bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of hypophosphatemia-occurring sorafenib with prognosis and hepatic impairment in patients with advanced hepatocellular carcinoma.
Authors: Aizawa M. , Mitsunaga S. , Okuyama H. , Nakachi K. , Ohno I. , Shimizu S. , Takahashi H. , Okusaka T. , Ochiai A. , Ikeda M.
Published: February 2017

188

Background: Hypophosphatemia is observed during sorafenib treatment. At the increased metabolic demand of the liver, hypophosphatemia is considered to be associated with a good clinical course. Hypophosphatemia associated with sorafenib treatment may also be a favorable event, but this has not yet been elucidated. The aim of this study was to evaluate the clinical significance of hypophosphatemia developing during sorafenib treatment for advanced hepatocellular carcinoma (HCC).

Methods: The data of 41 advanced HCC patients (median age: 68 years, female/male: 4/37, HBs-Ag(+)/HCV-Ab(+):10/22) who received sorafenib treatment (800 mg, daily) for more than 30 days were reviewed. There were 27 and 14 patients with Child-Pugh class A and B. UICC stage II/III/IV was observed in 13/10 /18 patients. Clinical data, including those on the serum level of inorganic phosphate (IP), were collected before and after 30 days of sorafenib treatment. Overall survival time (OS) was calculated from the start of sorafenib treatment. The significance level was set at p<0.05.

Results: Mean serum IP level before sorafenib treatment was 3.2mg/dL (range 2.4-4.5). After 30 days treatment, IP level was decreased (mean 2.6mg/dL, range 1.3-3.9), compared to that at pre-treatment (p<0.001). The patients in whom the serum IP was less than 2.4mg/dL at 30 days was assigned to the decreased IP group (N=14, mean IP 2.1mg/dL, range1.3-2.3). The decreased IP group showed a better prognosis (no event of death during the observation time) than the nondecreased IP group (MST 286 days, p=0.024). In the non-decreased IP group, the serum Alb (mean 3.6g/dL) and T.Bil (mean 0.8mg/dL) were worse after 30 days treatment (Alb 3.4g/dL p=0.007, T.Bil 1.1mg/dL p=0.037). However, deterioration of Alb (mean 3.7 vs. 3.6g/dL p=0.505) and T.Bil (mean 0.7 vs. 0.8mg/dL p=0.404) could be avoided in the decrease IP group.

Conclusions: Hypophosphatemia occurring during sorafenib treatment for advanced HCC was associated with a favorable prognosis. The serum Alb and T.Bil levels were indicators of liver function and were preserved in patients with decreased serum levels of phosphate.

No significant financial relationships to disclose.
The Virginia Mason Pancreatic Cancer Database.
Authors: Picozzi V. J. , Nguyen M. , Traverso L. W. , Kozarek R. A.
Published: February 2017

191

Background: Pancreatic cancer (PC) is associated with poor overall survival (OS);1-year PC OS PC is only 24% (ACS Facts and Figures 2010). We created a database (DB) intended to analyze clinical outcomes for the composite PC population treated at our institution.

Methods: Inclusion of patients (pts) in the DB required: 1) identification by ICD code 157.9, and 2) all active therapy elements (surgery, radiotherapy, and/or at least 1 cycle chemotherapy) executed at our institution. Among DB datafields are pt age, sex, and performance status, tumor stage, tumor size, node and margin status (resected pts), staging laparoscopy results (if performed), liver involvement (metastatic pts), anticancer therapies administered, time and site of disease progression (if applicable), cause of death and clinical trial participation. Data is updated quarterly; patients are censored for OS if care is transferred or death occurs.The DB can interface with other clinical/administrative databases within our system.

Results: From 1/1/2008 to 6/30/2010, 491 pts with ICD code 157.9 were identified. 307/491 (63%) pts did not meet DB inclusion criteria. Reasons included consultation only (n=211), palliative care only (n=52), therapy shared with other institutions (n=42), unknown (n=2). Of the remaining 184 pts, 38 pts (21%) were resected, 27pts (15%) were borderline resectable per institutional criteria, 44 pts (24%) were locally advanced/nonresectable and 75 pts (40%) had metastatic disease. 65% of pts wre >60 years old (median age 65 yrs) 30/184 pts (16%) were ECOG PS 2 or higher. 5/184 (3%) transferred care or were lost to c; thus 179 pts were fully evaluable for OS. Current median follow-up of all pts is 13.6 mo. 101/179 (61%) pts are presently alive; 1-yr OS of the entire patient population is 69% (Kaplan-Meier). 1-yr OS by disease category includes 94% resected, 81% borderline resectable, 78% locally advanced/nonresectable, and 44% metastatic disease. The DB will be continuously updated and developed.

Conclusions: 1) The general characteristics of pts in our DB are comparable to literature expectations. 2) The DB provides guidance as to the effectiveness of institutional therapy for our entire PC population. 3) A variety of potential DB applications exist. We anticipate continued DB development.

No significant financial relationships to disclose.
1H NMR–based metabolic profiling of serum for the detection of pancreatic cancer.
Authors: Owusu-Sarfo K. , Asiago V. , Gowda N. , Shanaiah N. , Xi B. , Chiorean E. G. , Raftery D.
Published: February 2017

193

Background: Pancreatic cancer (PC) is one of the leading causes of cancer deaths with a 5-yr mortality rate of 95%, and the lack of a suitable early detection method contributes to its poor prognosis. Metabolomics, the analysis of the metabolic profiles in biological samples such as serum and urine is emerging as an important tool to complement other “omic” techniques. In an effort to identify potential biomarkers for PC, we analyzed serum from PC patients (pts) focusing on altered metabolic profiles using 1H nuclear magnetic resonance (NMR).

