bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethnicity and benefit of first-line chemotherapy in metastatic gastric adenocarcinoma (GC).
Authors: Vaezi Mariam , Rahman Jawaria , Yang Dongyun , Barzi Afsaneh
Published: February 2017

218

Background: There is a significant difference in the incidence and mortality of GC across the world. Our group presented data on the differences in the outcome of GC based on ethnicity in patients in California Cancer Registry. Data from global trials have highlighted differences in the benefit from antiangiogenic therapy in different ethnic populations. We conducted a retrospective analysis of patients (pt) with stage IV GC, who received first line platinum based chemotherapy (CT) at Los Angeles County Hospital between 2003 - 2010. We explored the interaction between demographics and benefit from CT. Methods: We searched the administrative records for pt with diagnosis of GC and identified 308 pt of which 198 had metastatic GC with first line CT at our center. Time to progression (TTP), defined as time from start of chemotherapy to radiographic or clinical progression, was the primary end point of the study. Results: Of the 198 patients, 118 (60%) were male. 134(68%) Hispanics (H), 44 (22%) Asian (A), 6 (3%) African American (AA), 5(3%) white (W), and 9 (4%) other ethnicities. Primary site of the tumor was body (B) in 71(43%), antrum and pylorus (P) in 67(34%), and cardia/fundus or GEJ (GEJ) in 26 (16%). In 34 (17%) the primary site was unknown. The median TTP in the entire population was 17.7 months (M) (95%CI: 12.7 -125). TTP in H, A, and AA was 16.7(95%CI, 12.2 -125), 17.8 (95%CI, 8.2 - 79.2), and 10.2M(95%CI: 6.0 -106) respectively [p=0.75]. There was no difference in TTP between males and females or based on the location of the disease. Conclusions: In our small dataset, there was no difference in benefit from platinum based CT by ethnicity, demographics, or disease site. This suggests that CT benefit is similar across different ethnic populations, and observed differences in trials with antiangiogenic therapy are related to angiogenesis in different ethnic groups.
Treatment of nonresectable and metastatic gastrointestinal stromal tumors: Experience with the use of tyrosine kinase inhibitors in a third-level hospital in Mexico city.
Authors: Dip Borunda Abdel Karim , Silva Alejandro J.
Published: February 2017

224

Background: Stromal tumors of the digestive tract are uncommon malignant diseases, and are subclassified as leiomyosarcomas and gastrointestinal stromal tumors (GIST) depending on the molecular expression of CD117 (KIT). GISTs represent 1% of malignant tumors affecting this anatomical site. Located diseases are reasonably well controlled by surgical resection and several criteria define the need for adjuvant therapy. In the case of metastatic disease a poor prognosis has been reported with systemic treatment based on chemotherapy. Recently, significant advances have been shown since Tyrosine – kinase inhibitors were introduced, with median overall survival close to 5 years. Unfortunately in Mexico, even though the therapy has been long used there are no published data of the experience in the treatment of these tumors. Methods: We used an electronic data base to obtain clinical, radiological and histological data of patients diagnosed with GIST and treated in the oncological center of the Mexican Institute of Social Security, patients were subclassified by stage, symptoms at diagnosis as well as the initial and subsequent systemic treatment. Finally we made an analysis for progression free survival and overall survival identifying prognostic factors. Results: We obtained information of 71 patients with metastatic, nonresectable or recurrent GIST, treated with a TKI, we observed a predominant relation for women (60.4%), with median age of 58 years. Stage at diagnosis was predominantly metastatic (46.5%) most frequently affected sites were lung, liver and retroperitoneum. Median progression free survival was 23.6m and overall survival was 81.3 months. All patients were initially treated with imatinib at a dose of 400mg per day. Treatment was well tolerated in most cases. Conclusions: Metastatic GIST evaluated in our center shows a different affection in gender and age, our population shows a different response to TKI’s, than reported in other series with superior overall survival, Poor prognosis is associated with lung affection. Biological studies will be started for the molecular evaluation of these tumors.
Prognosis model for overall survival in locally advanced unresecable pancreatic carcinoma: An ancillary study of the LAP 07 trial.
Authors: Vernerey Dewi , Hammel Pascal , Paget-Bailly Sophie , Huguet Florence , Van Laethem Jean Luc , Goldstein David , Glimelius Bengt , Artru Pascal , Moore Malcolm J. , André Thierry , Mineur Laurent , Chibaudel Benoist , Louvet Christophe , Bonnetain Franck
Published: February 2017

