bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of the relationship between RARβ2 hypermethylation and invasive esophageal squamous cell carcinoma.
Authors: Li Ruei-nian , Yu Chun-chieh , Wu Ruei-shiang , Wu Ming-tsang 
Published: February 2017

23 Background: Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death among men in Taiwan, and the five-year survival rate is below 10%. The retinoic acid receptor beta2 (RARβ2) is frequently deleted or silenced at early stages in tumor progression. Most of RARβ2 repressions are associated with promoter hypermethylation in several epithelial carcinomas. In addition, the degree of whole genome methylation decreases as the lesion progresses from benign to invasive cells. The aim of this study is to investigate RARβ2 promoter methylation status and global methylation level in different stages of ESCC patients. Methods: We examined the methylation frequency of ESCC tissues by the method of methylation-specific PCR and pyrosequencing. The RARβ2 protein expression was determined by western blotting and cell mobility was measured by migration assay. Results: The methylation rate of RARβ2 was 21.1% (15/71) in tumor cases, but the normal control was unmethylated. The frequency of lymph nodes invasion and the frequency of tumor metastasis were 2-fold increased in RARβ2 promoter hypermethylated cases compared with normal counterparts. Furthermore, RARβ2 promoter methylation frequency was increased with 14.7% and showed significant decrease survival rate in advanced stage of ESCC patients. The level of LINE-1 methylation in ESCC tissues (mean 67%) was significantly lower than normal counterparts (mean 80%). But the level of LINE-1 methylation was not associated with tumor stage or survival rate. In vitro, ESCC cell line treated with 5-aza-dC was decreased in RARβ2 methylation level and was increased in RARβ2 protein expression. The migration ability of ESCC cell line was inhibited during demethylation of RARβ2 promoter. Conclusions: Our findings indicate that LINE-1 methylation level and RARβ2 hypermethylation could be useful for prognosis markers and invasion-migration markers in ESCC.
Phase I/II study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results.
Authors: Mitsunaga Shuichi , Ikeda Masafumi , Ueno Hideki , Nakachi Kohei , Morizane Chigusa , Kondo Shunsuke , Shimizu Satoshi , Kojima Yasushi , Suzuki Takuya , Tamai Toshiyuki , O'Brien James P. , Okusaka Takuji 
Published: February 2017

231 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFR-beta. Maximum tolerated dose (MTD) of lenvatinib for solid tumor pts was determined to be 25 mg once daily dosing (qd). The current study was planned to determined MTDs and pharmacokinetic profiles of lenvatinib in HCC pts with Child-Pugh grade (CP) A and B. Methods: Between Aug. 2009 and Nov. 2011, a total of 20 pts with advanced HCC were enrolled in phase I part (Ph I). Ph I consists of a standard dose escalation design in separate cohorts of CP-A (6 pts per cohort) and CP-B (3+3 pts). The initial dose level of lenvatinib for CP-A and for CP-B was 12 mg qd. Tumor response was assessed by RECIST 1.1. Results: Nine pts with CP-A and 11 pts with CP-B were enrolled and evaluable for safety and efficacy. Pt characteristics: median age: 63.5 years, Male: 85%, HBV: 35% / HCV: 45%. 1/6 pt in 12 mg qd and 2/3 pts in 16 mg qd experienced DLTs (fever/vomiting, hepatic encephalopathy and proteinuria) in the CP-A group. In the CP-B group 2/5 pts in 12 mg qd and 0/6 pt in 8 mg qd experienced DLTs (hepatic encephalopathy and AST increased/hyperbilirubinaemia/creatinine increased). The most common toxicities were hypertension (all grade (Gr):75%, Gr3:50%), diarrhea (all Gr:70%, Gr3:0%), anorexia (all Gr:65%, Gr3:0%), palmar-plantar erythrodysaesthesia syndrome (all Gr:65%, Gr3:5%), fatigue (all Gr:65%, Gr3:0%) and hyperbilirubinaemia (all Gr:50%, Gr3:15%). Confirmed partial responses were observed in 4 pts and stable disease were in 9 pts. Median time to progression was 3.7 mo. Following administration of 12 mg lenvatinib, trough plasma concentrations (Ctrough) of the CP-A (n=5), CP-B (n=2), and pts with other solid tumors were 49.7 ± 23.6 (mean ± standard deviation), 73.7 and 22.8 ± 9.8 ng/mL respectively. Conclusions: The MTD for lenvatinib in advanced HCC pts with CP-A and CP-B are 12 mg qd and 8 mg qd, respectively. Ctrough is substantially higher than in HCC pts than in pts with other solid tumors. Lenvatinib 12 mg qd in HCC pts with CP-A and 8 mg qd in HCC pts with CP-B were associated with manageable toxicity and preliminary evidence of antitumor activity. Clinical trial information: NCT00946153.
