bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of plasma angiogenesis-related factors to investigate the association of interleukin 8 and interleukin 6 levels with efficacy of sorafenib-based antiangiogenic therapy in patients with advanced hepatocellular carcinoma (HCC).
Authors: Shao Y. , Hsu C. , Huang C. , Cheng A.
Published: February 2017

199

Background: Anti-angiogenic agents have become the most important class of therapy for patients (pts) with advanced HCC. However, biomarkers predictive of the efficacy of anti-angiogenic therapy remain lacking.

Methods: Advanced HCC pts, enrolled in a phase II study (Hsu et al: J Hepatol 2010) and its extended cohort, were treated with sorafenib plus metronomic oral tegafur/uracil until disease progression. Plasma samples were collected before treatment and 4 weeks after the start of treatment. The levels of IL-6, IL-8, IL-13, CXCL10, PDGF and VEGF-A were analyzed by multiplexed bead suspension arrays (Bio-Rad, Hercules, CA, US). Levels of VEGF-C, VEGF-D, PlGF, fibroblast growth factor 2 (FGF2), SDF1-alpha and soluble VEGF receptor 2 were determined by ELISA. The baseline levels and post-treatment changes of these plasma factors were analyzed for their associations with treatment outcomes.

Results: Among 68 pts treated with the protocol treatment, 64 were enrolled to this study. There were 4 partial responder (PR) and 33 patients with stable disease (SD) according to RECIST 1.0. The disease control rate (PR+SD) was 58%. The median PFS and OS were 3.7 and 7.4 months, respectively. Patients with progressive disease, compared to those with disease control, had significant increase of post- treatment IL-6 (p = 0.016) and IL-8 (p = 0.021), borderline significant increase of post-treatment FGF2 (p = 0.078) and significant decrease of post-treatment CXCL-10 (p = 0.046). High baseline IL-8 was significantly associated with poorer PFS and OS (p = 0.002 and 0.001, respectively). More increase of post-treatment IL-6 was associated with poorer PFS and OS (p = 0.087 and 0.018, respectively). By multivariate analysis, high baseline IL-8 and more post-treatment increase of IL-6 remained independent predictors for poorer PFS and OS.

Conclusions: High baseline IL-8 and more post-treatment increase of IL-6 in plasma were associated with poor treatment outcomes in advanced HCC pts treated with sorafenib-based anti-angiogenic therapy. This study was supported by the grant of NSC 98-3112-B-002-038.

No significant financial relationships to disclose.
Intraductal papillary neoplasm of the bile duct (IPNB): A biliary equivalent to IPMN of the pancreas?
Authors: Rocha F. G. , Lee H. , Katabi N. , DeMatteo R. P. , Fong Y. , D'Angelica M. I. , Allen P. J. , Klimstra D. S. , Jarnagin W. R.
Published: February 2017

201

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a type of cholangiocarcinoma characterized by intraductal growth, mucin production and a better outcome compared to the more common nodular-sclerosing type. IPNB may be analogous to IPMN of the pancreas and may be a precursor of invasive cholangiocarcinoma, but its pathogenesis and natural history are ill-defined. This study examines the incidence, clinicopathologic features and outcome of IPNB in a single center.

Methods: A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic or distal) was reviewed and those with papillary features identified. Histopathologic morphology and immunohistochemical staining for cytokeratin and mucin proteins were utilized to classify IPNB into subtypes. Survival data were analyzed and correlated with clinicopathological parameters.

Results: Between 1993 and 2008, 40 IPNBs were identified in hilar (24/144), intrahepatic (4/86) and distal (12/113) bile duct cancer specimens (11.7%). Histopathologic examination revealed 27 pancreatobiliary, 4 gastric, 3 intestinal, and 6 oncocytic subtypes; cytokeratin and mucin staining was similar to that of IPMNs of the pancreas. Invasive carcinoma was seen in 29/40 (72%) IPNBs. Overall median survival was 59 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included depth of invasion (39 months for > 5mm, 128 months for < 5mm, and 144 months for none, p <0.05), R1 vs R0 resection (36 months vs 82 months, p <0.05), MUC1 expression (53 months for positive vs 144 months for negative, p <0.006), and CEA expression (42 months for positive vs 128 for negative, p<0.02). Expression of MUC2, MUC5A, MUC6, CDX2, mesothelin, p53, Ki67, HepPar1, and B72.3 were not predictive of outcome.

Conclusions: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all cases, occur throughout the biliary tract and share histologic and clinical features with IPMNs of the pancreas. These lesions may represent an alternative carcinogenesis pathway. Given their significant malignant potential, they should be treated aggressively with margin-negative resection.

No significant financial relationships to disclose.
Contribution of environment and genetics to oxidative stress in pancreatic cancer (PC) patients (pts).
Authors: Hocevar B. A. , Chiorean E. G. , Kamendulis L. , Perkins S. M. , Johnston E. L. , DeWitt J. , Li L. , Klaunig J. E.
Published: February 2017

211

Background: Several risk factors have been identified as contributors to PC development, including tobacco and alcohol use, and exposure to environmental chemicals. A common denominator of these risk factors is the ability to induce oxidative stress/damage. An individual's genetic makeup may also contribute to oxidative stress, as oxidative stress/damage genes exhibit single nucleotide polymorphisms (SNPs), which can alter protein expression or activity. The goal of this study was to (1) determine if increased oxidative stress/damage is observed in PC pts and (2) to assess the contribution of environmental and genetic factors to oxidative stress/damage parameters.