235

Background: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial and complex. Better discrimination for Overall Survival (OS) is needed to improve therapeutic decisions. We address this issue, with the largest Phase III cohort of LAPC, by establishing the first prognosis model for OS with the full spectrum of parameters currently available at diagnosis. Methods: We enrolled 442 LAPC patients recruited in LAP07, an international multicenter randomized phase III trial (NCT00634725). 30 baseline variables among demographic, cancer history, clinical, biological and radiological parameters were evaluated in univariate and multivariate analyses as prognostic factors for OS. The predictive value of the final model was evaluated with Harrell’s C index. This analysis was repeated 1,000 times with the use of bootstrap sample to derive 95%CI for the C. A prognostic score and nomogramm were then developed based on the identified prognostic factors in the final model. Results: Independent prognostic factors identified in multivariate analysis (n=370) for OS were: Age (HR= 1.01; 95%CI 1.00 - 1.03; p=0.0418), Pain (HR= 1.36 ; 95%CI 1.08 - 1.71; p=0.0094), Albumin (HR= 0.96; 95%CI 0.94 - 0.98; p=0.0001), and RECIST size (HR= 1.01; 95%CI 1.00 - 1.02; p=0.0033), Harrell’s C-statistic for the final model was 0.60 (95% bootstrap CI 0.56 0.63). A prognostic score between 0 and 4 was then calculated for each patient, based on the previous model. Three risk-groups for death could be identified: lower risk (n=17; median OS time = 18.8 months; group of reference); intermediate risk (n=166 ;median OS time = 13.4 months; HR=1.7); higher risk (n=187 ; median OS time = 11.8 months; HR=2.1); p = 0.0101 by the global log rank test. A score and nomogramm were also developped with the addition of CA19.9 information. Conclusions: Our results highlighted 4 OS’s independent pronostic factors among a broad spectrum of parameters at time of diagnosis. We identified 3 groups with different OS’s prognosis profile. The determination of this simple prognostic score allows risk stratification that may help guiding clinical management of patients and the design for future clinical trials.
Genetic and phenotypic characterization of families with familial pancreatic cancer and screening of high-risk individuals.
Authors: Guillen Carmen , Earl Julie , Mocci Evelina , Guerrero Carme , Montans Jose , Marquez Mirari , Vazquez Sequeiros Enrique , Gonzalez Gordaliza Cristina , Sanjuanbenito Alfonso , MuÃƒÂ‘oz Maria Jesus , Solera Jesus , Real Francisco X , Malats Nuria , Carrato Alfredo
Published: February 2017

242

Background: The prognosis of patients diagnosed with Pancreatic Cancer (PC) is dismal with a 5-year survival rate of around 5%. Familial Pancreatic Cancer (FPC) is an autosomal dominant rare syndrome defined as families with two or more first-degree relatives with pancreatic cancer that do not fulfill the criteria of any other inherited tumor syndrome. The Spanish familial pancreatic cancer registry, Pan-Gen-FAM was established in 2009 in order to identify and manage families at high risk of developing PC. Methods: Information on the family history of cancer is collected in order to determine the phenotype of individual families and patients are offered genetic testing of known FPC associated genes pertinent to their familial syndrome. An individualized clinical screening program is devised for the early detection of a pancreatic tumor consisting of periodic monitoring by imaging techniques (EUS and MRI) and the evaluation of minimally-invasive tumor biomarkers approaches including Circulating Tumor Cells (CTC) and circulating free DNA in blood. Results: To date the registry includes 125 individuals representing some 41 families. Of 17 families tested so far BRCA2 germline mutations were detected in 5 families and a BRCA1 mutation in 1 family. 43 individuals underwent clinical screening. More pancreatic abnormalities were found by EUS (41%) than by MRI (31%). The most frequent abnormal findings were parenchymal changes associated with chronic pancreatitis. Eight cystic lesions were identified. One lesion was identified as a well differentiated neuroendocrine tumor and another was shown to have benign cytology and whilst carcinoma was found in a third patient, this patient underwent a subsequent partial pancreatectomy. The remaining patients with cystic lesions are undergoing close clinical observation. Seventy three patients underwent CTC determinations and all patients tested negative. Conclusions: Periodic screening of high risk individuals by EUS and RMI can detect small tumors and premalignant lesions. We hypothesize that these persons will have a higher probability of long-term survival than sporadic cases.
Comparison of four models for end-stage liver disease in predicting the survival rate of patients with advanced hepatocellular carcinoma (HCC).
Authors: Chen Zhan-Hong , Ma Xiao-kun , Li Xing , Hong Yingfen , Wu Dong-hao , Dong Min , Lin Qu , Wu Xiang-yuan
Published: February 2017

251

Background: Prognosis of patients with advanced HCC is very poor, median overall survival varies from 3 to 6 months. Life expectancy more than 3 months is one inclusion criteria for molecular targeted drugs in clinical tirals. There exists four models for end-stage liver disease: 1.) MELD: The model for end-stage Liver disease; 2.) MELD-AS: MELD+4.53×c(Na)+4.46×Ascites [Serum Na: Na<135 mmol/L score 1, otherwise score 0; Ascites: persistent ascites score 1, otherwise score 0]; 3.) iMELD: MELD+(0.3×age)-0.7×c(Na)mmol/L+100; 4.) MESO:[MELD/c(Na)mmol/L]×10.Now we want to compare four models in predicting the survival rate of advanced HCC patients. Methods: From September 2008 to September 2010, a total of 183 patients with advanced HCC who were not amendable to locoregional therapy were analyzed. The median survival was 6.6 months. Data were collected to classify patients according to MELD, MELD-AS, iMELD and MESO at diagnosis.3-month survival and 6-month survival were the end points used in the analysis. Results: When predicting 3-month survival, ROC analysis shows AUC of MELD-AS, MESO, MELD and iMELD is 0.718, 0.691, 0.688 and 0.620. AUC of MELD-AS is significantly higher than that of the other three models (p<0.05 ).Cut-off point of MELD-AS is 9.54 with 76.9% sensitivity and 59.5% specificity.The cut-off point of MESO, MELD and iMELD is 0.44, 6.19 and 23.87. When predicting 6-month survival, ROC analysis shows AUC of MELD-AS, MESO, MELD and iMELD and is 0.574, 0.538, 0.533 and 0.507. AUC of MELD-AS is significantly higher than that of the other three models (p<0.05 ).Cut-off point of MELD-AS is 18.53 with 27.7% sensitivity and 89.1% specificity.The cut-off point of MESO, MELD and iMELD is 1.04, 13.83 and 40.76. MELD-AS, MESO, MELD and iMELD is dichotomized according to the cut-off point generated by ROC analysis when predicting 6-month survival.Log-Rank test shows P value of MELD-AS, MESO, MELD and iMELD is 0.001,0.008,0.02 and 0.0009 respectively. Conclusions: MELD-AS is the best model in prediction of 3-month survival and 6-month survival among the four models for end-stage liver disease analyzed for Chinese advanced HCC patients.
Can contrast-enhanced MRI using gadoxetate disodium (EOVIST) replace triphasic CT to derive future liver remnant?
Authors: Le Viet H. , Trocha Steven D. , Jones Wesley B. , Devane Michael A. , McKinley Brian
Published: February 2017

