bluuebunny/crossref_metadata_2025_split huggingface dataset:
Next-generation sequencing (NGS) in an advanced hepatocellular carcinoma (HCC) cohort: Analyses of TP53 and CTNNB1.
Authors: Kelley Robin Kate , Gordan John Dozier , Evason Kimberley , Bracci Paige M. , Joseph Nancy M. , Bocobo Andrea Grace , Rosenthal Blake K. , Nimeiri Halla Sayed , Venook Alan P. 
Published: February 2017

286 Background: Mutations in TP53 and CTNNB1 are common in early stage HCC resection samples. The frequency and prognostic impact of these mutations in advanced HCC is not known. We conducted this retrospective analysis using a large NGS panel to explore for association between tumor genetics, clinicopathologic features, and prognosis in an advanced HCC cohort. Methods: Eligible cases had diagnosis of unresectable HCC or mixed HCC-cholangiocarcinoma and were enrolled on NCT01008917 or NCT01687673 clinical trials of sorafenib plus temsirolimus with informed consent for specimen banking for future research including genetic testing. Paired tumor and germline (blood) DNA samples were sequenced using a capture-based NGS cancer panel to allow for determination of somatic variants. Analysis was based on the human reference sequence UCSC build hg19. Variants were called using GATK Unified Genotyper software. Somatic, non-synonymous, and exonic calls were curated using COSMIC, cBioPortal, and Pubmed. Results: Cases with HCC (n = 21) and mixed HCC-cholangiocarcinoma (n = 2) comprised the cohort (N = 23). Male/female: 83%/17%. Race: White 56%, Asian 39%. BCLC stage: B 35%, C 65%. Etiology: HBsAg+ 26%, HCV+ 39%. Immune infiltrates ( ≥ 1 on scale 0-3) were present in 7/12 (58%) evaluable tumor samples. TP53 mutations were present in 14/23 (61%, 95% CI: 38.5, 80.0). CTNNB1 mutations were present in 7/23 (30%, 95% CI: 13.2, 52.9). There was no significant difference between HBsAg+ and HCV+. Both TP53 and CTNNB1 mutation were present in 4/23 (17%). CTNNB1 mutation was present in 2/7 (29%) cases with immune infiltrate score ≥ 1, and 1/5 (20%) with score < 1 (not significant). Other mutations and variants will be reported. Conclusions: NGS in this advanced HCC cohort suggests a higher incidence of TP53 and coexisting TP53 plus CTNNB1 mutations than has been reported in early stage HCC which requires confirmation in a larger cohort. There was no clear relationship between these mutations, HCC etiology, or tumor immune infiltrates though interpretation is limited by small sample sizes. Analyses are ongoing to explore for association between TP53 and CTNNB1 mutations and prognosis in this advanced HCC cohort.
Lymphatic invasion as an independent prognostic factor in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1.
Authors: Kazama Keisuke , Aoyama Toru , Katayama Yusuke , Yamaoku Koichiro , Murakawa Masaaki , Higuchi Akio , Kanazawa Amane , Atsumi Yousuke , Shiozawa Manabu , Ueno Makoto , Morimoto Manabu , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro 
Published: February 2017

290 Background: The objective of this retrospective study was to clarify prognostic factors in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1. Methods: Both overall survival (OS) and recurrence-free survival (RFS) were examined in 122 pancreatic cancer patients who underwent curative surgery and received adjuvant gemcitabine or S-1 after surgery between 2005 and 2014. Results: When the length of OS was evaluated according to the log-rank test, significant differences were observed in lymphatic invasion and the T status. Univariate and multivariate Cox’s proportional hazard analyses demonstrated that lymphatic invasion was the only significant independent prognostic factor for both OS and RFS. The 5-year OS was 30.1% in the lymphatic invasion-negative group and 12.1% in the lymphatic invasion-positive group (p < 0.001). Moreover, the 5-year RFS was 20.5% in the lymphatic invasionnegative group and 10.4% in the lymphatic invasionpositive group (p = 0.006). Conclusions: Lymphatic invasion is the most important prognostic factor for OS and RFS in patients with pancreatic cancer who undergo curative resection followed by adjuvant chemotherapy. The present results suggest that adjuvant chemotherapy is not sufficient, especially in patients with risk factors. Such patients should be evaluated as a target group for clinical trials of novel treatments.
Myeloid deprived suppressive cell to mediate the prognostic value of neutrophil to hemoglobin ratio for hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization.
Authors: Li Xing , Yang Quan , Lin Zhi-Huan , Hong Yingfen , Liu Yu-Feng , Wu Dong-hao , Wang Tian-tian , Chen Zhan-hong , Lin Qu , Huang Mingsheng , Xing Yan-Fang , Wu Xiang-yuan , Zhou Jie 
Published: February 2017