Methods: The metabolite profiles from serum samples consisting of 55 PC pts and 32 healthy controls were analyzed using NMR combined with advanced supervised and unsupervised multivariate statistical methods such as partial least squares discriminant analysis (PLSDA) and principal component analysis (PCA). A number of metabolite markers selected based on p values and logistic regression rank the importance of each potential marker. Statistically significant metabolites between cancer and controls were used to build a prediction model.

Results: Based on multivariate logistic regression analysis of 20 targeted metabolites, 10 metabolite markers were selected from the variable selection process and used to build a regression model with high accuracy (AUROC >0.99), a sensitivity of 95% and specificity of 95% using a training set of samples. When the model was tested on an independent set of patient samples, it yielded a sensitivity of 95% and a specificity of 100% (AUROC >0.98). Box and whisker plots for individual markers verified the high performance of all 10 markers.

Conclusions: The high sensitivity of the metabolic profile that distinguishes PC pts from controls indicates the potential utility of 1H NMR metabolic profiling for the early detection of PC. The investigation has identified perturbations in several pathways such as glycolysis and amino acid metabolism, highlighting their contribution to disease onset. This study demonstrates the potential of metabolite profiling as an important tool toward detecting PC development. Future studies will involve metabolite validation on high risk pts, and additional mass spectrometry based metabolic discovery efforts.

No significant financial relationships to disclose.
Effect of raloxifene on human pancreatic adenocarcinoma growth in vitro and in vivo.
Authors: Seeliger H. , Seel N. , Camaj P. , Ischenko I. , Jauch K. , Bruns C. J.
Published: February 2017

207

Background: The role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we demonstated that expression of the isoform ER beta correlates with an adverse prognosis in patients with pancreatic cancer. Here, we show that raloxifene, a specific estrogen receptor modulator (SERM), suppresses in vitro and in vivo tumor growth by interfering with ER beta signaling in human pancreatic adenocarcinoma.

Methods: The human pancreatic adenocarcinoma cell line L3.6pl was cultured and exposed to raloxifene in vitro, and cell proliferation was determined by the BrdU assay. To analyze the specificity of raloxifene induced effects, ER knockdown was performed using siRNA specific for ER alpha and ER beta. In an in vivo model of orthotopic tumor xenografts in nude mice, raloxifene was administered daily, and tumor growth was monitored. Expression of ER beta and the proliferation marker Ki-67 were determined by immunohistochemistry.

Results: Raloxifene treatment resulted in a potent, dose dependent reduction of proliferation in vitro over a nanomolar dose range. This effect was completely reversed by siRNA knockdown of ER beta, but not ER alpha, indicating an ER isotype specific signaling. In vivo, orthotopic tumor growth, as well as lymph node and liver metastases, was significantly suppressed in raloxifene treated mice. Analogous to the in vitro data, Ki-67 expression in vivo was significantly reduced in raloxifene treated mice, while ER beta expression was not changed in vivo.

Conclusions: Inhibition of ER beta signaling by raloxifene results in a potent reduction of human pancreatic adenocarcinoma growth in vitro and in vivo. Treatment with SERMs may be an attractive therapeutic option in subjects expressing the ER beta isotype.

No significant financial relationships to disclose.
Relative value of serum cytokines and clinical factors in predicting weight loss in advanced pancreatic cancer (PC).
Authors: Fogelman D. R. , Wang X. S. , Hassan M. , Li D. , Javle M. M. , Varadhachary G. R. , Shroff R. T. , Overman M. J. , Wolff R. A. , Abbruzzese J. L.
Published: February 2017

208

Background: The identification of PC patients at high risk for cachexia may allow for early intervention to prevent this outcome. Symptoms such as pain, nausea, and anorexia might predict weight loss. Likewise, inflammatory cytokines are also associated with cachexia. We evaluated the ability of each to predict weight loss in patients beginning treatment for PC.

Methods: We evaluated 44 newly diagnosed advanced or metastatic PC patients for baseline symptomatology via the M. D. Anderson Symptom Inventory (MDASI). This survey assesses symptom severity, such as nausea, vomiting, fatigue, pain, diarrhea, and constipation, on a 1-10 scale. Baseline serum levels of IL-1a, IL-1b, IGF-1, CXCL-12, CXCL-16, CRP, IL-6, IL-8, VEGF, CEA, and CA 19-9 were assessed. Logistic regression analysis was performed to determine the odds ratio (OR) and confidence interval (CI) for the association of different parameters with 10% weight loss at 60 days from treatment initiation. Student t-test was used to compare the mean values across different strata.

Results: A weight loss of >10% was observed in 15 patients (34%). Only the use of mild (but not strong) opioids was associated with weight loss; estimated OR = 6.2 (C.I. 1.2-31.9, p=.03). No association was observed for the MDASI parameters. Baseline levels of cytokines were available for 23 patients. We observed significant differences in the mean values of CXCL-16 (p=.05) and IL-6 (p=.045) in patients with weight loss as compared to those without weight loss. Moreover, serum level of erythropoietin may be negatively associated with weight loss (p=0.06).

Conclusions: Alterations in serum cytokine levels may correlate more strongly with cachexia than clinical symptoms and underscore the importance of cytokine analysis in identifying PC patients at high risk for cachexia.