Targeted therapies in early-phase trials for the treatment of advanced fibrolamellar hepatocellular carcinoma.
Authors: Subbiah Ishwaria Mohan , Subbiah Vivek , Naing Aung , Fu Siqing , Kaseb Ahmed Omar , Falchook Gerald Steven , Tan Dongfeng , Herzog Cynthia E. , Janku Filip , Kurzrock Razelle 
Published: February 2017

232 Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy, affecting young adults w/o chronic liver disease. Limited data exists on the novel therapeutics for this disease. Methods: Given its rarity, we evaluated the characteristics, outcomes and performed molecular analysis for targetable pathways in patients with FLHCC enrolled on phase I trials with an emphasis on targeted therapies. Results: Ten FLHCC patients (8 female, 2 male; median age 23yrs) were evaluated in the Phase I Clinic. Eight had recurrence from prior resections. Eight patients enrolled on a phase I trial. Pt #7 (58F w recurrence post-resection), received sunitinib (inhibitor of PDGFR, VEGFR, FLT3, RET) with valproic acid (HDAC inhibitor) and had a 41% decrease per RECIST for 16.5 months without any high-grade toxicities. Pt #5 (24F) had a 22% decrease for 5.4 months pazopanib (inhibitor of VEGFR, PDGFR, FGFR, cKIT) and vorinostat (HDAC inhibitor). Pt #8 remains on study with bevacizumab+sorafenib now for 5 months with 9% decrease. Pt #1 received a novel proteosome inhibitor with stable disease >9 months while pts #3, #5, and #7 received HDAC inhibitors vorinostat and valproic acid. Analysis for molecular aberrations and next generation sequencing are in progress with preliminary data showing the activation of the PI3K/AKT/mTOR signaling pathway. Conclusions: This work is the first such to report on the use of targeted therapies in advanced FLHCC. Overall pts tolerate targeted therapy with early data showing clinical efficacy and biologic activity of multikinase inhibitors, specifically sunitinib and pazopanib, in combination with HDAC inhibitors, valproic acid and vorinostat. Li et al report morphoproteomic analysis showing high expression of phosphorylated (p)-NF-κBp65 (at serine 536, a putative site of activation) in FLHCC in comparison to normal liver (p < 0.001) in 7 of 8 (88%) tested FL-HCC samples, signifying the constitutive activation of the NF-κB pathway and the therapeutic potential of proteosome inhibitors and HDAC inhibitors. Given the lack of consensus on treatment of unresectable FLHCC, this analysis presents seminal data on targeted agents for these patients.
Single-institution experience with sorafenib for hepatocellular carcinoma (HCC) in the post-liver transplant setting (Ltx).