263

Background: Calculating future liver remnant volume (FLRV) is important in planning treatment of hepatic neoplasm. CE-MRI gadoxetate disodium (Eovist) has been shown to yield more information than 3p-CT, often narrowing the differential of hepatic neoplasms. The purpose of this study is to compare FLRV calculated from CE-MRI to those from 3p-CT. Methods: We performed a retrospective review of 28 patients with liver tumors evaluated with both 3p-CT and CE-MRI prior to treatment. Three-dimensional reconstructions were computed by manual tracing technique. 3p-CT is considered the gold standard. Results: The calculated total hepatic mean volumes for 3p-CT was 1,588 cm3 and 1,916 cm3 for CE-MRI, with spearman correlation (ρ) of 0.91 (p <0.01). The total volume difference was 327 cm3 (p <0.01). The right hepatic lobe volume was 1,028 cm3 (3p-CT) and 1,283 cm for (CE-MRI) (ρ 0.83, p <0.01). The left hepatic volume was 525 cm3 (3p-CT) and 638 cm3 (CE-MRI), (ρ 0.79, p <0.01). The difference in calculated volume for the right liver is 254 cm3, p <0.01 (3.23%, p 0.008) and 94 cm3, p 0.07 (2.09%, p 0.045) for the left liver. Conclusions: Our data demonstrated a strong and positive correlation between 3p-CT and CE-MRI. When the 30% FLRV cutoff used, there is variability in 5 out of 28 patients (17.8%). Our data suggest that patients with FLRV calculated by CE-MRI that are near the resectability cutoff or those with abnormally large calculated FLRV should undergo 3p-CT for verification. Future studies are needed to further validate CE-MRI ability to calculate FLRV.
Sarcopenia as a predictor of mortality in advanced pancreatic cancer.
Authors: Baldwin Ashley , Kundranda Madappa N. , Todd Eric , Whitehead Robert P. , Winston Rachel , Weber Jeffery , Weitz David J , Kelly Melinda , Kachaamy Toufic
Published: February 2017

268

Background: Pancreatic cancer (PC) patients have multiple risk factors for malnutrition including digestive enzyme deficiency, gastric outlet obstruction and post prandial abdominal pain. In order to assess prognosis and triage patients at risk for malnutrition, accurate nutrition assessment is crucial. Overweight (Ow) or obese (Ob) patients pose a particular challenge and weight status should not be the only determining nutritional assessment tool. Sarcopenia (Sp) is defined as muscle mass (MM) two standard deviations below the healthy adult mean. It has been demonstrated in multiple studies to be a more accurate indicator of nutritional status. Sp is associated with poor clinical outcomes and lower survival in other conditions such as cirrhosis. Radiologic assessment of MM can be obtained reliably from computed tomography (CT) scans. Methods: All patients with advanced PC who had baseline CT scans were included in this study. MM assessment was performed using an automated software (SliceOmatic, Tomovision, Montreal) and the skeletal muscle index(SMI) was calculated at level of the 3rd lumbar (L3) vertebrae. Multiple patient characteristics were assessed including demographics, weight, body mass index (BMI), cancer stage, treatment received and survival. Sp was defined as an L3 SMI of less than 38.5 in women and 52.4 in men. Survival analysis was performed using SAS software and Log-rank and Wilcoxon statistics. Results: 167 patients, 49% female, 62% with sarcopenia (S+), 44% Ow/Ob (O+) and 14% sarcopenic and Ow/Ob (S+O+). Patients received a variety of treatments including surgery, chemotherapy and radiation. There was a trend towards lower survival in S+O+ patients while patients who were S-O+ survived the longest. Median survival in months was 6.2 for S+O+, 7.1 for S+O-, 7.8 for S-O- and 10 for S-O+. Conclusions: Patients with sarcopenia appear to have decreased survival especially if overweight/obese. This suggests that overweight/obese pancreatic cancer patients with sarcopenia may derive the most benefit from aggressive nutritional interventions. Well powered prospective studies are needed to confirm this observation and study the effects of aggressive nutritional interventions in this subgroup of patients.
Role of inflammatory monocyte mobilization in growth of liver metastasis in a murine model of metastatic pancreatic cancer.
Authors: Panni Roheena Z. , Nywening Timothy M. , Belt Brian , Sanford Dominic E. , Goedegebuure Peter S. , Linehan David
Published: February 2017

