bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of SPARC expression in survival of pancreatic ductal adenocarcinoma patients after curative resection.
Authors: Murakawa Masaaki , Aoyama Toru , Miyagi Yohei , Atsumi Yousuke , Kazama Keisuke , Kobayashi Satoshi , Ueno Makoto , Morimoto Manabu , Yamamoto Naoto , Sato Tsutomu , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro
Published: March 2017

321

Background: The predictive roles of secreted protein acidic and rich in cysteine (SPARC) in resected pancreatic ductal adenocarcinoma (PDAC) patients have not been clarified. We investigated the correlations between the SPARC expression and the postoperative prognosis. Methods: We retrospectively analyzed the clinical data from consecutive patients who underwent curative resection for pancreatic cancer in our institution from 2005 to 2014. Stromal SPARC expression was analyzed by immunohistochemistry on tumor tissue microarrays (TMAs) from the patients. Results: 179 patients were enrolled to this study. The median follow-up period of the present study was 62.1 months. 70 patients had positive SPARC expression (39.1%). There were no significant difference between the positive SPARC expression group and negative group. In survival analysis, there was significant difference in the 5-year overall survival (OS) rates after surgery, which were 8.1% and 19.8% between the SPARC positive and negative groups, respectively (p = 0.0316). Univariate analysis showed SPARC expression, size of tumor, lymph node metastasis, and residual tumor as the possible prognostic factors. Multivariate analysis revealed SPARC expression (hazard ratio (HR) = 1.44 95%CI; 1.017-2.051), lymph node metastasis (HR = 2.019 95%CI; 1.318-3.091), and residual tumor (HR = 1.648 95%CI; 1.132-2.401)as the independent prognostic factor. Conclusions: Stromal SPARC expression in resectable pancreatic cancer patients might be useful as the predictive survival marker. The prognostic value of SPARC expression should be confirmed in another cohort or in a prospective multicenter-study.
Immune analysis of fibrolamellar hepatocellular carcinoma.
Authors: Akce Mehmet , Vence Luis M , Blando Jorge M , Sharma Padmanee , Hassan Manal , Kaseb Ahmed Omar
Published: March 2017

324

Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC) with about 200 annual cases reported globally. Surgical resection is the main treatment. Although FLHCC develops in the absence of cirrhosis surrounding hepatic parenchyma may have mononuclear cell and lymphocyte infiltrates. Immunotherapy by targeting programmed death 1 (PD-1) has emerged as a potential therapy for HCC and multiple clinical trials are being conducted, however little is known about immunological features of FLHCC. We aimed to analyze tumor microenvironment by immunohistochemistry and flow cytometry. Methods: Surgical samples of two FLHCC cases, 23 year old woman (case 1) and 25 year old man (case 2) who underwent neoadjuvant chemotherapy with 5 Fluorouracil + Interferon followed by surgical resection were analyzed. Expression of CD4, CD8, PD-1, programmed death ligand 1(PD-L1), CD45RO, CD 57, CD68, OX 40, inducible costimulator (ICOS), FoxP3, Gr-B was evaluated by immunohistochemistry. Flow cytometry analysis of CD8, CD4 effector (Teff) and regulatory (Treg) T cells were performed. Immune monitoring studies were conducted by the Immunotherapy Platform at MD Anderson Cancer Center. Results: By immunohistochemistry,expression of PD-1 and PDL-1 in the tumor sampleswas asfollows:PD-1 (5.9%) and PDL-1 (4.1%) of total cells in case 1 versus PD-1 (6.3%) and PDL-1 (3.5%) in case 2. FoxP3 expression was 0.3% and 1%, whereas ICOS expression was 0.2% and 1% in case 1 and 2, respectively. By flow cytometry analysis, case 1 presented the following frequencies: CD8+CTLA4+ (40%), CD8+PD1+ (40%) of total CD8 T cells, CD4+TeffCTLA4+ (55%), CD4+TeffPD1+ (30%), CD4+TeffICOS+ (15%) of total CD4 Teff cells and CD4+TregCTLA+ (90%), CD4+TregPD1+ (30%), CD4+TregICOS+ (70%) of total CD4 Tregs. Similarly, in case 2 the percentages were CD8+CTLA-4+ (20%), CD8+PD1+ (40%), CD4+TeffCTLA4+ (25%), CD4+TeffPD1+ (65%), CD4+TeffICOS+ (30%), CD4+TregCTLA+ (90%), CD4+TregPD1+ (70%), CD4+TregICOS+ (80%). Conclusions: PD-1, PDL-1, CTLA-4 and ICOS expression in FLHCC might render support to consideration of potential utilization of antibodies against PD-1, PDL-1 and CTLA-4 for treatment for a devastating cancer with unmet need for treatment.
Effect of advanced age, elevated bilirubin, and disease extent on outcomes of unresectable pancreatic cancer (UPC) patients receiving first-line chemotherapy: A population-based study.
Authors: Cherniawsky Hannah Marie , Wang Ying , Ghosh Sunita , Cheung Winson Y. , Ho Maria Yi
Published: March 2017