Methods: An oxidative stress/damage profile was generated from blood samples of newly diagnosed PC pts (n=20), from non-cohabiting genetic relatives (n=20) and/or from non-genetic relatives living in the same household (n=20). This profile consisted of measurement of total antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), direct and oxidative DNA damage (COMET), and malondialdehyde (MDA) levels. Expression of SNPs in selected oxidative stress/response genes was also evaluated. Environmental and dietary/lifestyle information was collected using a detailed questionnaire.

Results: PC pts, when compared to healthy nonrelated but cohabitating relatives, displayed a significant increase in direct DNA damage (p=0.002), while oxidative DNA damage, TEAC and MDA levels were similar. When comparing PC pts to healthy genetic relatives, increased levels of TEAC, direct and oxidative DNA damage approached or were statistically significant (p = 0.061, 0.002, and 0.062 respectively). Analysis of 26 selected SNPs in oxidative stress/ damage genes in the PC pts vs healthy controls revealed that expression of CYP2A6 (L160H), rs1801272, and TNF (-308G>A), rs1800629, approached statistical significance (p=0.05 and 0.20 respectively).

Conclusions: Increased oxidative DNA damage observed in PC pts vs healthy related, but non-cohabitating relatives, suggests that environmental exposures contribute to oxidative stress. In combination with a specific genetic background, environmental influences may increase the risk of PC.

No significant financial relationships to disclose.
Signal transducer and activator of transcription 5b (STAT5b) as a novel target for anti-neoplastic therapy in human pancreatic cancer.
Authors: Moser C. , Ruemle P. , Schenk H. , Geissler E. K. , Schlitt H. J. , Stoeltzing O. , Lang S. A.
Published: February 2017

217

Background: Activation of signal transducer and activator of transcription 5b (STAT5b) has been associated with tumor growth and metastases in various tumor entities. A number of cytokines, growth factors, and oncogenes that can induce STAT5b activity are also implicated in pancreatic cancer growth and metastases. Hence, we sought to determine STAT5b expression in human pancreatic cancer specimen and effects of selective STAT5b inhibition on pancreatic cancer cells.

Methods: Expression of STAT5b in human pancreatic adenocarcinomas was determined by immunohistochemistry. For in vitro experiments, human pancreatic cancer cell lines (BxPC-3, HPAF-II, L3.6pl) were used. Cancer cells were transfected with STAT5b shRNA plasmid to create stable STAT5b knock-down. Effects of STAT5b inhibition on growth and motility of tumor cells was investigated by MTT and modified Boyden chamber assays. In vivo effects of STAT5b blockade were determined in subcutaneous mouse model.

Results: Nuclear expression of STAT5b was detected in 42/80 human pancreatic adenocarcinomas. In human cancer cell lines, stable knock-down of STAT5b had no effect on growth of tumor cells in vitro. However, tumor cell motility was significantly reduced upon STAT5b blockade (p<0.05). Moreover, expression of various signaling intermediates and transcription factors including c-myc was impaired upon STAT5b knock-down. In a subcutaneous tumor model, inhibition of STAT5b led to significantly reduced tumor growth (p<0.05) which was also reflected by final tumor weights (p<0.05). Furthermore, as revealed by immunohistochemistry, blockade of STAT5b significantly reduced tumor vascularization in vivo (p<0.05).

Conclusions: STAT5b is expressed in human pancreatic adenocarcinomas. Blockade of STAT5b impairs cancer cell motility in vitro, suggesting antimetastatic potential. Moreover, inhibition of STAT5b significantly reduces tumor growth and tumor vascularization in vivo. Hence, STAT5b might be an interesting target for antineoplastic therapy in human pancreatic cancer.

No significant financial relationships to disclose.
Role of histone deacetylase expression on regulating cancer stem cells in intrahepatic cholangiocarcinoma.
Authors: Saito Y. , Shimada M. , Morine Y. , Iwahashi S. , Utsunomiya T. , Imura S. , Ikemoto T. , Mori H. , Hanaoka J.
Published: February 2017

219

Background: Histone deacetylase (HDAC) modulates gene expressions by chromatin remodeling during malignant transformation, and showed malignant behavior in intrahepatic cholangiocarcinoma (IHCC) (ASCO GI 2008). HDAC inhibitors have recently been found to repress the function of hypoxia inducible factors (HIF) through inducing hyperacetylation of histones. We also reported that the correlation between the expression of CD133, which was one of the cancer stem cell marker, and HIF-1α in IHCC (J Gastroenterol. 2010), and hypothesized that the cancer stem cell could be regulated by histone acetylation through the HIF-1α pathway. The aim of this study was to elucidate the potential mechanism of HDAC for the regulation of malignant behavior including the cancer stem cell in IHCC.

Methods: Thirty-five patients with IHCC who underwent hepatic resection were evaluated. The expressions of HDAC1 (sc-6298 Santa Cruz Biotechnology, USA), HIF-1α (NB100-105 Novus Biologicals, USA) and CD133 (Ab27699 Abcam Inc, UK) were determined immunohistochemically, and the patients were divided into two groups: HDAC1 positive group (n=21); and negative group (n=14). Clinicopathological variables including HIF-1α and CD133 expressions were analyzed according to these expressions.

Results: The HDAC1 expression correlated significantly with higher stage, lymph node metastasis, and vascular invasion. The prognosis in the HDAC1 positive group was poorer than in the HDAC1 negative group (5-year survival: 77.9% vs. 7.9%, p=0.001). In the multivariate analysis, HDAC1 positive expression was identified as the only independent prognostic factor for disease free survival (Hazard Ratio: 7.194, p=0.0018). There was a significant correlation between HDAC1 expression and HIF-1α expression (p=0.007), and also between HIF-1α expression and CD133 expression (p=0.10). Furthermore, co-expressions of these markers in same cancer cells were proven by immunofluorescent staining in the serial section.

