bluuebunny/crossref_metadata_2025 huggingface dataset:
Thromboembolic events associated with cisplatin chemotherapy in patients with gastric and esophageal cancer: A single-institution experience.
Authors: O'Reilly Aine , Doherty Mark , Grogan William , Breathnach Oscar S.
Published: February 2017

146

Background: Upper gastrointestinal tract malignancy, specifically gastric cancer (GC) , is associated with an increased risk of thromboembolic events (TEs). Cisplatin is important in the treatment of GC and oesophageal cancer (OC) but is associated with an increased risk of TEs. We aimed to characterise our experience of thromboembolism in patients (pts) with GC and OC receiving cisplatin. Methods: Patients with GC or OC who received cisplatin based chemotherapy from January 2011 to August 2013 were included in analysis. Retrospective review of patient’s clinical, laboratory and radiological data was pursued. Results: Seventy-four pts, 27 patients with GC and 47 pts with OC, received cisplatin based chemotherapy between January 2011 and August 2013. The median age at the start of chemotherapy was 67 (range 43-86), 48 patients (66%) were male. Nine pts experienced a TE. Seven pts experienced a venous TE (5 deep vein thrombosis (DVT), 1 pulmonary embolism (PE)), 1 pt experienced a middle cerebral artery occlusion and subsequently developed a PE while on therapeutic anticoagulation and 1 pt experienced 2 DVTs, the second occurred while therapeutically anticoagulated. Six pts received cisplatin in the context of metastatic GC, 3 (50%) pts experienced at least one TE. Haemoglobin level, leukocyte count, platelet count and body mass index (BMI) were not associated with TE risk. Twenty-one pts received cisplatin neoadjuvantly for locally advanced GC. Four pts (19%) in this subgroup experienced a least one TE. Haemoglobin level, leukocyte count and BMI were not associated with an increased risk of TE. Patients with a platelet count > 350,000/mm3 experienced more TEs (p<0.05). Forty seven pts were treated for OC, 7 pts with metastatic disease and 40 pts with locally advanced disease. Two pts experienced a single VTE (DVTs), both had locally advanced disease. Conclusions: Thromboembolic events are common in pts with metastatic and locally advanced GC, receiving cisplatin based chemotherapy. Future studies should focus on characterising the role of prophylactic anticoagulation in this subgroup and identifying biomarkers associated with increased risk of TE.
A mechanistic radiographic and biologic phase 2 study of sunitinib in relapsed/refractory esophageal (E) and gastroesophageal (GE) cancers.
Authors: Wu Christina Sing-Ying , Mikhail Sameh , Wei Lai , Martin Ludmila Katherine , Li Xiaobai , Timmers Cynthia Dawn , Chen James Lin , Tahiri Sanaa , Neal Alison , Walker Jon P , El-Dika Samer S , Rock Jonathan B , Clark Daniel , Yang Xiangyu , Foy Kevin , Liu James Jingyao , Knopp Michael V. , Kaumaya Pravin , Bekaii-Saab Tanios B.
Published: February 2017

149

Background: Patients (pts) with relapsed or treatment-refractory E and GE cancers carry a poor prognosis. Inhibition of the vascular endothelial growth factor (VEGF) pathway may be a potential treatment approach. We conducted a phase II trial to assess the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGFR 1 and 2. Methods: Pts received sunitinib 37.5 mg orally, daily. Primary endpoint was progression free survival (PFS) at 24 weeks. Secondary endpoints included overall response rate (ORR), overall survival (OS), PFS, and toxicity. Pts underwent serial functional imaging with DCE-MRI and measurements of serum VEGF, PIGF, VEGFR 2 and 3. Gene expression profiling and somatic mutational analysis using next-generation sequencing were also performed on tumor specimens (results to be presented at the symposium). Results: Clinical results are in the table. The PFS in the group that had clinical benefit [partial response (PR) + stable disease (SD)] with sunitinib was 99 days (95% CI: 74-161) vs. 39 days (95% CI: 26-42; Log-rank test p-value is <0.0001) in pts who had progressive disease (PD). By RECIST criteria, sunitinib non-responders demonstrated an initial reduction in tumor size but then subsequent rapid tumor size increase by week 6 as compared to baseline values. In contrast, sunitinib responders demonstrated at least stable disease through weeks 2-6. Changes in serum VEGF-A and VEGF-C levels from baseline to 2 weeks were associated with PFS (p=0.04 and p=0.03, respectively). Furthermore, baseline VEGF-C was also associated with PFS (p=0.03) and RECIST response (p=0.04). Conclusions: Although the primary endpoint was not met, these results suggest that there is a subgroup of patients with clinical response to sunitinib. Our correlative analysis indicated that circulating biomarkers, such as VEGF-C, are worthy of further research to help us identify this subgroup. Clinical trial information: NCT00702884. [Table: see text]
Association between polymorphisms of the FOXF1 and MHC locus genes and gastroesophageal reflux disease (GERD).
Authors: Liu Wei Fan , Lam Christine , Del Bel Ryan , Chan Kevin , Miller Linda , Brown M Catherine , Chen Zhuo , Cheng Dangxiao , Patel Devalben , Xu Wei , Darling Gail Elizabeth , Liu Geoffrey
Published: February 2017

