bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of KRAS G12D mutation with outcome in patients with pancreatic cancer after surgery.
Authors: Mikayama Yo , Morinaga Soichiro , Watanabe Takuo , Numata Masakatsu , Tamagawa Hiroshi , Yamamoto Naoto , Shiozawa Manabu , Akaike Makoto , Yoichi Kameda , Matsukuma Shoichi , Miyagi Yohei 
Published: February 2017

221 Background: The frequency of KRAS gene mutations in pancreatic adenocarcinoma is high and most mutations occur in codon 12 and 13. However, the association of KRAS mutation status with clinical outcome of pancreatic cancer patients after surgery is not clearly understood. The aim of present study was to clarify whether presence of mutation in KRAS is of prognostic significance, and to determine whether the different type of KRAS mutation have different impact on clinical outcome in pancreatic cancer. Methods: A total of 62 pancreatic adenocarcinoma tissues from patients underwent curative surgery were analyzed for KRAS mutation. DNA was extracted from the tissue microarray. The domain containing the KRAS gene codons 12 and 13 was amplified by PCR, and KRAS mutation was detected by loop hybrid mobility shift assay (LH-MSA). Results: KRAS mutation was detected in 41 of 62 tumors (66.1%). Mutations of KRAS codon 12 and codon 13 were detected in 37 of 62 tumors (59.7%) and in 4 of 62 tumors (6.5%), respectively. G12D mutation were detected in 35.5% (22/62) and G12V mutation in 19.4% (12/62) of all. The patients with KRAS mutations had a significantly shorter overall survival (OS) (log rank, p=0.0375) and disease free survival (DFS) (p=0.0175). When the type of mutation were evaluated, G12D mutation was significantly associated with both shorter OS (p=0.0410) and DFS (p=0.0214), whereas G12V mutation was associated with neither OS (p=0.6727) nor DFS (p=0.9854). Conclusions: The presence of KRAS mutation was significantly associated with poor outcome of pancreatic cancer patients after surgery. A specific mutation G12D demonstrated significant association with shorter OS and DFS in pancreatic cancer. The different type of KRAS mutation might have different impact on clinical outcome in pancreatic cancer.
Comparative analysis of myeloid-derived suppressor cell (MDSC) subsets in patients with gastrointestinal (GI) malignancies.
Authors: Duffy Austin G. , Zhao Fei , Fioraventi Suzanne , Greten Tim 
Published: February 2017

228 Background: Immune-based therapies have begun to demonstrate efficacy in GI oncology. However immune-suppressor mechanisms have been described which interfere with host anti-tumor immunity. Myeloid derived suppressor cells (MDSCs) constitute a heterogenous population known to be increased in patients with GI cancer. MDSCs inhibit the host anti-tumor immune response, limiting the effectiveness of both immune and non-immune treatments. Characterization of MDSCs in humans has been difficult with heterogeneous phenotype classification. Differences in processing are also potentially important. The aim of this study was to perform a comparative analysis of MDSC subsets in patients with GI cancer. Methods: Fluorescence activated cell sorting (FACS) analysis was performed on PBMC and whole blood (WB) lysates from both healthy adults and patients with advanced hepatocellular, colorectal and pancreatic cancer. Antibodies used for subtype characterization: anti-CD14, anti-CD15, anti-HLA-DR, anti-CD33, anti-CD11b. Functional studies performed to confirm MDSC status included thymidine proliferation assay on sorted cell populations. Results: Samples were obtained from 20 patients with advanced GI cancer and healthy volunteers and processed accordingly. Based on published data the following MDSC subtypes were analyzed: A) CD14+, HLA-DR−/low; B) CD15+,CD14-CD33+CD11b+.The frequency of each subset is shown in the table below. Functional studies will also be presented. Conclusions: Characterization of MDSCs in humans has been difficult with heterogeneous and often contradictory phenotype classification. In addition, there is considerable variability depending on which component of the blood is analyzed and how the sample is processed. This study confirms the increase in both MDSC populations in patients with GI cancer. [Table: see text]
Sorafenib-induced loss of polarity of zymogen granules in pancreatic acinar cells.
Authors: Ito Tatsuo , Doi Ryuichiro , Uemoto Shinji 
Published: February 2017

