bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination therapy with radiation and weekly paclitaxel/carboplatin as definitive treatment for locally advanced esophageal cancer.
Authors: Doherty Mark , Cowzer Darren , Kelly Ciara Marie , Battley Jodie Emma , Leonard Gregory , Power Derek Gerard
Published: February 2017

133

Background: Definitive chemoradiotherapy (CRT) is an established treatment option in localised esophageal cancer. While most patients are treated with cisplatin and fluorouracil, alternative chemotherapy regimens have been used. The combination of carboplatin and paclitaxel (CP) has been validated in a neoadjuvant CRT trial by the CROSS study. There has also been a phase II study (v. Meerten, ASCO 2010, e14508) showing efficacy and tolerability of this regimen in the definitive setting with radiation doses of 50.4Gy/28#. We report our experience using this strategy in two Irish centres. Methods: Patients treated with weekly CP and definitive radiation between Jan 2010 and Aug 2012 were identified from our pharmacy database. Clinicopathologic details were obtained from electronic medical records. The group contains patients with locally advanced unresectable disease, or those medically unfit for esophagectomy. Results: Between Jan 2010 and Aug 2012, we identified 22 patients. Thirteen patients had squamous histology, while 9 had adenocarcinoma. Staging was performed with CT, EUS, and PET/CT – 1 patient had T2 disease, while the remainder had T3/T4, and 10 patients had positive nodes. Reasons for not pursuing surgical resection were extent of disease and poor performance score. In total, 86% of patients received full dose treatment, with reasons for dose delay/reduction being grade 3 sepsis, grade 3 gastrointestinal toxicity, and decline in performance status. Overall 5 (23%) patients needed hospital admission during treatment. At a median follow up of 14 months (range 9-23 months), 19 patients are alive with no evidence of disease, 2 patients have died of disease, and 1 patient is alive with relapsed disease. Our 1-year recurrence free survival rate is 86%. Conclusions: Definitive CRT with CP is a tolerable regimen that can be administered on an outpatient basis, and provides a treatment option in those who are unsuitable for surgical resection or Herskovic type CRT. Our results compare favorably with previous studies in this population. Further investigation is warranted in a prospective study to validate the efficacy of this approach.
Brain metastasis from esophageal cancer: Changing pattern of failure?
Authors: Ashman Jonathan Ben , Jaroszewski Dawn E. , Patel Naresh P. , Fleischer David , Rule William G. , Pannala Rahul , Ramirez Francisco , Lanza Louis , Paripati Harshita , Harold Kristi L. , Faigel Douglas , Ross Helen J.
Published: February 2017

134

Background: Brain metastasis (BM) is an uncommon site of failure in patients (pts) with esophageal cancer (EC) with reported rates between 1-6%. EC pts are living longer with the wider adoption of trimodality therapy and, as with other malignancies, this may change the patterns of failure. We evaluated the incidence and outcomes of BM in EC at Mayo Clinic in Arizona. Methods: A retrospective review identified pts who developed BM from cancer of the esophagus or gastroesophageal junction. A total of 321 patients treated for stage I-IV EC (adenocarcinoma, n = 273; squamous, n = 46; small cell, n = 2) were identified between 1997 and 2012. Fisher’s exact test was used for comparisons. Actuarial survival was calculated using Kaplan-Meier analysis. Results: BM developed in 13 pts (4%), all of whom had adenocarcinoma. Nine pts initially presented with T3 and/or node-positive disease. Four pts presented with metastatic disease to other sites, but only 1 of this group was diagnosed with BM at initial presentation. The median time from initial diagnosis to BM detection was 12 months (range 0-40). All pts were symptomatic at diagnosis. BM was solitary in 6 pts, multiple in 6 pts, and unknown in 1 pt. The posterior fossa was involved in 9 pts. The brain represented the first site of failure in 9 pts. Treatment included surgical resection (n = 5), stereotactic radiosurgery (n = 4), and whole brain radiotherapy (n = 9). Median overall survival was 24 months from initial diagnosis and 5 months from BM detection. Among pts with adenocarcinoma, 3/119 (2.5%) were diagnosed between 1997-2006 compared to 10/154 (6.5%) between 2007-2012 (P = 0.1). Conclusions: The brain remains an uncommon site of failure among pts with EC. A recent series reported an incidence of BM in 13% of pts, raising the possibility of a changing failure pattern. In our series, BM was detected in only 4% of pts. Our study is suggestive of a trend towards increased incidence of BM in more recent years, although it did not reach statistical significance and could be a consequence of the retrospective nature of the study. Both series found BM limited only to pts with adenocarcinoma, and a possible association has been reported between HER-2 overexpression and BM in EC. Therefore, BM in EC may be an interesting area for future study.
Is neoadjuvant therapy beneficial in clinically staged T2N0 esophageal cancer?
Authors: Kaur Taranjeet , Dolan James P. , Diggs Brian S. , Luna Renato , Sheppard Brett C. , Schipper Paul , Tieu Brandon , Holland John M. , Thomas Charles R. , Gatter Ken , Vaccaro Gina M. , Hunter John G.
Published: February 2017