325

Background: Superiority of FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NG) over standard gemcitabine (GEM) monotherapy for UPC was shown in the PRODIGE and MPACT trials, respectively. However, both trials either excluded or limited enrollment of patients with locally advanced disease, elevated bilirubin and advanced age. We sought to determine the impact of age, bilirubin and disease extent on treatment outcomes in the real-world setting. Methods: We identified all patients newly diagnosed with UPC who received palliative chemotherapy at any 1 of 6 British Columbia Cancer Centers and the Cross Cancer Institute in Alberta from January 2014 to April 2016. Receipt of at least one cycle of chemotherapy represented treatment with group assignment based on the initial regimen delivered. Outcomes were compared while adjusting for age, bilirubin, extent of disease, and other measured confounders. Results: A total of 292 consecutive patients were identified of whom 161 (55%) were aged > = 65 years, 164 (56%) were male, 74 (25%) had elevated bilirubin, and 205 (70%) had metastatic disease at the time of presentation. Patients who received FFN or NG had a longer median overall survival (OS) than those treated with GEM alone after adjusting for age, ECOG, bilirubin and extent of metastatic disease (11 vs 10 vs 4 months, respectively; FFN: HR 0.297, 95% CI 0.199-0.445, p < 0.0001, and NG: HR 0.338, 95% CI 0.236 – 0.485, p < 0.0001). Similarly, FFN and NG patients also had longer progression-free survival (PFS) in comparison to GEM alone (8.8 vs 6.9 vs 2.9 months, respectively; FFN: HR 0.33, 95% CI 0.22-0.499, p < 0.0001, and NG: HR 0.47, 95% CI 0.33 – 0.67, p < 0.0001). Advanced age and elevated bilirubin were not significantly associated with OS and PFS (p > 0.05). Conclusions: The efficacy of FFN and NG were superior when compared to GEM alone for patients with UPC in the real-world setting. This population-based study showed that the benefits of FFN and NG persisted regardless of advanced age and hyperbilirubinemia.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors for locally advanced pancreatic cancer patients.
Authors: Lee Byung Min , Chung Seung Yeun , Chang Jee Suk , Lee Kyong Joo , Song Si Young , Seong Jinsil
Published: March 2017

326

Background: It is well known that locally advanced pancreatic cancer patients have a poor prognosis. Recently, hematologic markers showing systemic inflammatory status such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have aroused much attention due to its potential to predict patient survival. In this study, we investigated whether pre-treatment NLR and PLR independently and in combination would be significant prognostic factors for survival in locally advanced pancreatic cancer patients. Methods: A total of 497 locally advanced (borderline resectable and unresectable) pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) between January 2005 and December 2015 were included in this study. NLR and PLR prior to the start of treatment within 2 weeks were defined as pre-treatment NLR and PLR. We divided the patients with the median values of pre-treatment NLR and PLR; NLR < 2.44 group (n = 248), NLR ≥ 2.44 group (n = 249), PLR < 149 group (n = 248) and PLR ≥ 149 (n = 249) group. Overall survival (OS) and progression-free survival (PFS) were compared between each group for NLR and PLR. Results: Median overall survival was 15.7 months (range, 2.3-128.5 months). For NLR, the OS, PFS rates were significantly lower in the NLR ≥ 2.44 group, with 1-year OS rates of 67.9% and 61.5% (p = 0.003) and 1-year PFS rates of 38.1% and 32.4% (p = 0.003), for NLR < 2.44 and ≥ 2.44 group, respectively. The PLR ≥ 149 group also showed significantly poorer OS and PFS than PLR < 149 group. The 1-year OS rates were 68.1% and 61.3% (p = 0.029) and 1-year PFS rates were 37.9% and 32.5% (p = 0.027), for PLR < 149 and ≥ 149 group, respectively. When multivariate analysis was performed, NLR ≥ 2.44 remained as a significant adverse factor for OS (p = 0.011) and PFS (p = 0.026). PLR > 149 also proved to be a significant factor for poorer OS (p = 0.003) and PFS (p = 0.021). Conclusions: Elevated pre-treatment NLR and PLR independently and in combination significantly predicted poor OS and PFS. Pre-treatment NLR and PLR are useful prognostic factors for OS and PFS in locally advanced pancreatic cancer patients.
Expression of exportin 1 (XPO1/CRM1) in pancreatic adenocarcinoma.
Authors: Saulino David M , Younes Pamela S , Biley Jennifer M , Younes Mamoun
Published: March 2017

327

Background: Exportin 1 (XPO1/CRM1) is a nuclear export chaperone that mediates the nuclear export of several proteins that are essential to growth regulation and tumor suppression. It was found to be overexpressed in several types of human malignancies and overexpression was found to be associated with poor prognosis. Pancreatic adenocarcinoma (PAC) is associated with very poor survival and currently has no effective treatment. Selective inhibitors of nuclear export are currently undergoing phase I and II clinical trials in hematologic malignancies and solid tumors. The aim of this study was to determine the expression of XPO1/CRM1 in pancreatic adenocarcinoma (PAC) and its relation to survivin expression and proliferative activity as determined by the S-phase fraction (SPF). Methods: Sections of tissue microarray containing 77 formalin fixed and paraffin embedded human PAC were stained by immunohistochemistry (IHC) using monoclonal antibodies to XPO1/CRM1, survivin, and for Cyclin A. The levels of XPO1/CRM1 and survivin expression in tumor cells and the S-phase fraction (SPF) were determined using a quantitative digital image analysis solution (OTMIAS). Results: Sixty-six of the 77 (86%) cases were positive for XPO1/CRM1, with the mean expression value ranging from 0.3 to 53 units and the median ranging from 0.3 to 45 units. There was significant correlation between the mean and median expression values of XPO1/CRM1 in tumor cells with the mean and median values of expression of survivin (p < 0.001). Moreover, the mean and median XPO1/CRM1 expression levels in tumor cells correlated significantly with SPF (p = 0.005). Conclusions: XPO1/CRM1 is expressed in a significant proportion of PAC, and increased expression correlates with both survivin expression and increased proliferative activity, suggesting that selective inhibitors of nuclear export may be effective against PAC.
Identification of circulating microRNAs for the diagnosis of early-stage gastric cancer.
Authors: Brunet-Vega Anna , Ramírez-Lázaro María José , Lozano Juan José , Quílez María Elisa , Garcia-Martinez Lorena , Junquera Félix , Pericay Carles , Calvet Xavier , Lario Sergio
Published: March 2017