[Table: see text]
Use of DPC-4 immunostaining of diagnostic cytology specimens to predict the pattern of tumor progression in locally advanced pancreatic cancer patients (LAPC).
Authors: Crane C. H. , Yordy J. S. , Varadhachary G. R. , Haque W. , Wolff R. A. , Das P. , Krishnan S. , Fleming J. B. , Abbruzzese J. L. , Staerkel G. A.
Published: February 2017

209

Background: An autopsy study has identified DPC-4 as a potential biomarker of the pattern of disease spread in pancreatic cancer patients (Iacobuzio-Donahue et al, JCO, 2009). We sought to determine whether DPC-4 expression determined by immunohistochemistry (IHC) staining of primary tumor cytology specimens correlates with the clinical pattern of progression in patients with locally advanced pancreatic cancer (LAPC).

Methods: LAPC patients with ECOG 0-1 PS were treated with gemcitabine (1000 mg/m2), oxaliplatin (100 mg/m2), and cetuximab for (500mg/m2) q2wks for 4 doses followed by XRT (50.4 Gy to the gross tumor only) with capecitabine (825 mg/m2 twice daily, days of radiation) and cetuximab on a multiinstitutional trial. Forty-one of 58 patients treated at our institution had cytology specimens suitable for IHC staining. The patterns of progression were determined based on radiographic studies and clinical symptoms. Findings were blinded from the IHC results. Patients were categorized as 1) local disease dominant, 2) distant disease dominant, 3) indeterminate pattern, and 4) no progression. The IHC scoring of DPC-4 was determined by an experienced cytopathologist who was blinded from the clinical data.

Results: Median, 1yr and 3yr actuarial OS are 18.2 months, 67.2% and 18.5%. Dominant progression pattern was local (n=15), distant (n=14), indeterminate (n=8), and no progression (n=4). Intact DPC expression correlated with local dominant progression (11/15) and DPC-4 loss correlated with distant dominant progression (10/14), p=0.016. The median DM free survival rate was 18.0 for intact DPC-4 versus 12.5 mo for DPC-4 loss patients (p=NS). There was no significant difference in overall survival based on DPC-4 status.

Conclusions: Determination of DPC-4 expression from cytology specimens is feasible. DPC-4 expression correlated with the pattern of progression and is consistent with previous autopsy data. DPC-4 expression does not appear to be predictive or prognostic. Prospective validation of DPC-4 as a biomarker of disease progression is warranted and may lead to personalized treatment strategies for patients with LAPC.

[Table: see text]
Effect of transplantation of pro-angiogenic monocytes to pancreatic cancer-bearing mice on resistance to chemotherapy/radiotherapy.
Authors: Mizukami Y. , Kawamoto T. , Sugiyama Y. , Sasajima J. , Koizumi K. , Moriichi K. , Fujiya M. , Bardeesy N. , Chung D. C. , Kohgo Y.
Published: February 2017

212

Background: Hypoxic tumors are usually resistant to conventional chemotherapy and radiotherapies, which typically target actively dividing cells. The tumor vasculatures are unorganized and lack adequate pericyte coverage, which compromises delivery of drugs to tumors. How best to normalize the aberrant tumor vasculature to maximize anticancer drug delivery comprises an area of intensive investigation.

Methods: We tested out hypothesize that bone marrow (BM) cells may be able to restore appropriate vessel function in tumor vasculature using nude mice bearing pancreatic cancer xenografts and genetically engineered mice that develop pancreatic adenocarcinoma.

Results: Culturing BM mononuclear cells with endothelial growth medium resulted in the early outgrowth of spindle-shaped attached monocytic cells expressing CD11b/CXCR4 with a significant vessel stabilizing activity. Intravenous administration of these cultured pro- angiogenic cells into mice bearing pancreatic cancer significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Consistent with a marked reduction in gene expressions involved in drug resistance such as MDR1 and ABCG2 in monocytes-injected tumors, a combination of the transplantation and chemotherapeutic agents reduced tumor size and significantly increased areas of necrosis as compared to chemotherapy alone.

Conclusions: Our findings offer an alternate approach to improve delivery and efficacy of anticancer drugs to hypoxic tumors through a remodeling of the abnormal tumor vessels.

No significant financial relationships to disclose.
A novel p53-based strategy for protection of gastrointestinal track and bone marrow (BM) from 5-fluorouracil (5-FU).
Authors: Ha C. S. , Ganapathy S. , Yuan Z.
Published: February 2017

213

Background: Acute toxicity from DNA damaging agents such as radiation and chemotherapy is mainly mediated by p53 which, upon activation, induces massive apoptotic cell death in sensitive tissues such as GI track and BM. Expanding from our recent finding that low-dose arsenic can temporarily and reversibly suppress p53 activation and subsequent tissue damages in normal tissues but not in carcinomas due to distinct differences in p53 status, we used a mouse tumor xenograft model to test the potential of arsenic in protecting the GI track and BM from one of the most commonly used chemotherapeutic agents for GI malignancies, 5-FU, without compromising tumor control.

Methods: Arsenic pretreatment was done by feeding sex-matched mice (4-6 weeks old) with water with or without 1.0 mg/L sodium arsenic for 3 days. Mice were randomized into 4 groups: A. control; B. arsenic only; C. 5-FU (30 mg/kg body weight i.v. for 5 days) only; D. arsenic and 5-FU. 5- FU-induced GI track and BM damages were analyzed histologically with H&E staining 4 weeks after last treatment. Body weight was monitored as a measure of toxicity. Lung carcinoma NCI-H358 was used to generate a mouse xenograft model. Treatments were initiated 3 weeks after implantation when the lung carcinomas reached an average volume of 100 mm3. Tumor volumes were measured periodically. Two independent experiments were done with10 mice per group.

