bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating autophagy and glutamine metabolism as therapeutic targets for pancreatic cancer.
Authors: Jardon Mario , Kalloger Steve , Iggulden Christina , Erro Go Nancy , Sathiyaseelan Paalini , Yapp Donald , Renouf Daniel John , Schaeffer David , Gorski Sharon
Published: February 2017

381

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, for which new therapeutic approaches are urgently needed. We are developing novel combination therapy approaches based on the inhibition of glutamine metabolism and autophagy, to improve current treatments for PDAC. Since both processes are key mediators of multiple cancer hallmarks, and have inter-related but non-redundant roles, this combination may result in a more efficient disruption of cancer cell resistance to treatments. Methods: We interrogated the Pancreas Centre BC tissue micro-array, containing the epithelial component of 252 PDAC samples, for expression of three key glutamine-metabolizing proteins and two autophagy-related proteins: glutamine synthetase (GLUL), asparagine synthetase (ASNS), glutaminase C (GLS-GAC), microtubule-associated protein 1 light chain 3 beta (MAP1-LC3B or LC3B) and autophagy-related protein 4B (ATG4B). While previous efforts by other groups have focused on GLS-GAC, the role of GLUL in cancer has remained less well understood. We thus investigated the functional relevance of GLUL using a panel of PDAC cell lines. We are also investigating interactions between glutamine metabolism and autophagy, including the exploration of strategies to target GLUL and the evaluation of a new class of ATG4B inhibitors for the treatment of pancreatic cancers. Results: We found that GLUL, ASNS, GLS-GAC, LC3B and ATG4B were expressed in 31%, 58%, 99%, 51% and 73%, respectively, of PDAC samples. Furthermore, higher LC3B expression correlated with poor outcome. Our functional studies revealed that various PDAC cells express GLUL, which can be upregulated upon glutamine deprivation. In all cell lines tested, GLUL knockdown sensitized them to gemcitabine, as assessed by a long-term recovery assay. We also found that the candidate ATG4B inhibitors, shown to inhibit this target in cell-free assays, effectively inhibit PDAC cell proliferation at micromolar concentrations. Conclusions: Our study reveals that glutamine metabolism and autophagy are clinically relevant in PDAC and may have potential as therapeutic targets. Supported by Pancreas Centre BC, BC Cancer Foundation and VGH Foundation.
Localized pancreatic cancer (LPC) with isolated positive peritoneal cytology (PPC): A single-institution experience.
Authors: Oh Stephen Y , Edwards Alicia M , Hahn Hejin P , Mandelson Margaret T , Picozzi Vincent J.
Published: February 2017