33

Background: The development of gastric cancer (GC) is a stepwise progression from non-active gastritis (NAG), chronic active gastritis (CAG) and precursor lesions of GC (PLGC: atrophy, metaplasia). Early detection of GC improves survival rates. Recent evidence has proposed circulating microRNAs (c-miRNAs) as biomarkers. The aim was to explore the c-miRNA profile of a cohort of non-GC and GC patients in order to identify early biomarkers of GC. Methods: Thirty-eight patients were enrolled: ten with NAG, nine with H. pylori infected with CAG, eight with PLGC, and ten with GC. GC patients were at TNM stages I and II. As quality controls, synthetic RNA was added during the isolation, cDNA synthesis, and PCR steps. MiRNA profiling was performed using Exiqon Human Panel I. Exploratory significance was set at P<0.05 with fold change (FC)≥1.6. Results: Of the total of 372 miRNAs analyzed, 154 miRNAs were detected in all samples. miR-185-5p was used to normalize. Compared to NAG individuals, GC patients showed downregulation of three miRNAs. GC patients also showed reduced expression of miR-205 compared to H.pylori-infected patients with CAG. Five miRNAs were upregulated in GC patients compared to PLGC patients (miR-134, miR-204, miR-224, miR-409, miR-877). Finally, in comparison with non-GC, seven miRNAs were found to be deregulated in GC patients (miR-130b, miR-144, miR-205, miR-219a, miR-224, miR-451a, miR-501). Specificities calculated at 90% sensitivity were low and significant FC ranged from -3.2 to 2.8. Conclusions: Using miRNA qPCR quantification, we found a deregulation of c-miRNAs in early GC. However, our results also show low diagnostic accuracy for early GC due to the small FC observed and the overlap in the miRNA levels between non-GC and GC patients. Further validation in a larger cohort and a prospective study is needed to determine conclusively whether these miRNAs serve as biomarkers. In our opinion, new methods need to be developed in order to quantify c-miRNAs and improve their diagnostic accuracy. [Table: see text]
A phase II study of gemcitabine as adjuvant treatment for biliary tract cancer after surgical resection.
Authors: Woo Sang Myung , Yoon Kyong-Ah , Hong Eun Kyung , Park Weon Seo , Han Sung-Sik , Park Sang Jae , Joo Jungnam , Park Eun Young , Lee Ju Hee , Kim Yun-Hee , Kim Tae Hyun , Lee Woo Jin
Published: March 2017

330

Background: The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. Methods: This clinical phase II study was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patents received gemcitabine 1000 mg/m2as an intravenous 30-min infusion on day 1, 8, and 15 for every 28 days. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry and eight SNPs in the CDA, hENT1, dCK, hCNT3 and RRM1 genes were evaluated. The relationship of each with patients’ clinical outcomes was assessed. Results: From January 2010 to July 2014, a total of 72 BTC patients (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma) were enrolled. At a median follow-up was 38.09 months (range: 4.14-68.29), 2-year recur- free survival (RFS) was 43% (95% CI, 33% to 57%). The most common grade 3 and 4 toxicity was neutropenia, which occurred in 8 patients (11%). There was one treatment-related death from pneumonitis. The Cox proportion hazard model was performed with the following nine variables; gross type, degree of tumor differentiation. pathologic T factor, N stage, vascular invasion, perineural invasion, lymphatic invasion, dosage, and each protein expression. In the multivariable model, DCK expression, vascular invasion, and lymph node metastasis, were significantly associated with RFS. None of the tested SNPs was significantly associated with RFS or with any hematologic or non-hematologic toxicity. Conclusions: Although the primary hypothesis of this study, defined as a 2-year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted. Clinical trial information: NCT01043172.
Targeted pancreatic cancer drug-delivery utilizing sigma-2 ligand/receptor internalization is energy-dependent.
Authors: Jin Linda X , Vangveravong Suwanna , Cullinan Darren R , Goedegebuure Peter S. , Loza Andrew J , Mach Robert H , Spitzer Dirk , Hawkins William G.
Published: March 2017