Results: Tumor sizes at 9 weeks were (mean±SE in mm3): 528.1±62.81, 504.04±55.19, 133.02±35.74, 114.47±17.49 for groups A,B,C and D respectively (p=ns, C vs. D). The corresponding body weights were (in gm): 34.6±1.5, 36.4±2.1, 31±1.2, and 35.4±1.8 (p=0.0001, t-test, C vs D). 5-FU treatment was associated with severe damages to small intestine and BM, and such damages were significantly reduced by low-dose arsenic pretreatment by histological examination.

Conclusions: Our data demonstrate that a brief treatment with low-dose arsenic is associated with a marked protection of GI track and BM without compromising the ability of 5-FU to kill carcinoma cells.Our data have provided proof-of- principle for the use of low-dose arsenic to protect GI track and BM from toxicity of 5-FU, and for potential 5-FU dose intensification in clinical settings.

No significant financial relationships to disclose.
Effect of apricoxib, a novel COX-2 inhibitor, on the efficacy of standard therapy in human pancreatic cancer cell lines in vitro and in vivo.
Authors: Kirane A. R.
Published: February 2017

227

Background: Gemcitabine-erlotinib is standard of care (SOC) for pancreatic cancer, but this regimen can still be improved upon with regard to prolonging patient survival. Cyclo-oxygenase-2 (COX-2) is overexpressed in pancreatic cancer and implicated in pancreatic tumor progression. Inhibition of COX-2 decreases tumor growth, augments the activity of both gemcitabine and EGFR inhibition, and may play a role in preventing or reversing EMT. This study characterized the effects of COX-2 inhibition on pancreatic cancer cell lines and determined if the addition of apricoxib enhances sensitivity to chemotherapy.

Methods: Baseline EGFR and COX-2 expression were determined in 7 human pancreatic cancer cell lines and functional responses measured by changes in phospho-EGFR (p-EGFR) and prostaglandin E2 (PGE2) production by ELISA. Cytotoxicity was determined for gemcitabine, erlotinib, and apricoxib independently and in combination by MTS assay. The effect of SOC therapy alone or in combination with 10 or 30 mg/kg apricoxib PO on AsPC-1 and Colo357 tumors in vivo was determined in SCID mice bearing established orthotopic xenografts. Tissue was analyzed by IHC and VEGF levels were determined by ELISA.

Results: All lines expressed EGFR and COX-2, but expression alone was not predictive of p-EGFR level, PGE2 production, or response to drug therapy. In vitro, AsPC-1 cells had negligible COX-2 activity, whereas Colo357 cells displayed high levels of COX-2 and PGE2 production. Cell growth and COX-2 activity decreased in all cell lines in the presence of apricoxib and addition of apricoxib improved response to chemotherapy. In vivo, addition of apricoxib to SOC significantly reduced primary tumor growth and almost eradicated metastases in mice bearing Colo357 but not AsPC-1 xenografts. Plasma VEGF levels were unaltered by apricoxib treatment in AsPC-1-bearing animals but were suppressed to undetectable levels in Colo357-bearing animals. Markers of EMT were significantly decreased in animals treated with apricoxib.

Conclusions: Apricoxib enhances the efficacy of gemcitabine and erlotinib in vitro and in vivo and warrants clinical evaluation in patients with pancreatic cancer. A phase II study is ongoing.

No significant financial relationships to disclose.
Effect of AZD0530 (saracatinib) on biliary cancer cell motility and invasion.
Authors: Leone F. , Peraldo-Neia C. , Cavalloni G. , Colombi F. , Aglietta M.
Published: February 2017

231

Background: Biliary carcinoma (BC) has a poor prognosis and limited therapeutic options. The identification of new targets is essential. Among candidates we have studied the tyrosine kinase Src, which is involved in proliferation, invasion, and migration in many tumors.It has been demonstrated that the inhibition of Src significantly reduces proliferation and metastasis development in different solid tumors, such as pancreatic and head and neck cancers. Targeting Src tyrosine kinase may be therapeuticallyuseful in cholangiocarcinoma. We explored the antitumor activity of Src inhibitor saracatinib (AZD-0530) in BC preclinical models.

Methods: Four cholangiocarcinoma cell lines, TFK1, EGI-1, HuH28, and TGBC1-TKB, were treated with saracatinib and analyzed by western blot for the expression of Src and its downstream principal transducer FAK. The inhibition of proliferation was evaluated by cell titer glo assay after treatment with scalar doses of saracatinib alone or in combination with gemcitabine for 72 hours. The effect on migration of BC cells was tested by wound healing assay. Finally, we investigated the antitumor activity in EGI-1 xenografts in NOD/Shi-scidIL2rgnull mice treated with saracatinib at 10 mg/kg/die.

Results: Activation of Src pathaway was shown in all cell lines and saracatinib was able to inhibit its downstream molecules. Saracatinib inhibited BC cell proliferation in standard monolayer liquid culture only at very high concentration (median doses from 2.5 to 15 μM) and did not enhance the antiproliferative effect of gemcitabine. Evidence of anti-tumor activity of saracatinib was obtained in terms of migration inhibition: quantitation of the wound closure over time revealed a significant and dose-dependent inhibitory effect of saracatinib on BC cell motility. In the in vivo model, no reduction of tumor volumes was evidenced up to 14 days of treatment. Assays with prolonged treatments are ongoing.

