bluuebunny/crossref_metadata_2025_split huggingface dataset:
Payer current and future utilization of pathways: A research study.
Authors: Greenapple Rhonda 
Published: February 2017

273 Background: Clinical pathways are a growing payer management technique for controlling costs and standardizing care. Their use in other therapeutic areas has helped payers control costs and standardize care; however, use of pathways in oncology has not been assessed. Methods: There were a total of 49 respondents, including 19 Medical Directors and 30 Pharmacy Directors, covering 100 million lives in the US across all channels (Medicare, Commercial, and Medicaid). Approximately 39% of respondents were from small plans (covering less than 750,000 lives), 28% were from medium-sized plans (covering 750,000 – 2.5 million lives), and 33% of respondents represented large plans (covering more than 2.5 million lives). About 33% of respondents were from national plans, while 67% were from regional plans. Results: Only 39% of payers have actually implemented pathway programs in oncology. Of the payers surveyed that did not already have a clinical pathway, 59% said they are not currently implementing pathways. However, among those who are using pathways, a disproportionate share is commercial plans (42%) and Medicaid (40%), not Medicare (25%). Only 25% of Medicare-focused plans anticipate implementing clinical pathways in the future, while more than 40% of commercially-focused plans intend to do so. About half of plans (53%) anticipate that pathways also will be integrated into provider ratings, and a minority, (42%), see a role for pathways in product formulary placement or tier status. When payers have implemented pathways, the tumor types with the highest costs have been initial targets, with breast (84%), lung (63%), colorectal (63%), and prostate (37%) with the highest penetration of pathway implementation. Conclusions: Payers view clinical pathways as an important tool for reducing drug costs, especially with respect to tumor types that carry high treatment costs. Near-term strategies like step edits and coverage via the pharmacy vs. medical benefit will continue to play a significant role in oncology reimbursement decisions, but product companies need to understand how existing clinical pathway programs will impact provider access to products to more accurately forecast their future impact as the concept gains national traction.
The clinical significance of SWI/SNF complex in pancreatic cancer.
Authors: Numata Masakatsu , Morinaga Soichiro , Watanabe Takuo , Tamagawa Hiroshi , Yamamoto Naoto , Shiozawa Manabu , Yoichi Kameda , Ohkawa Shinichi , Oshima Takashi , Yukawa Norio , Rino Yasushi , Akaike Makoto , Masuda Munetaka , Miyagi Yohei 
Published: February 2017

149 Background: Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study is to clarify the clinical significance of SWI/SNF complex, one of the major chromatin remodeling machineries, in patients with pancreatic cancer. Methods: 68 cases with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180, and BAF47. The correlation of expression level and clinicopathological outcome including overall survival were analyzed. Results: Expression level of the SWI/SNF components was categorized as low or high according to the median value of Histo score. Statistical analysis revealed that related factors were tumor size, T factor, M factor, lymphatic invasion, and Stage in BRM, histology and Stage in BRG1, tumor size in BAF180, lymphatic invasion in BAF47, respectively. Multivariate Cox propotional hazard analysis showed high-BRM and low-BAF180 expression level were independent predictors of worse survival in patients with pancreatic cancer. The hazard analysis was also examined in the patients treated with adjuvant gemcitabine, indicating that high-BRM, and low-BAF180 were independent prognostic factors for poor survival. Conclusions: These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High-BRM, and low-BAF180 are useful markers for prognosis of pancreatic cancer.
Blood cell-derived nanovesicles as biomarkers of homeostasis in gastrointestinal cancer.
Authors: Jansa Rado , Stukelj Roman , Sustar Vid , Bedina Zavec Apolonija , Stabuc Borut , Kralj Iglic Veronika 
Published: February 2017