299

Background: Pancreatic cancer (PC) is currently the fourth leading cause of death and the mortality rate approaches 100% due to early metastatic spread. Liver is the most common site of metastasis in PC. Our group and others have shown that PC induces cellular changes in the liver which include increase in inflammatory monocyte and macrophage population, long before development of metastasis. Based on our preliminary data, we developed a murine model of metastatic PC to study the role of chemotherapy in addition to novel IM blocking agents in established PC metastasis. Methods: We implanted spontaneously derived murine PC cell line (KCKO) orthotopically in the tail of pancreas of WT mice. 10 days after tumor implantation, there was an increase in infiltrating IM and macrophages in the liver by flow-cytometry and IHC. There was also an upregulation of genes associated with development of metastasis and recruitment of myeloid cells i.e. CCL2, CSF1, s100a4, s100a8, CXCL12, LOX, VEGF-A (P<0.01) by RT-PCR. However, there was no evidence of tumor metastasis at this stage in the liver. We removed the primary tumor on day 10. At this time, mice were injected with βluc-KCKO in the inferior pole of the spleen which was removed. Liver metastases were detectable by bioluminescence in 100% mice after 15 days of splenic injection. Results: Mice with established liver metastasis were randomized to treatment with CCR2i, FOLFIRINOX, CCR2i and CCR2i+FOLFIRINOX or vehicle. Mice were treated for 4 weeks and were imaged biweekly in-order to quantify tumor burden in the liver. Mice were sacrificed after 4 weeks and flow-cytometry studies were performed on peripheral blood, bone marrow and liver. The peripheral blood IM were significantly increased in mice bearing liver metastasis. However, CCR2i efficiently blocked the recruitment of IM and macrophages in liver (p<0.01). The burden of liver metastasis was significantly decreased after four weeks of treatment. Interestingly, the lowest tumor burden was found in livers of mice treated with combination of CCR2i and FOLFIRINOX. Conclusions: We demonstrate that CCR2i in combination with FOLFIRINOX decreases macrophages in the liver and impairs growth of liver metastasis.
Coagulation factors in citrated plasma predict for benefit from bevacizumab (B) in patients with advanced pancreatic cancer (APC): Results from CALGB 80303 (Alliance).
Authors: Clarke Jeffrey Melson , Pang Herbert , Starr Mark D. , Hatch Ace Joseph , Kindler Hedy Lee , O'Reilly Eileen Mary , Innocenti Federico , Venook Alan P. , Hurwitz Herbert , Nixon Andrew B.
Published: February 2017

306

Background: CALGB 80303 evaluated gemcitabine (G) in combination with either B or placebo (P) in 602 patients (pts) with APC. No significant difference in overall survival (OS) between treatment arms was observed. Previously, plasma EDTA samples from CALGB 80303 were analyzed and potential predictive biomarkers for B were identified. This follow-up analysis evaluated citrated plasma samples for circulating proteins related to matrix remodeling and coagulation. Methods: Multiplex ELISA analysis was employed to assess the following circulating factors: E-selectin, matrix metalloprotease (MMP) 2, MMP9, von Willebrand factor (vWF), D-dimer, thrombospondin 1, and tissue factor (TF). Thrombin-antithrombin complex (TAT) was analyzed using a standard enzyme immunoassay. Prognostic characteristics were determined by associating baseline values with OS using a Cox model. Predictive markers were identified with inclusion of a treatment by marker interaction term. Results: Baseline citrated plasma samples from 109 pts were included in this analysis (59 pts G+P; 50 pts G+B). Negative prognostic factors for OS were identified, including E-selectin (p <0.01) for patients receiving G-based therapy, and E-selectin, TF, and vWF (p <0.05) in pts receiving G+P. Potential biomarkers predicting for OS benefit from B were also identified. Pts with low (< median) levels of TAT (interaction p=0.034) exhibited a median OS of 6.0 months (mo) vs. 8.3 mo (HR=0.49; 95%CI 0.28-0.88) when receiving G+P vs. G+B, respectively. Furthermore, pts with elevated levels of TF (>Q3) were found to benefit from B (interaction p=0.021), with median OS of 4.3 mo vs 4.8 mo (HR=0.44;95%CI 0.18-1.08), respectively. Longitudinal analysis of samples collected at baseline and at cycle 3 indicated that only vWF changed in pts receiving G+P, with an increase in vWF (p<0.05). Conclusions: In patients with APC, baseline levels of TAT and TF were identified as potential predictors of benefit from B. These data emphasize the importance of coagulation factors in modulating tumor angiogenesis. The potential predictive value of these factors warrants further validation.
Impact of STAT4 expression on cellular immunity and prognosis in hepatocellular carcinoma.
Authors: Yoshimoto Toshiaki , Ishikawa Daichi , Yoshikawa Masato , Teraoku Hiroki , Yamada Shinichiro , Saito Yu , Iwahashi Shuichi , Arakawa Yusuke , Ikemoto Tetsuya , Imura Satoru , Morine Yuji , Shimada Mitsuo
Published: February 2017

307

Background: Signal transducer and activator of transcription 4 (STAT4) mediates the intracellular effects of IL-12, leading to the production of IFN-γ and cytotoxicity. However, the significance of STAT4 expression in patients with hepatocellular carcinoma (HCC) remains unknown. Herein, we investigated the association of STAT4 expression with cellular immunity and clinicopathological factors in HCC. Methods: A total of 66 HCC patients who underwent hepatic resection were enrolled. RT-PCR was performed to determine STAT4 mRNA and IFN gamma mRNA expression. Immunohistochemistry was performed to examine CD8+ T cells. Results: STAT4 was differentially expressed in tumor and non-tumor tissues (p < 0.01), and positively correlated with IFN gamma and CD8+ T-cell infiltration (p < 0.01). Significant correlations were observed between STAT4 expression and tumor TNM stage, hepatic venous invasion, tumor size, and tumor differentiation. Patients with high STAT4 expression had significantly better disease-free survival (p < 0.01). In addition, low STAT4 expression (p < 0.03) were independent risk factors for tumor recurrence. Conclusions: Down-regulation of STAT4 in HCC indicated aggressive tumor behavior and predicted worse clinical outcome. STAT4 might be a useful biomarker to identify patients with high risk of tumor recurrence after hepatic resection.
Family members’ perspectives of caring for patients with terminal hepatocellular carcinoma.
Authors: Hansen Lissi , Rosenkranz Susan J. , Wherity Kathleen , Sasaki Anna
Published: February 2017