135

Background: The optimal treatment strategy for clinical stage T2N0 (cT2N0) esophageal cancer is poorly defined. The specific aims of this analysis were to determine the impact of neoadjuvant therapy (NAT) in cT2N0 esophageal cancer patients on overall survival, nodal metastasis, staging, and pathological complete responders (pCR) NAT. Methods: We reviewed a retrospective cohort of 27 patients with cT2N0 esophageal cancer at Oregon Health & Science University, an NCI-Designated Cancer Center from 1999 to 2011. All patients were staged pre-operatively using Endoscopic Ultrasound (EUS), CT +/- FDG-PET. Patients were identified into two cohorts: NAT followed by surgery and surgery alone. We compared overall survival between the cohorts using Kaplan-Meier analysis. Results: Eleven patients (41%) received NAT followed by surgery and sixteen patients (59%) underwent surgery alone. Minimal invasive esophagectomy and decreased length of stay (p < 0.05) were associated with the presence of neoadjuvant therapy. The difference in overall survival rate was not statistically significant between NAT and surgery alone groups (p = 0.96). Three of 11 patients (27%) had a pCR and 8 (73%) were partial or non responders after NAT. In the surgery only group, nine of 16 patients (56%) were understaged, 6 (38%) were overstaged and 1 (6%) was correctly staged. Despite being clinically node negative, 14/27 (52%) had node positive disease in both groups with 5/11 (45%) in NAT group and 9/16 (56%) in surgery group. Conclusions: The benefit of NAT in cT2N0 esophageal cancer patients remains unclear. However, our finding of significant clinical understaging and frequent positive nodes in clinically node negative patients suggests a clinical benefit to NAT for some cT2N0 patients before surgery. These observations support design of a prospective clinical trial to define the role of NAT in patients with cT2N0 esophageal cancer.
Induction of MT1-MMP expression and enhancement of gastric cancer cells invasion by DARPP-32-CXCR4 interaction.
Authors: Zhu Shoumin , Belkhiri Abbes , El-Rifai Wael
Published: February 2017

14

Background: Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) is amplified and overexpressed in approximately 70% of gastric cancers. The prognosis for gastric cancer patients remains poor, especially in more advanced stages. Recently, it was suggested that CXCL-12 and its receptor, CXCR4, are involved in gastric cancer metastasis. However, the detailed mechanism of gastric cancer metastasis is still not completely understood. Methods: Cells invasive activity was determined by invasion assay and HUVEC invasion assay. The association between DARPP-32 and CXCR4 was evaluated by immunofluorescence and co-immunoprecipitation assays. CXCR4 degradation was analyzed by Ubiquitination Assay. Results: Overexpression of DARPP-32 in AGS cells increased cell invasion with about as three-fold invasive cells as the vector control (p<0.01). As measured by HUVEC invasion assay, overexpression of DARPP-32 in AGS cells also had a significant increase in the invasive activity (p<0.001). We found that DARPP-32 led to increased CXCR4 and MT1-MMP protein levels in DARPP-32 expressing AGS cells. The co-immunoprecipitation and immunofluorescence experiments demonstrated the existence of DARPP-32 and CXCR4 in the same protein complex. AGS cells expressing DARPP-32 displayed stable protein levels of CXCR4. IP-Western blot showed reduced ubiquitination of CXCR4 protein following the overexpression of DARPP-32 and treatment with CXCL-12, as compared to controls. Using AMD3100 (0.2 ng/ml) overnight blocked DARPP-32-induced cell invasion. The knockdown of endogenous DARPP-32 by lentiviral DARPP-32 shRNA in MKN-45 cell line reversed these signaling effects and decreased cell invasive activity, as measured by invasion and HUVEC invasion Assay (p<0.01, p<0.05). Conclusions: The in vitro studies indicate that DARPP-32 plays a role in invasion and metastasis; DARPP-32 promotes invasion and metastasis of gastric cancer cells by interacted with CXCR4, delaying CXCL-12-induced CXCR4 Ubiquitination and blocking CXCR4 degradation, activating MMP2 by increasing MT1-MMP expression. The in vivo experiments are ongoing to determine the efficacy of DARPP-32 in mediating CXCR4 overexpression and metastasis.
Use of pharmacogenomic modeling in pancreatic cancer for prediction of chemotherapy response and resistance.
Authors: Sangar Vineet , Ricigliano Mark , O'Reilly Eileen Mary , Abou-Alfa Ghassan K. , Lowery Maeve Aine , Saltz Leonard , Crotty Joseph F , Gary Kristen , Choi Eun Yong , Yin Jing , Hidalgo Manuel , Yu Kenneth H.
Published: February 2017

142

Background: Pancreatic adenocarcinoma (PDAC) is uniformly lethal; despite this, modern cytotoxics (C) can induce tumor responses and extend life. Xenograft models have shown that pharmacogenomic (PGx) modeling of C can predict efficacy. Chemo-sensitivity and gene expression profiling of tumor progenitor (TP) cells isolated from peripheral blood may predict tumor response, progression and resistance. Methods: A prospective MSKCC study is ongoing with 46 of 60 planned patients accrued. 10 mL of peripheral blood is collected from patients with unresectable PDAC prior to C and at disease progression. Clinical data is prospectively collected. Circulating TP cells are isolated (Vita-Cap, Vitatex Inc.), total RNA is extracted and gene-expression analysis is performed. PGx models for twelve chemotherapy drug combinations used in PDAC were created from the GI50 data obtained from the NCI-60 cell lines (CellPath Therapeutics, Inc., Baltimore, MD). Expression data were normalized through GCRMA then probed to identify expression differences between the 35 patients with continued disease response and the 11 patients with disease progression. Analysis was performed at the pathway and individual gene level. Results: TP cells were isolated and gene expression and chemo-sensitivity patterns were obtained in all 46 evaluable patients prior to initiating C and in all 11 patients at 1st line disease progression. Preliminary analysis demonstrates clinical benefit for patients treated with C predicted to be effective versus C predicted to be ineffective (TTP 4.4 mo versus 2.7 mo, p=0.016). Changes in chemo-sensitivity patterns were evident at disease progression, reflecting treatment resistance. Hedgehog pathway over-expression was associated with resistance to gemcitabine but clinical response to 5-FU based treatment. Pathway analysis revealed that ErbB3, ARE/Nrf2 and Insulin pathways distinguished patients with disease progression. Conclusions: Isolation and gene expression profiling of TP cells can be performed reliably in unresectable PDAC. Preliminary analysis suggests that C profiling can predict response. Repeat PGx profiling identifies key pathways associated with treatment resistance. Clinical trial information: NCT01474564.
Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer (JASPAC-01 study).
Authors: Uesaka Katsuhiko , Fukutomi Akira , Boku Narikazu , Kanemoto Hideyuki , Konishi Masaru , Matsumoto Ippei , Kaneoka Yuji , Shimizu Yasuhiro , Nakamori Shoji , Sakamoto Hirohiko , Morinaga Soichiro , Kainuma Osamu , Imai Koji , Sata Naohiro , Hishinuma Shoichi , Nakamura Takayuki , Kanai Michio , Hirano Satoshi , Yoshikawa Yukinobu , Ohashi Yasuo
Published: February 2017