236 Background: Sorafenib is an oral multi-kinase inhibitor which is regarded as a key drug for HCC and RCC. It has been unexpectedly found that the compound causes an increase of serum pancreatic enzyme levels without clinically recognized pancreatitis. The reason for this event is not well understood yet. The aim of this study was to clarify the mechanisms involved in this phenomenon. Methods: Eight-week old BALB/cA male mice were used in in vivo studies. Sorafenib tosylate was administered per os once daily at a dose of 150 mg/kg body weight. Control mice were given vehicle alone. Mice were sacrificed 24 hr after 1-, 2-, 3- and 7-day administration of the compound, and blood samples and pancreatic tissue samples were obtained (n=5 for each group). The tissue samples were used for hematoxylin and eosin (HE) staining, immunohistochemistry, electron microscopy (EM), western blot and RT-quantitative PCR studies. Results: Serum amylase levels were elevated after sorafenib administration. The amylase level hit the peak after 2-day administration, and then gradually decreased. By HE staining, the control group without sorafenib showed a basophilic stained area in the baso-lateral site of the acinar cells. In contrast, the acinar cytoplasm after 2-day administration of sorafenib was totally eosinophilic. The typical findings of acute pancreatitis were not seen in the both group. By EM examination, zymogen granules (ZGs) of the sorafenib group spread into basal site of the acinar cells. ZGs mounted up on both of apical and baso-lateral plasma membrane and showed exocytosis. The levels of amylase mRNA were not elevated by sorafenib. In addition the expression of N-ethylmaleimidesensitive factor attachment protein receptor (SNARE) proteins was not changed. Conclusions: The results suggest that the amount of acinar amylase production was not changed but the distribution of ZGs was altered by sorafenib. Sorafenib seemed to cause temporary loss of polarity of ZGs secretion in acinar cells by blocking apical exocytosis. Acute pancreatitis was not evident; thus the current model was not similar to the pancreatitis model caused by the supra-maximal secretagogue stimulation which blocks the apical exocytosis.
Preclinical study of MEK1/2 inhibitor AZD6244 combined with gemcitabine for treatment of biliary cancer.
Authors: Xu Junyao , Knox Jennifer J. , Tsao Ming Sound , Chen Eric Xueyu , Cao Pinjiang , Sue Chow , Serra Stefano , Hedley David W 
Published: February 2017

240 Background: MEK1/2 is an integral component of the Ras/Raf/MEK/ERK signaling pathway, implicated in uncontrolled cell proliferation and cell survival, a key hallmark of cancer. AZD6244, a novel inhibitor of MEK1/2, is currently completing Phase II clinical trials in biliary cancer, with modest antitumor activity observed as monotherapy. Gemcitabine is a cytotoxic drug commonly used in biliary cancer therapy but many patients showed early resistance. In this preclinical study, we investigated the sequence-dependent antitumor effects of AZD6244 combined with gemcitabine in biliary cancer models. Methods: Two biliary cancer cell lines (EGI-1 and TFK-1) were used. In vitro the effects of single drug or three combination protocols(concurrently; AZD6244 followed by GEM or Gem followed by AZD6244) on cell proliferation, DNA synthesis, and cell cycle distribution were evaluated by MTS, clonogenic assay, EdU uptake and flow cytometry. Drug interactions were analyzed by Chou-Talaly method. In vivo, 4 tumor models subcutaneously xenografted in SCID mice from the two cell lines and 2 human patients were set up to compare the therapeutic effects of different sequence-scheduled combinations. Results: AZD6244 caused G1-S cell cycle arrest in biliary cancer cells in vitro and in vivo, and this effect is correlated with the MEK/ERK signaling pathway blocking. Synchronized progression of the population through S phase were observed in 15h after removal of AZD6244 in cell culture or 48h after final dose of acute AZD6244 treatment in vivo. Antagonistic or additive effects was observed in vitro when combination were given as concurrently(CI=2.03~2.46) or Gem followed by AZD6244(CI=1.34~1.78). In contrast, a synergistic antiproliferative activity was obtained when AZD6244 was given first followed by a drug-free interval before Gem treatment (CI=0.53~0.69). In vivo, the best therapeutic effects were obtained with the sequence of AZD6244 followed by Gem, compared with concurrent or reverse sequence. Conclusions: This study provides a sound rationale for a Phase II trial of a potentially synergistic sequence of MEK inhibitor AZD6244 followed by gemcitabine in patients with advanced biliary cancer.
Effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, on chemotherapy and antiangiogenic response in pancreatic cancer.
Authors: Ostapoff Katherine T. , Awasthi Niranjan , Yen Peter L. , Zhang Changhua , Schwarz Margaret A. , Brekken Rolf A. , Schwarz Roderich 
Published: February 2017