Conclusions: The findings suggested that histone acetylation regulated cancer stem cell through the HIF-1α pathway; therefore, HDAC1 might be a possible promising molecular target in IHCC.

No significant financial relationships to disclose.
Effect of the addition of algenpantucel-L immunotherapy to standard adjuvant therapy on survival in patients with resected pancreas cancer.
Authors: Hardacre J. M. , Mulcahy M. F. , Small W. , Talamonti M. , Obel J. C. , Rocha Lima C. S. , Safran H. , Lenz H. , Chiorean E. G. , Link C. J.
Published: February 2017

236

Background: Pancreatic cancer portends a poor prognosis with ∼4% long-term survival. Among the estimated 20% of patients who have resectable disease, the 1-/3-/5-year survival rates approximate only 70%/30%/18%, even with adjuvant therapy. Better treatment options are needed and addition of algenpantucel-L (HyperAcute-Pancreas) to standard adjuvant therapy is proposed to improve prospects for survival. Algenpantucel-L is composed of irradiated, live, allogeneic human pancreatic cancer cells expressing the enzyme α-1,3 galactosyl transferase (α-GT), which is the major barrier to xenotransplantation from lower mammals to humans (e.g., hyperacute rejection). Up to 2% of circulating human antibodies are directed against the α-GT epitope of algenpantucel-L and are the proposed mechanism of initiating the anti-tumor immune response.

Methods: Open-label, single arm, multi-institutional phase II study (NLG0205) to evaluate algenpantucel-L + standard adjuvant therapy (RTOG-9704, JAMA, 2008: gemcitabine + 5-FU-XRT) for pancreatic cancer patients undergoing R0/R1 resection. Disease-free (DFS) and overall survival (OS) are the primary and secondary endpoints, respectively.

Results: 73 patients (70 evaluable, 15 month median follow up) received gemcitabine + 5-FU-XRT + algenpantucel-L (mean 12 doses, range 1-14). Demographics and prognostic factors: median age 62 years, 47% female, 81.4% lymph node positive, median tumor size 3.2 cm (range 2-15 cm; 26% > 4cm) and 24% post-operative CA 19-9 > 90. Kaplan-Meier estimated survival rates at 12 and 24 months are 91% and 54%, respectively, comparing favorably to 63% and 32% expected based on the nomogram described by Brennan et al (Ann Surg, 2004). Likewise, the current median DFS of 16 months compares favorably to the 11 months observed in RTOG 9704. OS data continues to mature, with 74% still censored. Algenpantucel-L was well tolerated with no likely/directly attributable grade 3 SAEs. The most common adverse events were injection site pain and induration.

Conclusions: Addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A phase III study began patient enrollment in May 2010.

[Table: see text]
A randomized phase II study of gemcitabine (GEM) plus S-1 combination chemotherapy versus GEM monotherapy in patients (pts) with advanced biliary tract cancer (BTC).
Authors: Sasaki T. , Isayama H. , Ito Y. , Yasuda I. , Toda N. , Hanada K. , Matsubara S. , Maguchi H. , Yashima Y. , Kamada H. ,   Japanese Endoscopist & IVRists Group for Biliary Tract Cancer
Published: February 2017

250

Background: Our previous phase II study demonstrated that GEM/S-1 combination chemotherapy was tolerable and showed good efficacy in pts with advanced BTC (Sasaki et al, Cancer Chemother Pharmacol 2010). This randomized phase II study compared the response rate of GEM/S-1 combination chemotherapy and GEM monotherapy in pts with advanced BTC.

Methods: Pts with advanced BTC who had at least one measurable lesion were randomized into two groups. GEM/S-1: GEM 1,000 mg/m2 (day 1, 15) and S-1 80 mg/m2 (day 1-14) repeated every 4 weeks. GEM: GEM 1,000 mg/m2 (day 1, 8, 15) repeated every 4 weeks. Treatment was continued until disease progression. The primary endpoint was objective response according to RECIST version 1.0.

Results: From November 2008 to March 2010, 62 pts were enrolled from 13 institutions. Patient characteristics were: median age 72 (range 47-86); Male/Female 36/26; Performance status 0/1/2 (37/22/3). The primary tumor site was; 30 pts in gallbladders, 16 pts in intrahepatic bile ducts, and 16 pts in extrahepatic bile ducts. Seven pts had previous surgical resection. Response rates of GEM/S-1 and GEM were 16.7% and 9.4%, respectively. The median time-to-progressions of GEM/S-1 and GEM were 5.6 months and 4.1 months, respectively.

Conclusions: GEM/S-1 combination chemotherapy is more active than GEM monotherapy in pts with advanced BTC. Updated time-to-progression and overall survival data will be presented at the meeting.

No significant financial relationships to disclose.
Significance and reliability of pathologic marker Ki-67 in patients with neuroendocrine cancers.
Authors: Singh S. , Feinberg Y. , Rowsell C. , Law C.
Published: February 2017

264

Background: Molecular markers, especially Ki-67, in neuroendocrine cancers (NETs) have become increasingly important. Debate exists as to the optimal role of ki-67 in the treatment of this uncommon cancer. This study was designed to examine the significance of ki-67 as a clinical predictor and its reliability in the treatment of NETs.

Methods: A retrospectively assembled integrated database with prospectively collected data of patients undergoing multidisciplinary management for NETs between 2000 to 2009 was analysed. Clinical and outcomes data were collected. Ki-67 was then categorized to Group A (≤2%), B (3-15%) and C (>15%). We compared the original Ki-67 value to the reviewed value. We then used a kappa statistic to calculate the inter-rater agreement between the original and reviewed determination of Ki-67. Fisher's exact test was used to compare categorical variables. Survival was evaluated using the log-rank test. All analyses were carried out using SAS 9.1.3.