145

Background: Gemcitabine (GEM) has been a standard treatment of adjuvant chemotherapy for resected pancreatic cancer (PC). S-1 is an oral fluoropyrimidine, and shown to be non-inferior to GEM on overall survival (OS) for unresectable PC. The aim of this study is to determine non-inferiority of S-1 to GEM on OS as an adjuvant chemotherapy for resected PC. Methods: Patients (pts), who met the following criteria; histologically confirmed ductal adenocarcinoma of the pancreas, R0 or R1 resection, pathological stage I, II, or III with resection of the celiac axis, age >20, no prior chemotherapy or radiotherapy within 3 years, and adequate organ functions, were randomly assigned to GEM (1000 mg/m2, div on days 1, 8 and 15, repeated every 4 weeks, for 6 courses) or S-1 (40-60 mg according to the body surface, twice a day, for 4 weeks, repeated every 6 weeks, for 4 courses). Primary endpoint was OS. With 180 pts in each, the study had 80% power to prove non-inferiority with a non-inferiority margin of hazard ratio (HR) 1.25 on the basis of expected HR 0.87, at 0.05 two-sided alpha. An interim analysis was planned after 180 deaths. Results: From 4/2007 to 6/2010, 385 pts were enrolled (GEM: 193, S-1: 192) from 33 hospitals in Japan. In 378 pts (GEM: 191, S-1:187) of the full analysis set, background factors were well balanced between groups. Based on the interim analysis on survival data obtained by 7/2012, the independent data monitoring committee recommended to publish the results soon. The HR for S-1 to GEM was 0.56 (95% CI, 0.42-0.74, p<0.0001 for non-inferiority, p<0.0001 for superiority). The 2-year survival rates were 53% (95% CI, 46-60) for GEM and 70% (63-76) for S-1. The reasons for treatment discontinuation (recurrence/toxicity/patient’s refusal/others) were 27/48/5/2 in GEM and 9/40/3/0 in S-1. Incidences (%) of grade 3/4 toxicities in GEM/S-1 were fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1). Conclusions: S-1 adjuvant chemotherapy is shown non-inferior, and furthermore, even superior to GEM. S-1 may be considered as the new standard treatment for resected PC pts. Clinical trial information: UMIN000000655.
Venous thromboembolism in patients with pancreatic cancer: Incidence and effect on survival in east Asian ethnic groups.
Authors: Lee Jong-Chan , Cho Junhyeon , Park Yohan , Ro Young Sun , Choi Hyejin
Published: February 2017

151

Background: Pancreatic cancer is known to be most frequently associated with venous thromboembolism (VTE), with the incidence of 10~20% in Western countries. As for the East Asian ethnic groups, just one small retrospective study showed lower incidence (5.3%) than other ethnic groups. However, there have been no large retrospective cohort studies of VTE in pancreatic cancer of East Asian ethnic group. Methods: We retrospectively reviewed the medical records of patients diagnosed with pancreatic adenocarcinoma in 2005~2010 at Severance Hospital, Seoul, Korea. Principal outcomes were incident VTE events and mortality. Cox proportional hazards models were used to analyze associations between specific risk factors and principal outcomes. Results: We investigated 1334 patients with pancreatic adenocarcinoma and 218 (16.3%) patients were excluded due to incomplete medical records and loss to follow-up. Among 1116 eligible patients, the overall and 1-year cumulative VTE incidence were 13.9% and 11.2% respectively. The incidence rate during the half year, 1-year and 2-years were 23.4, 17.7, 15.6 events per 100 person-years, respectively. Among total of 155 VTE patients, abdominal VTE was 52.9%, deep vein thrombosis was 21.3%, pulmonary thromboembolism was 19.4%, and head and neck VTE was 18.7%. In multivariable analyses, significant predictors of developing VTE included advanced metastatic stage (HR=2.08, 95% CI 1.37 to 3.17) and treatment of chemotherapy or radiotherapy, including CCRT (HR=1.52, 95% CI 16 to 1.99). VTE was a significant risk factor of 1-year and overall mortality (HR=1.44, 95% CI 1.15 to 1.79 and HR=1.45, 95% CI 1.21 to 1.73). Among 155 VTE patients, head and neck (H&N) VTE revealed highest risk of overall mortality (HR=2.05, 95% CI 1.27 to 3.33, versus non-H&N VTE). Conclusions: Approximately 13.9% of pancreatic adenocarcinoma patients developed VTE in East Asian ethnic group and this incidence was not significantly different from other ethnic groups. Advanced metastatic stage was the strongest predictor of VTE which would be a significant risk factor of 1-year mortality. Among VTE patients, head and neck VTE was 18.7% and showed the highest risk of overall death.
Masitinib in nonresectable pancreatic cancer: Results of a phase III randomized placebo-controlled trial.
Authors: Deplanque Gael , Demarchi Martin , Hebbar Mohamed , Flynn Patrick J. , Melichar Bohuslav , Atkins James , Ruszniewski Philippe , Raymond Eric , Hermine Olivier , Hammel Pascal
Published: February 2017

