bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum adiponectin and overall survival in a prospective cohort of patients with hepatocellular carcinoma.
Authors: Siegel Abby B. , Goyal Abhishek , Hidalgo Rosa Denisse , Wang Shuang , Neugut Alfred I. , Brown Robert S , Emond Jean , Kato Tomoaki , Samstein Benjamin , Dove Lorna , Santella Regina 
Published: February 2017

205 Background: Hepatocellular carcinoma (HCC) is one of the most rapidly increasing causes of cancer death in the United States. Adiponectin, a regulator of glucose metabolism, is reduced in those with diabetes and obesity. Serum adiponectin levels have been shown to correlate with prognosis in several types of cancers, but have not been well studied in patients with HCC. Methods: We have an ongoing prospective study evaluating fasting adipokines and clinicopathological features in patients with newly-diagnosed HCC. We excluded patients who had any previous malignancy, and those with uncompensated Child Pugh (CP) B or C disease. We evaluated common non-pathological prognostic variables in uni- and multivariable models as predictors of all-cause mortality. Results: Of our first 82 patients, median age was 60, 82% were men and 63% had underlying hepatitis C. 65% had a Body Mass Index (BMI)>25, and 33% had diabetes. We found that CP class, AJCC stage, adiponectin and IGF-1 levels were all significantly associated with survival, while age, AFP, etiology of liver disease, leptin and insulin levels were not in univariable analyses. We then created a Cox model which included age, CP class, AJCC stage, AFP>400 ng/mL, serum adiponectin, and IGF-1, and found that stage, adiponectin, and IGF-1 levels were all independently predictive of overall survival. Increased AJCC stage had the highest HR for death (3.9), while increased adiponectin levels (>12,000 ng/mL) led to a 3-fold increased risk of death. IGF-1 was protective, with higher levels (>40 ng/mL) leading to about a 3-fold decreased risk of death. Conclusions: Novel predictive and prognostic biomarkers in patients with HCC are badly needed. We found serum adiponectin to be a robust predictor of all-cause mortality in a diverse prospective cohort of HCC patients in uni-and multivariable analyses. Adiponectin deserves further study as a simple and practical biomarker to assess outcomes in patients with HCC.
Platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma (PC) associated with BRCA mutations: A translational case series.
Authors: Tran Ben , Moore Sara , Zogopoulos George , Borgida Ayelet , Holter Spring , Gallinger Steven , Moore Malcolm J. 
Published: February 2017

217 Background: Prognosis of PC is poor and responses to chemotherapy are minimal and short lived. In prior randomized studies, cisplatin and gemcitabine provided no additional benefits over gemcitabine alone. Preclinical data and case reports suggest BRCA cancers have increased sensitivity to Pt-chemo. Our case series characterizes the benefits of Pt-chemo in germline BRCA mutated PC. Methods: Patients with PC and deleterious germline BRCA mutations treated with Pt-chemo were identified using the Ontario Pancreatic Cancer Study and pharmacy databases. Review of clinical records provided demographic, treatment and survival data. Radiology review assessed responses to Pt-chemo. RNA was extracted from tumor samples for gene expression studies using a panel of DNA repair genes and Nanostring technology. BRCA loss of heterozygosity (LOH) was also investigated. Results: We identified 5 PC patients with BRCA mutations (4 BRCA2, 1 BRCA1) who were treated with Pt-chemo: 1 had resectable disease, 1 locally advanced (LA) and 3 metastatic. The resectable patient (T1N0) had 3 cycles of neoadjuvant Pt-chemo, achieving a partial response (PR) and normalization of CA19-9; curative resection and adjuvant Pt-chemo (3 cycles) followed and the patient remains disease free after almost 3 years. The LA patient (T4N0) had 2 cycles of Pt-chemo, achieving a PR and becoming resectable; curative resection and adjuvant Pt-chemo (4 cycles) followed and the patient remains disease free for over 3 years. One metastatic patient remains on Pt-chemo (5 cycles) having achieved a PR and normalization of CA19-9. The other 2 metastatic patients completed 6 and 22 cycles of Pt-chemo, achieving best response of PR and complete response respectively, with progression free survival of 12 and 45 months. Gene expression and LOH results will be presented. Conclusions: Survival and responses to Pt-chemo observed in our case series of BRCA mutant PC adds to existing data supporting the use of Pt-chemo in this subgroup. Although the incidence of BRCA mutations in PC is small, potential survival benefits gained from personalizing treatment using Pt-chemo supports BRCA testing in selected patients.
Disease control rate at 8 weeks as a predictive marker for long-term clinical outcomes in patients with advanced gastric cancer.
Authors: Yi Junho , Kim Gun Min , Kim Hyo Song , Rha Sun Young , Chung Hyun Cheol 
Published: February 2017