Results: A total of 184 patients were seen at our clinic. Ki-67 correlated with metastases at presentation (36, 52, 63% for Groups A, B, C respectively, p<0.05), while influencing treatment with chemotherapy even in the absence of metastases (14, 29, 57% for Groups A, B, C respectively, p< 0.002). Ki-67 predicted overall survival (p=0.0005) in favor of Group A. 99 patients had an original Ki-67 reported from the referring center and then a review by an expert pathologist at the multidisciplinary clinic. In Group A, there was 94.4% agreement, with 3.7% of cases upgraded at review to Group B and 1.9% of cases upgraded to Group C. In Group B, there was 94.3% agreement, with 5.7% of cases downgraded to Group A, and 0% upgraded. In Group C, there was 90% agreement, with 10% of cases downgraded to Group B and none to Group A (kappa = 0.89).

Conclusions: Our previous report had demonstrated that Ki-67 influenced decisions regarding treatment options. In our updated population of NETs patients, Ki-67 continued to predict biology, influence treatment, and predict survival. In addition we demonstrated high reproducibility of Ki-67. It appears that with modern techniques Ki-67 can be highly reproducible and reliable tool in improving outcomes in this patient population.

No significant financial relationships to disclose.
Dose-escalated external beam radiotherapy in unresectable hepatocellular carcinoma.
Authors: Skinner H. D. , Sharp H. J. , Kaseb A. O. , Javle M. M. , Vauthey J. , Abdalla E. K. , Delclos M. E. , Das P. , Crane C. H. , Krishnan S.
Published: February 2017

267

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Data regarding the use of external beam radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with external beam radiotherapy in the modern era at a single institution.

Methods: A total of 29 patients with localized HCC treated from 2000 to 2009 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30-75 Gy) with a median biologically effective dose (BED) of 80.6 (range 60-138.6). Median tumor size at the time of radiation was 5.2 cm (range 2-25 cm).

Results: Median residual tumor following radiation was 80% (range 27%-278%), with a median residual α-fetoprotein of 47% (range 0.8%-8240%). Estimated one-year overall survival (OS) and in-field progression-free survival (PFS) rates for the study population were 56% and 79%, respectively. One year OS in patients treated to a BED <75 was 18% vs. 69% in patients treated to a BED ≥75 (p=0.002). One year in-field PFS rate (60% vs. 88%, p=0.023) and biochemical PFS duration (median 6.5 vs. 1.6 mos., p=0.001) were also significantly improved in patients treated to a BED ≥75. Grade 3 toxicity was seen in only 13.8% of patients.

Conclusions: In a population without endemic viral hepatitis, unresectable HCC demonstrates significant response toexternal beam radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased BED is associated with improved survival and local tumor control.

No significant financial relationships to disclose.
Effect of extrahepatic disease on transarterial chemoembolization for metastatic carcinoid.
Authors: Arrese D. , Feria-Arias E. , Khabiri H. , Guy G. , Schmidt C. R. , Shah M. H. , Bloomston M.
Published: February 2017

283

Background: Transarterial chemoembolization (TACE) is the locoregional therapy of choice for the management of patients with inoperable carcinoid liver metastases. Often, metastatic disease is not limited to the liver. The impact of extra-hepatic metastases on response and outcomes following TACE has not been described. Objective: We hypothesized that patients who have extra-hepatic disease would have similar tumor response and symptom control following TACE.

Methods: We reviewed 198 patients that underwent TACE for inoperable carcinoid liver metastases. Two groups were identified, those with (N= 129) and without (N= 69) evidence of extra-hepatic disease at the time of TACE. Demographics, clinicopathologic characteristics, response to TACE, complications, and survival were compared.

Results: The two groups were similar in demographics and histopathologic characteristics. Complications following TACE were similar. There was no difference between the groups with and without evidence of extrahepatic disease in symptomatic (76% vs 71%), biochemical (78% vs 90%) or radiographic response (35.0% vs 46%) to TACE. The group without extra-hepatic disease had a median survival of 88 vs 35 months with five-year survival of 65% vs 30% compared to patients with extra-hepatic disease at the time of TACE.

Conclusions: Patients with extrahepatic metastatic disease from carcinoid tumor experienced shorter overall survival following TACE compared to those without extrahepatic disease. However, patients with extra- hepatic disease had similar symptomatic, biochemical and radiographic response to TACE compared to those with disease confined to the liver. Although the long-term prognosis for patients with extrahepatic disease is worse than those with liver-only metastasis, meaningful response to TACE is possible and should be considered.

No significant financial relationships to disclose.
A randomized phase II study of gemcitabine (G) plus the cardiac glycoside huachansu (H) in the treatment of patients with locally advanced (LAPC) or metastatic pancreatic cancer (MPC).
Authors: Meng Z. , Liu L. , Shen Y. , Yang P. , Cohen L. , Huo Y. , Zhao Q. , Ng C. S. , Chang D. Z. , Garrett C. R.
Published: February 2017

284

Background: Wild toad venom has been used for over 1,000 years as a traditional Chinese medicine; H, the extract of dried toad skin glands, is a potent cardiac glycoside without significant toxicity. H has demonstrated preliminary evidence of antitumor activity in phase I clinical trial evaluation (Cancer 2009, 115:5309-18).