152 Background: Nanovesicles (NVs) are membrane-enclosed fragments of cell interior which are pinched off from membranes of cells of all types (including cancer) in the last stage of the budding process. They are involved in cell-cell communication and can promote tumor growth and invasion. Interactions of tumor-derived NVs with blood cells, especially platelets are hypothetically reflected in vesiculability of platelets by means of concentration of NVs in blood isolates. Also we hypothesized that in patients whose plasma mediates stronger attractive interaction between membranes the concentration of NVs in blood isolates would be lower. Methods: NVs were isolated from 2.7 ml samples of blood of 29 patients with gastrointestinal cancer, 44 patients with other gastrointestinal diseases, additional 13 patients who were treated by imatinib due to gastrointestinal stromal tumor (GIST) and 50 healthy volunteers, by repeated centrifugation and washing, and counted by flow cytometry. We followed patients with GIST for 32 months. Ability of blood plasma to mediate attractive interaction between membranes was assessed by the angle of contact between giant phospholipid vesicles prepared by electroformation, which adhered due to addition of plasma to the suspension of NVs. Results: The concentration of NVs was considerably (44%, p = 0.0005) higher in the blood isolates of patients with gastrointestinal cancer than in the population of healthy volunteers and considerably (34%, p = 0.025) higher in patients with gastrointestinal cancer than in patients with other gastrointestinal diseases. We observed a considerable (average 13 fold peak) but transient (about one month within 32 montth follow up interval) increase of concentration of NVs in blood isolates due to treatment with imatinib.We found a negative correlation between the concentration of NVs and the average contact angle between adhered giant phospholipid vesicles (r = –0.50, p = 0.031). Conclusions: Concentration of NVs is increased while the ability of plasma to mediate attractive interaction between membranes is decreased in patients with gastrointestinal cancer. Treatment with imatinib caused transient increase of concentration of NVs in isolates from blood.
Hepatocellular cancer tumor growth and metabolic risk factors.
Authors: Miksad Rebecca A. , Goyal Rohit , Wei Jesse , Shaikh Raja , Halpern Elkan F. , Gazelle G. Scott 
Published: February 2017

162 Background: Understanding hepatocellular cancer (HCC) tumor growth patterns is important for determining optimal treatment strategy. However, growth of untreated HCC tumors is unclear and prior studies are limited by older imaging technologies and small samples. We evaluated HCC growth patterns and predictors in a cohort of patients with serial modern computed tomography (CT) and magnetic resonance imaging (MRI). Methods: Two radiologists retrospectively evaluated CT and MRI imaging for 56 patients with 83 HCC tumors with at least two images. Tumor Volume (TV) = 4/3* π *average short axis (X)*average long axis (Y)*X. To assess the relative change in size, normalized tumor volume (NTV) = TV/ baseline TV. Growth curves were fitted using an exponential growth model for tumor >2 observations. Univariate analysis explored clinical and pathologic predictors of NTV. A multivariate model was built by backward elimination of significant univariate variables. Results: Among 56 patients: 77% male, 96% cirrhotic, 50% Child-Pugh Class (CPC) B, 59% Hepatitis C, 32% obese, 37% diabetic, and 12% used metformin. Mean baseline and end TV were 98.8 cm3 and 213.0 cm3, respectively. Mean follow-up=8.3 months and mean number of serial images=3. Exponential TV growth was observed on visual inspection. Diabetes predicted lower NTV (i.e. slower TV growth) in univariate and multivariate analysis (Table). Obesity decreased the impact of diabetes. Conclusions: Diabetic patients had slower growing tumors than non-diabetics, even when clinical and pathologic factors were controlled. Tumor growth fit an exponential pattern. Further study of the impact of metabolic conditions on HCC tumor growth may provide insights into growth factors and identify potential treatment targets. [Table: see text]
Pretreatment plasma concentrations of YKL-40 and IL-6 in patients with pancreatic cancer: Potential diagnostic and prognostic biomarkers.
Authors: Schultz Nicolai Aagaard , Christensen Ib Jarle , Werner Jens , Giese Nathalia , Jensen Benny Vittrup , Larsen Ole , Bjerregaard Jon Kroll , Pfeiffer Per , Calatayud Dan , Nielsen Svend Erik , Yilmaz Mette , Hollander Niels Henrik , Wøjdemann Morten , Bojesen Stig E. , Nielsen Kaspar , Johansen Julia S. 
Published: February 2017