331

Background: Pancreatic cancer is a devastating disease that is poorly responsive to traditional systemic therapies. Cancer-selective drug delivery can improve survival and reduce systemic toxicities. We have developed a pancreatic cancer drug delivery platform based on sigma-2 receptor ligands conjugated to small molecule drug cargos, which improves delivery and efficacy through efficient drug internalization. However, the mechanism of drug internalization via the sigma-2 receptor/ligand interaction remains unclear. Methods: Uptake of fluorescently conjugated sigma-2 ligand SW120 was studied in ASPC-1 human pancreatic cancer cells. Uptake was measured at 37C, 4C, after competitive inhibition with sigma-2 ligand SW43, and after pretreatment with Pitstop 2 (Abcam), an inhibiter of clathrin-mediated endocytosis. Uptake was visualized using live-cell imaging using A1Rsi confocal laser scanning microscope (Nikon). Image analysis was performed using FIJI (NIH) and Matlab (Mathworks). Results: SW120 (10 nM) was rapidly internalized into ASPC-1 cells at 37C with maximal fluorescence at 12 minutes. As a negative control, incubation of ASPC-1 cells with the unconjugated flourophore NBD Cl demonstrated no uptake after 15 minutes, indicating that uptake of SW120 depends on the specific sigma-2 receptor/ligand interaction. Fluorescence at 15 minutes was reduced by 85% in ASPC-1 cells incubated at 4C, indicating uptake of SW120 into cells is an energy dependent process. Pretreatment of cells with Pitstop 2 decreased total flourescence at 15 minutes by 76%, suggesting an important role of clathrin-mediated endocytosis in sigma-2 receptor uptake, while pretreatment with competitive inhibitor SW43 reduced uptake by 84%, suggesting that sigma-2 ligands are internalized via a specific receptor capable of saturation. Conclusions: Sigma-2 receptor ligands are rapidly internalized into pancreatic cancer cells via a specific, targetable, energy-dependent pathway that appears to rely on clathrin-mediated endocytosis. Further understanding of sigma-2 mediated drug internalization can help optimize targeted drug development and delivery for pancreatic cancer patients.
The clinical significance of KRAS monitoring in tumor tissues and blood of patients with pancreatic tumor.
Authors: Watanabe Fumiaki , Suzuki Koichi , Ichida Kosuke , Takayama Yuji , Fukui Taro , Kakizawa Nao , Noda Hiroshi , Rikiyama Toshiki
Published: March 2017

334

Background: Monitoring of gene alterations in blood to track circulating tumor DNAs has been attempted for a clinical application. For example, KRAS monitoring in colorectal cancer provides a valuable biomarker for diagnosis and prediction of treatment outcome. While half of of colon cancer has RAS mutation, 90% of pancreatic cancer shows KRAS mutation, suggesting that most of pancreatic cancer is a good candidate for KRAS monitoring. In this study, we elucidated the clinical significance of KRASmonitoring in patients with pancreatic tumor during treatments. Methods: KRAS mutation in tumor tissues was determined by Scorpion ARMS or RASKET methods in 39 patients with pancreatic tumors. KRASmutation in blood (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, Q61H) were investigated by using droplet digital polymerase chain reaction (ddPCR) in 24 patients treated with chemotherapy. Results: KRAS assessment in tumor tissues showed 33 patients with mutation and 6 patients without mutation. Thirty-three patients with mutation showed significantly poor prognosis of 49% in three years overall survival (OS) as compared with 100% in 6 patients with mutation (p=0.02). KRAS assessment in blood revealed that KRAS mutation was detected in 14 patients, but no detection was seen in 10 patients. Patients harboring KRAS mutation in blood exhibited significantly poor treatment outcome, including 12 patients with progressive disease, as compared with 10 patients without detection of mutation, including 6 patients with any treatment responses (stable disease in 4 patients and partial response in 2 patients, p=0.03). Fourteen patients with mutation in blood displayed poor prognosis of 20% in three years overall survival (OS), comparing to 69% in 10 patients without mutation in blood (p=0.06). Conclusions: KRAS status in tumor tissues was involved in prognosis; in addition, KRAS status in blood was implicated in treatment response of chemotherapy in patients with pancreatic tumor. KRAS monitoring in tumor tissues and blood provides useful information for the treatment strategy including chemotherapy in patients with pancreatic tumor.
Expression of estrogen receptor beta isoforms in pancreatic adenocarcinoma.
Authors: Younes Mamoun , Ly Charles J , Singh Kanchan , Ertan Atilla , Guha Sushovan , Younes Pamela S , Biley Jennifer M
Published: March 2017

337

Background: There have been several limited trials in which tamoxifen efficacy was tested in patients with pancreatic adenocarcinoma (PAC). Most of these studies were small series of patients with unresectable PAC and reported mixed results. In these studies, patients were not stratified by estrogen receptor status because estrogen receptor beta (ER-b) had not yet been identified, and PAC did not express the traditional ER-alpha. Recent studies showed that the effects of estrogens, phytoestrogens and tamoxifen on PAC cell lines depended on ER-b expression. The aim of this study was to investigate ER-b expression in human PAC and whether such expression correlates with any clinicopathologic parameters. Methods: Sections of tissue microarray containing 18 formalin fixed and paraffin embedded human PAC were stained by immunohistochemistry (IHC) using monoclonal antibodies to ER-b isoforms 1, 2, and 5 (ER-b1, ER-b2, and ER-b5, respectively), and for Cyclin A. The levels of ER-b isoform expression in tumor cells and the S-phase fraction (SPF) were determined using a quantitative digital image analysis solution (OTMIAS). Results: All isoforms were expressed in PAC, although at different levels. Higher mean ER-b2 levels correlated with male sex (p = 0.057), older age (p = 0.005), and lower pT stage (p = 0.008), but not with grade, pN stage, or SPF. Mean ER-b5 levels correlated negatively with SPF (p = 0.021), but not with sex, age, grade, pT or pN. Mean ER-b1 expression did not correlate with any of the above mentioned clinicopathologic factors. Conclusions: ER-b1, ER-b2, and ER-b5 are expressed in PAC. Higher ER-b2 and ER-b5 levels of expression are significantly correlated with lower tumor pT stage and with lower SPF, respectively, suggesting that they may play a tumor suppressive role in PAC. The association between ER-b2 levels and patient sex and age suggest that it could be influenced by endogenous/exogenous hormonal exposure.
Two randomized, placebo-controlled phase 3 studies of ruxolitinib (Rux) + capecitabine (C) in patients (pts) with advanced/metastatic pancreatic cancer (mPC) after failure/intolerance of first-line chemotherapy: JANUS 1 (J1) and JANUS 2 (J2).
Authors: Hurwitz Herbert , Van Cutsem Eric , Bendell Johanna C. , Hidalgo Manuel , Li Chung-Pin , Garrido Marcelo , Macarulla Teresa Mercade , Sahai Vaibhav , Sama Ashwin Reddy , Greeno Edward , Yu Kenneth H. , Verslype Chris , Dawkins Fitzroy W. , Walker Christopher , Clark Jason , O'Reilly Eileen Mary
Published: March 2017