15

Background: GERD predisposes to Barrett’s Esophagus (BE), a precursor lesion to esophageal adenocarcinoma (EA). Recently a large genome-wide association study found two germline markers to be associated with BE, FOXF1 rs9936833 (C Allele) and MHC rs9257809 (A allele). An additional study linked FOXF1 rs9936833 to EA. We assessed whether these same polymorphisms are associated with GERD. Methods: Patients with reflux symptoms referred for esophageal manometry/24-hr pH monitoring at University Health Network (Toronto) were enrolled. DNA extracted from blood was genotyped using a Taqman PCR assay. GERD cases were defined as having DeMeester scores of ≥14.7 or prior evidence of reflux esophagitis on endoscopy. DeMeester < 14.7 defined controls. Logistic regression analysis, adjusted for clinical risk factors, was used to calculate odds ratios (95% confidence intervals) for each polymorphism relative to GERD. Results: Of 182 patients, the median age was 50 years, 62% were female and, 52% met the definition for GERD. Males, higher BMI, alcohol consumption, FOXF1, and MHC polymorphisms were each individually associated with GERD. In the multivariate analysis, after adjusting for gender and BMI, FOXF1 rs9936833 remained significant, with an aOR of 1.82 (95%CI: 1.1-3.0; p=0.02) for an increase in each C allele. MHC rs9257809 also remained significant, with an aOR of 9.36 (2.9-30; p<0.001) comparing AA to AG (there were no patients with GG). When both polymorphisms were placed in the same model, the aORs were 2.10 (1.2-3.5; p=0.006) and 11.0 (3.3-36; p<0.001), per increase in each risk allele, respectively. Conclusions: There are strong, significant associations for increased GERD risk by the C allele in FOXF1 rs9936833 and the A allele in MHC rs9257809 among patients complaining of reflux symptoms. FOXF1 is associated with development of gastrointestinal smooth muscle, possibly contributing to the contractibility of the gastroesophageal junction. The MHC polymorphism is in linkage disequilibrium with HLA alleles involved in T-cell regulation, suggesting the possibility of T-cell involvement in reflux esophagitis. WFL and CL are co-first authors. GL and GED are co-senior authors.
Real-world treatment patterns among patients with advanced gastric cancer in South Korea.
Authors: Cuyun Carter Gebra , Kaltenboeck Anna , Ivanova Jasmina , Liepa Astra M. , San Roman Alexandra , Koh Maria , Lee Hyun Jung , Rajan Narayan , Ballal Shaila , Birnbaum Howard , Bang Yung-Jue
Published: February 2017

152

Background: This study explored treatment patterns, and cancer-related resource use of patients with metastatic and unresectable gastric cancer (MGC) in South Korea. Methods: Charts of patients ≥ 18 years old were reviewed by 30 physicians to collect de-identified data on MGC or gastroesophageal junction adenocarcinoma [diagnosis on or after January 1, 2009]. Patients received platinum/fluoropyrimidine first-line therapy followed by second-line therapy or best supportive care, had no other primary cancer, and did not participate in a clinical trial following MGC diagnosis. Patient characteristics and treatment patterns were summarized using descriptive statistics. Results: Of 198 patients, 74% were male; 78% were diagnosed with MGC after age 55 (mean=61 yrs); 47% were current or former smokers and 48% reported light to moderate alcohol consumption. The majority of tumors were located in the antrum/pyloris (52%); metastatic sites most often occurred in the peritoneum (54%), lymph nodes (48%), and liver (39%). At diagnosis, the mean Charlson comorbidity index was 0.4 (std dev=0.6). The most common comorbidities were chronic gastritis (23%) and cardiovascular disease (19%). Most patients (80%) received second-line treatment (ECOG scores: 0 -10%, 1 -66%, 2 -22%); 20% received best supportive care only. Single-agent fluoropyrimidine was reported for 22% of patients receiving second-line treatment; 20% were treated with irinotecan with a fluoropyrimidine or platinum agent. Second-line treatment was chosen mainly according to national guidelines (81%) and physician experience (35%). The most common symptoms during second-line treatment were nausea/vomiting (45%) and pain (11%), with antiemetics (45%), analgesics (37%) and nutritional support (11%) most often used as supportive care. Two-thirds of inpatient hospitalizations (30% of second-line patients had ≥ one) were for chemotherapy infusion. Outpatient hospitalization (16%) and visits to the oncologist (38%) were common among second-line patients. Conclusions: Most patients received second-line treatment, though regimens varied. Understanding MGC patient characteristics and treatment patterns in Korea will help address unmet needs.
Evaluation of usefulness of Royal Marsden Hospital prognostic index in second-line chemotherapy of advanced gastric cancer.
Authors: Sasaki Takahide , Komatsu Yoshito , Yuki Satoshi , Harada Kazuaki , Kobayashi Yoshimitsu , Fukushima Hiraku , Sakamoto Naoya
Published: February 2017

163

Background: Royal Marsden Hospital prognostic Index (RMH-I), which was based on performance status, ALP, liver metastasis and peritoneal metastasis, was reported as prognostic factor of advanced esophago-gastric cancer before first line chemotherapy (Chau I, et al. J Clin Oncol 22:2395-2403, 2004). Usefulness of RMH-I in second line chemotherapy is not elucidated. Methods: Advanced gastric cancer patients who started second line chemotherapy in Hokkaido University Hospital from July 2001 to May 2013 with prior fluoropyrimidine plus platinum administration were retrospectively analyzed. Univariate and multivariate analysis for overall survival were performed using patient characteristics (RMH-I, hemoglobin, CRP, CEA, Alb, TTP in first line, primary lesion resection, and bone metastasis). Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. Results: There were 77 eligible patients. Male/Female were 52/25, median age was 60 years (range 31-80) and unresectable/recurrent were 70/7. Median survival was 7.1 months. The distribution and median survival for RMH-I groups were as follows: good risk (n = 8), 8.2 months; moderate risk (n = 57), 9.6 months; and poor risk (n = 12), 4.4 months. Although poor risk group showed shorter survival time, there were not significant difference regardless of RMH-I in Cox multivariate analysis (HR 1.12, 95%CI 0.61-2.09, P=0.72). Conclusions: In this retrospective analysis, RMH-I was not independent prognostic factor in second line chemotherapy of advanced gastric cancer. Prognostic factors in this population need to be investigated further.
Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors.
Authors: Fine Robert Lance , Gulati Anthony Paul , Tsushima Dawn , Mowatt Kelley B. , Oprescu Anna , Bruce Jeffrey N. , Chabot John A.
Published: February 2017

