bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting occult metastatic disease: A hematogenously derived xenograft model of human pancreatic tumor growth in the murine liver.
Authors: Lindberg James M. , Adair Sara J , Newhook Timothy E. , Tilghman Robert , Parsons J Thomas , Bauer Todd W. 
Published: February 2017

198 Background: Most pancreatic cancer patients will die following surgery due to recurrent metastatic disease. Thus, better systemic therapies are needed to treat occult metastases to improve survival. We have developed a model of occult liver metastasis from pancreatic cancer in order to evaluate novel treatment strategies. Methods: Pancreatic cancer cells (MAD 09-366, 08-608, MPanc96) transduced with green fluorescent protein (GFP) and luciferase were injected into the spleens of athymic, nude mice to generate hepatic metastases. Ninety-six hours after injection, tumor-bearing mice were treated with MEK1/2 inhibitor (trametinib, 0.3mg/kg, daily), gemcitabine (100mg/kg, twice weekly), or vehicle control. Sequential bioluminescence imaging, flow cytometry, and histologic evaluation were used to assess hepatic tumor growth and behavior. Results: All injected cell lines generated hepatic metastases. Different cell lines exhibited different growth kinetics. MPanc96 injected mice demonstrated a 64% decrease in average luminescence from 6 to 72 hrs after injection followed by a 146-fold increase from 72hrs until sacrifice at 21 days. Extensive liver metastases were noted at necropsy. Flow cytometry analysis of digested mouse livers following MPanc96 injection revealed rapid clearance followed by sharp outgrowth of tumor cells that mirror the bioluminescent imaging data. MPanc96 injected mice treated with trametinib exhibited significant hepatic tumor growth inhibition relative to gemcitabine and control treated mice. At 21 days, trametinib treated mice demonstrated a 14.9-fold increase in average luminescence while on treatment compared to an 82.5-fold increased for gemcitabine treated mice (p = 0.028) and a 195.5-fold increase for control mice (p = 0.027). Conclusions: This in vivo model of pancreatic liver metastases has proven effective in assessing treatment effects on pancreatic metastatic growth. Trametinib appears to be a superior agent to gemcitabine at inhibiting metastatic pancreatic tumor growth and its effectiveness will be evaluated using this model with additional patient-derived tumor cell lines.
Circulating bone marrow-derived stem cells in patients with pancreatic cancer.
Authors: Starzynska Teresa , Dabkowski Krzysztof , Blogowski Wojciech , Zuba-Surma Ewa , Salata Daria , Budkowska Marta , Dolegowska Barbara , Marlicz Wojciech , Lubikowski Jerzy , Ratajczak Mariusz 
Published: February 2017

200 Background: Various experimental studies suggest that bone marrow-derived stem cells (BMSCs) may be involved in the development and progression of pancreatic cancer. However, these observations require further studies, and delineation of exact mechanisms responsible for mobilization of BMSCs from the bone marrow to peripheral blood. Methods: A total of 23 patients with newly diagnosed pancreatic cancer (17 with distal metastases) and 15 healthy individuals were recruited to this study. Using fluorescence-activated cell sorter circulating hematopoietic (HSPCs), mesenchymal (MSCs), endothelial (EPCs), and very small embryonic/epiblast-like stem cells (VSELs) were enumerated and sorted. Plasma levels of various growth/inhibitory factors (hepatocyte [HGF], vascular-endothelial [VEGF], leukemia [LIF]), stem cells’ chemoattractants (stromal-derived factor-1 [SDF-1], sphingosine-1-phosphate [S1P]), and complement molecules (anaphylatoxins [C3a, C5a] and complexes [C5b-9/MAC]) were measured. Results: Significantly higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (in both p<0.05), while the numbers of circulating HSPCs and EPCs were comparable between the analyzed groups. Among analyzed biochemical and immunomodulatory factors, levels of C5a, C5b-9/MAC, HGF and S1P, but not of SDF-1, LIF nor VEGF were associated with observed mobilization of BMSCs. Conclusions: In patients with pancreatic cancer selective mobilization of BMSCs from the bone marrow to peripheral blood is observed. This seems to be strongly associated with increased levels of immunomodulatory substances. Our study also highlights that it is S1P and HGF but not SDF-1 that seem to be associated with BMSCs mobilization from the bone marrow to peripheral blood in patients with pancreatic cancer. (MNiSW grant 402 423038).
Role of KRAS mutations in the carcinogenesis of mucinous tumors of appendiceal origin with pseudomyxoma peritonei (PMP).
Authors: De Braud Filippo G. , Pietrantonio Filippo , Perrone Federica , Deraco Marcello , Baratti Dario , Kusamura Shigeki , Milione Massimo , Tamborini Elena , Dotti Katia F , Di Bartolomeo Maria , Bertan Claudia , Fanetti Giuseppe 
Published: February 2017