292 Background: The prognosis of hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE) is far from being identified. The present study aimed to assess role of blood cell counts, routine liver function tests and neutrophil to hemoglobin ratio (NHR) in predicting the progression-free survival (PFS) of these patients. Methods: A total of 243 HCC patients receiving TACE were analyzed retrospectively. Results: Cancer of the Liver Italian Program (CLIP) score system was identified to be the best score system among current 12 staging systems for this patient subgroup according akaike information criterion (AIC) index and linear trend χ2. Then, the novel prognostic value of parameters was determined by integration into CLIP score system. As a result, NHR were confirmed to an independent predictor for PFS of HCC patients receiving TACE (p = 0.001) with the other parameters, including neutrophil and neutrophil-lymphocyte ratio (NLR), failed to reach statistical significance. Moreover, NHR improved the performance of CLIP by adjusted into it, thus improved the discriminatory ability. Furthermore, NHR were defined value ≤ 0.02 as low level and > 0.02 as high level, according to which patients were dichotomized into two groups. HCC patients receiving TACE with low NHR presented higher 1 year disease control rate (DCR) (50.0% vs 39.35%) and 2 year DCR (45.4% vs 27.0%) compared with patients with high NHR level. Besides, NHR level was associated with prognostic factors such as portal vein thrombosis and distant metastasis. Furthermore, in order to determine the mechanism of predictive value of AHR, we tested the proportion of myeloid deprived suppressive cell (MDSC) in peripheral blood mononuclear cells (PBMC) of 43 HCC patients. It was revealed that MDSC was positively correlated with neutrophil (P< 0.05). Since MDSC was cancer promoter, it might be the mechanism of the prognostic value of NHR. Conclusions: The present study firstly identified NHR as an independent prognostic factor in HCC patients receiving TACE. The positive correlation of MDSC and neutrophil might be the latent mechanism.
Second-line chemotherapy by FOLFIRINOX with unresectable pancreatic cancer (phase I, II study).
Authors: Kobayashi Noritoshi , Tokuhisa Motohiko , Goto Ayumu , Endo Itaru , Ichikawa Yasushi 
Published: February 2017

297 Background: The purpose of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and efficacy of the second-line chemotherapy (after gemcitabine based chemotherapy) by FOLFIRINOX with unresectable pancreatic cancer. Methods: The subjects were histopathologically proven unresectable pancreatic cancer patients. The schedule was oxaliplatin 85mg/m2 on day1, irinotecan on day1, leucovorin 400mg/m2 on day 1 followed by FU 400mg/m2 as a bolus on day 1 and 2400mg/m2 as 46-hour continuous infusion biweekly. We were planned the dose of oxaliplatin, leucovorin and FU were fixed and the dose of irinotecan was defined as follows: level 0: 100mg/m2, level 1: 125mg/m2, level 2: 150mg/m2, and level 3: 180mg/m2. We started level 1 and at least three patients were enrolled at same dose two cycles. If DLT was observed two patients in six or three patients, we suspected the level was MTD. We also evaluated this study as phase II. Primary end point was response rate (RR). We also evaluated progression free survival (PFS), overall survival (OS) and adverse event (AE). Results: Eighteen patients were enrolled in this study (man: n = 11, woman: n = 7). We evaluated initial eight patients as phase I study. One patient had neutropenia and another one patient had hyperglycemia and severe infection. We decided level 1 was MTD and recommended dose was level 0. According to phase II study, RR was 22.2% (CR: n = 0, PR: n = 4, SD: n = 7, PD: n = 7) and disease control rate (DCR) was 61.1%. PFS was 2.8 (0.7-11.7) months and OS was 9.8 (2.4-14.4) months. The most common severe AE was neutropenia (66.7%). Fibril neutropenia was occurred one (5.6%) case. Conclusions: Recommended dose was oxaliplatin 85mg/m2 on day1, irinotecan 100mg/m2 on day1, leucovorin 400mg/m2 on day 1 followed by FU 400mg/m2 as a bolus on day 1 and 2400mg/m2 as 46-hour continuous infusion. RR was 22.2% and major AE was neutropenia but FN was rare. Second-line FOLFIRINOX is marginally effective treatment for gemcitabine-base chemotherapy failure cases.
NEOSCOPE: A randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine (OXCAP) or carboplatin/paclitaxel (CarPac) based chemoradiation (CRT) as pre-operative regimen for resectable oesophageal adenocarcinoma.
Authors: Mukherjee Somnath , Hurt Chris , Gwynne Sarah , Bateman Andrew , Gollins Simon , Radhakrishna Ganesh , Canham Jo , Ray Ruby , Grabsch Heike I , Sharma Ricky A. , Maggs Rhydian , Hawkins Maria A , Sebag-Montefiore David , Maughan Tim , Griffiths Gareth , Crosby Tom David Lewis 
Published: February 2017