411

Background: Natural history (NHx) and overall survival (OS) of patients (pts) with LPC and PPC without gross metastasis (GM) at initial diagnosis are rarely studied. We assessed rate, time and pattern of disease recurrence (REC), impact of local therapy (Rx) and OS in this pt cohort from our institution. Methods: The Virginia Mason Pancreatic Cancer (PC) Database (Picozzi et.al. Proc GI Cancer Symp 2011) was used to identify pt cohort. Inclusion criteria were 1) laparoscopic PPC and 2) no other evidence of GM (radiographic/ laparoscopic). Local progression (LP) was defined as primary tumor growth with change/cessation of chemoRx. Systemic progression (SP) was defined as radiological/pathological metastastic progression. The database provided OS. Results: 39/884 (4.4%) pts initiating Rx at VMMC from 2003-2014 met these criteria. 13/39 pts were included in a prior report (Clark et.al. Am J Surg 2010). Pt characteristics include: 21/39 (54%) male; median (med) age 65 (range 49 – 83) yrs; 25/39 (64%) head lesions; med tumor size 39 (range 25 - 100) mm. Med pt follow-up is 13 mo. All pts received gemcitabine-combination chemoRx as initial Rx. 14/39 (36%) pts also received local Rx (13 consolidative chemoXRT, 1 surgery). 3 month (mo) disease control (DC) was 86% (31/36 pts, 3 pts followed <3 mo). 6 mo progression - free survival (PFS) was 72% (26/36 pts). 6/36 pts (16%, range 9+-15+ mo) are progression – free. 30/36 pts (83%) progressed (med time 8.1 mo). REC pattern was local (13/30 pts, 43%), distant (9/30 pts, 30%) and combined (8/30 pts, 27%). Pts given local Rx did not differ statistically from pts given systemic Rx only with respect to 3 mo DC, 6 mo PFS, REC rate, time, or pattern, or OS. OS for LPC with PPC was significantly better than pts with GM (n = 277) identified from the database from 2003-2014 (med OS 15 vs. 9.3 mo, p = 0.0002; 1-yr OS 68 vs. 32%, p = 0.01; 2-yr OS 34 vs. 12%, p = 0.007). Conclusions: 1)LPC with PPC is a rare PC pt cohort with high response rates to chemoRx and superior OS to those with GM. 2) However, long-term disease free OS was not seen. 3)Local Rx did not clearly alter pt cohort NHx. 4)This is the largest pt series of this pt cohort compiled from a US institution; their further study seems of value.
Adjuvant treatment patterns and clinical outcomes in patients with curative resected ampulla of Vater cancer.
Authors: Ha Hyerim , Oh Do-Youn , Kim Tae-Yong , Lee KyoungBun , Kim Kyubo , Lee Kyung-Hun , Han Sae-Won , Chie Eui Kyu , Jang Jin-Young , Im Seock-Ah , Kim Tae-You , Kim Sun-Whe , Ha Sung Whan , Bang Yung-Jue
Published: February 2017

415

Background: Ampulla of Vater cancer (AoV ca) is rare tumor, and its adjuvant treatment after curative resection has not been well established. The purpose of this study is to see the clinical outcomes of curatively resected AoV ca patients and to figure out the role of adjuvant treatment. Methods: We reviewed 227 AoV ca patients who underwent curative resection at the Seoul National University Hospital between 1997 and 2012. Clinical factors, pathologic findings, adjuvant treatment pattern, disease-free survival (DFS) and overall survival (OS) were analyzed. Results: Median age was 61.5 year old (range, 33.8-88.2) and 125 patients were male. T1/T2 stage was found in 63.9% of patients and T3/4 stage was in 36.1%. Seventy-seven patients (33.9%) had node positive disease (N+) and seventy-three patients (32.1%) had well-differentiated histology. OS of all patients was 90.9 months (95% CI: 58.4-128.09). 5-Year OS- and DFS- rate were 58.2% and 62.5%, respectively. On multivariate analysis, adverse prognostic factors for OS included poorly differentiated histology (HR 1.35, 95% CI: 1.01-1.81, p=0.045), elevated CEA (HR 2.55, 95% CI: 1.29-5.04, p=0.007), elevated CA 19-9(HR 1.86, 95% CI: 1.08-3.21, p=0.027), and stage (HR 2.34, 95% CI: 1.43-3.82, p=0.001). A total of 104 patients (46.3%) received adjuvant treatment (concurrent chemoradiotherapy (CCRT) 32, CCRT with maintenance chemotherapy 58, chemotherapy alone 9, radiotherapy alone 5). Most of the chemotherapies were 5-FU-based ones. Among patients with T1/T2 & N (-) (n=111), only 25 patients (22.5%) received adjuvant treatment. In contrast, among patients with T3/T4 or N (+) (n=116), 79 patients (68.1%) received adjuvant treatment. 5Y-OS rate was 74.1% in patients with T1/T2 and N (-) and that of patients with T3/T4 or N (+) was 43.0% (p<0.001). In T1/T2 and N (-) stage, OS was not different according to adjuvant treatment. In T3/T4 or N (+) stage, adjuvant CCRT with maintenance chemotherapy conferred the longest OS, which was not statistically significant. (5Y-OSR: 47.0% vs 41.4% in no adjuvant treatment.) Conclusions: Adjuvant treatment should be further defined in AoV ca, especially in T3/T4 or N (+) stage.
Effect of complications after pancreaticoduodenectomy on adjuvant therapy utilization and survival in pancreatic cancer.
Authors: Hnoosh Dima , Saeed Hayder M. , Huang Bin , Maynard Erin , Durbin Eric B , DeSimone Philip A. , Kudrimoti Mahesh R. , Anthony Lowell Brian , Hosein Peter Joel , McGrath Patrick , Tzeng Ching-Wei David
Published: February 2017