202 Background: Codon 12 KRAS and BRAF mutations may have a role in the mucinous differentiation pathway in colorectal cancer (Bazan V et al, Ann Oncol 2002; Tran et al, Cancer 2011). Elucidating the molecular mechanisms driving this disease is a priority for PMP, with the goal of identifying new markers and therapeutic targets needed to improve disease management. Due to the fact that neoplastic cells may be deceptively bland and sparse histologically within an abundant mucinous background, the adoption of high-sensitivity gene sequencing techniques may be extremely helpful. Methods: Mucinous tumors from 10 PMP cases of appendiceal origin treated in a multidisciplinary team at the National Cancer Institute of Milan were histologically classified according to Bradley classification. Following microdissection and DNA extraction, mutational analysis of KRAS exon 2-4 and BRAF exon 15 were performed by means of PCR, while KRAS exon 2 status was further confirmed through a specific mutant enriched PCR, shown to be a more sensitive approach in colorectal cancer (Molinari et al, Clin Cancer Res 2011). Results: Histological classification was low-grade in 6 and high-grade in 4 tumors. Codon 12 KRAS mutations were detected in 5/10 cases (50%). In the remaining 5 cases: sequencing of exon 4 lead to identification of a first-described A146V mutation in 1 case; with mutant enriched technique, we identified 3 additional codon 12 mutated cases. Due to use of high sensibility techniques and gene sequencing outside hotspot regions, we were able to identify KRAS mutations in 9/10 (90%) specimens. No BRAF exon 15 mutation was detected. Conclusions: The prognostic role of KRAS mutation in PMP patients is under investigation on a larger data-set of National Cancer Institute of Milan and will be presented at the Meeting. However, these preliminary data suggest a major role of KRAS in the carcinogenesis of mucinous tumors of appendiceal origin with PMP.
Correlating radiologic response criteria with pathologic tumor viability in HCC patients undergoing localized radiation followed by surgical resection.
Authors: Lee Ik Jae 
Published: February 2017

217 Background: Various radiologic response criteria have been developed for solid tumors. This study attempts to identify the optimal criteria for hepatocellular carcinoma (HCC) after localized treatment including radiotherapy. Methods: We reviewed 40 consecutive HCC patients who underwent surgical resection after radiotherapy of curative intent between 2000 and 2011. Radiation was delivered concurrently with intraarterial 5-fluorouracil/cisplatin (36), concurrently with capecitabine (2), and after receiving transarterial chemoembolization (2). For radiotherapy, 45 Gy in 25 fractions (32) or 50 Gy in 20 fractions (8) was delivered. Images from pre-RT and pre-resection CT were compared to determine treatment response according to Response Evaluation Criteria in Solid Tumors (RECIST), the World Health Organization (WHO) criteria, modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) criteria. Findings from pathologic reports including extent of tumor necrosis were correlated with degree of response from each set of criteria. Results: Intermodal agreement among criteria was highest between RECIST and WHO (p<0.0001) and between mRECIST and EASL (p<0.0001). All criteria showed strong correlation with reduction in α-fetoprotein (p=0.001 for EASL and mRECIST, 0.026 for RECIST, and 0.043 for WHO). Percent of viable tumor by EASL was most strongly correlated with percent of pathologic viable tumor (p<0.0001), followed by RECIST, mRECIST, and WHO (p = 0.011, 0.013, and 0.013). Resection was carried out after 2 complete (5%), 36 partial (90%), and 2 stable (5%) responses according to EASL criteria. Three year disease-free (DFS) and overall survival (OS) were 29 and 61 months. Complete necrosis showed trends toward improved DFS (p=0.136) and OS (p=0.088). Multiplicity was independent prognostic factor for both DFS and OS (p=0.005 and 0.001). Conclusions: EASL criteria showed strongest correlation with pathologic tumor viability after localized treatment for HCC. Prospective clinical trial is warranted.
Efficacy and safety of everolimus in patients with advanced low- or intermediate-grade pancreatic neuroendocrine tumors previously treated with chemotherapy: RADIANT-3 subgroup analysis.
Authors: Lombard-Bohas Catherine , Yao James C. , Hobday Timothy J. , Van Cutsem Eric , Wolin Edward M. , Panneerselvam Ashok , Castellana Ramon , Stergiopoulos Sotirios G. , Shah Gaurav D. , Shah Manisha H. , Pommier Rodney F. 
Published: February 2017