Conclusions: These results suggest that inhibition of Src kinase by saracatinib impairs the invasiveness of bile duct carcinoma. Further in vivo studies will provide information about the effect on metastasis inhibition by saracatinib.

No significant financial relationships to disclose.
Factors contributing to cure in T2 pancreatic cancer.
Authors: Maetani S. , Doi R. , Imamura M.
Published: February 2017

234

Background: It is crucial to determine whether cancer therapy achieves cure or merely prolongs time to death from cancer (failure time). Unfortunately, conventional survival tests such as log-rank test and Cox regression fail to distinguish between cure and prolonged failure time, both making a great difference in survival benefit. In 1994, Gamel extended the Boag model to three regressions, allowing us to study whether prognostic factors have significant effect on cure rate or failure time. Using the Gamel-Boag regressions, we study curative effects of clinicopathological factors in pancreatic cancer.

Methods: Follow-up data from 452 patients who underwent pancreatectomy for T2 ductal cell cancer were analyzed. The prognostic factors to be studied were converted to binary variables, which include sex, age (<=60 or >60 years), tumor size (<=2 or >2 cm) lymphnode metastasis, and six types of invasions, i.e., serosal, retroperitoneal, portal vain, common bile duct and duodenal invasions. By calculating coefficients of the three regressions and their confidence intervals, we evaluated whether each (or combinations) of these variables are associated with increased cure rate or prolonged failure time.

Results: Tthere were 11 relapse-free 5-year survivors. Except for tumor size (TS) and lymphnode metastasis (N), no factors were significantly associated with increased cure rate or prolonged failure time. The only factor found to significantly affect cure was TS; the estimated cure rate being 44% for patients with TS <= 2 cm and 4% otherwise (p=0.0001). This effect was not influenced by N and other factors. Only N significantly accelerated failure time; the median failure time being 11.9 months when N was negative and 6.7 months otherwise (p<0.0001). Thus, both TS and N affected the prognosis significantly but in different ways. By contrast the Cox regression showed that both TS and N were significantly associated with hazard reduction (p=0.003 and p<0.001, respectively), which, however, did no reveal a qualitative difference in survival outcome between TS and N.

Conclusions: In T2 pancreatic cancer, a highly significant increase in cure rate is found when TS≤2 cm. This increase is not affected by N or tumor extension to nonpancreatic tissues.

No significant financial relationships to disclose.
NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.
Authors: Diaz L. A. , Azad N. S. , Laheru D. , Le D. T. , Devoe C. E. , Cosgrove D. , Zheng L. , Arlen P. M. , Bristol J. A.
Published: February 2017

235

Background: NPC-1C (ensituximab) is a chimeric monoclonal antibody being developed as a novel biologic treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C epitope appears to be expressed specifically by human colon and pancreatic tumor tissues and cell lines.

Methods: Antitumor activity was established in vitro by measuring ADCC with a standard 4-hour 111-Indium release assay on pancreatic and colorectal cancer cell lines. In vivo antitumor efficacy of NPC-1C was tested using pre-established subcutaneous human pancreatic tumor xenograft models.

Results: In vitro, the NPC-1C antibody exhibits ADCC activity specifically against human colon and pancreatic tumor cells, but not against control tumor cell lines. The in vivo data showed significant, and reproducible, antitumor action, including some complete tumor regressions. The clinical application for this antibody was bolstered by several examples of human tumor tissues stained with biotin-conjugated NPC-1C that showed a strong correlation of NPC-1C staining against pancreatic and colon tumors. Approximately 45% of tumors stained strongly positive. The staining pattern was typical of elaborated mucin expression, but also showed cytoplasmic and cell membrane staining.

Conclusions: A phase I open label, multicenter dose escalation clinical trial with NPC-1C is currently accruing patients with advanced pancreatic and colorectal cancer who are refractory to standard therapy. The primary objectives of the phase I clinical trial are to determine the safety and tolerability of escalating doses of NPC-1C monoclonal antibody therapy and to assess pharmacokinetics and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore the immunologic correlates associated with administration of NPC-1C. Results from this trial will determine the minimum standard dosage levels to be used in further trials.

[Table: see text]
A multinational phase II study of liposome irinotecan (PEP02) for patients with gemcitabine-refractory metastatic pancreatic cancer.
Authors: Ko A. H. , Tempero M. A. , Shan Y. , Su W. , Lin Y. , Dito E. , Ong A. , Yeh G. , Chen L.
Published: February 2017

237

Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan (CPT-11) that has improved pharmacokinetics and tumor biodistribution of both CPT-11 and its active metabolite-SN38 compared to the free form drug. PEP02 has showed encouraging safety and efficacy in various tumor types, including significant antitumor activity in a human pancreatic cancer L3.6pl orthotopic nude mouse xenograft model. In previous phase I studies, PEP02 either alone or in combination with 5-FU/LV demonstrated prolonged disease control in 5 of 7 (71%) patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). This phase II study aims to evaluate PEP02 monotherapy as 2nd-line treatment in pts with metastatic, GEM-refractory PC.

Methods: Pts were eligible if they had metastatic pancreatic adenocarcinoma, KPS ≥ 70, and progressed following one line of GEM-based therapy. Treatment consisted of PEP02 120 mg/m2 administered as a 90-minute infusion every 3 weeks. A Simon's 2-stage design was used with 16 pts in the first stage and 39 pts in total; primary objective was 3-month survival rate (OS3-month).