243 Background: The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathway dysregulation is a prominent feature of pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM), a standard systemic treatment for PDAC, has limited clinical benefits. The present study investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Methods: Protein expression and cell proliferation were analyzed by Western blotting and WST-1 assay. Animal experiments were performed in murine xenografts. Results: BEZ235 inhibited phospho-AKT (Ser473) and phospho-mTOR (Ser2448) expression in PDAC (AsPC-1), endothelial (HUVECs) and fibroblast (WI-38) cells. NVP-BEZ235 also caused a significant dephosphorylation of downstream mTORC1 target proteins phospho-p70 S6K (Thr389) and phospho-4E-BP1 (Thr37/46). In vitro 72-hour proliferation of four PDAC cell lines was significantly inhibited by BEZ235. Additive effects on proliferation inhibition were observed in the BEZ235 and GEM combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with GEM and EMAP, induced apoptosis in AsPC-1, HUVECs and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. PDAC in vivo therapy demonstrated that compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and GEM monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235+GEM (30 days, p=0.007), BEZ235+EMAP (27 days, p=0.02), GEM+EMAP (31 days, p=0.001) and BEZ235+GEM +EMAP (33 days, p=0.004). Conclusions: BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that can be enhanced in combination with cytotoxic (GEM) and antiendothelial (EMAP) agents. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.
Significance of mortalin expression in gastric cancer with normal p53.
Authors: Ando Koji , Oki Eiji , Yan Zhao , Kitao Hiroyuki , Saeki Hiroshi , Ohga Takefumi , Kakeji Yoshihiro , Tsujitani Shunichi , Kohnoe Shunji , Maehara Yoshihiko 
Published: February 2017

25 Background: Gastric cancer still has the highest morbidity rate and the second highest mortality rate. As chemotherapy confers only a minimal survival advantage, the prognosis of patients with advanced or recurrent gastric cancer remains poor. Studying the mechanisms and underlying molecules that drives gastric cancer malignant, could contribute to finding a remedy for gastric cancer. Mortalin is a heat non-inducible member of the heat shock protein 70 family. Mortalin binds to p53 and prevents p53 from entering the nucleus, as well as cell stress. To understand the significance of mortalin in gastric cancer, we investigated the expression of mortalin and p53. Methods: The expression of mortalin and p53 were examined by immunohistochemical staining of 182 clinical samples of gastric cancer. Results: Mortalin-positive and aberrant-p53-positive samples were found in 75.2% and 62.6% of cases, respectively. Mortalin-positive tumors were deeper in invasion and had more lymph node and liver metastases compared with mortalin-negative tumors (p < 0.01, p < 0.05, respectively). Mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (p = 0.035). Moreover, in tumors with normal p53 expression, mortalin-positive tumors had especially worse prognosis compared with mortalin-negative tumors (p = 0.013). With multivariate analysis, mortalin expression appeared to be an independent prognostic factor in gastric cancer with expression of normal p53 (p = 0.0174). Conclusions: Mortalin has a great impact on gastric cancer with normal p53. Therefore, mortalin is a target molecule for treatment of gastric cancer, as well as a promising prognostic factor, especially in tumors with normal p53.
Percutaneous irreversible electroporation (IRE) in the treatment of hepatocellular carcinoma (HCC) and metastatic colorectal cancer (mCRC) to the liver: A retrospective analysis of the University of Miami experience.
Authors: Loaiza-Bonilla Arturo , Barbery Katuska J , Perez-Rojas Evelyn , Froud Tatiana , Yrizarry Jose M , Akunyili Ikechukwu Immanuel , Rocha Lima Caio Max S. , Feun Lynn G. , Hosein Peter Joel , Narayanan Govindarajan 
Published: February 2017