Authors: Mariano Elizabeth Ann , Bathini Venu Gopal , Barnard Graham , Anwar Nadeem , Bozorgzadeh Adel , Saidi Reza , Jabbour Nicholas , D'Antonio Angela , Barry Curtis , Switzer Bradley Alan 
Published: February 2017

237 Background: Sorafenib plays a role in the treatment of advanced HCC; however its role after Ltx has not yet been defined in the adjuvant setting. Patients at high risk for HCC recurrence, or those with recurrence after Ltx may benefit from this therapy. Methods: We present our institution’s experience of the use of sorafenib in the post Ltx setting in 11 patients. High risk for HCC recurrence (9 patients) was defined as vascular invasion, lymphovascular invasion, liver capsule invasion, or >3 tumors present in the liver explant. 2 patients had recurrent HCC post Ltx. The starting dose of sorafenib varied, but was most commonly 200mg po BID. Patients were seen monthly while on sorafenib, and 4-phase liver CTs or MRIs were performed every 3 months. Results: Median age at Ltx was 55 (range 48-77). Median time between Ltx and start of sorafenib was 150 days (range 30-543). Reasons for sorafenib use were high risk of recurrence 8/11 (72.7%), recurrence 2/11 (18.2%), rising AFP 1/11 (9%). Median duration of therapy was 152 days (range 21-295). Only 1/9 (11%) of patients could not complete 6 months of adjuvant therapy due to toxicity. 2 patients have yet to comple 6 months of adjuvant sorafenib. All 9 patients receiving therapy for high risk of recurrence are alive with longest survival of 40 months. Both patients with recurrent disease have died. Toxicity:36% (4 patients) had Grade 2 or 3 hand foot syndrome, 18% (2 patients) had grade 1 diarrhea and hypertension, 9% (1 patient) had grade 3 elevation in liver function tests, 9% (1 patient) had grade 3 parasthesias. Other side effects include grade 2 nausea (1 patient); grade 2 muscle weakness (1 patient), grade 1 lightheadedness (1 patient), grade 1 hair loss (1 patient), and grade 1 LFT elevation (1 patient). Zero patients reported no toxicity. Conclusions: Sorafenib in the post Ltx setting was well tolerated with manageable toxicities. The majority of patients at high risk for recurrent HCC were able to complete 6 months of adjuvant therapy. Further studies investigating this therapy in post transplant patients are warranted.
Recurrence of hepatocellular carcinoma after liver transplantation: Comparison between superselective and non-superselective chemoembolization.
Authors: Smith Andrew , Heckman Michael , Serie Daniel , Harnois Denise M , Nguyen Justin H. , Paz-Fumagalli Ricardo 
Published: February 2017

238 Background: To compare post-transplant recurrence rates of hepatocellular carcinoma (HCC) and differences in percent tumor necrosis in patients with pre-operative superselective chemoembolization (CE) vs. non-superselective CE. Methods: Retrospective review of 147 patients with liver transplant (LT) for HCC treated with pre-operative CE. Those transplanted less than 24 hours after CE and those who had other concomitant treatments were excluded. The angiographic studies and written reports were reviewed to categorize patients into superselective and non-superselective groups. CE was done with an emulsion of lipiodol, cisplatin, doxorubicin, mitomycin C, and contrast, with or without embolization particles. Superselective CE was defined as treatment directly into the vessel(s) feeding the tumor. Treatment from more proximal vessels was considered non-superselective. Data gathered included age, gender, date of CE, date of LT, tumor size and number, tumor stage, MELD score, Child-Pugh class, alpha fetoprotein, percent tumor necrosis at explant, date of recurrence, date and cause of death, and date of last follow-up. Patient and disease characteristics and percent tumor necrosis were analyzed with a Wilcoxon rank sum test or Fisher’s exact test. The Kaplan-Meier method was used to estimate the cumulative incidences of death due to recurrent disease after LT. Results: 99 patients were included, 53 had superselective CE and 46 non-superselective. HCC recurrence rates at 1, 3, 5, and 8 years were all significantly less for superselective CE compared to non-superselective CE (p = 0.039 single, p = 0.011 multivariable). Using multivariable analysis, superselective CE had a lower risk of death due to recurrent HCC at 1, 3, 5, and 8 years (p = 0.046). There was a trend toward more percent tumor necrosis after superselective CE, but it did not reach significance (p = 0.057). Conclusions: This study provides evidence that HCC recurrence after LT and death due to recurrent HCC is lower after pre-LT superselective CE versus non-superselective CE. The strong trend for greater percent tumor necrosis with superselective CE may explain the differences in recurrence rate.