422

Background: While adjuvant therapy (AT) completion is a necessary component of multimodality therapy for pancreatic adenocarcinoma (PDAC), its timing and utilization can be hindered by complications after pancreaticoduodenectomy (PD). The primary aim of this study was to evaluate the impact of post-PD complications on AT utilization and overall survival (OS). Methods: Patients treated with PD for PDAC at a single institution (2000-2012) were evaluated. Data on 90-day complications were extracted from the electronic medical record with postoperative major complications (PMC) defined as Grade ≥3. Patient records were linked to the Surveillance Epidemiology End Results - Kentucky Cancer Registry for AT and OS data. Early AT required a first dose before 8 weeks, while late was 8-16 weeks. Initiation after 16 weeks was not considered adjuvant. Chi-square statistics, Kaplan-Meier plots, and log-rank tests were used to examine associations among complication status and AT timing, AT utilization, and OS. Results: Of 84 total patients, 54 (64%) received AT (34 [41%] early; 20 [24%] late). Rates of patients with 90-day complications were as follows: 44 (52%) Grade ≥1, 37 (44%) Grade ≥2, and 18 (21%) Grade ≥3. Low-grade (Grades 1-2) complications were not associated with late AT or lack of AT (both p>0.082). However, PMC were associated with lower rates of AT (7/18, 39% with PMC vs. 47/66, 71% without PMC, p=0.011). Even patients who recovered from PMC were less likely to meet the early 8-week window (4/18, 22%, patients with PMC, vs. 30/66, 46%, patients with no PMC, p=0.039). PMC were associated with worse median OS (6.1 mo, 95% confidence interval, CI, 1.6-12.1, vs. 20.8 mo, 95% CI 17.3-23.8, with no PMC, p<0.001), while low-grade complications were not (all p>0.079). Conclusions: In this series,low-grade complications had minimal effects on AT timing, AT utilization, and OS, but PMC were associated with late and decreased AT utilization and negatively impacted OS.These data suggest that strategies to decrease PMC and/or treatment sequencing alternatives to increase multimodality completion rates in high-risk patients may improve oncologic outcomes.
Triptolide to induce cell death of pancreatic cancer cells via inhibition of 14-3-3γ expression.
Authors: Wang Wei , Luo Jinbing , Liang Yinghui , Chen Yubin , Lin Wenjie
Published: February 2017

