bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a bona-fide biomarker of microRNA in serum exosomes to predict recurrence of hepatocellular carcinoma after liver transplantation.
Authors: Sugimachi Keishi , Matsumura Tae , Ishibashi Masahisa , Akiyoshi Sayuri , Shirabe Ken , Maehara Yoshihiko , Mimori Koshi
Published: February 2017

183

Background: The predictive biomarker for the recurrence of hepatocellular carcinoma (HCC) has great benefit on the selection of treatment options including liver transplantation (LT) for HCC. Micro RNA (miR), a class of small non-coding RNA molecule, affect crucial processes in cancer development and offer great potential as biomarkers for cancer due to their remarkable stability in blood. The objective of this study is to identify specific miRs in exosomes of HCC recurrence from the serum and bone marrow of the patients and validate these molecules as novel biomarkers for HCC recurrence. Methods: We employed microarray-based profiling of miR expression from exosome in serum and bone marrow of the patient with HCC to define a biomarker that distinguishes between patients with and without HCC recurrence after liver transplantation or hepatic resection. This was followed by a real-time semi-quantitative PCR validation in a separate cohort of 63 HCC patients who underwent living related LT. Results: We found that 4 miRs which were differentialy (>2 folds) expressed in the serum exosome with HCC cases that had recurrence after LT compared to those without recurrence. They were associated with tumor aggressiveness of HCC in the validated cohort series. To disclose the original cell fraction of each identified miR in bone marrow, we divided bone marrow cells into 3 fractions by cell surface markers, such as CD14+ (macrophage), CD14-/CD45- (lymphocyte) and CD14-/CD45-/EpCAM+ (epithelial cell), then we performed microRNA microarray in each fraction. The increased expression of miR-150, miR-135a, and miR-1225-5p were observed in the CD14-/CD45+ fraction of bone marrow of HCC cases with recurrence, which suggested the association of CD4+ lymphocyte impairment and tumor recurrence. Conclusions: Circulating miR in serum exosome has potential as a novel biomarker to predict recurrence of HCC. MiR profiling of serum and bone marrow may help to clarify the mechanism of recurrence of HCC. The identified miR/gene axis indicated that the disruption of the immune systems after LT should provoke the recurrence of HCC in the future.
Preclinical evidence of ET-743 as a potential chemotherapy option for the treatment of biliary carcinoma.
Authors: Leone Francesco , Peraldo-Neia Caterina , Cavalloni Giuliana , Soster Marco , Gammaitoni Loretta , MarchiÃƒÂ² Serena , Aglietta Massimo
Published: February 2017

193

Background: The standard chemotherapy for unresectablebiliary tract carcinoma (BTC) is based on gemcitabine and platinum compounds. However, these combinations have not been shown to be effective in improving long-term survival. Thus, there is a real need to find new strategies that would impact in a significant way on clinical outcome. Ecteinascidin-743 (ET-743), a compound isolated from the marine tunicate Ecteinascidia turbinata. ET-743, is approved for the treatment of ovarian cancer and soft tissue sarcoma. Phase II and III clinical trials are ongoing for the treatment of different solid tumors. No preclinical data are available about the efficacy of ET-743 in BTC. In a phase I study, one patient received ET-743 plus capecitabine and experienced a long lasting complete metabolic response. Here, we investigated the antitumor activity of ET-743 in preclinical BTC models. Methods: Four BTC cell lines TFK1, EGI-1, HuH28 and TGBC1 were used to evaluate the effect of ET-743 on proliferation, cell cycle, apoptosis and on the activation of DNA damage proteins. The effect on proliferation was also investigated on a primary cell culture of a gallbladder carcinoma (GBC) resistant to gemcitabine and oxaliplatin. On the same cells, the inhibition of VEGF secretion mediated by ET-743 was analyzed by ELISA. The anti-tumor activity of ET-743 was tested on EGI-1 xenografts in NOD/SCID mice. Results: In vitro, ET-743 is able to markedly reduce cell proliferation of BTC cell lines through cell cycle blockage on G0/G1 phase and to inhibit the growth of primary cell culture derived from GBC patient. Moreover, ET-743 promotes apoptosis by caspase 3 activation, activates proteins involved in DNA damage and reduces VEGF secretion. In the in vivo model, ET-743 is able to slow tumor growth in BTC xenograft. The mechanism of anti-tumor activity involves DNA damage, the induction of hypoxia transcription factor-1, and angiogenesis inhibition. ET-743 has no significant effect on apoptosis in vivo. Conclusions: These data suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials of ET-743 in BTC patients.
Sequence dependence of MEK inhibitor AZD6244 combined with gemcitabine for treatment of biliary cancer.
Authors: Xu Junyao , Knox Jennifer J. , Ibrahimov Emin , Chen Eric Xueyu , Serra Stefano , Tsao Ming Sound , Cao Pinjiang , Vines Douglass , Green David E , McNamara Mairead Geraldine , Hedley David W
Published: February 2017

