bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter phase II study of donafenib in patients with advanced hepatocellular carcinoma.
Authors: Bi Feng , Qiu Meng , Chai Xiaoli , Niu Junqi , Ding Yanhua , Bai Yuxian , Wu Lihua , Shentu Jianzhong , Hao Ping , Chen Jinfei , Li Qiu 
Published: September 2018

e15682 Background: In an early dose-escalation study, Donafenib, a new oral multikinase inhibitor, showed antitumor activity and favorable tolerability in treatment of different type solid tumors including HCC at both 0.2g bid and 0.3g bid dose levels. This prospective study aimed to evaluate the safety and efficacy of Donafenib in the patients with advanced HCC. Methods: In this phase 2 study, patients with unresectable HCC, who had Child-Pugh class A liver function and received no prior systemic therapy were enrolled across 10 sites in China. All patients received oral Donafenib 0.2g bid or 0.3g bid for several 4-week cycles, based on 1:1 randomization ratio. The radiology assessment was done every 8 weeks. The primary end points were safety and tolerability; secondary endpoints were time to progression assessed by an independent radiology committ, ORR , DCR, and PK. Results: Between June 17, 2014, and May 4, 2015, total 106 patients were enrolled and included in the safety analyses. Of them, 52 received donafenib 0.2g bid and 54 received 0.3g bid. The most common adverse events that led to dose discontinuation or reductions were hand-foot skin reaction in 10 (9.4%) patients (2 vs 8), liver dysfunction in 4 (3.8%) patients (1 vs 3), and leukopenia in 2 (1.9%) patients (1 vs 1). Other reported AEs caused dose reductions were hypertension, thrombocytopenia, throat ache, and cough. The median duration maintained for the initial dose was 90 and 72 days, respectively. The full analysis set for TTP includes104 patients (51and 53, respectively) and the per-protocol analysis set for ORR and DCR includes 84 patients (40 and 44, respectively). Median TTP was 111 days in 0.2g group compared with 110 days in 0.3g group (HR 0.99, 95% CI [0.62, 1.60]). At the Week 16, there were no complete responses in both groups, but partial response was confirmed in 4 (4.8%) patients (2 vs 2); and stable disease was in 35 (41.7%) patients (17 vs 18). Conclusions: Donafenib 0.2g bid and 0.3g bid were well tolerated. Significant adverse events were reported more frequently in 0.3g group. Both regimens showed similar treatment responses for patients with HCC, while 0.2g bid seems to be an appropriate first line therapeutic option for the treatment of HCC. Clinical trial information: NCT02229071.
Prognostic factor for third-line chemotherapy in patients with advanced gastric cancer.
Authors: Choi Jonggwon 
Published: September 2018

e15702 Background: To evaluate prognostic factors for patients with advanced gastric cancer treated by Third-line chemotherapy, and to identify the characteristics of long-term survivors. Methods: Eighty seven advanced gastric adenocarcinoma patients, who received third-line chemotherapy, were enrolled in this retrospective study from January 2010 until December 2014. Univariate and multivariate analyses were created using log-rank tests and Cox’s proportional hazard model, respectively. Results: In univariate and multivariate analyses, poor prognostic factor were investigated and four independent factors were found to be associated with poor overall survival: time-to progression under first-line chemotherapy≤6 months (HR, 1.64; 95% CI, 1.18–2.25; P ≤ 0.01), CA 19-9 level > 50 ng/ml (HR, 1.78; 95% CI, 1.32–2.67; P ≤0.007), the presence of ascites (HR, 1.67; 95% CI 1.295– 2.37, P ≤0.001), the presence of greater than or equal to three metastatic sites of disease (HR, 1.45; 95% CI 1.19– 2.19, P ≤0.004). 87 patients were classified as low-risk group( no risk factor), intermediate-risk group (one to two risk factors), high- risk group (three to four risk factor), and median survival times for each groups were 14.3 months, 12.1 months, and 7.4 months, respectively (P ≤0.01). Conclusions: This model will help in selecting the patients with advanced gastric cancer who could benefit from proceeding with third-line chemotherapy.
Ex-vivo tumor resection and auto-transplantation: A single-institutional long-term experience.
Authors: Kato Tomoaki , Liou Peter , Schwartz Gary K. , Emond Jean 
Published: September 2018