425

Background: Pancreatic cancer is one of the malignant tumors which exhibit resistance to chemotherapy. Gemcitabine-based therapy is a standard for advanced pancreatic cancer though it brings severe side-effect and average median survival is only 6 months. Hence increasing interest has focused on new agent with targeted therapies. Here we investigated the growth-inhibitory and apoptotic effect of triptolide, a diterpenoid triepoxide, and the role of 14-3-3γ expression in the apoptotic pathway induced by triptolide in human pancreatic cancer cells (AsPC-1 and PANC-1). Methods: Cell proliferation was measured by SRB, apoptotic cells were assessed by flow cytometry for Annexin V/PI staining and western blot for cleaved caspase-8, 9, 3 and fluorescent substrate assay for activities of caspase-8, 9, 3. To explore further mechanism of triptolide triggering death receptor pathway, specific siRNA targeted for 14-3-3γ was used to knock down 14-3-3γ expression measured by ELISA. In vivo, AsPC-1 xenografts in the absence or presence of stable down-regulation of 14-3-3γ expression by RNAi were treated with triptolide for 4 weeks and the tumor growth was compared, tumor samples were tested by ELISA and western blot for 14-3-3γ level. Results: Triptolide inhibits the proliferation at extremely low concentrations (12.5-50 nM) and induces apoptosis of pancreatic cancer cells through activating the caspase cascade associated with Bid cleavage. Moreover triptolide inhibited 14-3-3γ expression at dose and time-dependent manner and 14-3-3γ down-regulation sensitized cells to triptolide-induced apoptosis. Likewise, in vivo experiment of AsPC-1 xenografts, stable down-regulation of 14-3-3γ expression by RNAi significantly enhances triptolide-induced apoptosis and tumor growth delay. Conclusions: Triptolide exerted significant growth inhibitory effects and induced apoptosis in vitro and in vivo. Triptolide may have a potential to be an effective agent against pancreatic cancer and its mechanism of action is mediated by the inhibition of 14-3-3γ expression. The role of 14-3-3γ expression involved in resistance to apoptosis pathway make it be a potential therapeutic target in pancreatic cancer.
Laboratory evaluation of hepatic synthetic function as a predictor of ethiodol retention during transarterial (chemo) embolization in hepatocellular carcinoma (HCC).
Authors: Dyer Brandon Alan , McCallum Raluca , Savitsky Leah , Kato Catherine , Fuss Martin , Thomas Charles R. , Naugler Wilscott , Kolbeck Kenneth , Kaufman John , Farsad Khashayar , Fung Alice , Tanyi James
Published: February 2017

431

Background: Image-guidance for HCC suffers due to a lack of contrast between tumor and liver parenchyma. To compensate for the inability to directly visualize the radiation target other IGRT strategies have been employed for target optimization. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are level 1, evidence-based treatments for HCC and improve survival by several months; however, local failure occurs in up to 50% of treated lesions by 6 months. The lack of durable local control provides a rationale to add a second treatment modality. If Ethiodol is used as an embolizing agent, the treated HCC becomes radio-opaque. In the current assessment, we correlated the quality of Ethiodol tumor stains with liver function parameters as prognosticators for Ethiodol stain retention prior to simulation for SBRT. Methods: Records of 31 patients undergoing staged TAE/TACE prior to SBRT (50 Gy/5) were evaluated under an institutional protocol. The quality of Ethiodol stains in simulation CT were graded as excellent (mean HU of >300), good (mean HU of 225-300), fair (mean HU 150-225), and poor (mean HU <150). A liver function panel, general labs, Child-Pugh and MELD scores prior to TACE/TAE were also recorded and correlated with the quality of Ethoidol stain at simulation. Results: Duration between TACE/TAE and simulation was 124+120 days. Simulation scans showed excellent, good, fair and poor tumor stains in 7 (mean HU =360+48), 3 (mean HU =262+17), 15 (mean HU =184+24) and 6 (mean HU =130+16) cases, respectively. Of all laboratory testing, only Child-Pugh score showed strong statistical correlation (p<0.0012) with the retention of Etioldol. Conclusions: TACE/TAE-based Ethiodol tumor stain facilitates tumor visualization for SBRT of HCC. While it is not conclusive that laboratory testing can serve as a predictor of Ethiodol stain retention between TACE/TAE and simulation for SBRT, the Child-Pugh score presents a unique matrix for patient stratification.
The referential survival data of borderline resectable pancreatic cancer (BRPC) patients who are candidate for neoajuvant chemotherapy followed by surgery.
Authors: Saito Kei , Ishii Hiroshi , Ozaka Masato , Osumi Hiroki , Yamada Ikuhiro , Sasaki Takashi , Matsuyama Masato , Takano Kouichi , Sasahira Naoki
Published: February 2017