164 Background: To test the hypothesis that high pretreatment plasma YKL-40 and IL-6 associate with pancreatic cancer (PC) and short overall survival (OS). Methods: 556 patients with PC from Denmark (N=445) and Germany (N=111) were included in the present prospective biomarker study. 152 (27%) patients were operated and treated postoperative with adjuvant gemcitabine. 404 (73%) had locally advanced or metastatic PC and received palliative chemotherapy (primarily gemcitabine). Pretreatment plasma YKL-40 and IL-6 were determined by ELISA with known reference intervals in healthy subjects. Results: The OR for prediction of PC in the whole study population was significant for all 3 biomarkers with CA 19-9 having the highest AUC (YKL-40: OR=4.50, 95% CI 3.99-5.08, p<0.0001, AUC=0.87; IL-6: OR=3.68, 3.08-4.44, p<0.0001, AUC=0.87; CA 19-9: OR=2.28, 1.97-2.68, p<0.0001, AUC=0.93). YKL-40, IL-6 and CA-19-9 increased with more advanced stage (YKL-40 median (IQR): Stage IA-IIA 100 (68-157), IIB-III 101 (59-179), IV 166 (89-296) μg/L, p<0.0001; IL-6: Stage IA-IIA 4.2 (1.9-8.9), IIB-III 4.0 (2.1-8.2), IV 7.4 (3.6-18) ng/L, p<0.0001); CA-19-9: Stage IA-IIA 58 (10-622), IIB-III 209 (54-856), IV 1041 (146-9178) ng/L, p<0.0001). Univariate Cox analysis in resected patients showed that only pretreatment IL-6 and CA 19-9 (dichotomized according to normal values) were associated with short OS (YKL-40: HR=1.38, 0.87-2.18, p=0.17; IL: HR=2.23, 1.41-3.52, p=0.0006; CA 19-9: HR=2.80, 1.54-5.09, p=0.0007). In non-resectable patients all 3 biomarkers were associated with short OS (YKL-40: HR=1.54, 1.23-1.93, p=0.0001; IL: HR=1.63, 1.29-2.06, p<0.0001; CA 19-9: HR=1.48, 1.02-2.15, p=0.039). Multivariate Cox analysis in non-resectable patients (YKL-40, IL-6, CA 19-9 (log transformed base 2), age, sex, and stage) demonstrated that YKL-40 (HR=1.12, 1.02-1.23, p=0.021), IL-6 (HR=1.20, 1.09-1.31, p=0.0001) and CA 19-9 (HR=1.10, 1.07-1.14, p<0.0001) were independent biomarkers for short OS. This was not found in resected patients. Conclusions: Pretreatment plasma concentrations of YKL-40 and IL-6 may be new diagnostic and prognostic biomarkers in patients with PC.
SMAD4 gene mutation and prognosis of pancreatic adenocarcinoma.
Authors: Derbel Olfa , de la Fouchardière Arnaud , Peron Julien , Desseigne Francoise , Heudel Pierre , Guibert Pierre , Rivoire Michel , Meeus Pierre , Peyrat Patrice , Lemaistre Anne-Isabelle , De La Fouchardiere Christelle 
Published: February 2017

180 Background: Pancreatic adenocarcinoma remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: Data of 46 patients with pancreatic adenocarcinoma were analyzed. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis and patterns of failure (locally advanced v metastatic disease). Using tissue microarray, we assessed the relationship of SMAD4 expression with the overall survival of patients. Results: Among the 46 treated patients, 32 underwent pancreaticoduodenectomy. 40% of patients died with metastatic disease and 15 % died with locally advance evolution. Loss of SMAD4 expression was found in 22% of patients and seems to be correlated with a high grade histologic features and progression to metastasis disease. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.
Phosphorylated Akt expression as a favorable prognostic factor for patients undergoing curative resection and adjuvant chemoradiotherapy for proximal extrahepatic bile duct cancer.
Authors: Kim Kyubo , Min Hye Sook , Chie Eui Kyu , Jang Jin-Young , Kim Sun-Whe , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue , Ha Sung W. 
Published: February 2017