323

Background: Hepatocellular carcinoma (HCC) is a growing problem worldwide and accounts for more than 700,000 deaths annually. There is no curative treatment for those diagnosed with terminal HCC. This group of patients differs from other populations with liver disease or cancer due to the combined disease processes of cancer and liver failure. Although family members often play an integral role in providing care, no study was found specifically examining family member experiences of caring for patients with terminal HCC. The aim of this study was to describe family members’ experiences and perceptions of providing care for patients with HCC as they near the end of life. Methods: This longitudinal, prospective pilot study described here presents the qualitative results of semi-structured in-person interviews with a convenience sub-sample of 13 family members conducted once a month for up to a 6-month period. The interview guide included questions about family member experiences of providing care for patients living with HCC and any current concerns of significance. Interview data were analyzed using conventional content analysis. Results: Analysis included a total of 39 family member interviews. Ten family members were female and three were male (mean age = 56 years, range = 22-68 years). Family members’ relationships to patients varied and included: spouses, siblings, adult children, parents, and ex-spouses. The analysis resulted in four major themes: perception of and response to terminal HCC diagnosis, HCC progression, symptom assessment and interpretation, and challenges of providing care. Findings were colored by complex relationships between family members and patients that changed or did not change as the disease progressed. Conclusions: This study contributes new knowledge to begin developing interventions that address family members’ need for support, help, and information as the disease progresses and at the end of life. Future research should include a larger sample size that is more ethnically and racially diverse, includes more male family members, and focuses on how care provided by family members may vary based on kinship, and relationship dynamics.
Preclinical immunotherapy studies using an orthotopic pancreatic cancer mouse model.
Authors: Siolas Despina , Aristizabal Orlando , Byrne Kate , Leichman Lawrence P. , Vonderheide Robert H. , Bar-Sagi Dafna
Published: February 2017

324

Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. The advent of new mouse models of pancreatic cancer have accelerated our understanding of tumorigenesis and enabled preclinical testing of experimental therapeutics with a desire to translate these findings into meaningful clinical treatments. Methods: We have developed a model where pancreatic cells obtained from a KrasG12D;Trp53R172H genetically engineered mouse can be cultivated in two dimensional cell culture and implanted into the pancreas of a immunocompetent syngeneic mouse allowing for tumor formation in situ. In addition, we are using this model to study the effectiveness of new drug combination therapy such as gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy using overall survival as a primary endpoint. Results: These cells generate tumors of five millimeter diameter within two weeks of implantation with 100% efficiency. Because cancer cells are seeded in the context of normal surrounding pancreatic tissue, this model is not hampered by the genetic field effect of expressing cancer mutations in the entire pancreatic organ, allowing for the study of the tumor microenviroment. Responses to therapeutic interventions can be non-invasively monitored through small animal high resolution ultrasound. Conclusions: Our orthotopic pancreatic cancer mouse system is an effective model for pre-clinical studies of tumorigenesis, immunotherapy and examination of the tumor microenvironment. Future experiments will focus on exploiting this system for identifying potent immunotherapy and chemotherapy combinations and for detecting biomarkers of efficiency.
In vitro synergistic cellular proliferation inhibition in pancreatic cancer cells Su86 and Mia-PaCa-2 with fluvastatin and nab-paclitaxel.
Authors: Feinsilber Doron , Whatcott Cliff , Matrana Marc Ryan , Cole John T. , Munoz Ruben , Luo Qingyang , Fuloria Jyotsna , Satti Suma
Published: February 2017

331

Background: Statins have been shown to possess antiproliferative activity in-vitro. Synergism with multiple drug combinations has been of great interest in pancreatic cancer. We examined 2 in-vitro cell models for synergism using a combination of fluvastatin and nab-paclitaxel. Methods: Pancreatic cancer cell lines Mia-Paca-2 (MP2) and Su86 were cultivated and seeded to 25,000 cells/mL and subsequently grown in 96 well plates for 24 hours. The cells were then treated with a fixed concentration of fluvastatin in 9 rows, 8 receiving serial 1:2 dilutions 16 times in triplicate of nab-paclitaxel, 1 fluvastatin only row, and 1 untreated. Upon dosing cells were incubated for 72 hrs. Cellular proliferation was determined by sulforhodamine B proliferation assays and read at 570 nm. A nab-paclitaxel only assay was done as well for comparison. Results: The lowest inhibitory concentration of fluvastatin in combination with nab-paclitaxel was between 500-600 micro mole (mm). Fluvastatin alone at these concentrations attenuated cellular proliferation. Synergism was seen on IC50 curves that are available. Anti-proliferative effects were reduced by 1:256 dilution. Conclusions: Preliminary studies show fluvastatin has an in-vitro anti proliferative effect on Su86 and MP2 cells and synergism in combination with nab-paclitaxel. Fluvastatin is more cytotoxic in Su86 than MP2. Future experimental design will focus on in-vivo models.
Effect of gemcitabine-ALK-014 combination on MMP9 expression in primary pancreatic adenocarcinoma CELL cultures (PCCs).
Authors: Funel Niccola , Genova Giuseppe , Perrone Vittorio , Caniglia Fabio , Boggi Ugo
Published: February 2017