224 Background: In the phase 3 RADIANT-3 trial, everolimus (EVE) demonstrated significantly improved median progression-free survival (PFS) versus placebo (PBO) (11.0 vs 4.6 months; HR=0.35, p < 0.0001) in patients (pts) with pancreatic neuroendocrine tumors (pNET) (Yao et al, NEJM, 2011). Here we present a planned exploratory analysis by prior chemotherapy (chemo) use. Methods: Pts with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemo use and randomized (1:1) to EVE 10 mg/d (n = 207) or PBO (n = 203) plus best supportive care. Results: Of the 410 pts, 206 (50%) had received prior chemo and 204 (50%) were chemo naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for pts with/without prior chemo. More chemo-naive pts were newly diagnosed (time since initial diagnosis ≤ 6 mo: 50 [25%] vs. 7 [3%] pts with prior chemo). A lower proportion of chemo-naive pts received prior somatostatin therapy (45% vs. 54% prior chemo). EVE significantly prolonged median PFS regardless of prior chemo use (with prior chemo: 11.0 vs. 3.2 months; HR = 0.35, 95% CI 0.25-0.49, p < 0.001; chemo naive: 11.4 vs. 5.4 months; HR = 0.42, 95% CI 0.29-0.60; p < 0.001). Stable disease was the best overall response in 73% of EVE-treated pts irrespective of prior chemo use. The benefit from EVE irrespective of prior chemo was further demonstrated by disease stabilization or minor tumor shrinkage and in the lower incidence of progressive disease in waterfall plots. Safety of EVE was consistent regardless of prior chemo use. The most common drug-related adverse events (chemo vs chemo naive) included rash (53% vs. 52%), stomatitis (52% vs. 56%), diarrhea (41% vs. 52%), and fatigue (37% vs. 51%). Conclusions: This planned subgroup analysis demonstrated the beneficial effects of EVE in pts with pNET regardless of prior chemo use. These findings support the possible first-line use of EVE for pts with pNET.
Effect of altering fibroblast integrin associated protein expression on the growth and protein expression of pancreas cancer cells.
Authors: Shea Jill E. , Hewitt Kelly C. , Scaife Courtney L. 
Published: February 2017

251 Background: The lack of success of current treatments for pancreatic ductal adenocarcinoma (PDA) may be due in part to the presence of the dense surrounding stromal response and the interactions between the stroma and cancer cells. We have shown that integrin associated proteins, in particular PINCH, are expressed to a higher degree in the stroma adjacent to the tumor cells and PINCH expression is positively correlated with poorer PDA patient outcomes. We hypothesize that decreasing PINCH protein expression in the tumor associated stroma will decrease the growth and expression of growth promoting proteins in PDA cells. Methods: Red fluorescent protein (RFP) stably expressing MiaPaCa-2 cells were co-cultured with WI38 fibroblasts, or WI38 fibroblasts with shRNA knockdown of PINCH protein (PINCH KD). Cell growth of the PDA cells alone and upon exposure to WI38 and PINCH KD fibroblasts was determined using RFP at 48 hours. PINCH, Akt, and pAKt protein expression in cultured PDA cells, exposed to media, WI38, or WI38 PINCH KD cells via a transwell system, were determined by western blot with values normalized to GAPDH protein expression at 48 hours. Results: MiaPaCa-2 cells grown in co-culture with WI38 cells had a 70%±5% increase in RFP, while those grown in co-culture with WI38 PINCH KD cells had a 40%±3% increase relative to MiaPaCa2 cells grown alone. In terms of relative PINCH protein expression there was an increase in MiaPaCa-2 (20%±5%) cells grown in co-culture with WI38 cells compared to alone but not when grown with PINCH KD (6%±3%). MiaPaCa-2 cells had a greater increase in AKT (47%±6% compared with 19%±4%) and pAKT (36%±5 and 22%±4%) in the cells grown with WI38 cells compared to PDA cells grown with WI38 PINCH KD. Conclusions: Reductions in fibroblast PINCH protein expression are associated with reductions in the growth of adjacent PDA cells, as well as the expression of growth enhancing proteins (PINCH, AKT, and pAKT). Since greater PINCH expression within PDA stromal cells is associated with poorer patient outcomes, understanding the mechanisms associated with this tumor-stromal interaction may provide intervention opportunities.
Hepatic imaging response to 90y-microsphere therapy administered for tumor progression during systemic chemotherapy in patients with colorectal liver metastases.
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Nutting Charles W. , Moeslein Fred M , Putnam Samuel G. , Rose Steven C. , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric 
Published: February 2017