182 Background: To evaluate the prognostic significance of phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression in patients undergoing adjuvant chemoradiotherapy for proximal extrahepatic bile duct (EHBD) cancer. Methods: Sixty-three patients with proximal EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled into this study. Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to a median of 40 Gy (range; 40-54). Fifty-nine patients also received fluoropyrimidine chemotherapy as a radiosensitizer. p-Akt, p-mTOR, and PTEN expression were assessed with immunohistochemical staining on the tissue microarray. Results: p-Akt, p-mTOR, and PTEN were expressed in 23 (36.5%), 17 (27.0%) and 25 patients (39.7%), respectively. p-Akt expression was associated with distant metastasis and overall survival, but not with loco-regional recurrence. The 5-yr distant metastasis-free and overall survival rates were 25.8% vs. 58.2% (p = 0.007), and 27.5% vs. 50.2% (p = 0.0167) in patients with negative and positive expression, respectively. On multivariate analysis, nodal involvement was the only significant prognosticator predicting inferior distant metastasis-free survival (p = 0.0105), while p-Akt expression had a borderline significance (p = 0.0541). As for overall survival, p-Akt expression was a marginally significant prognosticator (p= 0.0635), whereas other risk factors lost the statistical significance. Conclusions: p-Akt expression was a favorable prognostic factor for patients undergoing curative resection followed by adjuvant chemoradiotherapy for proximal EHBD cancer.
Effect of trametinib in combination with panitumumab and trastuzumab on tumor growth in an orthotopic xenograft model of human pancreatic cancer.
Authors: Lindberg James M. , Adair Sara J , Newhook Timothy E. , Kim Alison , Parsons J Thomas , Bauer Todd W. 
Published: February 2017

190 Background: Aberrant MAPK and EGFR family signaling are key drivers of pancreatic ductal adenocarcinoma(PDAC). We hypothesized that combination trametinib(MEK1/2 inhibitor), panitumumab(EGFR inhibitor) and trastuzumab(Her2 inhibitor) would more effectively suppress tumor growth than any of these monotherapies. Methods: Patient-derived PDAC cell line MAD09-366 was exposed to trametinib, panitumumab, trastuzumab, and combination therapies in vitro. Western blot analysis was performed on treated cell lysates. Athymic, nude mice were orthotopically implanted with patient-derived PDAC xenografts(MAD09-366, 08-608, and 08-738). Established murine tumors were treated with control, trametinib (0.3mg/kg, qDay), panitumumab (500ug, BIW), trastuzumab (200ug, BIW) or in combination. MRI was used to assess tumor response. Results: Two of 3 PDACs were Kras mutant, 2 of 3 demonstrated increased Her2 activity, and all 3 showed increased EGFR activity. In vitro studies showed increased growth inhibition of triple-therapy-treated cells relative to control or each inhibitor alone. Western blot analysis revealed that EGF stimulation increased Ras pathway signaling in this Kras-mutant cell line. With EGF stimulation, the greatest Ras pathway signaling inhibition was seen in triple-therapy-treated cells. In vivo studies in all PDAC xenografts revealed that triple therapy significantly decreased tumor growth rate relative to control, trametinib alone, panitumumab alone, or panitumumab plus trastuzumab. In 2 of 3 PDACs assessed, triple therapy was superior to trametinib plus panitumumab. Average tumor size in MAD08-738 triple-therapy-treated mice decreased by 9.3%. Conclusions: Triple therapy with trametinib, panitumumab, and trastuzumab demonstrated the greatest in vitro Ras signaling blockade. In vivo, this combination produced significant tumor growth inhibition or regression in all PDAC tumors studied. This regimen should be considered for a future clinical trial in pancreatic cancer patients.
Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas.
Authors: Overman Michael J. , Wang Huamin , Schnabel Catherine A. , Anderson Jeff , Erlander Mark G. , Wolff Robert A. , Varadhachary Gauri R. 
Published: February 2017