22 Background: Survival is the ultimate end-point in field of medical oncology. Although tumor response has been used as surrogate end-point in early phase clinical trial in patients with gastric cancer, clear correlation between tumor response and long-term survival has not been established yet. The objective of the current study is to determine whether early assessment could predict survival in patients with AGC. Methods: A total of 337 patients with AGC who had participated one of the three first-line, prospective, investigator-initiated, randomized trials carried out in Yonsei Cancer Center were included in the analysis. 238 had received fluoropyrimidine (F) + platinum (P), 61 had received F + taxane (T), 38 had received T + P. Response was assessed according to RECIST 1.1 at 8, 14 and 20 weeks after initiation of treatment. The correlation between response at each time point and the OS was evaluated using logistic regression test. Results: The median OS was 13.7 months. (95% CI 11.8 – 15.6) In terms of confirmed tumor response, 1 CR, 84 PRs, 104 SDs and 148 PDs were observed. At every landmark period, disease control rate (DCR, CR + PR + SD) was superior in predicting OS comparing with response rate. (RR, CR + PR) (Table). Among them, 8-week DCR was the most powerful predictor for OS. (HR 0.18, p< .001) There was no significant OS difference between patients with (13.7 months) vs. without (13.9 months) measurable lesions (p = .705) and between patients with 8-week response of PR (18.1 months) vs. SD (15.3 months) (p = .522). Conclusions: Disease control was a better predictor for OS in patients with AGC who had received first-line chemotherapy than response, with disease control at 8 week being the most powerful predictor. This could be used as a surrogate marker for long-term survival in early phase clinical trials. [Table: see text]
A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer.
Authors: Finn Richard S. , Javle Milind M. , Tan Benjamin R. , Weekes Colin D. , Bendell Johanna C. , Patnaik Amita , Khan Gazala Naaz , Laheru Dan , Anderson Lisa , Christy-Bittel Janna Lynn , Barrett Emma , Guthrie Kari , Litwiler Kevin S. , Bekaii-Saab Tanios S. 
Published: February 2017

220 Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival and is aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this Phase 1 expansion study were to characterize the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with biliary tract cancer (BTC). Methods: Pts with unresectable, locally advanced or metastatic BTC who had received ≤ 1 prior systemic therapy received oral MEK162 at 60 mg twice daily (BID). Mutation status of RAS, BRAF and other relevant genes were assessed from tumor samples. Tumor response was assessed every 6 weeks. Results: Twenty-eight pts, median age 64 years (range 30-86) with gallbladder (7), intrahepatic (14) or extrahepatic (7) cholangiocarcinoma (CC) were enrolled. All pts were ECOG 0-1 and 43% received previous first-line therapy (primarily gemcitabine combinations). Of the 23 tumors assessed, 17 were wild type (WT) on all loci tested and 6 had mutations (1 MET, 1 PIK3CA, 2 KRAS, 2 PTEN null). The most common treatment-related AEs were rash, nausea, vomiting, diarrhea, peripheral edema, fatigue and central serous-like retinopathy, and most were Grade (G) 1 or 2. G3/4 treatment-related AEs were anasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 each). Thirteen pts were dose reduced for AEs, of which, G1/2 central serous-like retinopathy was the most frequently reported event (6). Three pts were discontinued for treatment-related AEs (G2 central serous-like retinopathy, G1 nausea, G4 anasarca). Of the 26 pts evaluable for response, 1 CR, 1 PR and 11 SD (≥ 6 weeks) were observed. Of note, both responders were WT on all loci tested and had extrahepatic CC. The PK in this population was equivalent to that observed in prior studies. A consistent mean reduction (40-60%) of circulating TNFα was observed. Conclusions: MEK162 has an acceptable safety profile and desirable PK properties at 60 mg BID and RECIST responses were observed in pts with BTC. Additional expansion cohorts are ongoing in pts with KRAS- or BRAF-mutant metastatic colorectal cancer.
An experimental model of FOLFOX-induced sinusoidal obstruction syndrome.
Authors: Robinson Stuart M. , Mann Jelena , Manas Derek M , Burt Alastair D , Mann Derek A , White Steve A 
Published: February 2017