270 Background: Hepatic tumor progression after one or more lines of 5FU-based systemic chemotherapy, with or without biologic agents, is an indication for radioembolization using 90Y microspheres. Methods: An independent imaging review following resin-only 90Y microsphere treated cases of mCRC from July 2002 to December 2011 at 9 US institutions was conducted. A board certified radiologist systematically reviewed hepatic Computed Tomography (CT) images (portal-venous phase) at baseline and 3 months after 90Y treatment. Tumor response was assessed using RECIST 1.0 criteria, based on a maximum of 5 target lesions. Peri-tumoral edema and necrosis; known artifacts which can affect the interpretation of RECIST response, were documented for each lesion. Kaplan Meier analysis compared survival for responders [Partial Response (PR)] vs. non-responders [Stable Disease (SD) or Progressive Disease (PD)]. Results: A total of 184 patients were studied; male (61%) and Caucasians (61%) most common, mean age 62.5 years received a median of 2 (range 1–5) lines of chemotherapy prior to 90Y therapy. Median tumor/liver ratio at 90Y therapy was 15% (IQR 20%). Median 90Y activity administered was 1.18 GBq (IQR 0.55). RECIST response at 3 months was 9.8% PR (n=18), 72.3% SD (133) and 17.9% PD (33); Disease Control Rate = 82.1%. Peri-tumoral edema was documented in 33% (n=60); necrosis in 42% (79); both in 22% (40) of cases, respectively. No significant differences in background characteristics between responders and non-responders were evident (p>0.05). RECIST response at 3 months predicted survival: PR median 13.9 months (95% CI 9.2-30.3) vs. SD 11.0 (8.9-13.5) vs. PD 6.7 (5.5-8.1) [p=0.002]. Conclusions: Radiological lesion response to 90Y therapy at 3 months must be interpreted with caution due to the significant proportions of peri-tumoral edema and necrosis encountered. Both of these artifacts may lead to either the under estimation of PR/SD or the overestimation of PD, respectively. Given these caveats, early (3 month) hepatic radiological response to 90Y therapy appears to predict longer term prognosis.
Significance and clinical outcome of lymph node level assessment in biliary tract cancers.
Authors: Martínez-Galán Joaquina , Soberino Jesús , González Rivas Cynthia S. , Ruiz Vozmediano Julia , Portellano Lucia , Conde Veronica , Ortega Jose Antonio , Garcia Javier , González Vicente Aranzazu , Delgado Juan Ramon 
Published: February 2017

274 Background: Biliary tract cancers (BTCs) are relatively rare neoplasms encompass both cholangiocarcinoma (CC).The role of routine lymphadenectomy at the time of surgical resection remains poorly defined.We sought to identify factors associated with outcome following and examine the impact of lymph node (LN) assessment on survival. Methods: 43 pts who underwent curative intent surgery between 2000-10 were identified from a database.We calculated prognostic factors and impact lymph node assessment for survival. Results: A total 43 pts were identified with no metastatic BTCs.The median age was 65 years (29–82 years); PS0:33/43 (76%); PS1:8/43 (19%) and PS2:2/43 (5%) pts.A histological diagnosis of adenocarcinoma was confirmed in 100%.Surgical resection was performed in all patients.After resection 42% (18/43) had positive nodes.Adjuvant chemotherapy had 31/43(72%),preferred with gemcitabine and a median number of cycles 6. Grade 3 or 4 toxicities rarely occurred.During median follow-up of 6.6 years tumor recurrence or metastatic disease occurred in 63% with median survival global were 2 years and 1.5 years for disease free survival.For stage T, the median survival global rates were 58 months (95% CI 44.6-71.3) for T1-T2 and 35 months (95% CI 23.3-46.8) for T3-T4 p=0.015 and for median recidive-free survival were 23 months (95% CI 11.8-34) for T1-T2 and 14 months (95% CI 6.5-21) for T3-T4 p=0.05.For N stage, the median SG were 58 months (95% CI 50.5-65.4) for negative nodes and 26 months (95% CI 3.7-48.2) for positive nodes p=0.003 and for median recidive-free survival were 55 months (95% CI 31.7-57.5) for negative nodes and 10 months (95% CI 6.8-13) for positive nodes p=0.006.The pts who had nodal affectation in hepatic hilio had better recidive-free survival that those patients who had nodal affectation in celiac trunk p<0.05. Conclusions: This represents a biliary cancer cohort with survival benchmarks obtained in the modern era of multidisciplinary care.Surgical resection and adjuvant QT offers the optimal treatment outcome in patients with ICC.From our results depth of tumor invasion (T),the presence the lymph node metastases (N) and level nodal affections are the strongest predictors of relapse and survival.
Preoperative bowel preparation for pancreaticoduodenectomy: Is it necessary?
Authors: Newhook Timothy E. , Lindberg James M. , Adams Reid B. , Bauer Todd W. 
Published: February 2017