196

Background: MEK inhibition has clinical activity against biliary tract cancers, and might therefore be successfully combined with gemcitabine; one of the most active chemotherapy agents for these cancers. As gemcitabine is active in S-phase, and the ERK pathway has a major role driving cell cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 in vitro and in vivo. Methods: Two biliary tract cancer cell lines and 4 xenografts established from patients were used in this study. In vitro, cell cycle effects of AZD6244 and their impact on gemcitabine sensitivity were detected by Flow cytometry, EdU uptake assay, MTS assay and Clonogenic survival assay. In vivo, tumor-bearing SCID mice were treated for 48hr with AZD6244 and then monitored for 48hr off treatment. Plasma and tumor drug levels were assessed by LC-MS. The time course for recovery of ERK signaling, cell cycle distribution and cell proliferation were measured by Immunofluorescence staining, Flow cytometry, EdU uptake assay and 18F-FLT PET imaging. Based on these results, two different treatment schedules combining AZD6244 with gemcitabine were tested in four different biliary tract cancer models. Results: DNA synthesis was suppressed during treatment with AZD6244, and re-entry into S-phase was delayed by 15hr in vitro and 48hr post-treatment in vivo. Concurrent treatment showed antagonistic effect (IC50=2.02±0.91uM) compared to gemcitabine alone (IC50=0.09±0.04uM) whereas when gemcitabine treatment was delayed for 24 hr after AZD6244 removal, enhanced cytotoxic effect was observed (IC50=0.051± 0.012uM). Consistantly, strong schedule dependence was seen in all four biliary cancer models tested: combined treatment with AZD6244 plus gemcitabine exerts enhanced antitumor effect when gemcitabine is given following a 48hr interruption in AZD6244 dosing, rather than concurrently. Conclusions: The combination of AZD6244 plus gemcitabine is highly schedule dependent, and predicted to be more effective in the clinic using sequential rather than simultaneous dosing protocols.
The prognostic value of neuroendocrine differentiation in patients with undifferentiated-type gastric adenocarcinoma.
Authors: Makuuchi Rie , Tokunaga Masanori , Goto Hironobu , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Nakajima Takashi , Terashima Masanori
Published: February 2017