Methods: We conducted a randomized, single-blind, phase II clinical trial of G + H versus G + placebo in patients with LAPC or MPC. Plasma bufalin levels were performed in H-treated subjects. 80 evaluable subjects accrued from October 2007 to May 2010 and were treated with G 1,000mg/m2 (iv on days 1, 8, 15, q 28d) plus either H (20 mL/m2 iv daily for 21 days followed by 7 days off, q 28d) or placebo. Demographic data is demonstrated in the table below.

Results: Grade 3/4 adverse events, objective radiographic response rates (ORR), time to progression (TTP), quality of life (QOL), and overall survival (OS) were similar in the two groups (Table). There was not a statistically significant difference in the average plasma bufalin levels in patients with a radiographic partial response (PR) or stable disease versus those with progressive disease (PD) (0.098 ± 0.093 ng/mL vs. 0.071 ± 0.048 ng/mL, p=0.679).

Conclusions: H when added to G was well tolerated but did not improve OS, TTP, QOL, or ORR. Further investigation of a more potent oral formulation of H is planned. H provided by Shenzhen 999 Traditional Chinese Medicine & Development Co., Ltd. Supported by NIH U19CA121503-01.

[Table: see text]

No significant financial relationships to disclose.
Construction and validation of a practical prognostic index for patients with metastatic pancreatic adenocarcinoma.
Authors: Morizane C. , Okusaka T. , Morita S. , Tanaka K. , Ueno H. , Kondo S. , Ikeda M. , Nakachi K. , Mitsunaga S. , Yamaguchi T.
Published: February 2017

285

Background: The aim of the present study was to determine prognostic factors in patients with metastatic pancreatic adenocarcinoma (PC) receiving systemic chemotherapy and to construct and validate a prognostic index for metastatic PC.

Methods: The relationship between patient characteristics and outcome was examined by multivariate regression analyses of data from 409 consecutive patients with metastatic pancreatic adenocarcinoma who had been treated with a gemcitabine- containing regimen (GEM alone: 302 patients, GEM + cisplatin (CDDP): 39, GEM + 5-flurorouracil (5-FU): 27, GEM + S-1:41), and we stratified the patients into three risk groups according to the number of prognostic factors they had for a poor outcome. A validation data set obtained from 145 patients who had been treated with agents other than GEM (5-FU + CDDP, MTX+5- FU, docetaxel, UFT, S-1, CPT-11) was analyzed. The prognostic index was applied the each of the patients.

Results: The multivariate regression analyses revealed that the presence of pain (hazard ratio (HR): 1.692), peritoneal dissemination (HR:1.756), liver metastasis (HR:1.423), and an elevated serum CRP level by > 1.0 mg/dl (HR:1.540) significantly contributed to a shorter survival time. The patients were stratified into three groups according to their number of risk factors and their outcomes of the three groups were significantly different. The median survival times (MSTs) of the low-, intermediate-, and high-risk groups were 11.1, 7.3, and 3.2 months, respectively. When the prognostic index was applied to the validation data set, the respective outcomes of the three groups were found to be significantly differed from each other. The MSTs of the low-, intermediate-, and high-risk groups were 8.6, 5.2, and 2.3 months, respectively.

Conclusions: Pain, peritoneal dissemination, liver metastasis, and an elevated serum CRP value are important prognostic factors for patients with metastatic pancreatic adenocarcinoma.

No significant financial relationships to disclose.
Immediate impact of the FOLFIRINOX phase III data reported at the 2010 ASCO Annual Meeting on prescribing plans of American oncology physicians for patients with metastatic pancreas cancer (MPC).
Authors: Bendell J. C. , Britton S. , Green M. R. , Willey J. , Lemke K. E. , Marshall J.
Published: February 2017

286

Background: Since 2005 we at Xcenda, LLC have studied prescribing plans of American medical oncologists for first-line therapy in patients with MPC. In 2008 we reported the steady growth of prescribing plans for the gemcitabine-erlotinib (GE) combination from 23% in late 2005 to 46% in 2007. In 2007, gemcitabine (G) alone was the second most common regimen planned (27%) (Green MR. Proc GI ASCO 2008). No cytotoxic doublet consistently garnered >10% prescribing share in this clinical setting. At ASCO 2010 Conroy et al. (J Clin Oncol. 2010;28(15s): Abstract 4010) reported a survival advantage for the FOLFIRINOX regimen compared to package insert dose and schedule of G alone as first-line therapy in patients with MPC and excellent PS (0-1).

Methods: Between 7/31 and 8/28/2010 we again used our extensively tested, live research vehicle, NMCR Challenging Cases, to assess current prescribing plans of over 370 American medical oncologists for first-line therapy in a patient with metastatic pancreas cancer and either PS 1 or PS 2.

Results: The FOLFIRINOX data have produced an immediate change in the distribution of planned first-line prescribing with 18% share for the PS 1 scenario, largely substituted for previous use of GE for this setting (Table). In PS 2, plans for FOLFIRINOX are minimal with G alone followed by GE as the dominant selections.

Conclusions: The recently reported phase III FOLFIRINOX data are impacting first-line prescribing plans for patients with MPC. We will continue to quantitate physician-prescribing plans to more fully understand the additional impact the FOLFIRINOX data may have on overall chemotherapy management of these patients.

[Table: see text]

[Table: see text]
Everolimus versus placebo in Japanese patients with advanced pancreatic neuroendocrine tumors (pNET): Japanese subgroup analysis of RADIANT-3.
Authors: Ito T. , Okusaka T. , Ikeda M. , Tajima T. , Kasuga A. , Fujita Y. , Furuse J.
Published: February 2017

289

Background: Everolimus demonstrated a statistically and clinically significant improvement in PFS over placebo in a multi-national, randomized, placebo-controlled, phase III trial in patients with advanced low- or intermediate-grade pNET with disease progression within the prior 12 months (RADIANT-3) (Ann Oncol [2010] 21[suppl 6]: NP doi:10.1093/annonc/mdq340). Forty patients were enrolled from Japanese sites and randomized (n=23: everolimus; n=17: placebo) in that study. The purpose of this report is to investigate the efficacy and safety in the Japanese subgroup.