179

Background: We found in our lab that capecitabine (CAP), the prodrug of 5-FU, and temozolomide (TEM) were synergistic in inducing apoptosis in BON neuroendocrine tumor (NET) cell lines. We were the first to report in 2004 the use and mechanism of action of CAP and TEM (CAPTEM) in well differentiated NETs with promising results. Here we describe the interim analysis of an ongoing Phase II trial. Methods: 28 patients with metastatic well-moderately differentiated NET (ki-67 ≤20%) who had shown progression only on 60mg Sandostatin LAR (if octreotide scan positive) were treated with the following regimen: CAP 1,500mg/m2/day (PO divided BID, maximum 2,500 mg/day) on d1-14, and TEM 150-200mg/m2/day (PO divided BID, lower dose for patients who had prior chemotherapy or extensive radiation) on d10-14, with the next two weeks off, in a 28 day cycle. Primary objective was RR based upon RECIST, and secondary objectives included PFS, OS (from time of initiation of therapy), and toxicity evaluation. Other inclusion criteria were: age <80, ECOG PS 0-2, and adequate hematologic, renal, and liver function, and failure on high dose Sandostatin LAR. Results: 28 of 38 planned patients were enrolled with various NET subtypes (table). Overall RR was 43% (11% CR) and SD rate was 54%, with clinical benefit in 97%. ORR was 41% in carcinoid tumors. Ongoing mPFS is >20mo for all subtypes with 18/28 (64%) having progressed at this time. Twelve of 28 had died at this analysis with ongoing mOS of >25.3mo. The most common G3/4 toxicities were lymphopenia (32%), hyperglycemia (15%, unlikely related), thrombocytopenia (3%), and diarrhea (3%). No hospitalizations, opportunistic infections, or deaths occurred from CAPTEM. Conclusions: CAPTEM is an effective treatment for patients with progressive NET who failed high dose octreotide, with high PR and SD rates in carcinoids and insulinomas. The ongoing PFS in pancreatic NETs (>18.2 mo) is 150% greater than reported with everolimus and sutent. Clinical trial information: NCT00869050. [Table: see text]
TRC105 for the treatment of hepatocellular carcinoma: Preclinical data and preliminary results from two clinical trials evaluating monotherapy and combination with sorafenib.
Authors: Duffy Austin G. , Ma Chi , Ulahannan Susanna Varkey , Fioravanti Suzanne , Venkatesan Aradhana , Turkbey Ismail B. , Choyke Peter L. , Trepel Jane B. , Cao Liang , Compton Kathryn , Figg William Douglas , Greten Tim F.
Published: February 2017

211

Background: Endoglin (CD105), is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including in HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that acts by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) ± sorafenib (10 mg/kg daily p.o.) or sorafenib alone. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid; or (if sorafenib-refractory) a phase II study of TRC105 at 10 or 15mg/kg q 2wks. Correlative biomarkers: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors of mice treated with sorafenib. Anti-CD105 + sorafenib was more effective than sorafenib alone. Clinical trials (N=16): M:F 13:3; Median age = 55 (range 24-67); Phase I with sorafenib (N=8): 1 DLT (increased AST) occurred at 10mg/kg. The most frequent toxicity has been epistaxis. One patient with coronary stenosis developed a fatal MI and one patient with thrombocytopenia developed G3 cerebral tumor hemorrhage. Phase II (N=8): No grade 3/4 treatment-related toxicities . Most frequent toxicities headache (G2; N=3) and epistaxis (G1; N=4). No patient was progression free at 4 months. Median time on study: Phase I- 4 months; Phase II - 2 months. Preliminary evidence of biologic response seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in Ktrans and kep and 3pts (of 3 evaluable) with reduction in intra-tumoral color flow on Doppler. Conclusions: TRC105 is well tolerated both as single agent and combined with sorafenib. Evidence of biological activity was observed. Full preclinical, clinical and correlative data will be presented. Clinical trial information: NCT01306058, NCT01375569.
Correlation of KRAS mutational state with the expression of the hedgehog pathway in patients with pancreatic ductal adenocarcinoma.
Authors: Santoni Matteo , Bittoni Alessandro , Andrikou Kalliopi , Lanese Andrea , Loretelli Cristian , Conti Alessandro , d'Arenzo Marco , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano
Published: February 2017