20

Background: Neuroendocrine carcinoma (NEC) of the stomach is defined as carcinoma having prominent (>70%) neuroendocrine differentiation (NED), and is well known to be highly malignant tumor with extremely poor overall survival time. However the biological meaning of less NED in gastric adenocarcinoma is still unclear. The aim of this study is to identify the prevalence of NED in undifferentiated type gastric adenocarcinoma (UDGA) and to clarify the prognostic value of NED. Methods: A total of 112 patients with advanced UDGA who underwent curative resection at Shizuoka Cancer Center between January 2004 and December 2006 were included. We performed immunohistochemical analysis for neuroendocrine markers, and classified patients into four groups according to the result of the immunohistochemical study as follows: NEC group (n=6), NED > 70%; MANEC (mixed adenoneuroendocrine carcinoma ) group (n=0), 30-70%; NED+ group (n=46), 1-30%; NED- group (n=60), NED < 1%. In the present study, clinicopathological features were compared between the NED+ and NED- groups and independent prognostic factors were identified. Results: The patients in the NED+ group were significantly younger (61y) than the NED- group (63y, p=0.035). There were no differences in sex, tumor depth, lymph node metastasis, macroscopic type, tumor size, and histological type between the two groups. The five-year survival rates of the NED+ and the NED- groups were 75.7% and 56.5%, respectively. Overall survival was significantly better in the NED+ group than in the NED- group (p=0.030). Cox-proportional hazard model revealed that tumor invasion deeper than T3 (HR, 2.387; 95% CI, 1.114-5.114; p=0.025), lymph node involvement (HR, 3.000; 95% CI, 1.346-9.685; p=0.007) and presence of NED (HR, 0.478; 95% CI, 0.236-0.969; p=0.041) were selected as independent prognostic factors. Conclusions: The frequency of NED in UDGA was 41.1%. The long-term outcome in the NED+ group was better than that in the NED- group. Therefore, UDGA with NED might be clinicopathologically different from the NEC of the stomach and further large scale study should be warranted to determine the biological behavior and to estimate the proper treatment strategy.
Locally advanced or metastatic pancreatic tumors: Molecular biology may help to know it and to select the optimal treatment.
Authors: Faloppi Luca , Andrikou Kalliopi , Loretelli Cristian , Mandolesi Alessandra , Bianconi Maristella , Scartozzi Mario , Berardi Rossana , Bearzi Italo , Cascinu Stefano
Published: February 2017

201

Background: Pancreatic cancer have a multi step progression model with successive mutations like activation of KRAS and inactivation of SMAD 4. Various studies demonstrated that loss of SMAD 4 cooperate with an activating KRAS mutation to promote progression, leading to dysregulation of TGFb pathway. This plays a pivotal role in the formation of desmoplastic reaction by the activation of stellate cells. Stromal cells synthesize and secrete multiple proteins like SPARC which has been associated with worst prognosis. Early data have suggested that the identification of cancer stem cells in primary tumors is associated with shorter OS, resistance to therapy and metastatic potential. Emerging evidence suggest that the activation of the NOTCH 1 pathway is associated with molecular characteristics of stem cells. The aim of our study is to investigate the relationship and the potential prognostic role of these biomarkers. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed immunohistochemical evaluations of KRAS, and molecular biology assessment of NOTCH 1 CD133, OCT3/4, SMAD 4, SPARC. Results: Preliminary analysis showed lower rate of KRAS mutations (54%) and higher expression of NOTCH 1 in KRAS WT patients (57% vs 41%). Different expression of OCT3/4 and CD133 was found according to NOTCH1 expression. In patients with NOTCH1 overexpression, OCT3/4 is found overexpressed (59% vs 45%). Instead in patients with lower NOTCH1 expression CD133 is overexpressed (59% vs 42%). Furthermore KRAS WT compared to MT patients showed higher expression of SMAD4 (66% vs 37%) and lower expression of SPARC (44% vs 59%). Conclusions: Our data indicate that KRAS status can differentiate two prognostic categories of pancreatic tumors: one (KRAS MT) probably more aggressive and characterized by early metastatization, associated to desmoplastic reaction and stemness (higher SPARC and CD133), the other (KRAS WT) with a more favourable behavior, correlated with a prevalent local invasiveness, with lower desmoplasia and stemness profile (lower SPARC and higher OCT3/4). These data suggest that the latter tumors are good candidates to radiotherapy as a part of combinated treatment.
The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFR) polymorphisms in the prediction of clinical outcome for advanced hepatocellular carcinoma receiving sorafenib.
Authors: Faloppi Luca , Scartozzi Mario , Loretelli Cristian , Bianconi Maristella , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano
Published: February 2017