158

Background: Masitinib is a selective c-Kit inhibitor that efficiently inhibits mast cell function. Increased mast cell activity in the tumor microenvironment has been linked to poor prognosis in pancreatic cancer (PC) patients. Methods: In a randomized (1:1 ratio), double-blind, international phase III trial, chemo-naïve PC patients (n=348) received either masitinib (9 mg/kg/day) in combination with gemcitabine (1000 mg/m2/wk) (M+G) or placebo plus gemcitabine (P+G). Primary endpoint was overall survival (OS). An ancillary pharmacogenomic study, based on RNA extracted from whole blood prior to treatment, was conducted in a subset of patients. Results: In the overall population median OS was not significantly improved in the M+G arm as compared with the P+G arm (median OS: 7.7 vs. 7.0 months, respectively; p=0.74, HR=0.90 [0.71; 1.14]). However, M+G treatment led to a significant survival advantage in two subpopulations. First, in patients with ‘pain’ at baseline (defined as a VAS score >20 mm on a 100 mm scale) (44% of patients with pain intensity data available) median OS was significantly increased from 5.4 months in the P+G arm to 8.1 months in the M+G arm (p=0.010; HR:0.61 [0.42; 0.88]); OS rates at 12 and 18 months were respectively, 32.2% and 18.2% in the M+G arm vs. 17.8% and 7.8% in the P+G arm. Second, in patients with a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes (66% of patients with genetic data available), median OS was significantly increased in the M+G arm as compared with the P+G arm (11.0 vs. 5.0 months, respectively) (p=0.000038; HR=0.29 [0.17; 0.51]); OS rates at 12 and 18 months were respectively, 41.4% and 18.5% in the M+G arm vs. 11.1% and 4.2% in the P+G arm. In patients without pain (defined as VAS <5 mm and no need for opioid analgesics), median OS was 15.4 months in the P+G arm. In patients without the deleterious GBM, median OS in the P+G arm was 14.3 months. In these two patient populations M+G treatment was contraindicated. The general safety profile of the M+G combination regimen was acceptable. Conclusions: Masitinib in combination with gemcitabine provides a significant survival advantage over gemcitabine monotherapy in PC patients with ‘pain’ and patients with a specific GBM. Clinical trial information: NCT00789633.
Alteration of microbiota in esophagitis and Barrett's esophagus and further modification by PPI treatment.
Authors: Half Elizabeth E. , Amir Itay , Gophna Uri , Konikoff Fred M.
Published: February 2017

16

Background: Gastroesophageal reflux can cause inflammation, metaplasia, dysplasia and cancer of the esophagus. The incidence of esophageal adenocarcinoma (EAC) has increased almost six fold in the past 30 yrs despite the increased use of Proton Pump Inhibitors (PPIs) to treat reflux. Recently, erosive esophagitis has been shown to increase the risk of EAC relative to patients with normal esophagus (NE). The reason for this remains unknown. Aim: To determine whether the microbiota of gastric refluxate and esophageal biopsies differs between patients with heartburn and NE vs. patients with abnormal esophageal mucosa [esophagitis or Barrett's esophagus (BE)] and to elucidate the effect of PPIs on bacterial communities. Methods: Gastric fluid and esophageal biopsies were collected during endoscopy from 13 BE/esophagitis patients and from 7 with NE. To reveal how PPIs alter the microbiota, samples were obtained from 8 of the patients (2 NE, 4 esophagitis and 2 with BE), before and after 8 weeks of PPI therapy. DNA was extracted and 16S rRNA gene pyrosequencing of microbial communities was performed. Results: Significant differences in the composition of gastric fluid bacteria, but not the esophagus-associated microbiota, were found between patients with heartburn and NE vs. patients with esophagitis and/or BE. Notably, Enterobacteriaceae (specifically Escherichia and Enterobacter) were significantly enriched in gastric fluid of patients with BE/esophagitis (P=0.01) compared to NE. PPIs had a remarkable effect on microbial communities both in the stomach and the esophagus. In gastric fluid, Moraxellaceae were decreased (P=0.016), whereas Erysipelotrichaceae were increased (P=0.031) following PPI treatment. Esophageal biopsies revealed genera belonging to the Microccocaceae, known to be opportunistic human pathogens, which increased following PPIs (P =0.031). Conclusions: Gastric fluid microbiota is modified in heartburn patients with esophagitis and/or Barrett's esophagus compared to patients with normal esophagus. PPI treatment markedly alters gastric and esophageal microbial populations. These modified bacterial communities may predispose to inflammation, dysplasia and cancer.
The association between statin use and hepatocellular cancer outcome.
Authors: Chae Young Kwang , Kaseb Ahmed Omar , Mohamed Hesham , Sahin Ibrahim Halil , Khalil Mohamed Fahd , Li Donghui , Abbruzzese James L. , Hassan Manal
Published: February 2017