434

Background: The aim of this study is to clarify referential survival data of BRPC patients who are candidate for neoajuvant chemotherapy followed by surgery. Methods: This retrospective study included data from all consecutive patients who were diagnosed as having invasive ductal pancreatic cancer at our hospital between January 2008 and December 2013. Selection criteria were as follows: patients who 1) had histologically confirmed pancreatic adenocarcinoma, 2) were diagnosed as having non-metastatic disease by dynamic CT before treatment, 3) had received anti-cancer treatment, and had been observed for 3 months or longer. We reviewed CT stage (UICC) and treatment modality, and analyzed their survival data. Results: There were 428 patients who met the selection criteria. Among them, clinical CT stage I/II (Group A; potentially respectable) and stage III (Group B; locally advanced) were documented in 170 (40%) and 131, respectively. Laparotomy was performed in all patients in Group A. Of the 170 in Group A, 166 (98%) received resection with curative intent, and the remaining 4 did not received resection because of discovery of occult metastasis at laparotomy. Of the 131 in Group B, 36 (27%; Group B-1) received resection with curative intent, 7 did not received resection because of occult metastasis, and the remaining 88 did not receive laparotomy because they were diagnosed as having locally advanced unresectable disease by CT. Among Group B, patients other than Group B-1 received gemcitabine-based chemotherapy (Group B-2; N=95). The median survival time, 1-yr, 2-yr, and 3-yr survival rate were 28.7 months, 78.6%, 55.5%, and 38.9% in Group A, 16.8 months, 63.8%, 31.8%, and 19.8% in Group B-1, and 13.8 months, 60.1%, 21.7%, and 5.9% in Group B-2, respectively. Conclusions: Based on our historical data, we suppose that 16.8 months of median survival time or survival rate of 19.8 at 3-yr, i.e, Group B-1 survival data, may be an appropriate threshold value in the single-arm phase 2 BRPC study.
Outcomes and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC).
Authors: Ziogas Dimitrios , Thillai Kiruthikah , Korantzis Ippokratis , Chowdhury MH Ruhe , Papadatos-Pastos Dionysios , Suddle Abid , O'Grady John , Heaton Nigel , Ross Paul J. , Sarker Debashis
Published: February 2017

435

Background: HCC is the third commonest malignancy worldwide, with the highest incidence rates in patients over 75 years of age. Although sorafenib is used for patients with advanced HCC, there are concerns about the outcomes and tolerability in this age group. Methods: We conducted a retrospective study of 190 patients treated with sorafenib (177 with sorafenib alone, 17 patients with a combination of sorafenib and erlotinib/placebo within the SEARCH trial). Patient demographics and outcomes were recorded. Results: 190 patients were identified with a median age of 66 (26-87). 151 patients were <75 years old (yrs) and 39 patients were >75. 157 patients were male and 33 female. Underlying liver disease in the over 75 group were: non-alcoholic fatty liver disease (N=14, 35.9%), unknown aetiology (N=14, 35.9%), alcoholic liver disease (N=7, 17.9%), hepatitis C (N=2, 5.1%), hepatitis B (N=1, 2.56%,) and autoimmune hepatitis (N=1, 2.56%). 33 patients were Child-Pugh A status when starting sorafenib (A5=25, A6=8) and 6 patients were Child-Pugh B (B7=5, B8=1). There was no statistically significant difference in OS between patients over the age of 75 and younger (7.1m for >75 yrs and 10.4 <75 yrs p=0.360), or in PFS (4.2m vs. 6.8m [p=0.539]). There was also no increase in G3/4 toxicities between both groups of patients with comparable incidences of G3/4 diarrhoea (4.7% <75 vs. 2.6% ≤75 p=0.481), skin toxicity (6.6% vs. 5.1% p=0.537), fatigue (7.3% vs. 7.7% p =0.58) and deteriorating liver function (2.6% vs. 7.3% p = 0.25). There was no difference between the incidence of dose reductions or interruptions (34% vs. 35.9% p=0.5). Conclusions: Our study suggests that patients aged 75 or older appear to tolerate treatment with sorafenib well with comparable toxicities to those less than 75. We also found no significant differences in survival. With an aging population and increasing incidences of HCC, further prospective evidence is needed to identify safety and survival outcomes in this important group of patients.
FOLFIRINOX chemotherapy in locally advanced and metastatic pancreatic adenocarcinoma: A retrospective analysis of toxicity and outcomes.
Authors: Kerr Ashleigh , Grose Derek B , Hall Sally , McIntosh David , MacLaren Vivienne , Ali Clinton , Hennessy Aisling , McDonald Alexander , Graham Janet Shirley
Published: February 2017