208

Background: HCC still represents a medical challenge in cancer therapy. The introduction of new therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic stronghold is a TKIs directed against the VEGF family sorafenib. Polymorphisms of VEGF and its receptor genes are involved in regulating angiogenesis and lymphangiogenesis and thus in growth tumor control. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. Methods: 142 histologic samples (biopsies and surgical specimens) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP) and overall survival (OS) were analysed. Results: VEGF-A rs25648 polymorphism was statistically significant in OS (15.0 mo for C vs 9.4 for T p=0.025). VEGF-A rs10434 was statistically significant for TTP (4.1 mo for G vs 1.2 for A p=0.0076) and OS (14.2 mo for G vs 1.7 for A p<0.0001). VEGF-C rs7664413 was significant in TTP (13.4 mo for C vs 2.0 for T p=0.0125) and OS (14.7 mo for C vs 5.6 for T p=0.0007). VEGFR2 rs1870377 was significant in TTP (19.9 mo for A vs 3.0 for T p=0.0271) and OS (29.6 mo for A vs 11.9 for T p=0.0096). At multivariate analysis VEGF-C rs7664413 has been confirmed as an independent factor for TTP (HR=0,61) and OS (HR=0,65). Conclusions: In our analysis patients with G polymorphism at rs10434, C polymorphism at rs7664413 and A polymorphism at rs1870377 have a better response (PFS and OS) during treatment with sorafenib. Patients with C polymorphism of rs7664413 and A polymorphism of rs1870377 show a favourable impact in this setting. Notably, VEGFR polymorphism result closely related to the treatment response and the specific signalling of sorafenib. Thus analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumor growth.
Imaging approaches to assess mechanism-of-action and response in patients with advanced hepatocellular carcinoma treated with the novel oncolytic poxvirus JX-594.
Authors: Patt Richard H. , Kirn David H. , Breitbach Caroline , Burke James M. , Lencioni Riccardo
Published: February 2017

210

Background: The novel oncolytic virus JX-595 has demonstrated anti-cancer mechanisms of action, as defined in preclinical models, which includes cytolysis, intra-tumoral vascular disruption, and immune-mediated tumor targeting. Methods: To determine whether mechanism(s) of action (MOA) of the novel anti-cancer oncolytic virus JX-594 could be demonstrated by MRI imaging in patients with advanced hepatocellular carcinoma (HCC), dynamic contrast-enhanced MRI of the liver was performed at baseline, day 5, and week 8 following intra-tumoral injection. Images were evaluated by a central reviewer blinded to treatment and dose using both modified RECIST and Choi response criteria. 17/30 subjects underwent day 5 (D5) post-treatment imaging; 28/30 had week 8 (W8) imaging. Results: Choi responses correlated more reliably than RECIST with JX-594 MOA. Evidence of intra-tumoral vascular shutdown, manifest by areas of reduced or non-enhancement (Choi response), was observed in 6 of 17 subjects on D5 5 MRI scans. Day 5 Choi responses were a predictor of week 8 Choi responses in all but 1 subject. Of the 11/17 D5 Choi non-responders, 3 were Choi responders at 8 weeks. Increase in size at D5 of small lesions present at baseline (“unmasking”) is compatible with oncolytic flare due to intra-tumoral edema contributed to by cell lysis and immune infiltration. RECIST criteria tumor measurements did not identify MOA of JX-594, and resulted in the appearance of pseudoprogression at D5 in some subjects. Conclusions: Hyperacute MRI post-therapy can be used to detect activity of the JX-594, a novel oncolytic anti-cancer therapy. Day 5 Choi responses were a predictor of subsequent response at week 8. Clinical trial information: NCT00554372.
Investigating the prognostic value of a panel of biomarkers after curative intent resection of pancreatic ductal adenocarcinoma.
Authors: Johnson Benny , Khalil Maged F. , Blansfield Joseph , Lin Fan , Zhu Shaobo , Kirchner Lester
Published: February 2017