227

Background: Pancreatic ductal adenocarcinoma (PDAC) is commonly associated with mutations in the KRAS gene. However, how KRAS mutations promote pancreatic carcinogenesis has not been fully established. Here we examine the association between KRAS mutational state and the expression of different tumor markers in PDAC samples. Methods: Immunohistochemical analysis was performed on PDAC specimens to identify the levels of expression of 28 surface and nuclear proteins: BRCA1, BRCA2, NOTCH1, SPARC, SHH, DHH, IHH, SMO, PTCH1, PTCH2, ALCAM, OCT3.4, PROM1, CD44, CD24, LGR5, BMP4, KDR, FLT1, PDGFRB, VEGFA, VEGFB, PGF, CDKN2A, SMAD4, MET, HGF, MUC6. All samples were also tested for identification of KRAS isoforms (wild type (WT) vs mutated type (MT)) expression by means of RT-PCR. Levels of mRNA expression were matched with a common standard tissue marker. Expression levels of PDAC markers were compared between MT and WT KRAS groups. Differences between groups were tested using Mann-Whitney U test for unpaired samples. Exploratory univariate logistic regression was also performed to evaluate possible correlations between increasing levels of each marker and KRAS mutational state. Results: 110 samples were collected. Of them, data on KRAS were provided for 86 samples; 40 and 46 samples expressed the WT and MT KRAS isofo rms, respectively. Preliminary analysis showed that the expression of SHH and IHH resulted significantly higher in KRAS MT samples (U=1097 p= 0.013 and U=1072 p= 0.028 respectively), whereas higher levels of SMAD4 (U=634, p= 0.012) and HGF (U= 655, p= 0.03) were expressed in the KRAS WT group. A weak difference between groups was found for the MUC6 pathway (U= 666, p= 0.056). No differences of VEGFA, VEGFB and VEGFRB expression were found between MT and WT groups. At univariate logistic regression we found that increased levels of SHH correlated with the expression of KRAS MT phenotype (OR 57.5, p= 0.011), while IHH showed only a weaker significance level (OR 13.1, p= 0.069). Conclusions: These results indicate that oncogenic KRAS is directly associated with SHH expression in PDAC tissues. They also mark Hedgehog pathway components as relevant therapeutic targets for KRAS-mutant patients.
A phase I study of the anti-IGF-1R monoclonal antibody (MoAb), IMC-A12 (I), and everolimus (E) in well-differentiated neuroendocrine tumors (WD NET).
Authors: Dasari Arvind , Phan Alexandria , Gupta Sanjay , Hess Kenneth R. , Culotta Kirk Salvatore , Rashid Asif , Yeung S. J. , Chen Helen X. , Dong Mei , Halperin Daniel M. , Subbiah Ishwaria Mohan , Meric-Bernstam Funda , Yao James C.
Published: February 2017

232

Background: Octreotide LAR (LAR) and E have well known anti-cancer effects in WD NETs. Preclinical data also show that inhibition of the insulin like growth factor receptor (IGF-1R) may sensitize NETs to mTOR inhibitors such as E. Methods: Patients (pts) with WD NETs, ECOG performance status ≤ 2 and adequate organ function were treated with LAR 20 mg IM q 21days (d), E 10 mg po daily and escalating doses of I iv q 21 d in 21 d cycles in cohorts of 6 until maximum tolerated dose (MTD). Recommended phase II dose (RP2D) was defined as dose level below MTD. An expansion cohort of 9 pts was planned at RP2D. Plasma samples for everolimus pharmacokinetics (PK), IGF, mTOR pathway pharmacodynamics (PD) in addition to paired tissue biopsies were obtained. Results: 19 pts with previously treated (median prior systemic therapy, 1, range 0-3) WDNET (4 pancreatic NET, 11 carcinoid, 4 unknown primary) were enrolled in this single institution study. Ten pts in dose escalation and 9 in expansion phases received a median of 8.5 cycles (range, 3-19+). Dose limiting toxicities (DLTs) were grade (g) 3 mucositis in 2 pts at 2nddose level of I 15 mg/m2 q 21 d. Most frequent adverse events (AEs) observed while on study were fatigue, hyperlipidemia, weight loss (74%), dysguesia (68%), hyperglycemia and mucositis (63%). Most common g3 AEs were fatigue (21%), mucositis, transaminitis and electrolyte disturbances (all 11%). Other g 3 AEs included anorexia, anemia, injury, retinal detachment, dehydration and thromboembolism. One g 4 AE of hyperglycemia was noted during the expansion phase. One pt with pancreatic NET had confirmed partial response and 17 had stable disease as best response. The median progression free survival was 34+ weeks. Conclusions: The RP2D of this combination is I 10 mg/m2, LAR 20 mg IM q 21 d, E 10 mg po daily. PK, PD and other correlative analyses are ongoing and will be presented at the meeting. Although adequate safety and a sign of activity were noted in this study, these will need to be reconciled with data from larger studies of anti-IGF-1R MoAb in NET and other cancers that have been disappointing. Clinical trial information: NCT01204476.
ERCC1 mRNA levels as a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.
Authors: Uemura Shuichiro , Kuramochi Hidekazu , Nakajima Go , Sato Yasuto , Higuchi Ryota , Yamamoto Masakazu
Published: February 2017

239

Background: To date, no prognostic biomarker for biliary tract carcinoma has been identified. In previous studies of biliary tract carcinoma, no reliable data was found due to the varying composition of the cancer type (gallbladder, cholangiocarcinoma, and ampullary carcinoma), differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. Methods: Fifty extrahepatic cholangiocarcinoma patients who underwent a pancreatoduodenectomy with R0 resection at the Tokyo Women’s Medical University Hospital were examined. All patients were pathologically diagnosed as having papillary or tubular adenocarcinoma. T-RNA was extracted from FFPE samples, and mRNA expression levels were measured by real-time RT-PCR. Results: In the preliminary analysis, 10 patients who have survived more than 5 years (LS group) and 10 patients who had a relapse within 2 years (SS group) were selected. EGFR, AREG, EREG, MMP-9, CDH-1, PARP1, and ERCC1 mRNA expression were examined; only the ERCC1 mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7, p=0.0073). The median survival time (MST) of the patients with high ERCC1 levels was significantly higher than that in patients with a low ERCC1 level (MST: not reached vs. 16M). Then, 30 more patients with the same backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. The patients with high ERCC1 mRNA levels had a significantly greater overall survival rate compared with those with low ERCC1 levels (MST: not reached vs. 12.5M, 5-year survival rate: 92% vs 51%; p=0.04). In multivariate analysis, no lymph node metastases or high ERCC1 expression were significantly associated with better overall survival. Conclusions: ERCC1 mRNA expression seemed to be a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.
Survival benefits of adjuvant radiotherapy and lymph node dissection in pancreatic cancer treated with surgery and chemotherapy.
Authors: Mellon Eric Albert , Springett Gregory M. , Hoffe Sarah E. , Hodul Pamela Joy , Malafa Mokenge Peter , Meredith Kenneth , Fulp William J. , Zhao Xiuhua , Weber Jill , Shridhar Ravi
Published: February 2017