222 Background: Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy is a cause for major concern when undertaking liver resection for colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described limiting our ability to understand the pathogenesis of this condition. Methods: C57Bl/6 mice were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Organs were harvested for subsequent histological and biochemical analysis. Results: Mice treated with FOLFOX developed peri-venular sinusoidal dilatation and hepatocyte atrophy in keeping with features of SOS seen in patients treated with this regimen. In addition we noted up-regulation of genes within the liver associated with matrix remodelling such as MMP2 (p<0.001), pro-collagen I (p<0.001) and TGFβ (p<0.001). We also demonstrated up-regulation of pro-thrombotic genes PAI-1 (p<0.001) and vWF (p<0.001) and genes involved in angiogenesis e.g. VEGFA (p<0.01). Conclusions: We have provided the first direct evidence that FOLFOX directly results in the development of SOS in an experimental model. This system will enable us to gain a detailed understanding of the pathogenesis of this condition and provide a means to explore various strategies to prevent its development making major liver resection much safer after down-staging chemotherapy.
Effect of 2G8, a TGF-beta-R2 inhibitor, on TGF-beta signaling and migration in an immunocompetent pancreatic cancer model.
Authors: Ostapoff Katherine , Cenik Bercin , Schwarz Roderich , Brekken Rolf A. 
Published: February 2017

230 Background: TGF-beta functions as a tumor suppressor early in the development of pancreatic ductal adenocarcinoma (PDAC) but during tumor progression after undefined molecular changes TGF-beta switches to a promoter of metastasis, tumor angiogenesis and epithelial to mesenchymal transition (EMT.) A potential strategy is to target TGF-beta-R2, one of the major signaling receptors for TGF-beta. 2G8 is a anti-rat monoclonal antibody that binds specifically to and blocks murine TGF-beta-R2. Methods: Protein expression was analyzed using Western Blot. Cell proliferation was analyzed using Cell Titer Blue Assay and migration was determined using transwell migration assay. EMT protein expression was determined by ICC. PanO2-HY cells were used to establish an orthotopic and splenic metastasis model. In an orthotopic model, mice received saline, gemcitabine (Gem), 2G8 or 2G8 + Gem. For splenic metastasis model,mice received 2G8 on post injection day −1, +1 or +7 days or control IgG. Results: At baseline, PanO2-HY cells express TGF-beta-R2, alk5 and alk1 and express high levels of zeb1 and beta-catenin. 2G8 inhibits phosphorylation of smad2, ERK1/2 and p38 but not smad1/5 in vitro. 2G8 did not inhibit cell proliferation but did inhibit cell migration in vitro. After 7 days of treatment with 2G8, PanO2-HY cells had reduction in nuclear zeb1 staining by ICC. In the orthotopic model, 2G8 significantly inhibited metastasis to liver, peritoneum and gastrointestinal tract(p=0.02). In splenic metastasis assay, 2G8 treated mice livers weighed significantly less than control treated mice (p=0.0005). In the group of mice treated prior to tumor cell injection, none of them developed a primary tumor. Conclusions: Inhibition of TGF-beta-R2 with 2G8, results in inhibition of smad2 dependent pathways as well as non-canonical TGF-beta signaling in vitro. By inhibiting tumor cell migration in vitro and reducing EMT transcription factors, 2G8 may result in delayed tumor progression. In vivo data in both orthotopic and metastatic models suggest that inhibition of TGF-beta signaling via TGF-beta-R2 inhibits tumor cell metastasis. Further analysis are being conducted to understand changes within primary tumor and metastasis within this model.
Validating the woodchuck model for studying antiangiogenic therapies for human hepatocellular carcinoma (HCC).
Authors: Reddy Kaunteya , Ashton Edward , Buitrago Sandra , Hutson Alan , Tennant Bud Christopher , Iyer Renuka V. 
Published: February 2017