436

Background: The FOLFIRINOX chemotherapy regimen has been shown to improve overall survival in patients with metastatic pancreatic cancer, however, toxicity is increased. The aim of this analysis was to assess the tolerability and outcomes of this regimen in clinical practice. Methods: A retrospective analysis of patients treated with FOLFIRINOX chemotherapy in a tertiary referral centre between January 2013 and May 2014 was conducted. Toxicity was graded as per CTCAE version 4.0. Overall survival and tumour response were analysed. Results: A total of 80 patients were identified with locally advanced or metastatic disease in 47 and 33 cases respectively. The median patient age was 63 (range 30 –79) and the median number of cycles delivered was 6 (range 1-12). G3/4 neutropenia was recorded in 12.5% of patients, with a febrile neutropenia rate of 9.9%. G3/4 nausea and vomiting was reported in 17.5% and G3/4 diarrhoea in 15% of cases. G3/4 electrolyte disturbance occurred in 5%. Response rates assessed after 3-6 cycles showed PR 26%, SD 31% and PD 25%. Median duration of follow up for survivors is 8.7 months (range 3.6 – 20.8). Median OS is 11.4 months (95% CI 10.1 – 12.7). Median OS was reported as 11.4 months, 10.9 months and 2.3 months according to baseline PS 0, 1 and 2 respectively (log rank p <0.001). Conclusions: FOLFIRINOX can be safely delivered out with a trial cohort. Outcomes are strongly influenced by patient PS and careful patient selection is critical.
Phase I/II study of sorafenib in combination with intermittent hepatic arterial infusion chemotherapy using cisplatin for unresectable advanced hepatocellular carcinoma with portal vein tumor thrombus.
Authors: Ishizaki Morihiko
Published: February 2017

441

Background: Our purpose in the study was to ascertain the feasibility of a combination therapy with sorafenib and hepatic arterial infusion therapy (HAIC) using cisplatin (CDDP) for unresectable advanced HCC included portal vein tumor thrombus. Methods: Phase I study: Soraenib was administered continuously, whereas CDDP was given on day1, 8, and 15. The dose of sorafenib was escalated in two steps from 400 to 800 mg/body, whereas the dose of CDDP was escalated in three steps from 20 to 25 and 30 mg/m2. We estimate the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of this therapy, to determine the recommended dose (RD). Phase II study: Thirty-five patients with unresectable HCC received this therapy under RD, and the efficacy and safety were assessed. Results: Phase I study: 15 patients (11 male/4 female, median age: 73.1 years) with unresectable advanced HCC have been enrolled. None of the patients treated with sorafenib 400mg and cisplatin 20 mg/m2 experienced DLT. Three of three patients treatd with sorafenib 800mg and cisplatin 20 mg/m2 experienced DLTs (two serum bilirubin elevation and one hepatic encephalopathy). None of the patients treated with sorafenib 400mg and cisplatin 25 mg/m2 experienced DLT. One of six patients treated with sorafenib 400mg and cisplatin 30 mg/m2 experienced dose-limiting thrombocytopenia, and One of them experienced dose-limiting serum aspartate aminotransferase elevation. Phase II study: 35 patients (27 male / 8 female, median age : 69.2 years) with unresectable advanced HCC have been enrolled. The clinical response were rated as 9 partial response (PR), 18 stable disease (SD), and 8 progressive disease (PD). Conclusions: In this study, RD of this therapy was sorafenib 400mg/body and CDDP 30 mg/m2. Sorafenib in combination with intermittent HAIC using CDDP for unresectable advanced HCC was expected to be safe and effective treatment. Clinical trial information: 000008571.
Role of neoadjuvant treatment regimens for locally advanced pancreatic cancer.
Authors: Alfayez Mohammad , Graham Janet Shirley , Hall Sally , McIntosh David , MacLaren Vivienne , McDonald Alexander , Ali Clinton , Hennessy Aisling , Karteszi Hedvig , Jamieson Nigel , Carter Ross , McKay Colin , Dickson Euan , Grose Derek B
Published: February 2017