263

Background: Prior SEER analyses of the benefit of radiotherapy in surgically resected pancreatic cancer could not analyze chemotherapy recipients due to limited database information. Recent updates permit us to determine the effects of postoperative radiation therapy (PORT) and lymph node resection (LNR) on overall survival (OS) in pancreatic cancer among patients treated with both surgery and chemotherapy. Methods: An analysis of surgically resected pancreatic cancer patients receiving chemotherapy from the SEER database between 2004-2008 was performed. Survival was calculated by Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was by the Cox proportional hazard model. Results: We identified 2,966 patients who met inclusion criteria. PORT significantly improved OS in pancreatic cancer patients treated with surgery and chemotherapy (p=0.02). Median survival (MS), 1-year OS, and 3-year OS was 21 months, 77%, and 28% with PORT (n=1842) versus 20 months, 70%, and 25% without radiation (n=1124). On subset analysis, the benefit of PORT was limited to node positive patients. In N1 patients (n=2043) MS, 1-year OS, and 3-year OS was 19 months, 73%, and 25% with PORT versus 18 months, 67%, and 20% without PORT (p<0.01). For N0 patients (n=923) MS, 1-year OS, and 3-year OS was 26 months, 85%, and 36% with PORT versus 25 months, 79%, and 38% without PORT (p=0.87). Increasing nodal count on LNR correlated with improved OS on MVA for all and N1 patients (each p<0.001). Significant cut points for OS based on LNR in N1 patients were found for greater than 8, 10, 12, 15, 20, and 30 nodes resected (p<0.05 for all). Prognostic factors on MVA include receipt of radiation, age, female sex, well differentiated grade, N0 status, and disease contained within the pancreas (p < 0.03 for all). In N1 patients (n=2043), these factors remained significant except patient age. In N0 patients (n=923), only pancreas-confined disease and less than high grade tumor were associated with survival benefit. Conclusions: PORT and degree of LNR are both correlated with improved OS in pancreatic cancer patients treated with surgery and chemotherapy. Benefit of PORT and LNR seems limited to node positive patients.
Impact of ROS1, ALK, and/or MET expression level on the therapeutic efficacy of GEMOX with and without cetuximab in ABTC: A post hoc analysis of a randomized phase II trial.
Authors: Chiang Nai-Jung , Hsu Chiun , Chen Jen-Shi , Tsou Hiso-Hui , Chao Yee , Shan Yang-Shen , Huang Shiu-Feng , Chiu Chang-Fang , Lee Kuan-Der , Chen Li-Tzong
Published: February 2017

267

Background: Our randomized phase II trial showed adding cetuximab to GEMOX marginally improved the ORR and median PFS in ABTC patients regardless their KRAS mutation status. Recently, MET overexpression was noted in 11.7% to 16.2% of BTC, and associated with poor OS. ROS1 kinase fusion has also been detected in 8.6% of IHCC.The aim of the study is to evaluate the impact of ROS1, ALK and/or MET (RAM) overexpression on the clinical outcomes of ABTC patients. Methods: FFPE tissue sections that were prospectively collected for biomarker study from all 122 patients were subjected for determining the expression of ROS1, ALK and MET by IHC in a central laboratory. Results: Of 110 patients with enough tissue section for IHC of all three markers, 18 tumors were found to over-express ROS1 (in 9), ALK (in 5) and/or MET (in 6). One tumor over-expressed all three biomarkers. As compared with RAMlow tumors, the 18 RAMhigh tumors were significantly more of IHCC and without prior surgery, and with more frequent concurrent KRAS mutation. RAMhigh tumors was associated with significant inferior median OS than RAMlow tumors, 5.7 vs 11.8 months (p=0.04). Of the latter 92 patients, adding cetuximab improved the therapeutic efficacy of GEMOX in ABTC, with ORR of 31.8% vs 10.4% (p=0.02), DCR of 61.4% vs 37.5% (p=0.04) and median PFS of 7.0 vs 4.5 months (p=0.02). OS was only marginally affected, with median OS of 12.5 vs 10.4 months (p=0.36). The ORR in KRASwt and KRASmut patients receiving C-GEMOX and GEMOX was 34.5% vs 11.8% (p=0.04) and 26.7% vs 7.1% (p=0.33), respectively; whiles the DCR was 65.5% vs 50.0% (p=0.31) and 53.3% vs 7.1% (p=0.01), respectively, and the median PFS was 7.1 vs 5.8 months (p=0.07) and 7.0 vs 1.9 months (p=0.05), respectively. The results suggest that, the presence of KRAS mutation did not preclude the benefit of adding cetuximab to GEMOX in RAMlowsubpopulation. Conclusions: ROS1/ALK/METhigh ABTC had poor survival after C-GEMOX/GEMOX; while C-GEMOX significantly improved the ORR, DCR and PFS as compared to GEMOX alone in patients with ROS1/ALK/METlow tumors regardless their KRAS mutation status. Biomarker-driven design is warranted for future ABTC trials.
ELECT: A phase 3 study of efficacy and safety of lanreotide autogel/depot (LAN) treatment for carcinoid syndrome in patients with neuroendocrine tumors (NETs).
Authors: Vinik Aaron , Wolin Edward M. , Audry Helene , Gomez-Panzani Edda L. ,   ELECT Study Group
Published: February 2017