Methods: Subgroup analysis for the Japanese patients was performed comparing the efficacy and safety between everolimus 10mg/d orally plus best supportive care (BSC) and matching placebo plus BSC. The primary efficacy endpoint was progression-free survival (PFS). The safety was evaluated based on the incidence of adverse events (AEs).

Results: Treatment with everolimus resulted in a significant prolongation by 16.62 months in median PFS (19.45 months for everolimus, 2.83 months for placebo), with 81% reduction in the hazard ratio of progression/death (HR 0.19 [95% CI: 0.08, 0.48]; one-sided unstratified log-rank test: p<.001). The most common AE was stomatitis (73.9% everolimus vs 23.5% placebo); mostly grade 1/2. Grade 3/4 AEs occurred in 69.5% of the everolimus arm and 29.4% of the placebo arm, and amongst the most frequent included (% in everolimus vs % in placebo): neutropenia (17.4% vs 3%); anemia (8.7% vs 0%); pneumonitis (8.7% vs 0%); leukopenia (8.7% vs 0%). The remainder of grade 3/4 AEs was less than 3%. Median duration of exposure to everolimus was 57 weeks vs 47 weeks on placebo. Treatment discontinuation for AEs was 17% in the everolimus arm vs 0% in the placebo arm.

Conclusions: Everolimus demonstrated a clinically meaningful improvement in PFS over placebo in Japanese patients. Everolimus was well tolerated in Japanese patients, and no new safety concerns were noted. This result suggests that everolimus can be a standard treatment for Japanese patients with advanced pNET.

[Table: see text]
Correlation of clusterin with pancreatic endocrine tumors' size and stage.
Authors: Allam-Nandyala P. , Djeu J. , Coppola D.
Published: February 2017

291

Background: Clusterin, a ubiquitous multifunctional cytoplasmic and secretory sulfated glycoprotein (sCLU), plays a role in prevention of apoptosis and it is overexpressed in a variety of tumors. The role of sCLU in pancreatic neuroendocrine tumors (PET) has not been investigated. In this study sCLU expression was evaluated in a subset of PET, and the results were correlated with the clinical pathological features of the tumors.

Methods: sCLU expression was immunohistochemically evaluated in 106 cases of PET using the avidin-biotin-complex method and the tissue microarray analysis technology. The immunohistochemical reactions were qualitatively and semiquantitatively evaluated by 2 pathologists.

Results: Strong sCLU reactivity was identified in 36/65 (51%) PETs. In 23/65 (35%) cases the sCLU score was 3 or less. sCLU expression scores significantly correlated with tumor size (p-value= 0.03) and with tumor stage (p-value= 0.02). The IHC score index did not correlate with tumor grade (p= 0.15).

Conclusions: We report the novel expression of sCLU in PET. The correlation of sCLU with PET size and stage involves this molecule in pancreatic neuroendocrine tumorigenesis. sCLU may represent a new target of therapy for PET.

No significant financial relationships to disclose.
PET-guided treatment in locally advanced adenocarcinoma of the esophagogastric junction (AEG): The MUNICON-II study.
Authors: Lordick F. , Meyer Zum Bueschenfelde C. , Herrmann K. , Geinitz H. , Schuster T. , Friess H. , Molls M. , Schwaiger M. , Peschel C. , Krause B.
Published: February 2017

3

Background: Previous studies demonstrated that fluorodeoxyglucose (FDG)-PET can help to detect response early during neoadjuvant chemotherapy. The prognosis of metabolic non-responders is poor. Therefore, we initiated the prospective MUNICON-II study to determine the value of salvage neoadjuvant chemoradiation in early PET nonresponders.

Methods: 56 patients (pts) with locally advanced AEG type I and II (cT3/4 Nx M0) were included. Tumor glucose uptake was assessed by FDG-PET before and 14 days after initiation of chemotherapy. PET nonresponse was defined as a decrease of the tumor FDG standard uptake value < 35%. Nonresponders received salvage preoperative chemoradiation consisting of external beam radiation 32 Gy (1.6 Gy/fr x 2/day) plus daily cisplatin 6mg/m2 and then proceeded to surgery. Metabolic responders continued with chemotherapy (platin/5-FU-based) for 3 months.

Results: 33 pts had a PET response, 23 had a PET nonresponse. Resection was performed on 54 pts. R0 was achieved in 27 (82%) PET responders versus 16 (70%) nonresponders (p = 0.51). Major histologic remissions (< 10% residual tumor) were observed in 12 PET responders (36%) and 6 PET non responders (26%). After a median follow-up time of 38.0 mon, the median event-free survival (EFS) and the median overall survival (OS) were not yet reached in the PET responders, while EFS was 15.4 mon and OS was 18.3 mon in nonresponders.

Conclusions: This study confirms the prognostic value of early metabolic response evaluation during neoadjuvant chemotherapy. Histopathologic responses were observed after salvage chemoradiation, but the clinical outcome of early PET non-responders to chemotherapy remains poor, indicating a dismal tumor biology in this group of pts.