272 Background: Percutaneous ablation and transarterial chemo- or radioembolization are commonly used in the treatment of HCC and mCRC to the liver. IRE using the Nanoknif is more versatile than other ablative modalities (such as RFA) in that tumors abutting vascular structures can be treated with IRE without compromise of the vessels or concern for the heat sink effect of nearby blood flow. Methods: We examined the records of patients (pts) referred for IRE for HCC and mCRC. The procedures were all done percutaneously under general anesthesia using a standard protocol. The primary endpoint was progression-free survival (PFS). Responses were assessed using the modified RECIST criteria. Results: Between 1/2010 and 8/2011, 49 pts underwent percutaneous ablation of unresectable HCC and mCRC liver tumors using IRE – 33 with HCC and 16 with mCRC. A total of 76 lesions were treated in 62 sessions; the median number of lesions treated per patient was 1 (range 1-4) and the median tumor size treated was 2.1cm (range 0.8-6). After IRE, 20 pts (41%) had a complete response (CR), 19 (39%) had a partial response and 10 (20%) had stable disease as their best response. The Kaplan-Meier estimated median PFS was 11.3 months (95% CI 9.6-12.9) for all pts, 11.6 months (95% CI 10.2-12.9) for HCC pts, and 10.4 months (95% CI 5.4-15.4) for mCRC patients. The one-year PFS was significantly higher for pts achieving a CR compared to those who did not achieve a CR (75% versus 59%, log rank p = 0.05). The number of liver lesions at baseline and size of the treated lesions were not associated with any differences in survival. The IRE was complicated in 6 pts (12%) by pneumothorax (2), pleural effusion (2), and atrial flutter/fibrillation during anesthesia (2). All pts recovered fully from these complications. One pt died within 1 month of the IRE due to disease progression. Conclusions: IRE of liver tumors is safe. The PFS rates for pretreated mCRC and unresectable HCC are promising. A complete lack of enhancement of the treated lesion on the post-IRE CT scan appears to be associated with longer survival.
A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases (ILM) from colorectal cancer (CRC).
Authors: Magge Deepa , Zureikat Amer H , Bartlett David L. , Holtzman Matthew Peter , Choudry Haroon , Beumer Jan H. , Holleran Julianne L. , Strychor S. , Pingpank James F. , Zeh Herbert 
Published: February 2017

283 Background: IHP is a proven approach for regional delivery of chemotherapy in patients with unresectable ILM. This study sought to determine safety and MTD of administering 5FU in combination with fixed dose oxaliplatin via IHP. Methods: Prospective Phase I dose escalation with standard 3x3 dosing. Subjects with unresectable ILM from CRC scheduled to receive an HAI pump were eligible. IHP employed fixed dose oxaliplatin (previously established)with escalating doses of 5FU. 1 endpoint was to determine MTD for this combination. 2 endpoints were response to IHP alone, PFS, and OS for IHP + HAI-FUDR. Systemic and IHP plasma PK of 5FU, anabolites, total, and free platinum were determined by validated assays. Results: Between Aug 2007 - Mar 2011, 11 subjects were enrolled. All patients received at least one line of pre-IHP systemic chemotherapy. There were 4 Grade 3 SAE (36.3%) and no grade 4 events. 2 DLTs occurred in the second dose cohort of 300mg/m2. Dose escalation was terminated and 200mg/m2 5FU was determined to be the MTD. There was 1 DLT in the dose de-escalating phase of 200mg/m2. At first follow-up, 9 pts (82%) had a partial response, while 2 (18%) had stable disease. 64% of pts had a >50% decrease in CEA level. Actuarial 1 and 2 year survival was 100% and 75% respectively, with median follow-up of 23 mos. IHP exposures (AUC0-60min) were 10.9±4.5 µgPt·h/mL (platinum), 49.3±30.7 µg·h/mL 5FU (DL1) and 70.5±35.5 µg·h/mL 5FU (DL2). Free platinum represented 82±14% of total platinum. Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both total platinum (1.1±1.5%) and 5FU (0.09±0.10%). IHP exposure to metabolites relative to 5FU was 4.9±2.5% for FUrd and 0.23±0.14% for FdUrd, respectively. Conclusions: MTD for IHP with 5FU and oxaliplatin is 200 mg/m2 and 40mg/m2 respectively. Systemic exposure to the agents was minimal. The response and survival observed in this dose escalation study warrants assessment in a larger phase II trial. [Table: see text]
Using the decline in CA19-9 after the start of chemotherapy to predict survival in patients with inoperable bile duct cancer.
Authors: Grunnet Mie , Baeksgaard Lene , Laursen Inga , Lassen Ulrik Niels , Sorensen Morten 
Published: February 2017