343

Background: The JAK-STAT pathway plays a role in the pathogenesis of PC. In a phase 2 study, the JAK1/2 inhibitor Rux + C improved OS vs C alone in mPC pts with evidence of systemic inflammation. Methods: In two phase 3 studies, advanced/mPC pts with only 1 prior chemotherapy regimen and C-reactive protein > 10mg/L were randomized to 21-day cycles of Rux 15 mg BID + C 2000 mg/m2/d (day 1-14) vs placebo (Pb) BID + C 2000 mg/m2/d (day 1-14). The primary endpoint was OS. The studies were terminated early based on efficacy findings of a planned interim analysis for J1, with J2 enrollment incomplete. Results: 321 pts were randomized in J1 and 86 in J2. The median age was similar between groups (Rux + C vs Pb + C): J1, 68 vs 67 yrs; J2, 68 vs 69 yrs. The most common prior chemotherapy regimens were gemcitabine (gem) + nab-paclitaxel (J1: 50% vs 51%, J2: 42% vs 37%), gem alone (J1: 24% vs 21%, J2: 28% vs 33%). Median study treatment durations were 42 d for both Rux and Pb in J1; 40 d for Rux and 43 d for Pb in J2. Discontinuations were mainly due to disease progression (J1: 62% vs 65%, J2: 51% vs 58%), AEs (J1: 4% vs 10%, J2: 12% vs 12%) or death (J1: 8% vs 5%, J2: 7% vs 5%). Rux + C did not show a benefit over C alone in OS or PFS (see Table). Overall response rates were < 5% in each treatment group (NS).The most common grade 3/4 non-hematologic AEs were abdominal pain (J1: 7% vs 14%; J2: 14% vs 5%), palmar-plantar erythrodysesthesia syndrome (J1: 7% vs 4%; J2: 0% vs 12%), pulmonary embolism (J1: 4% vs 3%; J2: 10% vs 5%), dyspnea (J1: 2% vs 2%; J2: 10% vs 2%) and vomiting (J1: 5% vs 5%; J2: 2% vs 12%). The most common new/worsening hematologic labs abnormalities of grade 3/4 included: anemia (J1: 20% vs 6%; J2: 11% vs 8%) and lymphopenia (J1: 17% vs 9%; J2: 16% vs 8%). Conclusions: When added to C, Rux was well tolerated but did not improve clinical outcomes in the second-line treatment of mPC pts. Clinical trial information: NCT02117479 and NCT02119663. [Table: see text]
Significant upstaging of patients with stage I pancreatic cancer from clinical to pathologic staging.
Authors: Stuart Heather , Ripat Caroline , Azab Basem , Yakoub Danny , Franceschi Dido , Livingstone Alan S , Dudeja Vikas , Merchant Nipun B.
Published: March 2017

349

Background: Clinical staging of patients with pancreatic cancer is essential to determine if neo-adjuvant treatment, surgery or palliative treatment is required. Patients with early stage disease often receive upfront surgery, where as patients with more advanced disease often receive neo-adjuvant therapy. Therefore the accuracy of clinical staging significantly influences management decisions. This study investigates the correlation between clinical and pathologic staging for patients with stage I pancreatic cancer. Methods: A retrospective review of patients with pancreatic cancer in National Cancer Data Base from 1998-2006 was preformed. The clinical stage of patients with presumed stage I disease was compared to the postoperative pathologic stage. Cox proportional hazard ratio model and regression analysis were used to determine factors associated with mortality and upstaging, respectively. Results: 1697 patients with clinical stage I pancreatic cancer were divided into two groups. Group 1 was comprised of patients who were stage I postoperatively and Group 2 was comprised of patients that were upstaged to either stage II, III or IV postoperatively. There were 704 (41%) in group 1 and 993 (59%) in group 2. Within group 2, 595 (60%) were stage II, 321 (32%) were stage III and 77 (8%) were stage IV. Patients that were upstaged after surgery had an increased risk of mortality (HR 1.414, p < 0.001), whereas patients that received adjuvant chemotherapy had a decreased risk of mortality (HR 0.799, p < 0.001). Compared to Grade 1 tumors, Grade 2 and 3 tumors on biopsy were most likely to be upstaged on final pathology (p < 0.001). Conclusions: Patients with stage I pancreatic cancer are often candidates for upfront surgery, however this study demonstrates that a large number are upstaged on postoperative staging. Recognizing this may lead clinicians to administer neo-adjuvant treatment in a greater number of patients with early stage disease in order to optimize survival.
Development and validation of a prognostic nomogram and score to predict overall survival and usefulness of second-line chemotherapy in advanced pancreatic adenocarcinoma.
Authors: Vienot Angélique , Beinse Guillaume , Louvet Christophe , de Mestier Louis , Meurisse Aurelia , Fein Francine , Heyd Bruno , Cleau Denis , d'Engremont Christelle , Dupont-Gossard Anne Claire , Lakkis Zaher , Tournigand Christophe , Bouche Olivier , Rousseau Benoit , Neuzillet Cindy , Bonnetain Franck , Borg Christophe , Vernerey Dewi
Published: March 2017