No significant financial relationships to disclose.
Stereotactic radiation treatment planning with volumetric modulated arc therapy: Impact of duodenal sparing on pancreatic tumor coverage.
Authors: Kumar R. , Kang J. , Herman J. M. , Tuli R. , Pawlik T. M. , Tryggestad E. , Smith K. , DeWeese T. L. , Wong J. , Ford E. C.
Published: February 2017

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Background: Volumetric modulated arc therapy (VMAT) allows for intensity-modulated radiation delivery with faster treatment times and fewer delivered monitor units (MU). The dose-limiting structure for pancreatic stereotactic body radiation therapy (SBRT) is the duodenum. We evaluate VMAT dose distribution, delivery times, and the effect of duodenal sparing (DS) for pancreas SBRT.

Methods: Plans of 15 patients with unresectable pancreatic cancer (14 head/1 tail) were selected. VMAT treatment planning with the “SmartArc” function of Pinnacle v. 8.9 was used to plan one fraction of 25 Gy to the PTV (gross tumor + 2 mm expansion) normalized to the 80% isodose line. Two VMAT SBRT plans were conducted for each case; the first did not attempt to spare the duodenum (non DS) while the second did (DS). Constraints were stomach/duodenum any point max <30 Gy (for DS plan), liver D50 < 5 Gy, ipsilateral kidney D25 < 5 Gy, cord Dmax < 5 Gy and stomach D4 < 22.5 Gy.

Results: Gross tumor volume ranged from 58.4cm3 to 320.3 cm3. The average overlap volume between PTV and the duodenum was 8.4 cm3. In 10/15 non-DS plans, the duodenal Dmax exceeded 30 Gy. With DS optimization, only 1/15 plans exceeded the 30 Gy threshold. These differences were statistically significant (p<0.001). Typical MU and delivery times, as calculated by the planning software, were 5494 MU and 775 secs vs. 5296 MU and 703 secs for the DS and non-DS plans, respectively. The difference in delivery times was significant (p=0.01), but amounted to only 1.2 min on average. The average duodenal Dmax for non-DS plans was 30.4Gy, D4% was 23.4 Gy. With DS, the average Dmax was reduced to 28.1Gy and D4% to <19.7 Gy (p<0.001). As expected, VMAT plans with greater overlap between the duodenum and PTV had a higher duodenal Dmax.

Conclusions: This study demonstrates the feasibility of VMAT for high-dose SBRT treatment of pancreatic cancer incorporating constraints to limit the dose to the duodenum. Future studies will evaluate whether VMAT with fractionated SBRT results in improved duodenal sparing more efficiently than traditional IMRT.

No significant financial relationships to disclose.
Concurrent chemoradiotherapy with gemcitabine and S-1 for unresectable locally advanced pancreatic adenocarcinoma: A phase I study.
Authors: Ioka T. , Fukutake N. , Ikezawa K. , Tanaka S. , Nakamura S. , Nishiyama K.
Published: February 2017

305

Background: The primary objective of this study is to assess the toxicity of concurrent radiotherapy with a combination of gemcitabine (GEM) and S-1 for unresectable locally advanced pancreatic cancer.

Methods: Chemotherapy-naive patients with histologically or cytologically proven unresectable locally advanced pancreatic adenocarcinoma were enrolled to this trial. The patients received gemcitabine intravenously over 30 min on days 1 and 8 and S-1 orally b.i.d. from days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/msq/week) and S-1 (mg/msq/day) at five dose levels: 600/50 (level 1), 600/60 (level 2), 800/60 (level 3), 800/70 (level 4) and 1000/70(level 5). Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Dose-limiting toxicity (DLT) was defined as grade 4 thrombocytopenia, grade 4 neutropenia, or grade 3 nonhematologic toxicity. All patients were evaluated for response with RECIST criteria by a radiologist.

Results: Fifteen patients were enrolled in this study between 05/12 and 07/05. Treatment was well tolerated; 14 patients completed all protocol therapy, but one cannot because of anorexia. The maximum-tolerated dose was level 2, Gem 600mg/ S-1 60mg. Six patients experienced DLT (four patients with anorexia and two patients with Gr4 neutropenia). Response rate (RR) was 33.3% and disease control rate was 87.0%. And 1-year and 2-year survival rate was 86.7% and 44.4% respectively.

Conclusions: The chemoradiation therapy a combination of gemcitabine (GEM) and S-1 can be delivered almost safely for unresectable locally advanced pancreatic cancer.

No significant financial relationships to disclose.
Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib: A comparison with previously known prognostic models.
Authors: Baek K. , Kim J. , Um J. , Park S. , Lee J. , Park J. , Park Y. , Lim H. , Kang W.
Published: February 2017

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Background: Sorafenib, a multiple-targeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib.

Methods: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS).

Results: Chronic hepatitis B was the predominant cause of HCC (84%).Of 162 evaluable patients, four partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% confidence interval [CI], 2.3-2.7 months) and 5.3 months (95% CI, 4.4-6.3 months), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum alpha- fetoprotein (AFP) ≥400 ng/mL, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status, and baseline levels of AFP, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program (CLIP) scoring system and Okuda stages can better predict the hazard of failure or death than Child-Pugh classification.

Conclusions: Our results suggest that CLIP scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib.

No significant financial relationships to disclose.
Potential role of chemoradiotherapy for metastatic pancreatic cancer.
Authors: Lee D. Y. , Robertson J. M. , Huang J. , Margolis J. H. , Balaraman S. , Nadeau L.
Published: February 2017

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Background: Patients with metastatic pancreatic cancer have a poor outcome and the radiotherapy is typically only given to patients requiring palliation. We analyzed our institutional pancreas database to compare the outcome between chemotherapy alone vs. chemoradiotherapy.