Results: Between March 2009 and August 2010, 37 pts were enrolled at 3 centers in the U.S. and Taiwan. Characteristics for the first 31 evaluable pts: 13 M/18 F; age 39-82 yrs; 19 Asian/12 Caucasian, KPS 100/90/80/70: 5/14/4/8. Mean number of treatment cycles is 5 (range, 1-22). Disease control rate (minor response + stable disease >2 cycles) is 52%. 8 of 24 pts (33%) with elevated baseline CA19-9 have had >50% biomarker decline. To date, 23/31 pts (74%) have survived > 3 months, with 4 pts still alive after 1 year. Reasons for study discontinuation: 74% progressive disease, 9% drug-related toxicity, 17% other. Preliminary safety data is available for the first stage. Most common G3/4 adverse events included: fatigue (31%), neutropenia (25%), nausea/vomiting (19%), and diarrhea (13%).

Conclusions: This study has already met its primary endpoint (predicted OS3-month >65%). PEP02 appears to have both activity and tolerable side effects for pts with metastatic, GEM-refractory PC, and represents a promising option for this pt population with few standard options.

[Table: see text]
Prognostic value of duodenal invasion length in patients with gastric cancer.
Authors: Oshima N. , Tokunaga M. , Tanizawa Y. , Bando E. , Kawamura T. , Kondo J. , Kinugasa Y. , Kanemoto H. , Uesaka K. , Terashima M.
Published: February 2017

24

Background: Duodenal invasion (DI) has been considered as a poor prognostic factor of gastric cancer patients. Not all the patients would be able to undergo curative operation. Neoadjuvant chemotherapy (NAC) may improve the rate of curative operation of these patients. In this study, we investigated whether the length of duodenal invasion preoperative diagnosis can be one of factor to decide indication of NAC.

Methods: A total of 118 gastric cancer patients with clinically evident DI, who underwent laparotomy at our center, were enrolled in this study. 42 patients with DI length 20 mm or longer were categorized into long invasion group (LI), 76 patients with DI length shorter than 20 mm were categorized into short invasion group (SI). Clinicopathologic features, rate of direct invasion and lymph nodes involvement, R0 resection, and survival rate were compared between two groups.

Results: Resection rate was significantly different between two groups: SI group (85.5%; 65/76), LI group (69.0%; 29/42). Direct invasion to adjacent organs was significantly more frequently observed in LI group (21%; 6/29) than SI group (4 %; 3/65, p = 0.02). In LI group, pancreas invasion was observed in all patients except for one patient. Multivariate analysis to predict the adjacent organ invasion revealed that CT diagnosis (p = 0.005) and invasion length (p = 0.01) were selected as risk factors of direct invasion to adjacent organs. There was no significant difference of nodal involvement between LI group (83%; 24/29) and SI group (83%; 54/65 p = 0.99). The 5-year survival rate was 19% in LI group and 43% in SI group (p = 0.23). The number of patients who underwent R0 resection was more frequently in SI group (75.4%; 49/65) than SI group (69.1%; 16/29). The factors of R1 or R2 resection were metastasis of peritoneum or direct invasion to adjacent organs.

Conclusions: In patients with long duodenal invasion, direct invasion to the pancreas was more frequently observed, and resulted in low curative resection rate and poor survival. Preoperative chemotherapy may improve the curative resection rate and survival in these patients. Prospective study is warranted to evaluate the efficacy of NAC for these patients.

No significant financial relationships to disclose.
Minimally invasive surgery for resectable pancreatic cancer in the United States: From staging tool to treatment strategy.
Authors: Smith J. K. , Witkowski E. R. , Murphy M. M. , Ng S. , Shah S. A. , Tseng J. F.
Published: February 2017

243

Background: Debate exists regarding the use of laparoscopy in pancreatic malignancy. The goal of this study was to examine recent laparoscopy use in pancreatic resections for cancer in the US. We hypothesized that there would be two noticeable trends in the use of laparoscopy – the first reflecting staging laparoscopy, the second associated with advancement of laparoscopic pancreatectomy.

Methods: The Nationwide Inpatient Sample (NIS), 1998-2007, was used to identify patients ≥ 18 years old with pancreatic cancer who underwent pancreatic resection with or without associated laparoscopy. Patterns of laparoscopy use and correlated outcomes were examined.

Results: Among 47599 patients (nationally weighted) who underwent resection for pancreatic cancer, 2640 (5.5%) had procedures that included laparoscopy. Yearly trend analyses demonstrated a peak in laparoscopy in 2003 followed by decreased use, then steady increase after 2005. Laparoscopy at time of resection was not significantly associated with decreased complications (p=0.09), but was associated with lower mortality compared to open resection alone (3.2% vs. 5.9%, p = 0.008). On multivariate analysis, independent predictors of increased complications included older age, male sex, higher comorbidity (Charlson) score, urban location, and non-teaching hospital. For increased risk of death, predictors were older age, male sex, Charlson >2, non-teaching hospital, and non-use of laparoscopy.

Conclusions: Trends in the use of laparoscopy during pancreatic resections for cancer suggest initial increased use in the early 2000's following published staging recommendations, with a subsequent decrease contemporaneous with improving imaging techniques. A recent upward trend is likely associated with increased attempts at minimally-invasive resection. The use of laparoscopy is not associated with any difference in complication rate following surgery and is associated with improved perioperative survival. The effects of patient factors, selection, and volume status on minimally invasive pancreatectomy outcomes warrant further investigation.