165

Background: Preclinical evidence supports anti-tumoral activity of statins. Several observational studies have shown inverse association between statin use and hepatocellular cancer (HCC) incidence. However, little is known as to whether statins can delay the progression of HCC. Therefore, we investigated the association between statin use and the outcome of patients with HCC. Methods: 644 patients diagnosed with pathologically confirmed HCC were followed up from 2000 till 2011. Survival analysis was done using Cox regression model. Results: The mean age of the HCC cohort was 63.1 years (SD, ±11.5). 73.4% were men and 65.5% were Caucasians. 70.7% were diagnosed at TNM stage III and IV. 52.6% had no evidence of hepatitis B or C virus infection. 81.7% had local and systemic therapy, while 18.3% underwent surgical resection. The median survival of HCC patients was 19.2 months. 10.7% of patients reported statin use. We observed significant difference in overall survival between statin non-users and users; the median overall survival (95% CI) were 18.5 (16.4-20.5) months and 25.4 (19.8-31.1) months, respectively (log rank test p = 0.04). 30% mortality reduction was observed in statin users versus non-users (HR = 0.7, 95% CI, 0.5-0.9). This significant association was also observed in patients who received systemic and local therapy (p = 0.04). HCC patient without liver cirrhosis showed 40% mortality reduction (HR = 0.6, 95% CI, 0.4-0.9, P = 0.04) while patient with liver cirrhosis did not. History of hepatitis did not affect the association. Even after controlling for various clinical variables including age, sex, race, staging, HCV, HBV, liver cirrhosis, treatment, alcohol use and diabetes, statin use was still associated with favorable overall survival in HCC patients (HR = 0.7, 95% CI, 0.5-0.9, P=0.03). Conclusions: This is the largest study to date to evaluate the effect of statins on the outcomes of HCC patients. We found that statin use may reduce the risk of death in patients with HCC. Validation of our finding is warranted in a large prospective study.
Prognostic impact of lymph node retrieval and ratio in gastric cancer: A single-center U.S. experience.
Authors: Wong Joyce , Rahman Shams , Saeed Nadia , Lin Hui-Yi , Almhanna Khaldoun , Shridhar Ravi , Hoffe Sarah , Meredith Kenneth
Published: February 2017

17

Background: Recommendations for extended lymphadenectomy in gastric cancer is thought to be associated with improved overall survival (OS), although defining adequate lymphadenectomy remains controversial. Methods: A single-institution, prospectively-maintained database of patients referred for surgical care of gastric cancer was reviewed. Patients were stratified by number of examined lymph nodes (eLN): <5, 6-10, 11-15, and >15 and positive LNs (LN+) stratified by 0, 1-2, 3-6, 7-15, and >15. Lymph node ratio (LN+:eLN) was evaluated, stratified by 0, 0.01-0.2, 0.21-0.5, and >0.5. Disease-free-survival (DFS) and OS were the primary endpoints, determined by Kaplan-Meier analyses. Results: From 1997-2012, 222 patients were included; most were male (N=122, 55%) with median age 67 (range 17-92) years. Of 220 (99%) patients surgically explored, 164 (74%) ultimately underwent resection. Median OS of the entire cohort was 22 months. Gender, ethnicity, and smoking status did not impact OS. Pathologic factors such as perineural invasion, lymphovascular invasion, and poor differentiation adversely affected OS, P<0.05. A median 14 lymph nodes (LN) were retrieved (range 0-45), with a median of one positive LN (range 0-31). No OS or disease-free survival (DFS) difference was observed when comparing <5, 6-10, 11-15, and >15 eLN, P=0.30. LN+ affected both OS and DFS: median OS was 52 months for 0 LN+ and decreased to 21 months with 1-2 LN+, 34 months 3-6 LN+, 25 months 7-15 LN+, and 11.5 months with >15 LN+. Similarly, median DFS decreased from 35 months with 0 LN+ to 19 months with 1-2 LN+, 9 months with 3-6 LN+, 13.5 months with 7-15 LN+, and 7.5 months with >15 LN+. Lymph node ratio demonstrated worse median OS with increasing ratio: 49 months for ratio of 0, 37 months for 0.01-0.2, 27 months for 0.21-0.5, and 12 months for >0.5, P<0.0001. DFS was similar: 35months for ratio of 0, 22 months for 0.01-0.2, 13 months for 0.21-0.5, and 7 months for >0.5, P<0.0001. Conclusions: Extent of lymphadenectomy does not impact OS or DFS. Presence of LN+ adversely impacts OS and DFS. Lymph node ratio may be a better prognostic indicator than number of eLN or LN+ in gastric cancer.
Comparison of HER-2 expression in diagnostic biopsies and surgical specimens of gastric and esophageal adenocarcinoma: Influence of neoadjuvant chemotherapy.
Authors: Watson Sarah , Validire Pierre , Cervera Pascale , Zorkani Nabila , Scriva Aurelie , Lemay Frederic , Garcia Marie Line , Bennamoun Mostefa , Tournigand Christophe , Ropert Stanislas , Svrcek Magali , Louvet Christophe
Published: February 2017