268

Background: Somatostatin analogs (SSAs) are the mainstay treatment for carcinoid syndrome. LAN is a long-acting SSA approved for this indication in >50 countries, but not yet in the US. ELECT is a large multinational phase 3 study evaluating rescue therapy use as a novel alternate endpoint for carcinoid symptom control with LAN. Methods: Eligible patients were age ≥ 18 years with histologically-confirmed NET and a history of carcinoid syndrome, and naïve to SSA treatment or responsive to conventional doses of octreotide LAR (≤ 30 mg/4 weeks) or short acting (≤ 600 µg/day SC). Design: a 16-week, randomized (LAN 120 mg [n=59] vs placebo [n=56] every 4 weeks) double-blind phase, followed by a 32-week long-term open label phase on LAN. Patients had access to short acting octreotide as rescue for breakthrough symptoms throughout the study. Primary endpoint: % of days the patient used rescue octreotide during the double-blind phase. The study was designed to have 90% power to detect a treatment difference of 30%. NCT00774930. Results: Among thestudy population, 83 (72%) had symptoms for ≥ 1 year, and51 (44%)had no prior SSA therapy. Mean [95% CI] % of days with rescue medication use was statistically lower with LAN (34% [25, 42%]) vs placebo (49% [40, 57%]), absolute difference –15% [–27, –3%], p=0.02; however, the pre-defined difference was not met. Complete/partial success (≤3 days use) rather than failure (> 3 days use) was more likely with LAN than placebo (OR 2.4 [95% CI 1.1, 5.3]; p=0.04). Treatment emergent AEs: 15 (26%) LAN patients vs 11 (19%) placebo patients; few AEs were serious (2 [3%] vs 5 [9%]) or led to study withdrawal (1 [2%] vs 1 [2%]). Most frequent AEs were GI disorders, 9 (16%) on LAN vs 5 (9%) on placebo. Conclusions: In the ELECT study, LAN significantly reduced need for short acting SSA use with a favorable safety/tolerability profile. This confirms LAN’s positive benefit-risk profile, which is consistent with experience from previous trials and many years of clinical practice in many countries around the world. Clinical trial information: NCT00774930.
Novel Kras-directed therapy in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.
Authors: Golan Talia , Hubert Ayala , Shemi Amotz , Segal Amiel , Khvalevsky Elina Zorde , Domb Avi , Ben-David Eliel , Raskin Stephen , Goldes Yuri , Lahav Maor , Dancour Alan , Galun Eithan
Published: February 2017

270

Background: K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-RasG12D(siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - is a miniature biodegradable polymeric matrix that encompasses anti K-RasG12D siRNA drug, designed to release the drug regionally along 4 months. The siG12D LODER is placed with Endoscopic US biopsy. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in a dose escalation, dose cohorts were: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m2IV was given on a weekly basis, following the siG12D LODER insertion, until disease progression. The RP2D (recommended phase II dose) was further examined in highest dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2 followed by a Fluorouracil continuous IV infusion 2,400mg/m2 46 hours every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results: 15 patients with locally advanced PDAC have been enrolled. Two patients were omitted from study but followed for safety due to metastatic disease detected on day 1 post siG12D LODER implant imaging. Median age = 70 (range 52-85); male:female =8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE). No DLTs were observed. CT performed 8-12 weeks following the procedure showed tumor regression in 66% (8 of the first 12 patients, 7/8 from 2nd and 3rd cohorts).Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. Median overall survival was 16.26 months, 14.01 months and 15.11 months in the 0.025 mg, 0.75 mg and the 3 mg treatment groups respectively. Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced pancreatic cancer with durable responses. NCT01188785. Clinical trial information: NCT01188785.
Surgical strategy for borderline resectable pancreatic body cancer.
Authors: Yamaue Hiroki , Okada Ken-Ichi , Tani Masaji , Kawai Manabu , Hirono Seiko , Miyazawa Motoki , Shimizu Atsushi
Published: February 2017

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Background: The indications for distal pancreatectomy with en-bloc celiac axis resection (DP-CAR) in pancreatic carcinoma remain controversial. Moreover, the incidence of delayed gastric emptying (DGE) is high in patients undergoing distal pancreatectomy with DP-CAR. Methods: Fifty-two consecutive patients with pancreatic cancer who underwent distal pancreatectomy, including 36 standard distal pancreatectomies (standard DP) and 16 DP-CAR were reviewed. To determine the incidence of DGE, 37 consecutive patients who underwent DP-CAR were evaluated for the incidence of DGE, including 23 patients with left gastric artery (LGA)-resecting DP-CAR (conventional DP-CAR) and compared it with 14 patients who underwent distal pancreatectomy with preservation of the LGA (modified DP-CAR). Results: The estimated overall 1- and 2-year survival rates after standard DP / DP-CAR were 81/81% and 52/53%, and the median survival times were 32/25 months, respectively, with no significant difference comparing standard DP. There were no differences in the mortality rates and the incidence of each complication between the two groups except for delayed gastric emptying. In the conventional DP-CAR group, the LGA were involved in 20 patients (87.0%). The ISGPS grades were: no DGE = 43%, grade A = 26%, B = 13% and C = 17% in the conventional DP-CAR group, and no DGE = 93%, grade A = 7%, grade B/C = 0% in the modified DP-CAR group. The R0 rate was higher in the modified DP-CAR group (79%) compared to the conventional DP-CAR group (43%) (p=0.048). On multivariate analysis, resection of the LGA was an independent risk factor for increased incidence of DGE. Conclusions: DP-CAR was a feasible and safe procedure, similar to standard DP. Modified DP-CAR significantly reduced the incidence of DGE in comparison to conventional DP-CAR.
Harvesting lymph nodes in gastric cancer surgery: A prospective randomized controlled study.
Authors: Aoyama Toru , Fujikawa Hirohito , Shirai Junya , Yoichi Kameda , Cho Haruhiko , Hayashi Tsutomu , Rino Yasushi , Hasegawa Shinichi , Oshima Takashi , Masuda Munetaka , Oba Mari Saito , Morita Satoshi , Yoshikawa Takaki
Published: February 2017