e15705 Background: Conventionally unresectable tumors involving mesenteric vasculature or critical areas of the liver may be amenable for resection using novel techniques developed from organ transplantation. The concept of ex-vivo resection allows tumor removal and vascular reconstruction in cold perfusion while ensuring visceral preservation, followed by autotransplantation of the remaining organs. Methods: A retrospective chart review of 34 patients at a single-center who underwent ex-vivo tumor resection and auto-transplantation between the years of 2008 and 2016. Results: Indications for ex-vivo resection were tumors involving the hepatic vasculature (hepatic tumors involving vasculature n = 13, pancreatic tumors involving hepatic vasculature n = 7), mesenteric vasculature (n = 9), or both (n = 4) and renal vasculature (n = 1). Tumors included cholangiocarcinoma (n = 6), liposarcoma (n = 6), leiomyosarcoma (n = 4), pancreatic adenocarcinoma (n = 3), and others. 27 out of 34 patients underwent attempted treatments including surgery or chemoradiation prior to ex-vivo resection, with a mean of 2.5 treatments. Types of procedures included: hepatic autotransplantion (n = 11). Whipple procedure with hepatic autotransplantion (n = 8), intestinal autotransplantion (n = 9), and multivisceral autotransplantion (n = 4). The median age was 48 (range 5 to 71). Thirty-day and ninety-day mortality were 8.8% and 11.8%, respectively. Three patients died within 30 days with hepatic artery anastomotic rupture (n = 1) and sepsis (n = 2). Thirty-one patients (91.2%) were discharged alive from the hospital at a median of 20 days. One-year and three-year overall survival rates were estimated at 64.7% and 42.4%, respectively. At the time of submission, 14 patients are alive and 13 are disease free with a median follow-up of 5.8 years. Conclusions: Ex-vivo tumor resection is a highly complex procedure associated with significant morbidity and mortality. Nevertheless, for carefully selected patients with conventionally unresectable tumors, ex-vivo surgery may be a viable option offering reasonable long-term outcomes.
Retrospective review of FOLFIRINOX in local advanced pancreatic cancer: Single institution experience.
Authors: Manne Ashish , Reddy Sushanth , Heslin Martin , Jacob Rojymon , Vickers Selwyn M. , Contreras Carlo M. , Kasi Anup , Christein John , Li Peng , Posey James , Paluri Ravi Kumar 
Published: September 2018

e15714 Background: Although combination of fluorouracil, irinotecan, Leucovorin and oxaliplatin [FOLFIRINOX] significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine based on ACCORD trial, the efficacy and toxicities may be different in non-metastatic setting. We reviewed our institution’s experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC). Methods: We performed a retrospective review of clinical outcomes in patients diagnosed with LAPC and receiving between June 2010 and July 2015, with at least one year of follow up from diagnosis, at University of Alabama at Birmingham. Results: Total of 41 patients with ECOG performance scale of 0 or 1, who underwent neoadjuvant chemotherapy with FOLFIRINOX were assessed for clinical and pathological characteristics. Median age was 61 years (range 38-81) with 23 (56.1%) males, 28 (68.3%) Caucasians and 16 (39.0%) underwent surgery (whipple operation) post-neoadjuvant. Median OS (time of diagnosis to last follow up/death) is 83.5 months for whole cohort, survival rates are 94.9% at 1 year, 58.4% at 2 year, and 33.3% at 5 year.Median OS for those who underwent surgical resection following the chemotherapy is 38.6 months; 100% at one year, 85.1% at 2 year, 55.3% at 5 year; while median OS for those who did not undergo surgery is 21.8 months; 91.7% at one year, 41.5% at 2 year, 20.7% at 5 years. Among those who underwent surgery, the median recurrence free survival (time from surgery to relapse/progression) is 19.9 months with liver being common recurrence site (81%). There was no post-operative mortality in 30 days. Grade 3-4 toxicity occurred in 46% ( vomiting (12%), fatigue (28%) and neutropenia (54%), febrile neutropenia (9%)). There is a significant difference between surgery and non-surgery groups (p = 0.012) for improved OS by log-rank test. Conclusions: Neoadjuvant FOLFIRINOX treatment associated with high response rates leading to surgical resection in our cohort. Patients who underwent neoadjuvant chemotherapy followed by resection for LAPC have statistically significant improved OS compared to those who did not.
Brain metastases (BM) in pancreatic ductal adenocarcinoma (PDAC): Clinical and molecular characteristics.
Authors: Jordan Emmet , Kaley Thomas Joseph , Capanu Marinela , Estrella Hayley , Leach Steven D , Basturk Olca , Klimstra David S. , Allen Peter J. , Berger Michael F. , Yu Kenneth H. , Lowery Maeve Aine , O'Reilly Eileen Mary 
Published: September 2018