18

Background: HER-2 is overexpressed in 15 to 20% of gastric and esophageal adenocarcinoma (ADK), and is a target for trastuzumab in metastatic patients (Bang YJ et al, Lancet 2010). The main objective of this study was to compare HER-2 expression between diagnostic biopsies and surgical specimens of gastric ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens and biopsies of patients operated on with a curative aim in two French hospitals (Institut Mutualiste Montsouris and Saint-Antoine hospital) between 2004 and 2011 were collected; two cohorts treated or not with a NAC were constituted. Blind HER-2 analyses on biopsies and on surgical specimens were performed using IHC and ISH methods, with two independent pathological readings. HER-2 overexpression was defined by a score 3+ in IHC, or by a score 2+ in IHC with a positive ISH test. Results: Paired samples of 201 patients wereanalyzed. HER-2 overexpression rates were 16.4% on biopsies and 19.4% on surgical specimens. HER-2 positive tumors were mainly cardial or esophageal tumors, with a well-differentiated, intestinal histological type. Surgical specimens seemed to allow better identification of HER-2 positive tumors than diagnostic biopsies for patients that had not received NAC (13.5% of HER-2 positivity on biopsies versus 24.3% on surgical specimens), whereas this trend was reversed for patients with NAC (18.1% of HER-2 positivity on biopsies versus 16.5% on surgical specimens). HER-2 status differed between biopsies and surgical specimens in 10% of patients. Conclusions: The determination of HER-2 status on biopsies provides results that completed those obtained with the analysis of surgical specimens. Analyzed only on surgical specimens, HER-2 status is underestimated in particular after NAC. This study suggests the interest of repeating HER-2 evaluations to optimize the identification of patients that can benefit from trastuzumab treatment.
Inhibition of cMET in an experimental model of pancreatic cancer.
Authors: Lang Sven A. , Brandes Franziska , Geissler Edward K.
Published: February 2017

185

Background: In human pancreatic cancer, expression of cMET is associated with poor survival. So far, activation/expression of cMET by hepatocyte growth factor (HGF) has been shown to induce proliferation and motility in cancer cells. Therefore, we hypothesized that inhibition of cMET in human pancreatic cancer cell lines impairs oncogenic signaling and tumor growth. Methods: Pancreatic cancer cell lines (HPAF-II, MiaPaCa2, L3.6pl, BxPC3, Panc02) and the cMET inhibitor INC280 (Novartis Oncology, Basel) were used. MiaPaCa2 and L3.6pl pancreatic cancer cells were grown with gemcitabine up to 500 and 250 nM, respectively (then called MiaPaCa2(G500) and L3.6pl(G250)). MTT and Boyden Chamber assays were used to determine effects of INC280 on growth and motility of cells in vitro. Expression of growth factor receptors, activation of signaling intermediates and expression of transcription factors were assessed by Western blotting. Finally, in vitro results were validated in an orthotopic tumor model using L3.6pl pancreatic cancer cell line. Results: All pancreatic cancer cell lines showed expression of cMET. In vitro treatment of cancer cells with INC280 led to a minor, dose-dependent inhibition of growth even when cells were supplemented with HGF. In contrast, migration assays showed a significant reduction of cancer cell motility upon INC280 when cells were stimulated with HGF (P<0.05). Regarding oncogenic signaling, INC280 led to inhibition of HGF-induced phosphorylation of AKT, ERK and FAK. In addition, c-Myc expression was diminished in cancer cells. Interestingly, gemcitabine resistant cell line MiaPaCa2(G500) showed higher cMET expression levels compared to the normal MiaPaCa2. Stimulation of MiaPaCa2(G500) with HGF led to strong induction of oncogenic signaling and tumor cell motility, an effect that was significantly diminished by INC280. Moreover, results from in vivo experiments show that therapy with INC280 (10 mg/kg/d) significantly reduces tumor growth as determined by final tumor weight (P<0.05). Conclusions: In pancreatic cancer cell lines, targeting cMET with INC280 abrogates oncogenic signaling in vitro and impairs tumor growth in vivo. Therefore, the concept of cMET inhibition warrants further preclinical evaluation.
Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary study Circe 07 of the LAP 07 trial.
Authors: Huguet Florence , Bidard François-Clément , Louvet Christophe , Mineur Laurent , Bouche Olivier , Chibaudel Benoist , Artru Pascal , Desseigne Françoise , Bachet Jean-Baptiste , Gasmi Mohamed , Nguyen Suzanne , Wander Lionel , Mathiot Claire , Pierga Jean-Yves , Hammel Pascal
Published: February 2017

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Background: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At time of diagnosis, 30% of patients present with a locally advanced unresectable but non metastatic carcinoma (LAPC). Theoretically, patients with micrometastatic dissemination at diagnosis should benefit from systemic treatments, whereas radiation therapy should be favored in the others. Based on the hypothesis that circulating tumor cells (CTC) count is a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. Methods: LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of gemcitabine-based chemotherapy whether to administrate a chemoradiotherapy could increase overall survival versus continuation of chemotherapy alone. A subgroup of patients included in LAP 07 trial were prospectively screened for CTC before the start of the chemotherapy and after two months of treatment, using the CellSearch technique. Clinico-pathological characteristics and survival of patients were obtained prospectively and were correlated with CTC detection. Results: Seventy-nine patients were included in this ancillary study. One or more CTC/7.5ml were detected in 5% of patients before treatment and in 9% of patients after two months of chemotherapy (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (p=0.04), and with shorter overall survival in multivariable analysis (RR=2.5, p=0.01), together with anemia (p=0.005). Conclusions: The evaluation of micrometastatic disease using CTC detection appears as a promising tool which could help to personalize treatment modalities in LAPC patients. Clinical trial information: CDR0000589283.
Phosphorylated ERK (pERK) as biomarker in patients with advanced pancreatic cancer treated with erlotinib within a randomized phase III trial (AIO-PK0104).
Authors: Boeck Stefan Hubert , Ormanns Steffen , Laubender Ruediger Paul , Jung Andreas , Siveke Jens T , Haas Michael , Neumann Jens , Vehling-Kaiser Ursula , Winkelmann Cornelia , Fischer von Weikersthal Ludwig , Clemens Michael R. , Gauler Thomas C. , Marten Angela , Klein Stefan , Kojouharoff Georgi , Geissler Michael , Greten Tim F , Kirchner Thomas , Heinemann Volker
Published: February 2017