444

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality worldwide. Lymph node involvement and resection margin status play important roles in predicting relapse. Resectable disease occurs in only 15–20% of total patients who present with PDAC. Unfortunately, margin involvement (R1) occurs in 70–80% of these patients. Emerging evidence has shown that the use of neoadjuvant chemotherapy and localised radiotherapy to downsize the tumours and increase the margin clearance (R0) rate may improve the overall survival of PDAC patients.We report a neoadjuvant therapy approach in the non-clinical trial setting of our large, tertiary cancer centre. Methods: We prospectively collected the outcome data and toxicity of 53 patients diagnosed with borderline resectable or initially non-resectable PDAC between 2012 and 2014. These patients received either FOLFIRINOX (FFX) or Gemcitabine/Capecitabine (GemCap) combination chemotherapies. Following restaging by computed tomography (CT), the patients proceeded to preo-operative 5-FU-based chemo-radiotherapy, immediate resection or subsequent palliativetherapies. Results: The median age was 65 (range 30 – 79) at PDAC diagnosis. Sixty-one percent (n=32) were male with the commonest anatomical location being the head of the pancreas (58%, n=31). The median follow up for survivors is 13.7 months (range: 5.3–24.4). The median overall survival was 18.3 months (95%, CI: 12.0–24.5). There was no statistical difference between overall survival in patients receiving FFX and GemCap chemotherapies. The margin clearance rate (R0) was 36% (4/11) in patients who proceeded to resection after neoadjuvant chemotherapy alone. The rate was 100% (4/4) in patients who received additional chemoradiation prior to surgery. Conclusions: This case series reveals that neoadjuvant therapy improved survival of patients with PDAC. In addition, we showed an increase in the R0 resection rate in patients who underwent chemoradiation prior to surgery. Further work is ongoing but based on historical data we believe that this neoadjuvant approach may lead to a long term survival benefit.
Induction FOLFIRINOX followed by chemoradiation with capecitabine for unresectable locally advanced pancreatic cancer (LAPC): Preliminary data.
Authors: Carvalho Rafael Ferreira de , Gil Erlon , Moreira Raphael Brandao , Peixoto Renata D'Alpino , Amarante Marcus Paulo Fernandes , Zanuncio Pedro , Ferrigno Robson , Moraes Paulo , Maluf Fernando C. , Buzaid Antonio C. , Cruz Marcelo Rocha De Sousa
Published: February 2017