354

Background: In advanced pancreatic ductal adenocarcinoma (aPDAC), there is no consensual strategy for second-line chemotherapy (L2). Better discrimination of overall survival (OS) may help clinical decision-making in this setting. We aimed to predict OS from the beginning of L2 and to assess the benefit from chemotherapy among the identified risk groups. Methods: Analyses were derived from all consecutive aPDAC patients treated at Besancon hospital, France, during 11 years. The association of 50 parameters with OS was evaluated using univariate and multivariate Cox analyses. Based on the final model, a prognostic nomogram and score were developed, and externally validated in patients receiving L2 in three other French centers, between 2010 and 2016. Results: The development cohort included 462 patients. 395 patients (85%) were eligible for L2, of which 261 (66%) were treated. Age, smoking status, liver metastases, Eastern Cooperative Oncology Group performance status, pain, jaundice, ascites, duration of first-line chemotherapy, and type of L2 regimen were identified as independent prognostic factors for OS in L2. The final model exhibited excellent calibration and discrimination (C-index = 0.75, 95% confidence interval 0.72 to 0.78), and robust internal validity. Based on the final model, a prognostic nomogram was built. The nomogram total points were input into a prognostic score that delineated three risk groups with median OS of 11.3, 3.6 and 1.4 months (P < 0.0001). By applying the score in the population eligible for L2 but untreated, the chemotherapy benefit was significant across all groups but with a magnitude of the effect decreased significantly from low to high-risk groups (P = 0.0123 for treatment and risk groups interaction term). The clinical benefit centered accuracy of the final model was confirmed by a decision curve analysis. The score ability to discriminate OS was externally confirmed in 162 patients, by identifying the same risk groups. Conclusions: These prognostic tools in patients with aPDAC can accurately predict OS before administration of L2 and strengthen the prognosis-based decision making for clinicians.
Impact of timing of adjuvant chemotherapy initiation on survival in pancreatic adenocarcinoma.
Authors: Palacio Sofia , Ripat Caroline , Stuart Heather , Yakoub Danny , Merchant Nipun B.
Published: March 2017

355

Background: Pancreatic adenocarcinoma (PDAC) is now the third leading cause of cancer death. Surgical resection followed by adjuvant chemotherapy has been the standard of care. Due to the significant risk of morbidity following pancreatic surgery, initiation of adjuvant chemotherapy is often delayed. Prior prospective adjuvant trials have suggested that adjuvant therapy can be initiated as late as 12 weeks without detriment, but data regarding the effectiveness of beginning adjuvant therapy beyond that time remains unknown. Methods: We retrospectivelyreviewed data from the National Cancer Data Base (2004-2014) and included adult patients (pts) with PDAC with pathologic stage I-IIB who underwent surgical resection with curative intent. The primary outcome was overall survival (OS) based on time to adjuvant chemotherapy post-surgery as defined by postoperative weeks. Data were analyzed using Cox proportional hazard model and Kaplan-Meier survival curves. Results: 5279 pts. had surgery alone and 4,537 pts. received adjuvant chemotherapy. The median age was 64 years. 52% were male, 88% were white, 46% were treated at comprehensive community cancer centers. The primary surgical approach was whipple procedure in 61% of pts. 63% pts. received single agent chemotherapy and the mean time from surgery to chemotherapy was 61 days. Adjuvant chemotherapy was associated with improved OS irrespective of disease stage compared to those undergoing surgery alone (median OS for surgery alone 14 months vs adjuvant chemotherapy 21 months, p < 0.001). Cox proportional hazard model controlling for stage, surgical technique, lymph node dissection and margin status revealed improved OS in pts. receiving adjuvant chemotherapy. No significant differences in OS were seen for pts. starting adjuvant chemotherapy at 3, 6, 9, 12, 16, 20 or 24 weeks after surgical resection. Conclusions: Current guidelines recommend initiation of adjuvant chemotherapy prior to 12 weeks after pancreatic resection. Initiating adjuvant chemotherapy even up to six months post-operatively improves OS compared to those undergoing surgery alone. Our data supports the use of adjuvant chemotherapy if indicated regardless of time of surgery.
Hepatocellular carcinoma (HCC): Resection with adjuvant hepatic artery infusion chemotherapy (HAIC) versus resection alone—A systematic review and meta-analysis.
Authors: Moran Alexandra , Flor Ramos Lorena , Picado Omar , Stuart Heather , Dudeja Vikas , Pendola Fiorella , Sleeman Danny , Merchant Nipun B. , Yakoub Danny
Published: March 2017