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Background: Validated biomarkers for patients (pts) with advanced pancreatic cancer (APC) treated with anti-EGFR drugs have not yet been defined. pERK represents the downstream target of the RAS-RAF-MEK cascade. Methods: Within AIO-PK0104 281 pts with APC were randomized between gemcitabine/erlotinib followed by capecitabine and capecitabine/erlotinib followed by gemcitabine. Archival formalin fixed paraffin embedded (FFPE) tumor tissue for central pERK analysis by immunohistochemistry (IHC) was available from 153 pts. Within a retrospective subgroup analysis, pERK data (either as dichotomous or continuous variable) were correlated with AIO-PK0104 biomarker results on KRAS mutation status and EGFR expression and with efficacy study endpoints using a Cox regression model. Results: A semi-quantitative immunohistochemistry scoring system considering cytoplasmic and nuclear pERK expression (staining intensity & % of positive cells) was developed (score 0-12). FFPE samples with a score of 6-12 were defined a pERKhigh. 98/153 pts were classified as pERKhigh and 55/153 pts as pERKlow, respectively. The median pERK score was 7 (range 0-12). No significant correlation of pERK with baseline characteristics like stage of disease, gender, age, KPS or CA 19-9 was detected. Median OS in pERKhigh pts was estimated with 5.7 months and with 6.2 months in pERKlow pts (HR 1.29, 95% CI 0.90-1.83, p=0.16). However, when analysing pERK as continuous variable, a significant association between the pERK score and OS was found (HR 1.06, 95% CI 1.0-1.12, p [log rank]=0.050, p [likelihood ratio]=0.047), indicating an increase in the hazard for death by a factor of 1.06 for each score level of pERK expression. There was no correlation of pERK expression with the objective disease control rate (OR 0.99, p=0.91) or the occurrence of skin rash (OR 0.93, p=0.41). Pts with a KRAS mutation had a similar rate of pERKhigh expression compared to patients with KRAS wildtype (61% vs 71%, p=0.32). Conclusions: pERK expression may have an impact on OS of APC pts treated with the anti-EGFR agent erlotinib. Prospective validation of these results is recommended. Clinical trial information: NCT00440167.
Molecular profiling (MP)-selected therapy for the treatment of patients with advanced pancreaticobiliary cancer (PBC).
Authors: Epelbaum Ron , Shacham-Shmueli Einat , Geva Ravit , Hubert Ayala
Published: February 2017

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Background: For patients (pts) with advanced PBC who are able to pursue additional therapy, treatment selection is often empiric and clinical benefits are usually modest. Our goal was to study clinical outcomes of MP-guided treatment in advanced PBC. Methods: This retrospective analysis included pts with advanced PBC whose tissue samples underwent MP (IHC, microarray [MA], and sequencing analyses) using Target Now (Caris Life Sciences, Irving, TX). These pts received ≥1 lines of therapy for advanced PBC before their treatment was guided by MP. The MP-guided therapy was considered to have clinical benefit if the TTP ratio between the longest TTP on MP-guided therapy and the TTP on the last therapy pre-MP was ≥1.3. Results: Out of 20 pts included in the analysis, 16 had advanced cancer of the pancreas. Median age was 59 yrs (range: 30-81), 85% were male, and 60% had PS of 1. Pts had 1-4 treatment regimens (median: 1) prior to MP. MP identified 1-7 (median: 4) actionable targets per pt. The most commonly identified targets by IHC were: negative or low TS (80%), high TOPO1 (70%), negative or low ERCC1 (52%), and high SPARC (40%). In all 14 pts that had MA results, multiple actionable targets were identified. Of 14 pts with KRAS sequencing analysis, 10 pts (71%) had mutations. Post-MP, pts had 1-4 (median: 1) treatment regimens, most commonly FOLFIRI/XELIRI, FOLFOX/XELOX, capecitabine, and nab-paclitaxel. The total number of regimens post-MP was 33, of which 29 were evaluable for decision impact analysis. In 24 (83%) of cases, treatment decision was modified due to the MP results. Out of the 20 pts, 4 received ≤1 cycle of MP-guided therapy during rapidly progressing disease and were excluded from the clinical outcome analysis. Of the 16 evaluable pts, 6 (37.5%) had a TTP ratio of ≥1.3 (one-sided exact binomial test vs a null hypothesis of ≤15% with TTP ratio ≥1.3, P=0.0056; therefore the null hypothesis is rejected). Conclusions: In our retrospective analysis of a small, yet well-defined, cohort of pts with advanced PBC, MP often influenced treatment decisions and over a third of pts experienced a longer TTP (compared to the last regimen pre-MP), highlighting the promise in MP for treatment selection.
HER2 testing in esophageal adenocarcinoma (EAC) using parallel tissue-based methods.
Authors: Yoon Harry H. , Shi Qian , Sukov William R. , Sattler Christopher A. , Wiktor Anne E. , Wu Tsung-Teh , Diasio Robert B. , Jenkins Robert B. , Sinicrope Frank A.
Published: February 2017