e15728 Background: BM from PDAC represents a rare clinical entity (<0.6%) of PDAC cases for which the clinical and molecular features are not well described. We reviewed detailed clinical characteristics and molecular profiling performed in a cohort of PDAC pts with BM evaluated at MSKCC. Methods: Patients (pts) with BM from PDAC diagnosed from 01/1990-08/2016 were identified from a prospectively maintained database, following IRB approval. Clinicopathological data including time to BM development, overall survival (OS) from PDAC diagnosis (dx) and OS from BM dx was recorded. Molecular profiling was performed by MSK-IMPACT testing (>340 key cancer genes) or via Seqeunom testing (8 gene panel). Results: We identified n= 24 pts with BM from PDAC. Twenty-three/24 pts had imaging for symptoms. Mean no. of systemic regimens was 3 (range 0-7). Three/24 (13%) had BM at initial dx. Median time from PDAC dx to BM development was 17 months (mths) (range 0-79). Median survival from BM was 50 days (range 7-975). BM treatment included; surgery; n=4, RT; n=13 or supportive care; n=7. Two pts had survival of 21 & 31 months post BM, both had resection. Median OS from PDAC dx was 18 mths (0-82). 10 pts had consent/pathology for molecular testing (MSK-IMPACT n=7, Sequenom n=3). Results are available for 6 pts, 3 by IMPACT. 6/6 pts had KRAS mutations (MUT); G12D (4), G12V (1), Q61K (1). 0/6 pts had ERBB2 AMP or MUT. One tumor arising from an IPMN had concurrent GNAS and KRAS MUT. By MSK-IMPACT; 2/3 pts had MYC AMP, 2/3 TP53 MUT, 1/3 ARID1A loss, 1/3 CDKN2A loss. 5/24 pts had germline testing, 3 had BRCA MUT; BRCA1 (2), BRCA2 (1). Conclusions: The presence of BM portends a poor prognosis. In general pts who develop BM are younger at initial PDAC dx and may have a better OS from dx [median OS 18 mths (all pts); OS de novo stage IV pts; 17 mths]. Somatic profiling identified KRAS MUT in all resulted pts with alterations in TP53 and MYC also detected. Although speculative, germline BRCA MUT occurred in 13% (60% of pts tested). See table. [Table: see text]
Hypoxia induced HIF1a-mediated O-GalNAc glycosylation of cytosolic O-GlcNAcylated proteins to regulate signaling pathways in pancreatic cancer.
Authors: Wolters-Eisfeld Gerrit , Mercanoglu Baris , Strohmaier Alina , Guengoer Cenap , Izbicki Jakob R. , Bockhorn Maximilian 
Published: September 2018

e15739 Background: Hypoxia induced reprogramming of cell energy metabolism and changes in glycosylation are hallmarks of cancer promoting the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development. We examined the impact of hypoxia on O-GalNAc glycosylation in human HEK293, PDAC cell lines and clinical specimens. Methods: We profiled the expression of 88 glycosylation related genes by qPCR in HEK293 cells subjected to hypoxia either induced by 1% O2 or 200 mm CoCl2 identifying key O-GalNAc glycosyltransferases downregulated. Functional assays and glycoprotein analysis displayed a pronounced rate of O-GalNAc modified cytosolic proteins derived from hypoxia treated cells and PDAC specimens. Glycosidase assays could validate specificity of detection method used. Aberrant glycotype could be induced by HIF pathway activator ML 228 and inhibited using Echinomycin. PTK and STK analysis of cell lysates displayed correlation between phosphorylation and O-glycosylation in hypoxic samples. Results: Mechanistically we could show, that hypoxia induced decreased levels of C1GALT1C1 results in reduced T-Synthase activity with subsequent expression of truncated O-glycans (Tn antigen). Differential O-GalNAc glycosylation is inducible using HIF pathway activator ML228 under normoxia and the effect is reversed using 5 µM Echinomycin under hypoxia underscoring the role of HIF1a regulated transcription. Interestingly, the pattern of Tn antigen modified proteins derived from hypoxic samples differs significantly from engineered COSMC deficient cells, displaying O-GalNAc moieties in addition to O-GlcNAc in cytosolic protein fractions. Conclusions: Our findings point to a novel crosstalk of O-GalNAc and O-GlcNAcylation under hypoxia extending the knowledge base of differential O-GalNAc glycosylation in pancreatic cancer.
Phase II study of regorafenib (Reg) in patients with previously treated advanced pancreatic cancer (APC).
Authors: Salmon John Stuart , Hwang Jimmy J. , Robinson Myra M. , Symanowski James Thomas , Dillon Lloye M , Das Roy Lopamudra , Beldner Matthew A. , Preston Kelry , Buige Sharon , Nazemzadeh Reza , Mukherjee Pinku , Farhangfar Farhang , Kim Edward S. 
Published: September 2018