357

Background: HCC have a recurrence rate of up to 70% in 5 years after resection detrimentally lowering survival. The role of adjuvant HAIC in management of HCC in patients who are not candidates for transplantation is controversial. We aimed to evaluate overall and disease free survival in these patients. Methods: A comprehensive online search of MEDLINE, EMBASE, PubMed, SCOPUS and the Cochrane database was conducted (Jan 1994 - August 2016). Comparative studies including patients with HCC, who are not transplant candidates, undergoing surgical resection and adjuvant HAIC vs surgical resection alone were reviewed. Study quality was assessed using STROBE checklist. Pooled risk ratios and 95% confidence intervals (CI) for overall and disease-free survival at 1, 3 and 5 years were calculated. Results: Overall, 10 studies with 595 HCC patients were included; 283 underwent resection followed by HAIC and 312 underwent resection alone. Mean age was 61 ± 10.1 years with a male/female ratio of 6/1. Meta-analysis of all included studies showed better overall survival in patients undergoing resection followed by HAIC compared with resection alone at 1-YR (Average 90.1% vs 79.5%, RR:1.15, CI:1.07 – 1.24, p=0.095, NS), 3-YR (Average 72.1% vs 49.4%, RR:1.57, CI:1.34 – 1.77, p<0.01) and 5-YR (Average 51% vs 30.2%, RR:1.71, CI:1.33 – 2.20, p<0.01). Median survival time for the resection with HAIC group was 54.94 months compared to 31.5 months for the resection alone group. In addition, disease-free survival was better with HAIC at 1-YR (RR:1.36, CI:1.21 – 1.54, p<0.01), 3-YR (RR:1.59, CI:1.27 – 1.98, p<0.01) and 5-YR (RR:1.85, CI:132. – 2.61, p=0.011). The median disease-free survival time for the resection with HAIC group was 17.5 months compared to 7.35 months for the resection alone group. Subgroup analysis showed that this survival advantage was more significant in patients with tumors ≥7cm (p<0.05). Conclusions: Combination of HCC resection with HAIC improve overall and disease-free survival of patients with HCC who are not candidates for transplantation, especially in tumors ≥ 7cm.
Analysis of the effect of adjuvant therapy on overall survival for resected gallbladder adenocarcinoma using the National Cancer Database.
Authors: Brauer David G. , Lim Kian-Huat , Doyle Maria Majella , Hawkins William G. , Chapman William C. , Fields Ryan C
Published: March 2017

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Background: The effect of adjuvant chemotherapy on survival after resection for gallbladder adenocarcinoma (GBC) is based on limited evidence. Since prospective trials are not generally practical for GBC, we sought to evaluate current best evidence to evaluate the role of adjuvant chemotherapy in multiple clinical scenarios by analyzing data from the U.S. National Cancer Database (NCDB). Methods: Patients who underwent resection for GBC diagnosed between 2004 and 2012 were identified in the NCDB. The effect of adjuvant therapy on overall survival (OS) was assessed using Kaplan-Meier analysis and Cox proportional hazards regression modeling. Results: 10,402 patients met inclusion criteria. Median follow-up was 14 months. Median survival was 16 months. One- and five-year OS were 57% and 23%, respectively. 3,509 patients (34%) received any modality of adjuvant therapy. Receipt of adjuvant therapy improved one-year OS (63% vs 55%, p < 0.01), but median OS was minimally changed (17 vs 15 months, NS). Adjuvant therapy was associated with improved one-year OS in T3 and T4N1 disease (Table 1). Only chemoradiation therapy was associated with improved one-year OS for T2 disease. Adjuvant chemotherapy was associated with worse one-year OS in T1N0 disease. Conclusions: Using data from the US NCDB, adjuvant therapy for resected gallbladder adenocarcinoma is associated with improved one-year overall survival with the exception of T1N0 disease. In the absence of prospective studies in this rare disease, retrospective data can provide insights into successful treatment strategies and guidelines for GBC. [Table: see text]
Prognostic value of immunohistochemical factors in esophageal small cell carcinoma (ESCC): Analysis of clinicopathologic features of 73 patients.
Authors: Li Cong , Zhang Yigong
Published: March 2017

37

Background: Esophageal small cell carcinoma (ESCC) is a very rare but aggressive disease with poor prognosis. The objective of this study was to describe immunohistochemical and clinicopathological features of patients with ESCC in Chinese population, and to clarify how the utilization of different marker combinations affects prognostic outcome. Methods: We retrospectively reviewed a total of 73 patients with ESCC. The tumor samples obtained were immunohistochemically analysed of neuron specific enolase enolase (NSE), synaptophysin (Syn), chromogranin A (CgA), and Thyroid Transcriptional Factor-1 (TTF-1). The positivity of these four factors and their correlation with clinical characteristics was described. The relation between positive expression of them and survival was also analysed. Results: The median age at the time of diagnosis was 57 (ranging from 36 to 77 years). 55 patients were male (75.3%) and 18 patients (24.7%) were female. Immunological reactivity of the samples was Syn 68.5%, TTF-1 46.6%, NSE 90.4%, CgA 43.8%. There were sixteen cases with four biomarkers positive (21.9%), twenty-six cases with three biomarkers positive (35.6%), fourteen cases with two biomarkers positive (19.2%), and twelve cases with only one biomarker positive (16.4%). Five cases (6.8%) were all negative. The expression of NSE was insignificantly associated with primary tumor location (P = 0.01). The 2-year and 3-year cancer-specific survivals were 24.8% and 19.9%, respectively. The median OS was 13.5 months. Although not statistically significant, expression of any factor was tended to positively affect survival. And the median OS of patients without expression of four factors was significant worse than those with at least one factor of positive expression (6.1 months vs 15.3 months, P = 0.002). Conclusions: Chinese ESCC patients have a poor prognosis even after local or systemic treatment. Relatively high percentages of positive labeling of Syn, CgA, NSE and TTF-1 implicated their diagnostic value in ESCC. More important, these four biomarkers might be probable favourable prognostic factors for ESCC.
Necuparanib combined with nab-paclitaxel + gemcitabine in patients with metastatic pancreatic cancer: Phase 2 results.
Authors: O'Reilly Eileen Mary , Mahalingam Devalingam , Roach James M. , Miller Paul Justin , Rosano Molly E. , Krause Silva , Avery William , Bekaii-Saab Tanios S. , Shao Spencer H. , Richards Donald A. , Vaickus Louis , Wolf Julie , Flaherty Keith , Ryan David P.
Published: March 2017