332

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth highest cause of death in the western world. The adjuvant chemotherapy can increase the overall survivor (OS) of PDAC patients. The Gemcitabine (GEM) and alkaloids mixture (ALK-014) combination shows the increase two time the OS non resectable in PDAC patients with respect to gemcitabine treatment alone. Indeed the Alkaoids compound modulated the Matrix MetalloProteinase 9 (MMP9) in PDAC cell clines. AIM: Our goal was to investigate the MMP 9 protein modulation in primary cell cultures (PCCs) of PDAC by Gem and ALK-014 combination treatment. Methods: Two PCCs (LPc006 and LPc028) were seeded in 4 multi-well chamber slids (8,000 each/well) for cytotoxicity study by Gem [10 Nm], ALk-014 [1µm]and their combination. After 48 h of treatment the cells were stained Immunocytochemistry (IHC) using polyclonal antibody for MMP9. We used no-treated cells to evaluate basic level of MMP9 protein. No–stained cells were used as negative control. All experiments were done in triplicates. We evaluated protein expression and cellular morphology by computer for imaging analysis (D-Sight, Menarini, Italy). The expression differences was evaluated by ANOVA and t-test analyses. Results: We found a significant reduction of MMP9 expression in both cell lines treated with Gem/ALK-014 combination with respect to their controls ( p<0.01). The same drug combination reduced significantly the number of proliferating cells and showed the modification of the structure of nuclei with respect to untreated cells (p<0.001). Conclusions: New therapeutic approaches are warranted to reduce the metastatic behavior of PDAC. The present drug combination seems to be a promising tool for PDAC treatment in vitro. The new computerized approach for MMP9 evaluation could be a first quantitative attempt for protein quantification in preclinical model.
A randomized phase II open label multi-institution study of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) in the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Thomas Melanie B. , Garrett-Mayer Elizabeth , Anis Munazza , Anderton Kate Robertson , Bentz Tricia A , Adelman Andie Ray , Brisendine Alan , Duddalwar Vinay , Weiss Geoffrey R. , Siegel Abby B. , Bendell Johanna C. , Baron Ari David , El-Khoueiry Anthony B.
Published: February 2017

337

Background: HCC is the 2nd most common cancer worldwide. Most pts present with advanced disease and require systemic therapy. S, a multi-targeted tyrosine kinase inhibitor (TKI) is the only approved drug for HCC. B is a mAb that binds circulating ligand of the transmembrane VEGF receptor; E is a TKI that inhibits EGFR signal transduction. Published single-arm trial data suggest clinical benefit from B+E in HCC. Methods: The study was designed to estimate the HR for OS of B+E vs S with its 95% confidence interval for a sample size of 90 evaluable pts. A difference in OS favoring the B+E arm with a HR of 0.67 was expected and of interest, based on median OS for B+E and S of 15 and 11 mos. seen in previous trials.Secondary endpoints include event-free survival (EFS), toxicity, and RR. Eligible pts had advanced HCC, Childs-Pugh Class A-B7, no prior systemic therapy, preserved organ function, ECOG PS 0-2. Patients were randomized 1:1 to receive S 400 mg orally twice daily, continuously, or B 10 mg/kg IV every 14 days and E 150 mg orally daily. Treatment cycles were 28 days, restaging every 2 cycles by investigator-assessed RR per RECIST 1.1 and subsequent independent radiologic review. Results: A total of 95 pts were registered, 43 in the S arm and 47 in the B+E arm. Pts who received at least 1 dose of study drug(s) were evaluable. Data are summarized in the table. Conclusions: Based on initial data analysis, the OS of advanced HCC pts treated with B+E is consistent with that of S, and the toxicity profile and EFS of B+E compare favorably to S. Clinical trial information: NCT00881751. [Table: see text]
The clinicopathological characteristics of understaging and overstaging of the preoperative assessment for gastric cancer by endoscopic ultrasonography and computed tomography.
Authors: Lee Ae-Ra , Lee Dong Ho , Hwang Jae Jin , Shin Cheol Min , Yoon Hyuk , Park Young Soo , Kim Nayoung
Published: February 2017

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Background: Despite the development of EUS and CT technology, there are no clinically relevant imaging tools to detect accurate preoperative staging such as lymph node (LN) metastases. The aim of this study was to elucidate of the clinicopathological characteristics of understaging and overstaging of the preoperative assessment for the gastric cancer by EUS and CT. Methods: In total, 180 patients who underwent EUS and CT, followed by gastrectomy at Bundang Hospital, Seoul National University, from July 2012 to June 2014, were analyzed. The results from the preoperative EUS and CT were compared to the postoperative pathological findings. Results: For T staging, a total of 180 patients who underwent CT and EUS have been recruited and 99 patients with visualized primary lesions on CT were analyzed. For N staging, 180 patients who underwent EUS and CT were analyzed. The overall accuracy of EUS and CT for T staging was 63.7% and 69%, respectively. The overall accuracy for N staging was 74.3% and 69.6%, respectively. Compared with variables of under and over staging group with accurate staging group, Accuracy of T staging for lesions at the cardia (36.4% vs. 63.6%, P = 0.021), advanced gastric cancer group (55% vs. 90.9%, P = 0.005) and advanced T stage group (24.4% vs. 5.2 %, P = 0.001) was higher than that non-cardia lesions and EGC group. Ulcerative lesion (38.5% vs. 61.5%, P < 0.001) and histologically undifferentiated type (3.8% vs. 93.8%, P = 0.002) had significantly lower accuracy in N staging than non-ulcerative lesions and the differentiated cancer. Conclusions: Caution is required in interpreting the T staging of the advanced T stage (T3 and T4) lesions, lesions at the cardia and advanced gastric cancer lesions. The ulcerative and undifferentiated lesions needed careful interpretation for N staging. However, there seemed to be no significant differences of clinicopathological characteristics between EUS and CT. The accuracy of CT was close to that of EUS and both modalities were useful and complementary for the locoregional staging of gastric cancer.
CA19-9 and surgical margin status (SMS) associations with local-regional (LRF) and distant failure (DF) in patients (Pts) with pancreatic cancer: RTOG 9704 secondary analysis.
Authors: Regine William , Winter Kathryn A. , Kessel Ivan , Chen Yuhchyau , Fugazzi James A. , Donnelly Eric Donald , DiPetrillo Thomas A. , Narayan Samir , Plastaras John Peter , Gaur Rakesh , Delouya Guila , Suh John H. , Meyer Joshua E. , Haddock Michael G. , Didolkar Mukund S. , Padula Gilbert D. A. , Johnson David B , Hoffman John Parker , Crane Christopher H.
Published: February 2017