211

Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States. 80% of tumors are discovered with distant metastasis upon presentation. Of patients eligible for curative intent surgery, the 5-year survival rate is only 20%. Identification of a panel of biomarkers correlated with patient specific prognosis upon diagnosis can serve as a way to individualize treatment options. Methods: A retrospective cohort study analyzing pathology of patients who underwent curative intent surgery at our institution from 1998-2011 to identify whether the expression patterns of six biomarkers:S100P, Maspin, KOC, CEA, p53, and Ki-67 can be predicative of patient specific prognosis. Tissue microarrays of specimens were assessed by immunohistochemistry. Results: A total of 62 patients are included. Comparisons between groups on overall survival (OS) and progression free survival (PFS) are estimated using the Kaplan-Meier method and the log-rank test. Each biomarker was represented as low and high expression by categorizing the expression score at >4, based on intensity and extent of cells stained. 40 deaths occurred in the sample. Distant metastasis and differentiation (well/moderate vs. poor) were borderline related to OS (p=0.0120, p=0.0086). Interestingly, patients with a poor differentiation were less likely to die due to any cause (HR=0.41, 95% CI: 0.21, 0.82). 29 patients progressed in their disease. High/low KOC expression were significantly related to progression free survival (p=0.0556). Incorporating previously reported data on KOC, patients with a high KOC expression were more than 2 times more likely to progress compared to those with a low KOC expression (HR=2.04, 95% CI: 0.97, 4.29). Conclusions: In our study S100P, Maspin, CEA, p53 and Ki-67 expression patterns were not statistically significant in identifying PFS or OS in PDAC patients. However, our data is suggestive of KOC being a useful prognostic biomarker for identifying those patients with PDAC who have a high risk for early progression and distant metastasis. Larger studies are needed to determine whether KOC can be a therapeutic target in the treatment of pancreatic cancer.
Expression of programmed death ligand 1 (PD-L1) in malignant and nonmalignant pancreatic tissue.
Authors: Razzaque Saqib , Ashraf Noman , Chavez Julio C. , Malafa Mokenge Peter , Coppola Domenico , Springett Gregory M. , Helm James , Kim Richard D.
Published: February 2017

215

Background: Programmed death 1 (PD-1) protein and its ligands (PD-L1 & L2) play a key role in the evasion of the host immune system by tumor cells via inhibition of T-cells. It is of therapeutic interest that a number of tumor types selectively over-express PD-L1, since antibodies directed against PD-L1 have recently been shown to induce durable tumor regression. Methods: In this study we evaluated the expression of PD-L1 in pancreatic tissue obtained from 145 patients with localized pancreatic adenocarcinoma who underwent curative resection at our institution (stage IA – IIB). Of the 145 patients, 44 had paired pancreatic tissue samples of the tumor and adjacent non-malignant pancreatic tissue. These paired samples were used to compare expression of PD-L1 in malignant and nonmalignant tissue. Immunohistochemical staining was performed using rabbit primary antibody against PD-L1 (CD274/B7-H1) on formalin-fixed, paraffin-embedded core sections in tissue microarrays. Immunostain intensity and percentage cells stained were each scored on a scale of 0 to 3, with 3 being maximal. The product of intensity and percentage was used as a semi-quantitative measure of PD-L1 expression. Only patients with a product score greater than 0 on either the malignant or non-malignant tissue were included in this study. Results: PD-L1 expression (product score) was higher in 81% (36/44) of the malignant tissue samples than in paired non-malignant samples, equal in 7% (3/44) and lower in 11% (5/44). PD-L1 expression in malignant tissue (mean product score = 4.23) was significantly higher than the non-malignant pancreatic tissue (mean product score = 1.73) (p < 0.0001). The median product score was also statistically significantly higher for malignant versus non-malignant (4 vs. 2) tissue. Conclusions: Pancreatic adenocarcinoma tumor cells express PD-L1 at a higher level than their non-malignant counterparts. Future trials should evaluate drugs targeting the PD-1/PD-L pathway in the treatment of pancreatic cancer.
Conditional survival in gastric cancer: Does race influence prognosis in long-term survivors?
Authors: Luyimbazi David , Nelson Rebecca A. , Chen Steven L. , Kim Joseph
Published: February 2017