28

Background: Harvesting lymph node (LN) after gastrectomy is essential for accurate staging. Conventional method (CONV) to retrieve LN immediately after surgery is accepted in Japan but its efficacy and quality highly depends on the case and examiners. Another method is to retrieve LN stained by methylene blue dye (MBD), by which the physicians may easily pick up blue LN. This trial evaluated the efficiency and quality of both methods in randomized fashion. Methods: Key eligible criteria are as follows. (i) Histologically proven adenocarcinoma of the stomach, (ii) Clinical stage I-III, (iii) R0 resection is planned by gastrectomy with D1+ or D2 lymphadenectomy. Examiners for harvesting LN are qualified based on the experience. After curative surgery, LNs are harvested from the specimen immediately after surgery in the CONV group and from the specimens who had been fixed with 10% buffered formalin with methylene blue for 48 hours in the MBD group. The primary endpoint is the ratio of the pathological number of the harvested LNs per time (minutes) as an efficacy measure. The secondary endpoint is the pathological number of harvested LNs as a quality measure. The sample size was determined to be 60 considering the primary measurement as 40 LNs / 30 minutes in CONV and 40 LNs / 22.5 minutes in MBD with two-sided alpha error of 5% and statistical power of 80%. Results: Between August 2012 and December 2012, 60 patients were assigned to CONV (n=29) and MBD (n=31). Total/subtotal gastrectomy was 12/17 in CONV and 12/19 in MBD, respectively. D1+/D2 was 17/12 in CONV and 15/16 in MBD, respectively. Baseline demographics were well balanced between the both. The number of pathological harvesting LNs (median, range) was 32 (11-57) in CONV and 41 (17-79) in MBD (P=0.005). The time per case for harvesting LN (median, range) was 33 (15-58) minutes in CONV and 25 (13-102) minutes in MBD (p=0.743). The ratio of the number of the harvested LNs per time (median, range) was 1.12 (0.42-2.07) in CONV and 1.42 (0.50-3.07) in MBD (p=0.01). Conclusions: When harvesting LN in gastric cancer surgery, methylene blue dye-assisted technique is superior in the efficacy and quality as compared with conventional method. Clinical trial information: UMIN000008624.
Differences in clinical characteristics and treatment in hepatocellular carcinoma between Asians and non-Asians.
Authors: Wong Kit Man , Lee Jonghun John , Wong Amy , Liu Geoffrey , Sherman Morris , Cleary Sean P. , Knox Jennifer J.
Published: February 2017

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Background: Studies have demonstrated clinical differences in hepatocellular carcinoma (HCC) between Asians (AS) and non-Asians (NAS). In the US, AS are less likely to undergo liver transplant compared to Caucasians. Despite the large immigrant population in Canada, there has been no prior comparison of HCC in AS and NAS in the context of the Canadian universal health care system. We retrospectively evaluated the ethnic differences in HCC at the largest cancer centre in Canada. Methods: We analyzed 268 patients who enrolled in a Genetic Epidemiology Study of HCC (April 2010 to February 2013), where patients were asked to complete a questionnaire and give a blood sample at their first visit. Relevant clinical data were extracted and analyzed by descriptive statistics, t-test or Chi-square test. Results: The study population had a mean age of 61 years and 83% males. There were 45% AS, 49% Caucasians, and 6% other ethnicities. Etiologies of HCC included: Hepatitis B (HBV) 34%, Hepatitis C (HCV) 32%, non-alcoholic steatohepatitis 15%, alcohol 18%. Compared to NAS, HCC patients of Asian ancestry had significantly higher rates of HBV (60% vs. 12%, p<0.001). At diagnosis, 83% of patients were Child-Pugh A (mean MELD score 9.2). Ethnicity had no impact on Child-Pugh class, multifocal disease or macrovascular invasion. However, MELD scores were lower in AS (p=0.02). Overall, 71% of cases were initially treated with curative intent. Patients underwent various treatment modalities: liver transplant 13%, resection 31%, radiofrequency ablation 39%, transarterial chemoembolization (TACE) 21%, radiation 17%, systemic therapy 27%. AS had higher resection rates (41% vs. 22%, p<0.001), while no differences were observed for other treatments. Duration of response was 11.7 months for TACE (AS 14.2, NAS 10.5), 7.5 months for sorafenib (AS 6.8, NAS 8.1). Rate of intolerance to sorafenib was 24% (AS 27%, NAS 22%, p=0.63). This analysis was limited by inherent bias in the selection of study patients. Conclusions: AS with HCC tend to have HBV and lower MELD scores, and to undergo resection in a public health care setting with no differences in the uptake of other therapies. An analysis of survival based on ethnicity will be reported.
Relationship of novel genetically engineered mouse and the epithelial-mesenchymal transition in the metastastic progression of gastric cancers.
Authors: Kim Hark K. , Park Jun Won , Green Jeffrey E.
Published: February 2017