Evaluation of the antitumoral effect sunitinib eluting beads in VX2 liver tumour in a rabbit model.
Authors: Bize Pierre E. , Jordan Olivier , Fuchs Katrin , Dormond Olivier , Duran Rafael , Doelker Eric , De Baere Thierry , Denys Alban 
Published: February 2017

247 Background: We demonstrated that DC Bead (Biocompatibles UK, Ltd) could be loaded with sunitinib and injected intra-arterially in the rabbit without unexpected toxicity. The purpose of this study is to evaluate the antitumoral effect of sunitinib eluting beads in the VX2 tumor model of liver cancer. Methods: VX2 tumors were implanted in the left liver lobe of New-Zealand white rabbits. Animals were assigned to 3 groups: Group 1 (n=6) received 1.5mg of sunitinib loaded in 0.05ml of 100-300um DC Bead, group 2 (n=5) received 0.05ml of 100-300um DC Bead, group 3 (n=5) received 0.05ml NaCl 0.9% in the left hepatic artery. One animal in each group was sacrificed at 24 hours and the others were followed for survival until day 15. Liver enzymes were measured daily. In group 1, plasmatic sunitinib concentration were measured daily by LC MS/MS tandem mass spectroscopy. At day 15 all living animals were sacrificed. After sacrifice, the livers were harvested for determination of the VEGF receptor tyrosine kinase activity by western blot and histopathological examination. Results: In group 1, no animals died during follow-up. In group 2, 2 animals died during follow-up on day x. In control group 3, 3 animals died during follow up on day x. In group 1 plasmatic sunitinib levels remained under therapeutic concentration throughout the experiment. Very high concentrations of sunitinib were measured in the liver tissue 24 and 15 days after embolization. Inhibition of the phosphorylation of the RTK was demonstrated at 24h and 15 days in groups 1. Sunitinib eluting beads seemed to penetrate in the tumor more effectively and there was more necrosis around the beads than their bland counterparts. Conclusions: Administration of sunitinib eluting beads in VX2 carrying rabbits resulted invery high drug concentrations at the site of embolization with minimal systemic passage. Despite the very high tissular sunitinib concentration we did not observe any additional toxicity with loaded beads. Sunitinib eluting beads inhibit the activation of RTK’s triggered by ischemia and seem to prolong survival of the treated animals. Therefore we consider that local treatment with sunitinib may provide a promising approach for the treatment of liver cancer.
CA19-9 as an independent risk factor for survival in hepatocellular carcinoma.
Authors: Hsu Christine Cho-Shing , Goyal Abhishek , Hidalgo Rosa , Verna Elizabeth , Emond Jean , Brown Robert S. , Siegel Abby B. 