279 Background: Preoperative bowel preparation (PBP) before pancreaticoduodenectomy (PD) is commonly performed; however, the effect of PBP on intraoperative fluid requirements and acute renal failure (ARF) after PD has not been reported. The goal of this study was to determine the effect of PBP on postoperative complications, intraoperative fluid requirements, and ARF after PD. Methods: In this retrospective sequential analysis, all patients undergoing PD consecutively from September 2005 to July 2012 by a single surgeon were identified. Clinical data from patients who received PBP from September 2005 to November 2008 was compared to those without PBP from December 2008 to July 2012. Results: In all, 140 consecutive patients were identified with 49 (35%) having received PBP. There was no significant difference in the frequency of chronic renal failure between groups. The PBP group received a larger total intraoperative fluid volume (9.33 vs 6.54 L, p<0.001) and had a higher incidence of postoperative ARF (22.4% vs. 5.4%, p = 0.003) compared to those without PBP. There was no significant difference in the rates of superficial, deep, or organ space surgical site infections between the two groups. Additionally, there was no significant difference in the rates of pancreatic leak, other GI tract leak, or postoperative ileus between the groups. Conclusions: Surgical site infections are not significantly reduced with PBP prior to PD. In contrast, PBP is associated with a 2.8 L increase in intraoperative fluid administration and a 17% increase in the incidence of postoperative ARF. Thus, PBP should not be offered routinely prior to pancreaticoduodenectomy. [Table: see text]
Prognostic factors for achieving resection following neoadjuvant radiation therapy for borderline resectable pancreatic adenocarcinoma.
Authors: Dholakia Avani Satish , Hacker-Prietz Amy , Wild Aaron Tyler , Raman Siva P. , Wood Laura D. , Laheru Daniel A. , Zheng Lei , De Jesus-Acosta Ana , Le Dung Thi , Rasheed Zeshaan , Ellsworth Susannah G. , Kumar Rachit , Fan Katherine Y. , Pawlik Timothy M. , Makary Martin , Hruban Ralph H. , Cameron John L. , Fishman Elliott K. , Wolfgang Christopher Lee , Herman Joseph M. 
Published: February 2017

285 Background: Margin-negative (R0) surgical resection is the only potentially curative therapy for pancreatic cancer. For patients deemed borderline resectable (BL), neoadjuvant chemoradiotherapy (NCRT) increases the likelihood of subsequent R0 resection and improves overall survival. Prognostic factors for achieving resection following NCRT have yet to be clearly identified. Methods: 50 consecutive patients diagnosed with BL pancreatic cancer by a multidisciplinary tumor board from 2008-12 were retrospectively identified. Pre- and post-NCRT CT scans and surgical specimens were centrally reviewed by a blinded radiologist and pathologist, respectively. Results: 29 patients underwent resection following NCRT, while 21 remained unresectable. Between the two groups, age, gender, mean RT dose, and proportion of pancreatic head tumors were not significantly different. Lack of the following factors was favorably associated with resection: SMV/PV encasement (p=0.01), SMA involvement (p=0.02), ascites (p=0.01), and questionable/overt metastases (p=0.01). Notably, celiac artery involvement/encasement, common hepatic artery encasement, and percentage change in tumor volume were not significant predictors of resectability (all p>0.05). Additionally, tumor volume and degree of individual vessel involvement did not significantly change from scans before and after NCRT (all p>0.05). Median OS was 22.9 vs.13.0 months in resected and unresected patients, respectively (p<0.001). Of resected patients, 93% had negative margins, 28% had positive nodes, 27% demonstrated <10% viable tumor, and 12% had pathologic complete response at surgery. Conclusions: Certain radiographic features appear more strongly associated with resectability after NCRT than others. Despite the fact that tumor-vessel interactions do not change significantly due to NCRT, subsequent R0 resection rates are high, nodal involvement is low, nearly 1/3 of patients have minimal residual tumor, and outcomes are improved. Further studies are needed to elucidate novel biomarkers or functional imaging predictors for successful resection following neoadjuvant therapy.