e15751 Background: APC that has progressed after treatment with gemcitabine has a dismal prognosis and novel treatment approaches are needed. Reg is a potent oral inhibitor of VEGFR 1-3, PDGFR, TIE-2, FGFR-1, KIT, and the RAF kinases, and has activity in pancreatic xenograft models. We tested the activity of Reg in patients (pts) with refractory APC. Methods: This single arm, single center phase II study evaluated Reg (120mg/d, for 21 days, followed by 7-day break, with escalation to 160mg after the 1st cycle if tolerated) in pts with metastatic pancreatic cancer whose disease had progressed after at least one prior line of therapy and treatment with gemcitabine. Pts underwent radiographic evaluation every 2 cycles. The primary endpoint was 16-wk PFS. Kaplan Meier techniques were used to estimate PFS and OS. Serum tumor MUC1 antigen (tMUC1) concentrations were measured at baseline, end of cycle 1, and off-treatment using the TAB 004 antibody (Agkura Personal Score blood test, OncoTAb, Inc). Relative change of tMUC1 from baseline to end of cycle 1 was compared between those with and without 16-wk disease control. Results: 20 pts were enrolled into the study. Median age = 65 (47-79), and 80% (16/20) had 2 or more prior lines of therapy for advanced disease. Landmark 16 wk PFS = 10% (2/20), crossing a predefined futility boundary to demonstrate 20% improvement over historical controls with BSC. ORR was 5% (1/20), and DCR at 8 wks was 20% (4/20). Median PFS was 6.1 wks (95% CI: 2.9 – 7.1), and median OS was 9.4 wks (95% CI: 8.1 – 17.0). 10% of pts (2/20) had protocol defined Reg dose escalation to 160mg, and 30% (6/20) had dose reduction to 80mg. The most frequent grade 3-4 adverse events included hyponatremia (35%), fatigue (20%), and hypoalbuminemia (20%). Baseline tMUC1 varied substantially, mean 69.6ug/mL, median 51.3ug/mL (10.8 – 310.5). Serum tMUC1 decreased by a mean of 20.8% in the pts with disease control at 16 wks (n = 2), but increased by 65% (mean) in pts with disease progression or death within 16 wks (n = 13, p = 0.048). Conclusions: Reg has minimal activity as a single agent in pts with heavily treated APC. Serum tMUC1 levels measured by TAB 004 antibody may be a novel tumor marker in this disease. Different treatment approaches are needed. Clinical trial information: NCT02080260.
Non-invasive diagnosis and tracking of tumor evolution by targeted sequencing of circulating tumor DNA in metastatic pancreatic cancer patients.
Authors: Seufferlein Thomas , Berger Andreas W. , Schwerdel Daniel , Ettrich Thomas Jens , Schmidt Stefan A. , Kleger Alexander , Marienfeld Ralf 
Published: September 2018

e15769 Background: Treatment of stage IV pancreatic ductal adenocarcinoma (PDAC) has made substantial progress over the last years, therapy monitoring still is at an early stage. This could be substantially supported by tools that allow to establish and monitor the molecular setup of the tumor even during treatment. In particular, non-invasive approaches are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: We analyzed a cohort of 20 patients with histologically confirmed metastatic PDAC (mPDAC) prior to and during palliative treatment including disease progression. ctDNA and corresponding tumor tissue were analyzed by targeted NGS and droplet digital PCR for the 7 most frequently mutated genes in PDAC ( TP53, SMAD4, CDKN2A, KRAS, APC, ATM, FBXW7). Findings were correlated with clinical and imaging data to establish its prognostic and predictive value. Results: ctDNA was analyzed at baseline prior to initiation of the respective line of treatment. Mutations in either of the genes examined were detectable in 15/20 patients (75%). Tissue-blood concordance was 80% in therapy naïve patients. 96% of mutations in ctDNA of therapy naïve patients were in KRAS and/or TP53. The combined mutated allele frequencies (CMAF) of theese 2 genes significantly decreased (p = 0.0173) during therapy and increased at progression (p = 0.0145) across all treatment lines. By sequential ctDNA analyses we detected a change in the mutational landscape compared to the respective baseline ctDNA status in 7/11 patients during 1st line, in 3/7 patients during 2nd line and 2/2 patients during 3rdline treatment. In therapy naïve patients, the decline of the CMAF during therapy significantly correlated with progression-free survival (p = 0.0013). Conclusions: Molecular genotyping of ctDNA in mPDAC patients proved to be feasible and there was a high concordance between tumor tissue and ctDNA. The molecular genotype changed significantly during treatment and changes correlated with outcome. Monitoring of ctDNA may enable to adapt therapeutic strategies to the specific molecular changes present at a certain time during treatment of mPDAC.
Prognostic factors in duodenal adenocarcinoma.
Authors: Huffman Brandon M , Jin Zhaohui , Sanhueza Cristobal T. , Hartgers Mindy L. , Johnson Benny , Shubert Christopher R. , Mahipal Amit 
Published: September 2018