370

Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.
Adjuvant therapy (AT) following resection of pancreatic ductal adenocarcinoma (PDAC): Are patients from rural, remote areas disadvantaged?
Authors: Bertens Kimberly A , Massman John , Garbus Samuel , Mandelson Margaret T , Lin Bruce , Picozzi Vincent J. , Alseidi Adnan , Biehl Thomas , Helton William Scott , Rocha Flavio G
Published: March 2017

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Background: AT with chemotherapy (CT) + radiation (RT) has been shown to improve PDAC survival over surgery alone. Although race and socioeconomic status can affect outcomes in PDAC, the impact of rural or remote residence on the delivery and effect of AT has not been studied. Methods: Patients undergoing pancreatectomy for PDAC were identified from the National Cancer Data Base between 2006 and 2013. Individuals were classified as living in a metro area, urban/rural adjacent to metro area (URA), and urban/rural remote area (URR). Patients with less than 6 months follow-up were excluded. Logistic regression was performed to assess residence as a predictor of receiving AT. Overall survival (OS) as a function of inhabitance was estimated by the method of Kaplan and Meier and prognostic factors were identified by Cox regression. Results: A total of 32,521 individuals underwent pancreatectomy for PDAC. The majority of AT was delivered in academic research facilities in 56% of patients while only 29% of patients received both CT and RT. Univariate analysis demonstrated individuals in URR were less likely to receive CT (55% vs 58%, p < 0.01) but not RT (30% vs 31%, p < 0.261) and had a longer interval to AT (82 vs 75 days, p < 0.009) than those in metro areas. However on multivariate analysis URR inhabitance was no longer predictive of any form of AT (OR = 0.892, 95% CI: 0.792-1.006, p = 0.062). Hispanic ethnicity, Medicaid insurance, uninsured status, and lower education were all predictive of decreased likelihood of receiving AT. Median OS was inferior for URR dwellers with pathologic T2 and T3 tumors compared to those in metro areas (19.8 vs. 24.4 months, p = 0.044 and 17.5 vs. 19.4 months, p < 0.001). Cox regression revealed URR location remained independently associated with poorer OS (HR 1.076, 95% CI: 1.008-1.149, p < 0.029). Conclusions: While living in a URR does not lead to reduced access to AT, it is associated with a worse OS in resected PDAC. This may be due to inadequate AT or other socioeconomic factors present in URR patients. Attention must be focused on improving oncologic care for groups susceptible to treatment disparities.
Role of aggressive surgical debulking in older adults with gastrointestinal neuroendocrine tumors.
Authors: Jutric Zeljka , Lewis Aaron G , Raoof Mustafa , Ituarte Philip HG , Singh Gagandeep , Li Daneng
Published: March 2017

377

Background: Carcinoid and neuroendocrine tumors are often diagnosed in older adults. However, limited evidence currently exist regarding the role of aggressive surgical debulking of primary gastrointestinal-neuroendocrine tumors (low to medium grade-pancreas, small bowel, colorectal) (GI-NETs) in older adultsage > 70 years. Methods: Patients age 70 years or older with a diagnosis of GI-NETs were identified using the California Cancer Registry between the years 2000 to2012. Linkage to patient discharge records provided information including resection of primary site (RPS), resection of liver metastases (LR), and liver directed therapy (LDT). Treatment group effects on overall survival (OS) were compared by Cox proportional hazard models. Results: A total of 2,039 patients were identified. Among the 1,661 patients without metastases, 74% (n = 1,234) received RPS and demonstrated improved survival (HR 0.50, p < 0.001) compared to those without RPS. Of the 378 number of patients with liver metastases, LDT alone (n = 23) was not significantly associated with survival (HR 0.65, p = 0.082). Reduced risk was similar for RPS alone (n = 149; HR 0.44, p < 0.001) when paired with LDT (n = 17, HR 0.45, p = 0.007). RPS with LR, either with or without LDT, indicated the greatest impact in survival risk (n = 25; HR 0.14, p < 0.001). Conclusions: Surgical management of the primary tumor and liver metastases in older adults age > 70 years with GI-NETs demonstrated a significant survival benefit.Aggressive surgical debulking should be considered among older adultsage > 70 years. Future studies among older adults with GI-NETs are warranted to better identify patients most likely to benefit from aggressive surgical management.