197 Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of periampullary adenocarcinomas (PAA) is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 45 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination (pancreatic, extrahepatic biliary, ampullary, or duodenal). Blinded FFPE tumor sections underwent molecular testing and were compared for concordance to histopathological tumor types and prognostic performance. 28 of these samples had previously undergone whole-genome RNA profiling (Overman et al. GI ASCO 2011 a161). Results: Molecular classification of 43 (96%) evaluable samples (13 ampullary, 10 pancreatic, 10 biliary, 10 duodenal) showed 91% concordance: ampullary [5 intestinal (int), 7 pancreaticobiliary (pb)], pancreatic [10 pb], duodenal [3 int, 7 gastroesophageal (ge)], biliary [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 ampullary and 2 biliary samples, and ovary for 1 biliary case. Previous unsupervised RNA hierarchical clustering of all 13 ampullary cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 cases (5 int and 7 pb). These two ampullary subgroups were prognostic with median OS of 63 vs. 24 m, P=0.07, respectively. Conclusions: The 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA. These results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.
Circulating tumor cells (CTC) in metastatic hepatocellular carcinoma (HCC): Comparison to control patients with nonmalignant liver diseases (NMLD) and exploratory characterization by next generation sequencing (NGS).
Authors: Kelley Robin Katie , Magbanua Mark Jesus Mendoza , Butler Timothy M , Sidiropoulos Nikoletta , Hwang Jimmy , Evason Kimberley , Hameed Bilal , Wayne Elizabeth M , Yao Francis Y , Siah Iche , Park John W. , Venook Alan Paul , Collisson Eric Andrew 
Published: February 2017

207 Background: Noninvasive biomarkers are urgently needed to improve diagnosis, prognosis, and molecular characterization in HCC. Detection of CTC by EpCAM-enrichment methods is associated with poor outcomes in other tumors. Approximately 35% of HCC are EpCAM+. We hypothesized that CTC are detectable in a subset of metastatic HCC but not in NMLD and that CTC DNA might serve as a source of tumor DNA for biomarker detection and discovery. Methods: Whole blood was obtained from (1) patients with metastatic HCC and (2) NMLD controls. CTC were enumerated using CellSearch by blinded investigators. If > 10 CTC/7.5 mL, immunomagnetic enrichment for EpCAM followed by fluorescence-activated cell sorting (FACS) was also performed to collect highly purified CTC for whole genome amplification (WGA) by GenomePlex WGA4 kit. NGS using 46-gene AmpliSeq Cancer Panel (Ion Torrent) was performed on DNA from CTC, formalin-fixed paraffin embedded tumor (FFPE), and peripheral blood mononuclear cells (PBMC) if available. Results: 20 HCC and 10 NMLD were enrolled. FFPE was available in 7 HCC. In HCC cohort, median alpha-fetoprotein (AFP) was 492 ng/mL (range: 3.8-587,134) and vascular invasion (VI) was present in 13/20 (65%). CTC ≥ 3/7.5 mL were detected in 6/20 (30%, 95% CI: 0.08, 0.52) HCC and 0/9 (95% CI: 0, 0) eligible NMLD (p=0.07). One NMLD had CTC > 3/7.5 mL but was found to have HCC on surveillance ultrasound and excluded. CTC ≥ 3/7.5 mL were associated with AFP ≥ 400 (p=0.01) and VI (p=0.05) by Fisher’s exact test. NGS identified mutations listed in COSMIC in the majority including TP53 and CTNNB1. Variants appeared more frequent in CTC than FFPE in this small sample. Coverage was significantly lower in CTC than FFPE (coverage 20x mean 50% vs 93%, p < 0.02 by unpaired t-test). Conclusions: CTC are a promising biomarker in metastatic HCC and merit further study, including non-EpCAM methods. CTC were associated with AFP and VI. NGS of CTC WGA DNA is feasible and identified characteristic mutations but was limited by coverage bias. Updated NGS findings including 5 cases with paired CTC, FFPE, and/or PBMC will be presented.