e15797 Background: Duodenal adenocarcinoma is a rare tumor representing approximately 0.3% of all gastrointestinal tract cancers. Prognostic factors in relation to survival outcomes for these patients are sporadically reported in the medical literature. We aimed to evaluate outcomes of patients with duodenal adenocarcinoma who underwent pancreaticojejunostomy treated at Mayo Clinic Rochester from January 1, 2006 to December 31, 2016. Methods: Clinicopathological data of 52 duodenal cancer patients were collected. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 65.9 years (range 39-81). The median overall survival was 51 months (95% CI 31.3-105.4) and the median progression free survival was 30.4 months with median follow up of 73.4 months. There were 3, 9, 21, and 19 patients with stage I, II, III, and IV disease, respectively. Depth of tumor invasion (p = 0.0156) and lymph node metastasis (p = 0.0441) were associated with overall survival on multivariate analysis. Advanced clinical staging influenced overall survival in univariate analysis, but lost prognostic significance in multivariate analysis. Age, gender, surgical technique, presence of metastases, tumor size, number of lymph nodes removed, location of duodenal segment involvement, and adjuvant treatment had no significant impact on overall survival. Laparoscopic approach did not influence survival but was associated with less hospital days (p = 0.0437). Conclusions: Depth of tumor invasion and lymph node status were associated with improved overall survival in patients with duodenal adenocarcinoma. Laparoscopic procedure decreased the hospital stay without affecting outcomes.
Estrogen receptors expression in human bladder cancer and urogenital schistosomiasis.
Authors: Bernardo Carina , Tavares Ana , Amaro Teresina , Oliveira Julio , Afreixo Vera , Vale Nuno , Costa Jose M , Livramento Júlio H , Brindley Paul J , Costa Céu , Amado Francisco , Helguero Luisa , Santos Lúcio Lara 
Published: September 2018

e16013 Background: Epidemiological and molecular findings suggest that estrogen may play a role in bladder carcinogenesis and in urogenital schistosomiasis (UGS). Methods: A comprehensive analysis of expression of estrogen receptors (ER) in urothelial carcinomas (UC), n = 80 from non-infected patients and UGS-related bladder carcinoma (BlaCa) n = 27 was undertaken. I n vitro, we evaluated the effect of estradiol (E2) and anti-estrogens on the survival of human BlaCa cells. In addition, molecular dynamics simulations are ongoing to assess the ability of estradiol-like metabolites produced by the Schistosoma haematobiumto bind ERs. Results: Tumor cell expression of ERα was found in 17.5% of the non-infected cases, and was associated with proliferative tumors (p = 0.004, ES = 0.326) and lower overall survival. Expression of ERα was also found in normal urothelium adjacent to the tumor and in tumor stromal cells, particularly in T2 and late stage tumors (p = 0.034, ES = 0.498and p = 0.037, ES = 0.357, respectively). In UGS-related BlaCa, 22% of tumor cells were ERα positive. Presence of parasite eggs was associated with higher ERα expression in cancer cells and adjacent urothelium (p = 0.038, ES = 0.399 and p = 0.020, ES = 0.600, respectively). ERβ was found in 91% of non-infected UC and 78% of the UGS-related tumors. ERβ was equally expressed across different tumor stages and grade but more intense in tumor cells than in urothelium of normal appearance and in non-infected than in UGS-related cases. In the latter group, staining intensity was increased in women and in samples with parasite eggs. Using 3 human BlaCa cell lines, HT1374, T24 and 5637, we observed that 5637 cells express ERα and can be stimulated by E2 and inhibited by the anti-estrogens (4OH-tamoxifen and ICI 182 780). T24 cells expressed ERα at very low levels and did not respond to E2, but were inhibited by anti-estrogens; HT1376 do not express ERα. ERβ mRNA was not detected in any of the cell lines. Conclusions: Our results document an association between expression of ERα and aggressive features. The potential of expression of ERs as a prognostic tool and as therapeutic target should be further investigated especially for tumors with aggressive profile and during UGS-related carcinogenesis.