239 Background: Anti-angiogenic agents have become the backbone of advanced HCC treatment and provide clinical benefit despite infrequent radiographic response. Animal models that mimic human HCC and treatment response are greatly needed. The laboratory woodchuck (Maramota monax) is a unique animal model that replicates the complex human liver milieu of HCC in the context of chronic hepatitis B viral infection and was selected for this translational study. Methods: Humans: Patients with inoperable HCC were consented and prospectively treated with sunitinib 37.5mg PO qd for one week prior to liver directed therapy(chemoembolization). Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was done pre-sunitinib and after one week as part of the trial. Woodchucks: Laboratory bred eastern woodchucks were inoculated at birth with known titers of sera from a chronic infectious pool of chronic woodchuck hepatitis virus (WHV), confirmed by ultrasound exam at 12-18 months to have developed HCC. Methods for assessment of woodchuck HCC blood flow using DCE-MRI were optimized. Woodchucks received sunitinib 12mg/kg/day poQD and identical image acquisition and analysis techniques were used for both species and identical parameter sets were obtained for cross comparison done by Dr. Ashton in a blinded fashion. Results: A total of seven patients and eight woodchucks with HCC were included (2 scans per patient/woodchuck, pre and post sunitinib). The “Exact Wilcoxon rank-sum test” was used for statistical analysis. Comparison between median Ktrans, AUCBN(90), necrotic and total volumes of the tumors in both groups revealed all parameters to be similar and only total tumor volume reached statistical significance (P=0.002). Conclusions: Our data indicate similarities between human and woodchucks in the tumor histology, blood flow and baseline and post antiangiogenic therapy functional imaging assessment by DCE-MRI. The current sample size of n=7+8 can detect large differences of roughly 1.5 standard deviation units between humans and woodchucks for our measures at alpha=0.05 and power=0.80. Further studies that explore the translational potential of this unique animal model are warranted.
Development of a tissue-equivalent human liver phantom for 90Y-microsphere dosimetry studies and testing of other local ablation therapies.
Authors: Kennedy Andrew S. , McNeillie Patrick , Dezarn William 
Published: February 2017

244 Background: 90Y-microsphere brachytherapy for unresectable hepatic cancers is an increasingly popular therapy. The beta radiation dosimetry involved is not well understood and there is lack of pre and post treatment planning capabilities. Methods: A phantom was developed with tissue equivalent electron density, accurate anthropomorphic size, shape and volume to an adult human liver, with similar properties in response to heat, cold, radiation and diagnostic imaging as human liver tissue. Space-occupying masses were created to accommodate implantation of microspheres to simulate a human treatment. Imaging included MRI, CT and SPECT gamma scans pre and post implantation of 90Y-microspheres. Results: A phantom was produced that was shaped from a mold of an adult human liver. A mass with a different density than the liver was created in the right lobe that had a 3mm – 6mm rim for microsphere implantation. A known quantity of 99mTc was implanted into the left lobe. 90Y-microspheres of known activity were implanted in the periphery of the right lobe tumor. CT contrast was mixed with the microspheres to improve localization on subsequent CT scans. The electron density of the phantom was identical to human liver. Microsphere implantation was limited to the outer 6 mm of the right lobe tumor and 99mTc limited to the left lobe. Spatial resolution in 3D was excellent on all three modalities (MRI, CT and SPECT gamma). Conclusions: A human liver phantom as described will be a useful tool in future studies of beta radiation dosimetry, cross sectional and nuclear imaging and tissue responses. The next generation phantom is being developed with blood vessel-like branching channels to allow fluids to pass into and through the phantom similar in scale and diameter to hepatic vessels and tumors.
Selective reoperation for locally recurrent or metastatic pancreatic ductal adenocarcinoma following primary pancreatic resection.
Authors: Thomas Ryan Michael , Truty Mark Joseph , Fleming Jason B. , Pisters Peter W. T. , Lee Jeffrey Edwin , Rice David C. , Hofstetter Wayne Lewis , Wolff Robert A. , Varadhachary Gauri R. , Wang Huamin , Katz Matthew H.G. 
Published: February 2017