No significant financial relationships to disclose.
An interim analysis of a phase II study of the combination of TACE and sorafenib in patients with unresectable hepatocellular carcinoma in National Cancer Center Korea (COTSUN KOREA, NCT00919009).
Authors: Park J. , Kim H. , Shim J. , Woo S. , Choi J. , Nam B.
Published: February 2017

253

Background: Transarterial chemoembolization (TACE) is the palliative treatment for patients with unresectable HCC. TACE-induced ischemic injury is known to increase circulating VEGF and related with poor prognosis.The aim of this study is to evaluate efficacy and safety of combined TACE with sorafenib, VEGFR inhibitor in unresectable HCC patients.

Methods: This study is a non-randomized, open-labeld, single-arm, phase II investigator-initiated clinical study. Estimated number of subjects was 50 under the assumption of 3.2 months of median time to progression (TTP) with TACE alone. All patients are Child-Pugh class A or superb B. Sorafenib begins to be administered on 3 days after the first session of TACE and will be subsequently administered up to 24 weeks. Efficacy of TACE was evaluated after 4 weeks from TACE by dynamic CT. Repeated TACE is performed “on demand” in case of PR or SD according to CT/MRI evaluation.

Results: A total of 50 patients were enrolled for this interim analysis. Male was 84% and mean age was 61.5years. Causes of underlying chronic liver disease were HBV in 28 patients (65.1%). Patients were categorized into modified UICC stage II (15, 30.0%), III (24, 48.0%) and IVA (11, 22.0%). Median follow-up period was 5.3 months (range, 1.0–13.1). The size of index lesions was ranged from 1.0 cm to 13.1 cm, and number of lesions was between 1 and 5. Number of TACE sessions was 1.0 (range, 1–4). Common adverse events (AE) during sorafenib therapy were elevation of serum AST/ALT (96.8%), hypocalcemia (90.0%), thrombocytopenia (84.0%), and hyperbilirubinemia (76.0%). Hand-foot skin reaction was most frequently observed among AE of NCI CTCAE grade 3 or higher (40.0%), followed by elevation of serum ALT (38.0%). Dose reduction of sorafenib was needed most commonly due to hand-food skin reaction (n=29). Median TTP was 5.1 months (range, 3.8–6.3).

Conclusions: Adverse events were approved as acceptable by independent monitoring system. Preliminary evidence of antitumor activity was also observed. This trial can be safely performed with close monitoring in inoperable and/or unresectable HCC patients.

No significant financial relationships to disclose.
Activity of a novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 to enhance antitumor activities of gemcitabine and EMAP II in pancreatic cancer.
Authors: Awasthi N. , Yen P. L. , Schwarz M. A. , Schwarz R.
Published: February 2017

255

Background: Gemcitabine (Gem, G) has limited benefits as single agent or in combination for pancreatic ductal adenocarcinomas (PDACs). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in diverse human cancers including PDAC. NVP-BEZ235 (BEZ, B) is a novel dual PI3K/mTOR inhibitor that has been shown to have antitumor activity in multiple tumor types. Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic agent that enhances Gem and docetaxel activity in PDAC. We tested the combination benefits of BEZ and Gem in addition to EMAP in experimental PDAC.

Methods: In vitro cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo animal survival experiments were performed in NOD-SCID PDAC xenografts.

Results: Cultured cells of PDAC (AsPC-1), endothelial (HUVECs), and fibroblast origin (WI-38) all expressed AKT and mTOR protein. BEZ inhibited in vitro cell proliferation of AsPC-1 and HUVECs cells, with some additive effects in combination with Gem or EMAP, after 72 hours of incubation. In AsPC-1, treatment of BEZ (100 nM), Gem (100 nM) and EMAP (1 μM) caused 34, -7, -16, 62, 51, 3, and 59 percent inhibition in proliferation in the B, G, E, B+G, B+E, G+E and B+G+E groups. In HUVECs, percent inhibition in proliferation was 35, 33, 15, 55, 35, 31 and 53 in the B, G, E, B+G, B+E, G+E and B+G+E groups, respectively. Compared to controls (median survival: 16 days), an animal survival increase after BEZ and EMAP therapy alone (both 21 days) and Gem therapy alone (28 d) was observed. Further increases in survival occurred in combination therapy groups B+G (30 d, p=0.007), B+E (27 d, p=0.02), G+E (31 d, p=0.001) and B+G+E (33 d, p=0.004).

Conclusions: Bez has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of Gem and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

No significant financial relationships to disclose.
Downstaging in pancreatic cancer: A matched analysis of patients resected following systemic treatment of initially locally unresectable disease.
Authors: Bickenbach K. A. , Gonen M. , Brennan M. F. , D'Angelica M. I. , DeMatteo R. P. , Fong Y. , Jarnagin W. R. , Allen P. J.
Published: February 2017

257

Background: Patients with locally unresectable pancreatic cancer (AJCC stage III) have a median survival of 10–14 months. Standard treatment for these patients is systemic therapy with or without radiation. The objective of this study was to evaluate outcome of patients who respond to this treatment and undergo resection.

Methods: Using a prospectively collected database (2000-2009), we identified patients who were initially deemed unresectable due to vascular invasion and had sufficient response to non-operative treatment to undergo resection (initial stage III). Overall survival (OS) was compared between this group and a matched group of patients who were resected during the same time period without receiving preoperative treatment (stage I and II). Case-matching was performed using a previously validated pancreatic cancer nomogram.