287 Background: CA 19-9 has been approved by the FDA as a tumour marker in pancreatic cancer. The prognostic value of CA19-9 in cholangiocarcinoma is unclear.The aim of the study was to determine if an early CA 19-9 response after the first cycle of chemotherapy is predictive of survival in patients with inoperable bile duct cancer. Methods: CA 19-9 response was defined as a 20% decline in CA 19-9 compared to baseline after four weeks of chemotherapy, in patients with a baseline CA 19-9 level above 1.5 times the upper limit of normal (ULN). Patients were identified retrospectively database at a single institution. Chemotherapy used was gemcitabine day 1 and 15 (1g/m2), oxaliplatin day 1 and 15 (60 mg/m2) and capecitabine (1g/m2 BID) days 1 to 7 and days 15-21 for six cycles. Patients with a baseline CA 19-9 above 1.5 the ULN and at least one CA 19-9 value measured four weeks after the start of chemotherapy were included in the study. Survival in CA 19-9 responders was compared to non-responders by use of the log rank test. A Cox regression analysis was performed using performance status, gender, disease extent and location, need for endoluminal stenting, baseline CA 19-9, and CA 19-9 response as co-variables. Results: 212 patients were registered from Feb 2004 until Nov 2010. Among these, 170 were treated with chemotherapy for cholangiocarcinoma and 131 had a baseline CA 19-9 value and at least one follow-up CA 19-9. Patients with baseline CA 19-9 less than 1.5 times the ULN (n=45) or inconclusive measurements (n=7) were excluded leaving 79 patients in the study. Fifty per cent of patients had a CA 19-9 response to chemotherapy. The median survival in the CA 19-9 response group was 11.7 months (95%CI: 7.5 – 16.0) vs. 8.2 months (95% CI: 6.4 – 9.8) in the non-response group. CA 19-9 response (HR: 0.535 (95%CI; 0.331-0.866), p=0.01) and disease extent (metastasis vs. no metastasis) (HR: 0.604 (95%CI; 0.369-0.99) p=0.046) were independent predictors of survival in a Cox model. Conclusions: CA19-9 response is useful as predictor of survival in patients with inoperable cholangiocarcinoma undergoing chemotherapy.
Sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (HCC): Safety and efficacy in Child-Pugh (CP) class A and B patients.
Authors: Pressiani Tiziana , Boni Corrado , Rimassa Lorenza , Labianca Roberto , Fagiuoli Stefano , Ardizzoni Andrea , Foa Paolo , Cortesi Enrico , Giordano Laura , Santoro Armando 
Published: February 2017

306 Background: S is the first systemic agent that has been shown to prolong survival in pts with CP A advanced HCC. However, its safety and efficacy have not been extensively evaluated in pts with CP B cirrhosis. Methods: We performed a descriptive analysis on pts with histologically documented advanced HCC and CP A/B cirrhosis, enrolled in a multicenter phase II randomized, open-label trial (data reported elsewhere), in order to assess the feasibility and efficacy of treatment with S in CP B pts. Written informed consent was obtained from all pts. Results: From April 2007 to July 2008, 297 pts were prospectively treated with S 400 mg bid, 234 (78.8%) CP A, 63 (21.2%) CP B. 232 pts were male (76%), median age was 68.3 yrs (range 19.8-89.2 yrs), 217 pts had no extra hepatic disease (73.1%). The two subgroups, according to CP class A or B, were homogeneous for all considered parameters. Median treatment duration was >3 months (mos) for 59.4% of CP A pts and for 27% of CP B pts (p <0.001). Median PFS for the total population was 3.9 mos, 4.3 mos for CP A pts and 2.1 mos for CP B pts (p<0.001). Median OS was 10 mos for CP A pts and 3.8 mos for CP B pts (p<0.001). Adverse events (all grades) were similar in type and incidence for CP A and B pts, with fatigue, stomatitis, diarrhea and weight loss having the highest incidence (44%, 41%, 38% and 38%, respectively). Specifically, no differences in terms of grade 3-4 events have been documented between the two groups. Conclusions: This study supports the feasibility of S also in advanced HCC pts with CP B status. Tolerability data suggest that pts with CP B status might potentially be treated safely with S for its potential survival benefits. Further prospective trials, specifically designed to investigate S in CP B pts, are eagerly advocated.