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Background: 9,704 was the first phase 3 pancreatic cancer trial to validate the prognostic value of postresection CA19-9 for overall survival (OS), with values > 90/180 associated with worse OS. All pts received adjuvant gemcitabine or 5-FU and chemo-radiotherapy (RT). This analysis evaluates patterns of disease failure. Methods: SMS was negative, positive, or unknown. CA19-9 was analyzed at cut points 90, 180 and continuously. LRF and DF were estimated by cumulative incidence and Gray’s test compared. Cox hazard models were used for multivariate analyses (MVA) and included treatment, tumor site, size and nodal status. To adjust for multiple comparisons a p-value < 0.01 is statistically significant and 0.01 to < 0.05 a trend. Results: 538 pts accrued, with 451 eligible and analyzable for SMS and 385 for CA19-9. For CA19-9, 132 (34%) were Lewis Antigen negative (no CA19-9 expression), 200 (52%) < 90 and 220 (57%) < 180. 188 (42%) had negative margins, 152 (34%) positive and 111 (25%) unknown (i.e., no margin comment in path report; shown to have outcomes similar to negative margin pts). Pts with CA19-9 ≥ 180 were more likely to have tumors ≥ 3 cm and pts with positive SMS more likely to have KPS 60 - 80, T3/T4, or N1 disease. On univariate analysis (UVA) CA19-9 cut at 90 was associated with significant increases in both LRF (trend) and DF; in the gemcitabine arm this was seen in DF, not in LRF; in the 5-FU arm it was seen in both. Results were similar at the 180 cut point and continuously. SMS on UVA was not associated with increase in LRF/DF; see Table. On MVA, CA19-9 > 90 was significantly associated with LRF and DF; positive SMS showed only a trend for DF. Conclusions: Postresection CA19-9 has significant association with both LRF and DF not seen with SMS. These findings support continued use of RT in trials and consideration of dose intensification among pts with elevated postresection CA19-9. Grants: NCI U10, CA21661, CA37422, CA180868, CA180822. Clinical trial information: 0000000. [Table: see text]
Do recurrent and de novo metastatic biliary tract cancer patients have the same outcome on treatment?
Authors: McNamara Mairead G , Aneja Priya , Maganti Manjula , Horgan Anne M. , Cleary Sean P. , Knox Jennifer J.
Published: February 2017

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Background: Biliary tract cancers (BTCs) include cholangiocarcinoma, which refers to cancers arising in the intrahepatic, perihilar or distal biliary tree, ampulla of vater and gallbladder carcinoma. Even after complete surgical resection, a large number of BTC patients develop recurrence. Whether recurrence after surgery and de novo metastatic BTC should have comparable stratification in first-line palliative systemic therapy clinical studies is unknown. Methods: 480 patients who received palliative chemotherapy as first-line treatment for advanced BTC between January 1987 and May 2014 in Princess Margaret Cancer Centre, Toronto were reviewed. Probability of overall survival (OS) was estimated using the Kaplan-Meier method, and independent prognostic factors for OS were identified using the multivariable Cox proportional hazard model. Results: There were 171 recurrent and 309 de novo metastatic patients. Median age at diagnosis was 62 years, performance status<2; 436 (91%) patients, male; 262 (55%). In the recurrent group, 91 (53%) had indwelling stents, ampulla of vater; 50 (29%), gallbladder; 29 (17%), cholangiocarcinoma; 92 (54%). In the de novo metastatic group, 185 (60%) had indwelling stents, primary site was ampulla of vater; 16 (5%), gallbladder; 94 (30%), cholangiocarcinoma; 199 (65%). Systemic treatment received was gemcitabine/platinum doublet in 134 (28%), gemcitabine/5-FU doublet; 186 (39%), gemcitabine; 97 (20%), other; 63 (20%). Median OS for the recurrent group who received first-line palliative chemotherapy was 15.6 months (95% confidence interval [CI] 13.5-18.0) and 14.4 months (95% CI 12.0-16.0) in the de novo metastatic group. Multivariable analysis for OS revealed that gallbladder as the primary site (P=0.03) and ECOG performance status ≥2 (P=0.001) were prognostic for worse OS. De novo metastatic status was not prognostic for worse OS compared with recurrent status (Hazard ratio 1.1, 95% CI 0.82-1.50, P=0.51). Conclusions: Similar treatment of patients with recurrent disease after surgery and de novo metastatic BTC, with first-line palliative chemotherapy is acceptable.
Chemotherapy for surgically resected intrahepatic cholangiocarcinoma: Influence of lymph node status on treatment efficacy.
Authors: Miura John Thomas , Johnston Fabian McCartney , Tsai Susan , George Ben , Thomas James P. , Christians Kathleen K. , Turaga Kiran , Pawlik Timothy M. , Gamblin T. Clark
Published: February 2017