22

Background: Conditional survival (CS) estimates of gastric cancer patients have used standard clinical and pathologic factors to predict prognosis during the follow-up period. However, there are known racial disparities in gastric cancer outcomes that have not been previously considered in these CS estimates. Therefore our objective was to evaluate the role of race in CS of gastric cancer patients. Methods: Data from SEER was used to identify gastric cancer patients who underwent curative surgical intervention from 1988-2006. 3-year relative conditional survival (RCS) was computed for patients who had survived 1, 2 and 3 years from diagnosis. RCS was calculated by dividing observed survival by expected survival using an age-, sex-, and race-matched standard population. Results were compared across time and across select racial groups (white, black and Asian/Pacific Islander [API]) using the z test statistic. Results: Of 25,728 patients, 67% were white, 20% API and 13% black. Each racial group had increased RCS over all time periods (p<0.05). For 3-year survivors, we observed a trend towards equivalence of RCS values for all racial groups. This trend is supported by the highest percent improvement in RCS from diagnosis for both white and black patients, with 89% and 95% respectively (p<0.05). In contrast, API patients had a 62% improvement from diagnosis. Conclusions: Our study shows that although pronounced at diagnosis, disparities in RCS values decrease over time as patients approach 3 years after diagnosis. Therefore, while race is a significant prognostic indicator at diagnosis of gastric cancer, it has less impact the longer patients survive. [Table: see text]
Rates of pathologic complete or near complete response following neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer.
Authors: Chuong Michael , Mellon Eric Albert , Hoffe Sarah , Shridhar Ravi , Springett Gregory M. , Hodul Pamela Joy , Malafa Mokenge Peter , Figura Nicholas , Centeno Barbara
Published: February 2017

221

Background: While the clinical response from induction chemotherapy followed by stereotactic body radiation therapy (SBRT) has been reported for borderline resectable pancreatic cancer (BRPC) patients, response from a histopathologic standpoint has not been described. Methods: This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by 5-fraction SBRT. All patients were restaged and underwent resection. A pathologist (B.C.) specializing in pancreatic cancer reviewed each surgical specimen and assigned two Tumor Regression Grade (TRG) scores, one from the College of American Pathologists (CAP) and one from the MD Anderson Cancer Center (MDACC). Overall survival (OS) and progression free survival (PFS) were correlated to TRG score using the Kaplan-Meier method. Results: This study evaluated 35 resected BRPC patients with a median follow up of 13.8 months (range, 6.1-24.8). All received induction gemcitabine-based chemotherapy, most commonly GTX (gemcitabine, docetaxel, capecitabine) (82%), followed by 5-fraction SBRT with a median 35 Gy (range, 30-40). TRG scores according to the CAP were as follows, from best to worst response: 0 (n=3), 1 (n=13), 2 (n=15), and 3 (n=4). TRG scores according to MDACC were as follows, from best to worst response: IV (n=3), III(M) (n=6), IIB (n=11), IIA (n=10), and I (n=5). Any neoadjuvant treatment effect according to MDACC scoring (IIA-IV vs. I) was associated with improved OS and PFS (both p=0.019). Conclusions: This study demonstrated a significant pathologic response with a gemcitabine based neoadjuvant regimen containing SBRT and suggests a survival benefit based on response as measured by the MDACC scoring system.
Emerging concepts in combination chemotherapy for metastatic pancreatic cancer: A systematic review of randomized controlled trials.
Authors: Njei Basile M. , Ditah Ivo C. , Shimanovsky Alexei , Owusu Priscilla , Birk John W
Published: February 2017