Published: February 2017

253 Background: High alpha-fetoprotein (AFP) is associated with worse survival in hepatocellular carcinoma (HCC) patients. CA19-9 is a glycoprotein biomarker of biliary and pancreatic cancer. To our knowledge, no prospective study has examined CA19-9 as a prognostic biomarker in HCC. We hypothesized that it may add to our ability to risk stratify patients. Methods: We prospectively enrolled 122 patients with newly diagnosed HCC between 10/2008 and 7/2012 and followed until July 23, 2012. HCC was defined by AASLD criteria. CA 19-9 and AFP were measured on enrollment: 50% patients had CA19-9 >37 U/mL and 22% had CA 19-9>100. Pathology specimens were available for 50% of patients and none were consistent with mixed HCC-cholangiocarcinoma (HCC-CC) or pure CC. We evaluated the relationship between CA19-9 and overall survival using Kaplan Meier curves, univariate, and multivariate Cox Proportional Hazards Models. Results: The mean age of the cohort was 62.1 and 79% were male. 59% had underlying HCV and 16% had HBV. In univariate analysis, CA19-9>100 predicted worse survival (HR=3.44, 95% CI: 1.79-6.61, p=0.0002). Other cut-points for CA19-9 yielded similar results, although not all were significant. In a multivariate model including CP Score (B vs. A), Milan (outside vs. within), and AFP (>100 vs. ≤100), CA19-9 >100 remained an independent risk factor for increased mortality (HR 3.95, 95% CI: 1.95-7.97, p=0.0001). CP score and Milan status had HRs of 2.57 (95% CI: 1.31-5.02, p=0.006) and 5.27 (95% CI: 2.05-13.57 p=0.0006). AFP was not an independent risk factor for worse survival with a HR of 1.69 (95% CI: 0.85-3.37, p=0.14). We also looked at models using different cut-points for AFP; CA19-9 added additional risk stratification in all models. Among patients with AFP>100, median survival was 15.5 months vs. 3.8 months when comparing those with CA19-9 ≤100 with CA19-9>100 (p=0.01, log-rank). Conclusions: CA 19-9 is a readily available biomarker that may be a novel predictor of survival in HCC patients. In our multivariate model, CA 19-9>100 almost quadrupled mortality risk. It might be particularly useful to risk stratify patients with normal AFP and those with very high AFP being considered for transplant.
First report of the correlation of PET Response Criteria in Solid Tumors (PERCIST) criteria and pathologic change in patients with rectal cancer treated with neoadjuvant radiation.
Authors: Kumar Rachit , Dholakia Avani Satish , Smith Jessica A. , Leal Jeffrey P. , Chaudhry Muhammad Ali , Wild Aaron Tyler , Hacker-Prietz Amy , Raman Siva P. , Hruban Ralph H. , Efron Jonathan , Wick Elizabeth C. , Azad Nilofer Saba , Diaz Luis A. , Le Yi , Armour Elwood , Ellsworth Susannah G. , Herman Joseph M. , Gearhart Susan 
Published: February 2017

261 Background: High-dose-rate endorectal brachytherapy (Endo-HDR) is a promising technique using a short course of radiation therapy in the neoadjuvant setting for rectal cancer. While clinical exam and standard imaging (CT and MRI) suggest outstanding radiation response in these patients, they cannot reliably predict pathologic complete response (pCR) or high tumor regression grade (TRG). In this study, we investigate the utility of PERCIST criteria to predict pathologic change. Methods: We treated nine patients on a prospective clinical trial investigating Endo-HDR as a single agent neoadjuvant therapy (6.5 Gy x 4 fractions, total dose of 26 Gy) for stage II-III rectal cancer patients. A pre-radiation PET/CT scan was compared to a post-treatment PET/CT scan performed one month following the completion of radiation. All nine patients proceeded to surgical resection with the pathologic specimen analyzed for residual disease. TRG (Mandard et al.) was used to quantify response to treatment. A 50% decrease in SUVpeak by PERCIST criteria was correlated with a TRG 1 or 2 (none or minimal residual cancer cells on the final pathologic specimen). Results: As demonstrated in our table, 3/5 (60%) of patients achieving a TRG 1 or 2 had a SUVpeak that decreased by 50% or more; contrarily, zero of 4 (0%) of patients without a TRG 1 or 2 had a SUVpeak of 50% or more. Despite a trend, the small patient sample limited statistical significance (p=0.17). A minimum decrease of 50% in SUVpeak resulted in a positive predictive value of 100%, a negative predictive value of 67%, a specificity of 100%, and a sensitivity of 60% for predicting TRG 1 or 2. Conclusions: Our results demonstrate the first report of utilizing PERCIST criteria in rectal cancer treated with neoadjuvant Endo-HDR. Reliable clinical predictors following Endo-HDR for excellent pathologic response may identify patients in whom a non-operative rectal cancer treatment is possible. [Table: see text]
Attenuated dose of gemcitabine with cisplatin in patients (pts) with unresectable or metastatic biliary tract cancer (ABC): Results of single Thai institution.