3 Background: NEOSCOPE compared toxicity and efficacy of 2 pre-op CRT regimens. Methods: Eligibility: Resectable ACA of the oesophagus/GOJ ≥ T3 and/or ≥ N1. Randomisation: 1:1 to OXCAP-CRT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 bd on days of RT) or CarPac-CRT (Carboplatin AUC2; paclitaxel 50 mg/m2 Day 1,8,15,22,29); concurrent RT: 45Gy/25 fractions/5 weeks. Both arms received induction chemo: 2 cycles of OXCAP (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m2D1-21, q 3wk). Surgery: 6-8 weeks after naCRT. Detailed RT and pathology quality assurance was built into the protocol. Primary end-point: pathological complete response (pCR). Secondary: toxicity, surgical morbidity/mortality, R1 rate, OS. Statistics: A pCR of 15% would not warrant further investigation but a pCR of 35% would. 76 patients (38/arm) gave 90% power and one-sided type I error of 10% meaning that either arm having ≥10 pCR out of first 38 patients would be considered for Phase III. 85 patients to be recruited (allows 10% loss to follow up). Results: 85 patients were randomised between Oct 2013 and Feb 2015 from 17 UK centres. Patient characteristics: median age 65 yrs, Male (81%), WHO PS 0 (85%). Tumour characteristics: T3 (86%), N1 (48%), lower third/GOJ (90%), median tumour length 5.8cm. CTCAE grade 3/4 toxicity rate during CRT was OXCAP-CRT 42.1%, CarPac-CRT 52.4% (p=0.358). Protocol dose RT OXCAP-CRT 90.5%, CarPac-CRT 93%. Conclusion:Both regimens were well tolerated. CarPac-CRT passed the criteria for taking forward to a phase III study but OXCAP-RT did not. Funding: Cancer Research UK (C44694/A14614), ClinicalTrials.gov: NCT01843829, coordinated by Wales Cancer Trials Unit. Clinical trial information: NCT01843829. [Table: see text]
Treatment of pancreatic ductal adenocarcinoma (PDAC) by argyrin F (AF) + gemcitabine (G).
Authors: Plentz Ruben R , Chen Xi , Barat Samarpita , Bozko Przemyslaw , Bui Cuong , Sipos Bence , Kalesse Markus , Malek Nisar P 
Published: February 2017

310 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of < 5%. Early diagnosis is rare and treatment options are often limited. Recent studies have reported that the proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. The aim of the present study is to explore the anti-tumor activity of this analogue Argyrin F (AF) + Gemcitabine (G) in PDAC carcinogenesis. Methods: We analyzed the effect of AF on proliferation and epithelial plasticity of different human pancreatic cancer cell lines by using MTT-, wound healing-, invasion-, colony formation-, apoptosis- and senescence assay, as well as cell cycle analysis and Western Blot. In vivo, we assessed the effects of AF and combinational (AF + G) therapy in a genetically engineered mouse model (Pdx1- Cre; LSL-KrasG12D; p53 lox/+) of PDAC. Results: AF inhibited pancreatic cancer cell proliferation, migration, invasion and colony formation compared to their respective untreated controls (DMSO). We also found that AF impairs epithelial-mesenchymal-transition (EMT) and induces considerable apoptosis and senescence in a dose-and time-dependent manner. AF application resulted in cell cycle G1/S phase transition. Most importantly, double treatment by AF + G showed prolonged survival and caused significant tumor reduction. Expression of Ki67 (anti-proliferative marker) and CD34 (tumor angiogenesis marker) was reduced both after AF and AF + G treatment of PDAC tumors in mice. Conclusions: Our work demonstrates that treatment with AF can successfully inhibit the growth of PDAC cells and combinational treatment with AF + G might be also a new and promising combinational therapy for human PDAC treatment.
Valproate as a novel radiosensitizer in selective internal radiation therapy (SIRT) for unresectable hepatocellular carcinoma.
Authors: Chin Kenneth , Udumala Sunil Kumar , Kannadorai Ravi Kumar , Yu Sidney Wing Kwong , Chow Pierce K. H. 
Published: February 2017