228

Background: Even though gemcitabine monotherapy is commonly used as first-line treatment for metastatic pancreatic cancer, many novel treatment approaches have focused on combination chemotherapy. FOLFIRINOX, a combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin, has recently been shown to improve survival compared to gemcitabine. However, it is unclear whether survival benefits are counterbalanced by a poor quality of life due to the adverse effects. The aim of this study was to review emerging strategies that enhance treatment of patients with metastatic pancreatic cancer. Methods: Two authors independently conducted a comprehensive search of the Cochrane library PUBMED, and published proceedings from major oncologic and gastrointestinal cancer meetings from January 1980 to July 2012. Only published randomized controlled trials were eligible for inclusion. Our primary outcome measures were: progression-free survival (PFS), overall survival (OS) and serious adverse events (grade 3 or 4). Results: Thirty-one studies involving 7,957 patients were included in the analysis. There was an overall statistically significant increase in OS (RR 1.10, 95% CI 1.03-1.30) and PFS (RR 1.27, 95% CI 1.14-1.46) for the gemcitabine-based combination therapy group versus the gemcitabine monotherapy group. Subgroup analysis showed that only patients with fluoropyrimidine and platinum containing regimens showed prolonged survival: RR 1.33, 95% CI 1.04-1.76 and RR 1.38, 95% CI 1.08-1.76, respectively. The most common severe adverse event (neutropenia) was found in 45% of patients treated with FOLFIRINOX. Conclusions: Overall, gemcitabine in combination with fluoropyrimidine or platinum containing regimens can improve overall survival in patients with metastatic pancreatic cancer compared to gemcitabine alone. Even though, FOLFIRINOX therapy is associated with better survival outcomes than gemcitabine, the prolonged survival comes at the cost of poorer quality of life due to a higher incidence of adverse events. More data is needed from studies involving novel combination therapy such as hedgehog pathway inhibitors and radio-immunotherapy.
Reduction of interobserver variability (IOV) by FDG-PET–based tumor volume delineation (TVD) in radiotherapy planning for pancreatic cancer.
Authors: Branagan Jennifer Mary Rose , Halle Charlotte , Falk Stephen , Radhakrishna Ganesh , Roy Rajarshi , Crosby Thomas , Hurt Chris , Brunner Thomas B. , Mukherjee Somnath
Published: February 2017

229

Background: Wide IOV has been reported for CT-based TVD during radiotherapy planning for pancreatic cancer (Yamazaki, Anticancer Research 27: 2965-2972, 2007). PET-CT has been successfully incorporated into treatment planning in other tumour sites and has been shown to reduce IOV, but no study has looked at its role in pancreatic radiotherapy. Methods: Six radiation oncologists from 6 oncology centers in the UK were asked to outline GTVs in two cases with pancreatic head tumors. DICOM data set of planning CT, diagnostic CT and FDG-PET-CT scans were made available. GTV was first outlined using the information on the diagnostic CT scan alone, without access to PET scans (GTV_CT). The GTVs were then re-outlined using additional information from the PET scan (GTV_PET). A PTV was grown from the GTV, using a margin of 2cm sup-inf and 1.5cm radially from the GTV, as per standard UK practice. Results: A total of 48 countours (24 GTV contours and 24 PTV contours) were analysed, and the results are presented below (Table). Conclusions: The incorporation of PET scan resulted in a prominent reduction in standard deviation around tumor volumes, smaller largest:smallest GTV ratios and a larger percentage of overlap between investigator volumes, suggesting a reduction in Inter-Observer Variability. PET based RT planning should be considered in multicenter radiotherapy trials in pancreatic cancer to reduce IOV. [Table: see text]
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.