2

Background: Testing for HER2 in EAC has become routine given its ability to predict benefit from HER2-targeted therapy. HER2 protein analysis by immunohistochemistry (IHC) is more rapid and generally less expensive than assessment of gene amplification by fluorescence in situ hybridization (FISH). However, the accuracy of IHC for predicting HER2 amplification has not been examined in a large EAC cohort. Methods: Surgical EAC specimens were examined from 675 patients who underwent curative resection at a single institution without preoperative therapy. Tumors were located in the esophagus (47%) or gastroesophageal junction (53%); most were node-positive (73%). Every tumor was evaluated by IHC in parallel with FISH in a blinded manner using FDA-approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0 or 1+; equivocal, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17ratio ≥ 2. Results: HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0-1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value (PPV) of a positive IHC test (3+) was 89% (79/89 [95% CI 82%-95%]), and the negative predictive value of a negative IHC test (0-1+) was 96% (401/417 [94%-98%]). Importantly, the PPV of an equivocal IHC score (2+) for detecting HER2 amplification was 13% (22/169 [8%-18%]). Conclusions: In the largest study to date comparing HER2 testing methods in EAC, a negative IHC result (0 or 1+) nearly excludes the presence of gene amplification by FISH. Whereas a positive IHC result (3+) strongly predicts for the presence of amplification, an equivocal IHC result (2+) is a weak predictor. These findings in EAC support a HER2 testing algorithm where IHC is used for initial screening and FISH testing is restricted to cases with equivocal IHC results. [Table: see text]
Comparison of microRNA (MiRNA) expression profiles between opisthorchis viverrini-associated cholangiocarcinoma (OV-CCA) and non-opisthorchis viverrini-associated cholangiocarcinoma (non-OV CCA).
Authors: Tanasanvimon Suebpong , Rashid Asif , Wongkham Sopit , Churi Chaitanya , Tong Zhimin , Fogelman David R. , Silsirivanit Atit , Blechacz Boris , Klaikaew Naruemon , Bhudhisawasdi Vajarabhongsa , Vauthey Jean-Nicolas , Javle Milind M.
Published: February 2017

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Background: Cholangiocarcinoma in Thailand and Laos is associated with the liver fluke Opisthorchis viverrini (OV). Molecular differences between OV-CCA and Non-OV CCA remain to be defined. MiRNAs are regulators of mRNA that result in transcriptional repression or gene silencing. MiRNA profiles of OV vs. non-OV CCA have not yet been studied. Methods: 50 OV-CCA and 16 non-OV CCA pathological samples were obtained from Liver Fluke and Cholangiocarcinoma Center, Khonkaen University, Thailand and University of Texas, MD Anderson Cancer Center (MDACC), USA, respectively. Macrodissected common bile duct samples from MDACC were used as control groups. Global miRNA expression profiling was performed using the miRCURY LNA microRNA Array (Exiqon).qRT-PCR and in situ hybridization (ISH) were used to validate the miRNAs noted to be significant on the microRNA array. Results: Ten samples of OV and non-OV CCA were analyzed for global miRNA expression; 46 were used for validation. MiRNA microarray identified 71 miRNAs that were differentially expressed between OV-CCA and non-OV CCA (p<0.05). Of the 25 miRNAs with increased expression in OV-CCA, miR-141 and miR-200c were highly significant (p<0.01). These were overexpressed in OV-CCA as compared to control bile duct samples. The validation set on qRT-PCR showed significant miR-200c overexpression in 12 OV-CCA samples (p=0.02) and under expression in four non-OV CCA samples (p=0.006). ISH demonstrated miR-200c overexpression in 32 of 45 (71.1%) OV-CCA samples and 2 of 8 (25%) non-OV CCA samples. There was a trend toward better survival in OV-CCA patients with high miR-200c expression (9.5 vs 5.2 months, p=.08). Conclusions: MiRNA expression profiles differ between OV-CCA and non-OV CCA. MiR-200c was overexpressed in OV-CCA but under expressed in non-OV CCA. MiR-200C is known to repress epithelial-mesenchymal transition and its overexpression in OV-CCA may provide important insight into the distinct pathogenesis and prognosis of OV-CCA.
Combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced hepatocellular carcinoma.
Authors: Kasai Kazuhiro , Sawara Kei , Suzuki Kazuyuki
Published: February 2017

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Background: Two recent phase III clinical trials have shown that sorafenib improves the survival in patients with advanced hepatocellular carcinoma (HCC). However, patients with HCC and portal vein tumor thrombosis (PVTT) usually have very short survival even when treated with sorafenib. On the other hand, recent advances in implantable drug delivery systems have made it possible to administer repeated hepatic arterial infusion chemotherapy (HAIC) agent. Since 2006, we have treated the patients displaying advanced HCC with PVTT by combined HAIC of 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)α-2b, and reported favorable results. In this article, we evaluated the efficacy of combined 5-FU and PEG-IFN α-2b, and compared outcomes between advanced HCC patients with PVTT treated using sorafenib. Methods: Forty patients with HCC and PVTT were enrolled. Of these, 21 patients were treated using subcutaneous administration of PEG-IFNα-2b and intra-arterial infusion of 5-FU [5-FU / PEG-IFN group], 19 patients were treated using continuous oral treatment with 400-800 mg of sorafenib [Sorafenib group]. We compared the early response to the therapy and the cumulative survival rate between these two groups. Results: The objective early response rate in the 5-FU / PEG-IFN group was significantly higher than that in the Sorafenib group (71.4 vs. 10.5%, P<0.01). The cumulative survival rates at 6, 12, 18, and 24 months, respectively, were 83.8, 77.8, 55.6, and 55.6% in the 5FU / PEG-IFN group, and 68.4, 37.7, 16.2, and 16.2% in the Sorafenib group. The cumulative survival rates was significantly higher in the 5FU / PEG-IFN group than in the Sorafenib group (P=0.03). Serious complications and treatment-related deaths were not observed in the 5FU / PEG-IFN group. On the other hand, the rate of discontinuation of treatment due to adverse events was 36.8% of the patients who were treated sorafenib. Conclusions: Based on our findings, this newly developed combination therapy may be useful for patients with advanced HCC, although a large-scale randomized controlled study by comparison with sorafenib is needed.