314 Background: A large majority of Hepatocellular Carcinomas (HCC) present in locally advanced or metastatic stages; patients are usually poor candidates for surgical resection. Yttrium-90 Selective Internal Radiation Therapy (SIRT) is employed in both palliative and bridging therapy for unresectable HCCs. Histone Deacetylase Inhibitors (HDACi) are an emerging class of chemotherapeutics which exert their cytotoxicity through epigenetic modification. By maintaining DNA in an open conformation, it increases the surface area exposed for radiation damage- a postulated mechanism of its radiosensitizing effect. It is envisioned that HDACi will greatly augment therapeutic efficacy in brachytherapy. Here, the radiosensitizing effects of valproate, a known HDACi is investigated as potential adjunct with SIRT. Methods: 3 HCC cell lines were studied: HepG2, Hep3B and JNN4. They were first treated at various concentrations of valproate and cell viability was assessed. Next, a Caspase-3/7 assay was carried out to assess cell apoptosis. Westernblot analysis was performed on treated cells to elucidate histone acetylation status with Anti-Acetyl H3/H4 Antibodies. Finally, a clonogenic survival assay compared the effect of Yttrium-90, Lutetium-177, valproate and combination treatment on clonogenic proliferation. Results: Cell viability studies showed that valproate is cytotoxic to all HCC cell lines at concentrations from 10mM. Westernblot analysis demonstrated that valproate treatment maintained histone acetylation across all HCC cell lines validating it’s mechanism of action. Clonogenic Survival demonstrated a significant reduction of cell survival for all HCC cell lines treated with valproate and Isotope as compared to monotherapy. Conclusions: The use of HDACi such as valproate is not only novel in SIRT but showed great promise as an adjunct therapy. Experiments not only demonstrated its cytotoxicity, but also, reduction in clonogenic and proliferative ability of cancer cells. It can be postulated that the co-administration of valproate with SIRT will enhance therapeutic efficacy, allowing more aggressive and efficacious treatment of HCC.
Pancreas resection for unresectable locally advanced pancreatic cancer (LAPC): Resection rate in the era of FOLFIRINOX and GEM+nabPTX.
Authors: Takahashi Shinichiro , Ikeda Masafumi , Gotohda Naoto , Kato Yuichiro , Konishi Masaru 
Published: February 2017

317 Background: Resection for unresectable LAPC after down-staging by chemo(radio)therapy sometimes leads to long-term survival in highly selected pts. However, neither the pts who have best possibility for resection nor resection rate according to the specific treatment were elucidated in LAPC. Methods: A retrospective single-institutional study. From a prospective database, 130 pts received any treatment for LAPC from Jan. 2010 to Mar. 2015 were identified. Main criteria for unresectability were tumor contact with superior mesenteric artery, celiac axis or common hepatic artery > 180°, aortic involvement, and unreconstructible portal vein /superior mesenteric vein due to marked invasion. All MDCT findings before and during treatment of 130 pts were reviewed to check the resectability by a surgeon. Conversion rate to resection according to treatment and situation of tumor-vessel contact before treatment were analyzed. Conversion was considered when tumor was down-staged to borderline resectability. Results: Of 130 pts, gemcitabine (GEM) was administered as initial treatment to 75; GEM and erlotinib to 18; modified FOLFIRINOX to 15; S-1 and concurrent radiotherapy (S1/RT) to 12; GEM and nab-paclitaxel (GEM+nabPTX) to 4; and other regimens to 6. Six patients underwent resection after down-staging. Of the 6 pts (4.6%), 4 received S1/RT, and 1 each received GemErlo and FOLFIRINOX. Furthermore, 7 pts (5.4%) seemed to deserve further examination to check resectability because marginal resectability was shown in follow up MDCT during treatment. Resection rates among treatments were not different significantly. On the other hand, unresectability because of single-vessel invasion and the tumor-vessel contact less than 360° at the same time before treatment showed best opportunity for conversion to resection. The 6 resected pts (MST 30m) showed marginal superiority over unresected 124 pts (MST 16m) in survival (p = 0.17). Conclusions: Resection rate of LAPC did not increase significantly even after FOLFIRINOX or GEM+nabPTX treatment. Pts with LAPC due to single tumor-vessel contact less than 360° have best chance of convert to resection after effective treatment.
Pattern of CA19-9 response to neoadjuvant chemotherapy in locally advanced, borderline resectable pancreatic cancer to predict progression.
Authors: Rose J Bart , Edwards Alicia M , Alseidi Adnan , Biehl Thomas R , Lin Bruce S. , Picozzi Vincent J. , Rocha Flavio G. , Helton Scott 
Published: February 2017

