP53+, relatively less advanced stage and localized macroscopic type tumor was predominant. In MSS/TP53-, relatively advanced stage and invasive macroscopic type tumor was predominant. Although the follow-up period is insufficient, relapse-free survival was the worst in MSS/EMT and no patient recurred in MSI. Conclusions: Classification of gene expression profiling based on ACRG was possible in Japanese gastric cancer. Distribution and tumor characteristics were almost identical to ACRG cohort. Gene -expression profiling may be comprehensively used for tumor classification and further clinical trials of molecular targeting agents.
A multicenter phase II study on the feasibility and efficacy of neoadjuvant chemotherapy for locally advanced rectal cancer.
Authors: Goto Saori , Hasegawa Suguru , Matsumoto Takuya , Hida Koya , Kawamura Junichiro , Yamanokuchi Satoshi , Yamaguchi Takashi , Matsusue Ryo , Kadokawa Yoshio , Kato Shigeru , Manaka Dai , Nishitai Ryuta , Nomura Akinari , Kanazawa Akiyoshi , Kawada Kenji , Kyogoku Takahisa , Sakai Yoshiharu 
Published: February 2017

730 Background: The aim of this prospective multi-center phase II study was to evaluate the feasibility and efficacy of neoadjuvant chemotherapy (NAC) for locally advanced rectal cancer (LARC). Methods: Patients with LARC (cStage II–III) were included; those with cT4b tumor were excluded. Six cycles of mFOLFOX6 plus either bevacizumab (bev) or cetuximab (cet), depending on KRAS status, were administered before surgery. Primary endpoint was R0 resection rate. Secondary endpoints included completion rate of NAC, response rate, postoperative complications, pathological complete response (CR) rate, overall and disease-free survival, and quality of life. Results: Sixty patients from 7 institutes were enrolled. mFOLFOX6 was administered with bev to 40 patients who had wild-type KRAS and with cet to 20 patients who had K-RAS mutations. Completion rate of NAC was 88.4% and overall response rate was 81.7%. Sphincter-preserving surgery and abdominoperineal resection were performed in 43 and 17 patients, respectively. Median operation time was 335 min and median blood loss was 40 g. R0 resection rate was 98.3% and pathological CR rate was 16.7%. Overall postoperative complication rate ( ≥ grade 2) was 21.7%, including anastomotic leakage (11.6%), surgical site infection (6.7%), and urinary dysfunction (3.3%). There were no significant differences between patients with wild-type KRAS and those with KRAS mutations in response rate, postoperative complication rate, and pathological CR rate. Conclusions: NAC was a feasible and promising treatment option for LARC. Clinical trial information: UMIN000005654.