Methods: From January 2000 to December 2008, 199 metastatic pancreatic cancer patients were retrospectively analyzed. 13 (6.5%) patients received chemoradiotherapy and 186 (93.5%) patients received chemotherapy alone. Chemotherapy regimens consisted of 5-fluorouracil, gemcitabine, erlotinib, or cisplatin. The follow-up time was calculated from the time of diagnosis to the date of death or the last contact. Kaplan-Meier analysis was used to calculate the overall survival (OS).

Results: Median OS was 5.3 months for all patients. Median OS was 4.9 months (0.4–27.0) for patients treated with chemotherapy alone and 7.8 months (0.6–44.1) for those treated with chemoradiotherapy (p = 0.013). Univariate survival analysis of categorical variables for patients treated with chemoradiotherapy revealed that age, race, gender, location of metastatic site, T stage (T3 v. T4) or nodal stage were not significant. However, ECOG performance status (1 v. 2/3) and the dose of radiation (<35 v. >35 Gy) received were associated with improved survival (p = 0.013, p=0.049). Median OS was 12.9 months for ECOG 1 vs. 5.6 months for ECOG 2/3. Median OS was 11.1 months for patients treated with radiotherapy dose > 35 Gy vs. 5.9 months for those who received less than 35 Gy. 3/13 (23%) patients who received chemoradiotherapy lived nearly two years or more.

Conclusions: Metastatic pancreatic cancer patients with good performance score may benefit from chemoradiotherapy. Long-term survival was observed in this selected group.

No significant financial relationships to disclose.
Adjuvant FOLFIRI with or without cetuximab in patients with resected stage III colon cancer: NCCTG Intergroup phase III trial N0147.
Authors: Huang J. , Sargent D. J. , Mahoney M. R. , Thibodeau S. N. , Smyrk T. C. , Sinicrope F. , Nelson G. D. , Alberts S. R.
Published: February 2017

363

Background: Irinotecan (CPT-11) has demonstrated antitumor activity against metastatic colorectal cancer used alone or with 5-fluorouracil (5FU)/leucovorin (LV). Two arms with CPT-11, 5FU, and LV (FOLFIRI) +/- cetuximab (Cmab) were originally included in N0147. However, after CALGB 89803 (J Clin Oncol. 25:3456, 2007), PETACC-3 (J Clin Oncol. 27:3117, 2009), and Accord02 (Ann Oncol. 20:674, 2009) showed no benefit to the three-drug combination in adjuvant therapy, the CPT-11 arms of N0147 were discontinued. We report the outcomes for patients given FOLFIRI +/- Cmab.

Methods: Following a signed informed consent patients with resected stage III colon cancer were randomized to one of 6 arms including 12 biweekly cycles of CPT-11 180 mg/m2 d1 with LV 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 without (Arm B, FOLFIRI) or with Cmab (Arm E) 400 mg/m2 d1 cycle 1 then Cmab at 250 mg/m2 d1 and 8. Primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity.

Results: 156 patients (Arm B-111, Arm E-45) were enrolled; median follow-up on 81 patients in Arm B was 60.3 months and 58.2 months in Arm E for 41 patients. wtKRAS (vs mt) status was associated with improved DFS (HR=0.6 [95% CI 0.4-1.1], p = 0.09) and OS (HR 0.7 [95% CI 0.4-1.5], p = 0.38). The addition of Cmab improved DFS and OS in the overall group and within wtKRAS pts. Grade greater than III non-hematologic adverse effects were significantly increased in the Cmab arm (46% vs. 64%, p = 0.05).

Conclusions: In this randomized phase III trial adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX. Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients, regardless of KRAS status. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer.

[Table: see text]

[Table: see text]
Long-term update of U.S. GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: Comparison of concurrent chemoradiation with 5FU-mitomycin versus 5FU-cisplatin for disease-free and overall survival.
Authors: Gunderson L. L. , Winter K. A. , Ajani J. A. , Pedersen J. E. , Benson A. B. , Thomas C. R. , Mayer R. J. , Haddock M. G. , Rich T. A. , Willett C. G.
Published: February 2017

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Background: On initial publication of GI Intergroup RTOG 98-11, concurrent chemoradiation with 5FU+mitomycin (MMC) decreased colostomy failure (CF) vs induction plus concurrent 5FU+cisplatin (CDDP), but did not significantly impact disease free or overall survival (DFS, OS). The intent of the current analysis is to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free [CFS]), CF and relapse (local-regional [LRF], distant [DM]) in this patient group.

Methods: Stratification factors included gender, clinical node status, and primary size. DFS/OS were estimated univariately by Kaplan-Meier method and treatment arms compared by log-rank test. Time to relapse/CF were estimated by cumulative incidence method and treatment arms compared by Gray's test. Multivariate analyses were done with Cox proportional hazard models to test for treatment differences, adjusting for stratification factors.

Results: Of 682 patients accrued, 649 were analyzable for outcomes. As seen in the table, 5-yr DFS and OS were statistically better for RT+5FU/MMC vs RT+5FU/CDDP (67.7 v 57.6%, p=.0.0045; 78.2 v 70.5%, p=0.021) with trends toward statistical significance for CFS, LRF, and CF (71.8 v 64.9%, p=0.053; 20 v 26.5%, 11.9 v 17.3%, p=0.092 and 0.075). Similar results were seen in multivariate analysis.

Conclusions: Concurrent chemoradiation with 5FU-MMC has a statistically significant impact on DFS and OS vs induction + concurrent 5FU-CDDP and borderline significance for CFS, CF and LRF. Therefore, RT+5FU/MMC remains the preferred standard of care. Potential strategies to improve outcomes include treatment intensification and individualized molecular-based treatment. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI).

[Table: see text]

No significant financial relationships to disclose.