321 Background: As neoadjuvant therapy of locally advanced, borderline resectable pancreatic cancer (BRPC) is becoming more widely utilized; better indicators of progression are needed to help guide therapeutic decisions. The aim of this study is to determine if CA19-9 response during treatment predicts disease progression. Methods: A retrospective review was performed on all patients with BRPC (by AHPBA/SSO consensus criteria) between 2008-2015 who received 24 weeks of neoadjuvant gemcitabine and docetaxel. Patients with medical comorbidities limiting treatment completion were excluded. Serum CA19-9 levels were checked at baseline and every 3 weeks while on therapy. A normal CA19-9 level was defined as < 37.5 units/mL and levels with concomitant biliary obstruction were censored. CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. Results: Eighty patients were included with a mean of 11 CA19-9 levels checked per patient during treatment. Thirty-two (40%) progressed on treatment (18 local and 14 distant) and 48 (60%) were resected (79% R0). CA19-9 responses were categorized into 5 groups: 1) Always normal [n = 13]; 2) Increasing [n = 3]; 3) Slow decline [n = 7]; 4) Rapid decline with plateau [n = 41]: and 5)Rapid decline with late rise [n = 16]. Univariate logistic regression analysis found that a final CA19-9 decline > 50% of baseline (OR 0.06, p = <.0001), a normal final CA19-9 (OR 0.08, p = <.0001), pattern group 1 (OR 0.16, p =.0001), and group 4 (OR 0.10, p =.0001) were predictive of non-progression. Baseline or maximum CA19-9 levels were not predictive of progression. All patients in group 2 progressed; none were resected. Patients in pattern group 5 that underwent resection had an increased risk of recurrence (HR 12.5, p =.0005). Median overall survival for groups 1-5 were 20.4, 9.3, 20.8, 31.4, and 16.4 months respectively. Conclusions: Patients with measurable CA19-9 levels who do not have rapid decline with sustained low or normal levels should be considered high risk for progression or recurrence and alternative treatment strategies should be entertained prior to curative resection.
Effect of preoperative bilirubin on outcomes of completely resected hilar cholangiocarcinoma: A multi-institutional analysis.
Authors: Mogal Harveshp , Dodson Rebecca , Fino Nora , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Fields Ryan C. , Jin Linda , Weber Sharon M. , Salem Ahmed I. , Martin Robert C. G. , Scoggins Charles Raben , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar , Shen Perry 
Published: February 2017

326 Background: Perioperative and long-term outcomes of patients with Hilar cholangiocarcinoma (HC) and preoperative hyperbilirubinemia have not been clearly defined. Methods: Patients with HC undergoing hepatectomy with a complete (R0/R1) resection between 2000 and 2014 were identified within a 10-institution prospectively maintained database. Using receiver operating characteristic curves from logistic regression models, a peak bilirubin cutoff point that minimized the difference between the sensitivity and specificity, was determined. Factors affecting perioperative complications were estimated using logistic regression. Results: 191 of 328 (58.2%) patients who underwent complete resection with a hepatectomy, with available preoperative bilirubin data were analyzed. 37.2% (n = 71) had bilirubin > 7.9. Patients with higher preoperative bilirubin were more likely to have a higher CA 19-9 (1776±3721.5 vs 302.1±518.6, p = 0.0006), more comorbidities (1.6±0.8 vs 1.4±0.9; p = 0.002), preoperative biliary drainage (PBD) (91.4% vs 75.6%, p = 0.007), positive lymph nodes (48.5% vs 31.5%, p = 0.025) and perioperative death (14.5% vs 5.2%, p = 0.0292). Multivariate analysis identified PBD (OR 3.2, CI 1.4-7.5; p = 0.008) and smoking (OR 2.3, CI 1.2-4.4; p = 0.016) to be independent predictors of any and major complications. Peak bilirubin > 7.9 (OR 3.1, CI 1.1-8.9; p = 0.04) and preoperative systemic sepsis (PSS) (OR 5.0, CI 1.2-21.5; p = 0.03) were associated with increased risk of postoperative mortality. However, on multivariate analysis only PSS was significant (OR 14.4, CI 2.2-93.9; p = 0.005); 5/13 (23.1%) of patients with PSS died within 30 days after surgery. Conclusions: PSS portends increased operative mortality in HC patients undergoing hepatectomy, independent of preoperative peak bilirubin levels. Prevention and aggressive treatment of PSS should be the priority in the preoperative optimization of these patients.