252 Background: Resection of recurrent disease in malignancies such as colorectal cancer has been shown to prolong survival but resection for recurrent pancreatic ductal adenocarcinoma (PDAC) is viewed as futile. We sought to identify factors that may be associated with prolonged survival following resection of recurrent PDAC. Methods: A retrospective review of a prospectively-maintained pancreatic tumor database was performed to identify all patients from 1992-2010 who developed recurrent PDAC after intended surgical cure. The group was screened for those who underwent a second operative procedure with curative intent. Clinicopathologic features were correlated with disease-free interval (DFI) and survival to identify factors that may be associated with prolonged survival in patients undergoing reoperation for PDAC. Results: Of 700 patients who underwent resection for PDAC, 426 (61%) recurred after a median of 8mo and 21 (5%) of those had a locoregional [pancreas (n=5), other (n=2)] or distant [lung (n=7), liver (n=6), brain (n=1)] recurrence that were selected for a second, potentially curative operation. Sixteen of 21 patients received chemotherapy prior to reoperation. Those selected had a single, technically resectable lesion, good performance status, and prolonged median DFI compared to patients not selected (22mo v. 8mo, p<0.01). The median DFI from initial resection to recurrence for those with lung (52mo) or locoregional (41mo) recurrence was longer than those with liver recurrence (10.5mo, p=0.03). The interval between reoperation and second recurrence in patients with lung metastasis (NR) was longer than for liver (6mo) or locoregional recurrence (7.5mo, p=0.02). Patients still alive include 4/7 of lung, 3/7 of locoregional, and 1/6 of liver recurrences with a median follow-up after reoperation of 30mo, 14mo, and 18.5mo, respectively. Conclusions: Patients who develop a solitary recurrence of PDAC in the lung after a long disease-free interval should be considered for reoperation. Those with recurrence in other sites are likely to re-recur relatively quickly after reoperation regardless of disease-free interval.
Phase I trial of radiotherapy with concurrent bevacizumab, erlotinib, and capecitabine for locally advanced pancreatic cancer (LAPC).
Authors: Skinner Heath Devin , Javle Milind M. , Wolff Robert A. , Clemons Marilyn V. , Munsell Mark F. , Delclos Marc E. , Fleming Jason B , Das Prajnan , Crane Christopher H. , Krishnan Sunil 
Published: February 2017

254 Background: The addition of bevacizumab to capecitabine-based chemoradiotherapy (CRT) for LAPC has been shown to be safe. The aim of this study was to determine the safety, tolerability and maximum tolerated dose (MTD) of the addition of erlotinib to this treatment regimen. Methods: Seventeen patients with CT-staged biopsy-proven non-metastatic unresectable LAPC were enrolled between March 2008 and October 2010. Prior chemotherapy was permitted. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose was escalated using a continual reassessment method. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. Bevacizumab was escalated from 5mg/Kg every two weeks (DLs 1-4) to 10mg/Kg (DL 5); erlotinib from 100 mg/day (DLs 1-2) to 150 mg/day (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 600mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. Results: With a median follow-up of 10 months (range 3-23), no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrheas and 1 rash). No grade 4 or 5 toxicities were seen. DL 4, with a posterior probability of 0.122 of dose limiting toxicity, was selected as the MTD. Median survival was 19.4 months and time to distant progression was 9.8 months. Patients treated at DLs 4 and 5 had a median survival of 24 months. Of 5 patients who underwent margin-negative resections, 4 were originally deemed unresectable and 1 was borderline; 4 were treated at DLs 4 or 5 (36% of patients treated at these DLs); 3 patients had excellent pathological responses (complete response, 5% viable tumor, and 20% viable tumor) at pancreatectomy and are alive at 13, 21 and 22 months respectively with no local or distant failures. Conclusions: The combination of erlotinib, bevacizumab and capecitabine with radiotherapy for LAPC is safe and tolerable. Both the promising survival and the high rate of resectability at the higher dose levels suggest that this strategy of dual inhibition of growth factor receptor pathways during CRT warrants continued evaluation.