3

Background: By creating mice deficient in E-cadherin, Smad4, and p53, we evaluated whether and how Cdh1 heterozygosity may accelerate the development and progression of gastric cancer, in combination with loss of Smad4 and p53. Methods: Compound conditional knockout mice of Smad4, p53, and E-cadherin were mated with Pdx-1-Cre transgenic mice. Offsprings were monitored for the development of gastric adenocarcinomas. Results: Gastric adenocarcinomas spontaneously arose in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice and recapitulated human diffuse type gastric cancers in histopathology. Gastric adenocarcinoma was more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F mice. When compared to Pdx-1-Cre;Trp53F/F;Cdh1F/F mice, Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas more rapidly, suggesting that Smad4 and E-cadherin cooperate to constrain the development of gastric adenocarcinomas. Lung metastases were identified in three Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. The epithelial-to-mesenchymal transition (EMT), characterized by increased vimentin expression, was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the suppression of EMT by E-cadherin or Smad4 may reduce metastatic signaling pathways in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Conclusions: Loss of E-cadherin and Smad4 cooperate with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human diffuse type gastric cancer. Thus, our novel genetically-engineered mouse models reveal the importance of EMT in the metastatic progression of gastric cancers, providing a unique model to test agents targeting the metastatic progression in gastric cancers.
Incidence and risk factors of thromboembolism (TE) in advanced gastric cancer (AGC) receiving chemotherapy: A prospective observational study (NCT01047618).
Authors: Ryoo Baek-Yeol , Ryu Min-Hee , Park Sook Ryun , Kang Myoung Joo , Park Kwon-Oh , Kim Jeong Hye , Kang Yoon-Koo
Published: February 2017

31

Background: The incidence of TE in gastric cancer patients (pts) is known to be high. But because the previous reports were retrospectively analyzed in heterogeneous population, they give us only limited information. We therefore conducted a prospective study to investigate the incidence of TE and prognostic factors related with TE in AGC pts receiving chemotherapy. Methods: We checked D-dimer and coagulation battery at the start of chemotherapy and every 3 months thereafter. If there developed symptoms or signs of TE, or if D-dimer elevated 5 μg/mL or more we checked imaging studies to detect TE. The chemotherapy regimen mainly included fluoropyrimidine plus platinum-based for 1st-line, taxane-based for 2nd-line, and irinotecan-based for 3rd-line chemotherapy. Results: Between Nov 2009 and Apr 2012, 241 pts were analyzed. They received median 9 (range 1 - 42) cycles of chemotherapy. During the median observational duration of 16.7 months, 32 events (13.3%, 95% CI; 8.9 - 17.7%) of TE were detected. The types of TE were as follows; deep vein thrombosis (DVT) only in 18 (56.3%), pulmonary embolism (PE) only in 4 (12.5%), DVT and PE in 5 (15.6%), cerebral infarction in 4 (12.5%), and intra-abdominal arterial thrombosis 1 (3.1%) pts. The 1-year and 2-year cumulative incidences of TE were 15.0% (95% CI, 9.6 - 20.0%) and 20.0% (95% CI, 12.1 - 26.9%), respectively. The incidence rate of TE was 14.1 (95% CI, 9.6 - 19.9) events/100 person-years. In univariate analysis, the previous gastrectomy history, baseline CA72-4 level and baseline D-dimer level were statistically significant risk factor related with TE development. But in multivariate analysis, baseline D-dimer level was the only independent risk factor associated with TE development (Hazard ratio 2.46 [95% CI, 1.08 - 5.63], P= 0.033). Among 32 pts with baseline D-dimer 5.0 μg/mL or higher, 8 pts (25.0%) developed TE, while for pts whose baseline D-dimer was lower than 5.0 μg/mL, 24 out of 209 pts (11.5%) developed TE. Conclusions: The incidence rate of TE in AGC pts receiving chemotherapy was 14.1 (95% CI, 9.6 - 19.9) events/100 person-years. D-dimer was an important prognostic factor related with TE development. Clinical trial information: NCT01047618.
Prognostic factors and long-term outcomes of resected pancreatic adenocarcinoma: A comparison between two decades.
Authors: Serrano Aybar Pablo Emilio , Kim Peter Tae Wan , Leung Kenneth , Cleary Sean P. , Moulton Carol-anne , Greig Paul David , Gallinger Steven , Wei Alice Chia-chi
Published: February 2017

318

Background: There have been improvements in short and long-term survival rates for patients with resected pancreatic adenocarcinoma over time The main objective of this study was to evaluate differences in long-term survival in a cohort of patients with resected pancreatic adenocarcinoma. Methods: This is a retrospective cohort study of patients who underwent pancreatic resection for pancreatic adenocarcinoma over 2 decades at a high volume academic centre. Univariate and multivariate analysis using Cox proportional hazards model were performed to evaluate prognostic factors associated with long-term survival. Time trend analyses were performed to evaluate differences between decades. Results: There were 489 patients identified, 179 patients during the early (1991-2000) and 310 during the recent decade (2001-2010). Main differences between early and recent decade were: node-positive disease rate (59% vs. 69%), number of lymph nodes collected (median 7 vs. 17), perioperative mortality (6.7% vs. 1.6%) and percentage of patients receiving adjuvant therapy (33% vs. 68%), respectively. There were no differences in sex distribution, age, margin positivity rate or tumor grade. In the multivariate analysis, node, margin status, tumor grade, adjuvant therapy and decade of resection were independently associated with overall survival for the entire cohort. Patients who received adjuvant therapy had better median overall survival: 17 [95% confidence interval (CI): 14-22] vs. 26 months (95% CI: 24-31). Median overall survival for the early and recent decade were 16 months (95% CI: 14-20) and 27 months (95% CI: 24-30, p<0.001), respectively. Conclusions: Factors associated with improved long-term survival remain comparable over time: low tumor grade, node and margin negative disease. Short and long-term survival for patients with resected pancreatic adenocarcinoma has improved in the recent decade. This is due to decreased perioperative mortality and increase use of adjuvant therapy.