Results: A total of 36 patients with initial stage III disease were identified who underwent resection after treatment with chemotherapy or radiation therapy. Initial unresectability was determined by operative exploration (n=15, 42%) or by cross-sectional imaging (n=21, 58%). All patients received chemotherapy prior to resection and 58% of patients received radiation. Resection consisted of pancreaticoduodenectomy (n=31, 86%), distal pancreatectomy (n=4, 11%), and total pancreatectomy (n=1, 3%). Pathology revealed T3 lesions in 27 patients (73%), nodal positivity in 6 patients (16%), and a negative margin in 30 patients (83%). There were no operative mortalities. Median follow-up was 13 months (range 2 to 44 months). The median OS in this series was 25 months from resection and 30 months since treatment initiation. There was no difference in OS from time of resection between the initial stage III patients and matched patients who presented with resectable disease (p=0.35).

Conclusions: In this study, patients who were able to undergo resection following treatment of initial stage III pancreatic cancer experienced similar survival as those who presented with stage I and II disease. Resection is indicated in this highly select group of patients.

No significant financial relationships to disclose.
Evaluation of the Charlson comorbidity index to predict outcome after esophagectomy in older patients.
Authors: Kothari A. , Bretl T. , Weigel T.
Published: February 2017

27

Background: Esophagectomy remains a preferred treatment for several neoplastic and non-neoplastic conditions; however it is often avoided in elderly patients with several co-morbid conditions. Several centers endorse the use of the Charlson comorbidity index to predict surgical outcomes in high risk patients. To date, this standard measure of co-morbidity has not been used to predict surgical outcomes following esophagectomy in elderly (age ≥70) patients.

Methods: We reviewed data from an IRB-approved, prospectively maintained thoracic surgery database over a three-year period (March, 2006 – March, 2009). We compared incidence of post-operative events, total length of stay, 30-day mortality, rate of readmission, and calculated Charlson comorbidity indices (CCI) for all patients. A validated electronic application was used to calculate CCI based on patient age, BMI, substance use, malignancy, and co-morbid diseases (CV, respiratory, GI, endocrine, inflammatory, psychiatric, neurologic, and immunologic).

Results: There were 75 patients below the age of 70 and 41 patients ≥ 70 years old who underwent esophagectomy over the 3-year period studied. Patients over the age of 70 had a significantly higher CCI (5.02) than patients under the age of 70 (3.19, p < 0.05). However, the 30 day mortality in patients ≥ 70 (0.0%) and under 70 (2.3%) was not significantly different between groups (p = 0.33). There was no difference in median length of hospital stay (7 days vs. 7 days, p = 0.95) and rate of readmission (7.5% vs. 9.3%, p = 0.74) when comparing patients ≥ 70 and < 70 years old, respectively. Patients ≥ 70 had a significantly lower incidence of complications than patients under the age of 70 (34.1% vs. 60.0%, p < 0.05).

Conclusions: Patients ≥ 70 years old had higher Charlson comorbidity indices than patients < 70 years old, however surgical outcomes in both groups following esophagectomy were similar. In this population, CCI may not be a valid tool for measuring surgical risk perhaps due to the inclusion of age in the index. Future study will focus on the development of a co-morbidity index which can predict outcomes following esophagectomy and is not biased by age.

No significant financial relationships to disclose.
Correlation between pancreatic tumor size as measured on 3D CT scan versus pathologic specimen: Impact on radiation treatment volume.
Authors: Qiu H. , Hsu C. C. , Fishman E. K. , Tuli R. , Wolfgang C. L. , Edil B. H. , Hruban R. H. , Zheng L. , Laheru D. , Herman J. M.
Published: February 2017

276

Background: Definition of the target volume for irradiation of pancreatic cancer (PCA) must balance coverage of micrometastatic disease with toxicity. To determine differences between radiographically defined tumors and true pathologic tumor specimens, we correlated the maximum tumor diameter (TD) of preoperatively imaged tumors with resected tumor specimens.

Methods: With IRB approval, a retrospective chart review of patients who underwent resection of PCA between 2006 and 2010 was conducted. 73 patients were identified with preoperative CT imaging and pathologic analysis of tumors. 70 of 73 patients had a preoperative 3D CT performed. The TD as measured by a radiologist (EF) on contrast CT and 3D CT reconstruction was compared with that measured by pathological analysis of the resected specimen.

Results: 70 patients underwent resection with preoperative CT imaging; 14.1% of these patients had CT performed >6 weeks prior to surgery. The mean (SD) pathologic maximum TD was 31.3 mm (11.3) with range 3 mm to 60 mm. Whereas TD was underestimated by 1.9 mm (1.7 SE) with CT relative to pathologic analysis, this difference was not statistically significant (paired t-test, p=0.27) with a correlation coefficient of 0.265. 3D CT imaging had a smaller mean difference with a mean 3D CT diameter 0.4 mm (1.76 SE) larger than the pathologic specimen (p=0.82) with correlation coefficient 0.222. However, the max TD on 3D CT imaging was on average 2.3 mm larger than on CT (p=0.016) with correlation coefficient 0.798. Of patients with R0 resections (N=48), CT underestimated path size by 3.1 mm (p=0.020), whereas 3D CT was slightly larger (0.1 mm, p=0.949). For R1 resections (n=22), both CT and 3D CT overestimated size (0.8 mm and 1.1 mm, respectively, p>0.5).

Conclusions: PCA TD is generally underestimated on CT imaging, yet better approximated with 3D CT. Improved correlation was seen between CT and pathologic specimens following R0 resection. Alternatively, R1 resection specimens were slightly overestimated by CT/3D CT imaging. As a result, clinical target volumes should be expanded accordingly during radiotherapy planning to properly account for these discrepancies in the gross tumor.

No significant financial relationships to disclose.