Authors: Charoentum Chaiyut , Chotirosniramit Arnon , Chitapanarux Taned , Sirivanichai Chusak , Lertprasertsuke Nirush , Chewaskulyong Busyamas , Thongprasert Sumitra 
Published: February 2017

265 Background: Combination of gemcitabine/cisplatin becomes a recent standard regimen for pts with advanced (ABC). We previously reported the encouraging activity of gemcitabine (1250 mg/m2) with cisplatin and reported grade 3/4 toxicities of anemia and neutropenia in 33% and 22% respectively. (Charoentum et al. World J Gastroenterol 2007.). This study examines the toxicity and activity of attenuated dose gemcitabine (1000 mg/m2) with cisplatin in Thai pts with ABC. Methods: Chemotherapy-naive patients with histological/cytological proven ABC, aged > 18 years, ECOG 0-2 and adequate organs function were treated with gemcitabine (1000 mg/m2 in a 30-min infusion D1, 8 q 21 d) followed by cisplatin (75 mg/m2D1) for maximum 6 cycles. Results: From November 2007 to June 2012, 37 patients were evaluated. Median age was 56 yrs (range 34 - 66), 54% were male, 76% were metastatic disease and 97% were ECOG PS 0/1. The median number of cycle was 4 (range 3-6). Among the 34 pts with measurable disease, there were 11 PR, 15 SD and 8 PD (response rate 32%). The most common hematologic toxicity of interests was gr 3 anemia in 11% and gr 4 neutropenia in 6%. Non-hematologic toxicity was generally mild. No cases of febrile neutropenia or treatment-related death were observed. The median progression free survival was 6 months (range 3-13). Conclusions: Treatment with attenuated dose of gemcitabine in combination with cisplatin in this study appears more tolerable than our previous reports in Thai pts with advanced ABC. The efficacy of both regimen appears similar.
Analysis of gene mutations in KRAS, NRAS, BRAF, and PIK3CA in patients who received systemic chemotherapy with metastatic gastric cancer.
Authors: Fukahori Masaru 
Published: February 2017

27 Background: Previous studies showed that gene mutations of KRAS, NRAS, BRAF, and PIK3CA are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer. On the other hand, the frequency and clinical significance of these gene mutations have not been clarified in metastatic gastric cancer (mGC). Methods: We gathered formalin-fixed paraffin-embedded tumor samples from 168 patients who were diagnosed gastric cancer and underwent gastrectomy between September 1995 and March 2008. Among 168 patients, we selected the mGC patients who received systemic chemotherapy. We retrospectively evaluated the mutation status of KRAS (exon2, 3, 4), NRAS (exon 2, 3), BRAF (exon 15) and PIK3CA (exon 9, 20) and prognosis in patients who received chemotherapy by gene mutation status. Results: A total 125 of patients were included in this analysis. Regimens of first line chemotherapy were 5-FU (24.0%), CPT-11/CDDP (31.2%), S-1 (33.6%), 5-FU/MTX (8.0%) and others (3.2%). Mutations of KRAS codon 12/13 (6.4%), PIK3CA exon9 (4%), PIK3CA exon20 (0.8%), and NRAS codon 12/13 (2.4%) were detected by direct-sequence method. Mutations of KRAS codon 61, KRAS codon 146, BRAF V600E and NRAS codon 61 were not detected. There were no significant differences in overall survival (OS) by mutation status of KRAS and PIK3CA. Patients with NRAS codon 12/13 mutation had poor prognosis (MSTF15.5 vs 9.4 months, adjusted HR: 5.327(95%CI: 1.566-18.096)). Conclusions: Mutations in KRAS codon 61, KRAS codon 146, BRAF V600E, NRAS codon 61 were not detected, and frequency of mutation in PIK3CA exon 9, PIK3CA exon 20 and NRAS codon 61 were rare in mGC. Although our study has several limitations, mutation in NRAS codon 12/13 may be a poor prognostic factor in mGC who received systemic chemotherapy and further accumulation of cases are needed.