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Background: High rates of recurrence following surgery (S) for intrahepatic cholangiocarcinoma (ICC) have prompted treatment strategies that incorporate chemotherapy (CT). However the benefit of CT remains poorly defined. The present study sought to determine the survival impact of CT for surgically resected ICC. Methods: Patients with non-metastatic ICC that underwent curative intent surgery (R0) were identified from the National Cancer Database (1998-2011) and stratified by receipt of CT. Log rank tests and cox proportional hazards models were used to examine overall survival (OS). Results: A total of 1,729 patients were identified (median age: 66 years, 53% female); 520 (30.1%) received CT. Patients receiving CT were younger (61 vs 66 years, p<0.01), had larger tumors (>5cm: 47 vs 40%, p<0.01), and had a higher frequency of lymph node metastasis (23 vs 12%, p<0.01). However, lymph node evaluation was not conducted in 30% (n=519) of the collective cohort. In the entire series, there was no difference in unadjusted median OS between patients receiving CT compared to S alone (30 vs 32 months, p=0.31). In multivariate models, advanced tumor stage and lymph node status (p<0.05) were associated with shorter OS. When stratified by lymph node status, CT demonstrated a significant improvement in median OS among N1 patients (HR: 0.47, 95%CI: 0.25-0.87; p=0.02). In contrast, patients with N0 disease derived no benefit from CT (HR: 0.95, 95%CI: 0.65-1.39; p=0.80). Conclusions: The use of CT was associated with a survival benefit only for ICC patients with nodal metastasis. Assessment of lymph nodes at the time of surgical resection is critical when attempting to identify a subgroup of patients best suited for CT.
Effect of dose-escalation of IMRT for unresectable pancreatic cancer 1 cm away from the luminal mucosa on long-term survival.
Authors: Crane Christopher H. , Chanda Awalpreet Singh , Koay Eugene Jon , Varadhachary Gauri R. , Das Prajnan , Javle Milind M. , Suh Yelin , Wolff Robert A. , Fleming Jason B. , Katz Matthew H. G. , Fogelman David R. , Shroff Rachna T. , Lee Jeffrey Edwin , Krishnan Sunil
Published: February 2017

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Background: The use of chemoradiation (CXRT) for locally advanced pancreatic cancer (LAPC) is controversial. Delivery of high doses of RT capable of leading to local tumor control is challenging. We reviewed outcomes of treatement with dose-escalated IMRT with curative intent. Methods: Of 211 patients treated from 5/2006 to 8/2014 with CXRT for LAPC, 49(23%) had tumors > 1 cm from the luminal organs ere selected for dose-escalated IMRT using integrated boost (SIB) technique, inspiration breath hold, and computed tomographic (CT) image guidance. Fractionation was optimized for coverage of gross tumor (GTV,Table 1). A 2-5mm margin on the GTV, was treated as an SIB within a microscopic dose. Forty-seven (96%) patients received a median of 4.0 months of induction chemotherapy and 45 (92%) received concurrent capecitabine or gemcitabine. Results: Mean GTV coverage was 86% (95% CI 78% to 94%). Median FU was 32 mo. Median OS and 1, 2, 3 and 5 year OS rates were 22.6mo (95% CI 16.4 to 43.9mo), 83%, 49%,38%, and 18% from the date of diagnosis and 17.8mo, 63%, 38%, 33%, and 18% from the start of RT. Degree of GTV coverage and Biological Equivalent Dose (BED) did not appear to affect outcome. Freedom from progression at 3 y were 40.6% (local) and 37.1% (distant). Acute toxicity was uncommon: grade 2 pain, diarrhea, anorexia, nausea or fatigue in 18 (37%), and grade 3 diarrhea in one patient (2%). Four patients (13%) required transfusion for anemia. One patient had a GI bleed possibly related to treatment. Conclusions: Dose-escalated IMRT across a BED range of 70-100Gy for inoperable patients selected with induction chemotherapy appears well tolerated and may improve the likelihood of long term survival. These results are similar to the best outcomes reported for patients after surgical resection. Incomplete high-dose GTV coverage does not appear to be detrimental. A randomized phase II trial is testing IMRT (RTOG 1201, 63Gy/28fx, with stratification by SMAD4 expression). [Table: see text]
Patient-reported outcomes after treatment for cancers of the pancreas and biliary tract.
Authors: Metz James M. , Vachani Carolyn , Hampshire Margaret K. , Hill-Kayser Christine E.
Published: February 2017

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Background: Pancreas and biliary (PBT) cancers are generally associated with poor overall prognosis, despite aggressive, multimodality therapy. The population of cancer survivors after these diagnoses may be largely ignored, despite risk of late effects. This Internet-based study seeks to evaluate patient-reported outcomes and survivorship care patterns after treatment of PBT cancers. Methods: Patient-reported data were gathered via a convenience sample frame from PBT survivors voluntarily utilizing a publically available Internet-based tool for creation of survivorship care plans. Available through the OncoLinkwebsite, the tool asks survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, PBT survivors are queried regarding late effects associated with specific treatments. Results: 134 PBT survivors utilized the tool from 2010-2014, 67% with pancreas cancer, 20% biliary, and 12% liver. Of the entire group, 59% were female and 81% Caucasian. Median diagnosis age was 59 and median current age 61. Average time since diagnosis was 2 years (range <1-8). Most reported having had multimodality therapy - 71% surgery, 78% chemotherapy, and 46% radiation. Most patients (70%) reported not receiving continued care from an oncologist, and >90% had never received previous survivorship information. Of 35 patients queried, 6 had metastatic disease and 7 had recurrent disease. When the entire group was queried regarding possible side effects of treatment, 44% reported persistent neuropathy, 24% chronic diarrhea, 21% bowel stricture or obstruction, and 15% chronic skin changes in the radiation portal. Conclusions: Although the prognosis after PBT cancers remains relatively poor, a population of long-term survivors exists. Survivors using this tool have generally not received survivorship information and most are no longer followed by an oncologist despite having received multimodality treatment. Neuropathy and gastrointestinal side effects appear to be the most bothersome to this group. This tool represents a potential way to provide information to underrepresented survivorship groups such as PBT survivors in the future.