458

Background: FOLFIRINOX was found to have higher response rates and overall survival (OS) compared to gemcitabine-based regimens in the metastatic setting. However, the contribution of chemoradiotherapy to outcomes after FOLFIRINOX in LAPC remains uncertain. We aim at evaluating our experience with FOLFIRINOX followed by chemoradiation (IMRT) with capecitabine for patients with LAPC. Methods: Patients with unresectable LAPC who received induction FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) followed by chemoradiation with capecitabine at our institution were screened and accrued at the time of radiotherapy and are being followed prospectively. Radiation technique consisted of IMRT with simultaneous integrated boost (SIB) - dose of 45 Gy (1.8Gy/day) to high-risk lymph nodes and 55 Gy (2.2Gy/day) to the primary tumor. Progression-free survival (PFS) and OS were estimated by the Kaplan-Meier method. Results: Fourteen patients (58% female) were included in the analyses. Median age at diagnosis of LAPC was 61 years (range 38-78). Median number of FOLFIRINOX cycles was 11 (range 4-13). With a median follow up fo 11.7 months, 43% of the patients have died. Median PFS and OS were 15.9 (95% CI 6.8 – 25.1) and 16.7 months (95% CI 10.9 – 22.4), respectively. There were no treatment-related deaths. Conclusions: Our data suggest that sequential treatment with FOLFIRINOX followed by chemoradiation with capecitabine is feasible and may offer promising PFS and OS among selected patients with LAPC. Randomized trials are urgently needed to assess the role of sequential treatment in this population.
Early radiotherapy versus late radiotherapy after incomplete transarterial chemoembolization in hepatocellular carcinoma.
Authors: Kim Mi Sun , Kim Do Young , Han Kwang-Hyub , Won Jong Yun , Lee Do Yun , Seong Jinsil
Published: February 2017

459

Background: To investigate the efficacy of early RT (ERT) in comparison to late RT (LRT) in HCC patients after incomplete TACE. Methods: Between January 2006 and December 2011, 99 BCLC B and C stage HCC patients were reviewed. We defined ERT as curative aimed additional RT after the first TACE, and LRT was defined as salvage aimed additional RT for recurrent or re-growing remnant tumors after repeated TACE. The median prescribed dose was 45 Gy (range, 21.6 Gy–60 Gy) given in daily dose of 1.8 Gy–3 Gy. Three-dimensional conformal RT or intensity modulated RT was used for all patients. The in-field tumor response rate (IFTR) was evaluated using the modified response evaluation criteria in solid tumors. Results: Fifty eight (58.6%) patients received ERT and 41 (41.4%) patients received LRT. All patients had BCLC B-C stage HCC and the characteristics between two groups were not different significantly. However, vessel invasion was observed more often in the LRT group (p=0.039). The median interval between last TACE and RT was 2weeks in the ERT group, and 4 weeks in the LRT group. The IFTR at one month and three months were significantly higher in the ERT group. The one-year in-field progression-free survival rates were 79.5% and 45.9% in the ERT and LRT groups, respectively (p=0.007).The one-year overall survival rates were 75.9% and 48.8% in the ERT and LRT groups, respectively (p = 0.01). In the multivariate analysis, vessel invasion and treatment group (ERT vs.LRT) were independent predictor of OS (p=0.039 and p=0.035). PVTT and treatment group (ERT vs.LRT) showed correlation with IFPFS in the multivariate analysis (p=0.002 and p=0.01). Conclusions: While this finding may reflect differences in biological characteristics between the two groups, ERT within 2weeks after incomplete TACE should be considered.
An investigation of the safety of continued treatment with sorafenib in patients with unresectable hepatocellular carcinoma after the first disease progression: Multicenter, open-label, phase II safety study.
Authors: Akutsu Noriyuki , Sasaki Shigeru , Takagi Hideyasu , Kaneto Hiroyuki , Yonezawa Kazuhiko , Yawata Atsushi , Adachi Takeya , Yokoo Hideki , Kamiyama Toshiya , Hamamoto Yasuo , Shinomura Yasuhisa
Published: February 2017

462

Background: Randomized studies showed that sorafenib significantly improved outcome in patients with unresectable hepatocellular carcinoma (HCC). However, there is no clear evidence to support the safety and benefit of continued treatment of sorafenib beyond disease progression (PD) in patients with HCC treated with sorafenib. We prospectively evaluated the safety and efficacy of sorafenib beyond PD in patients with HCC whose disease has progressed after first-line treatment with sorafenib. Methods: Unresectable HCC patients with evaluable lesion were treated with sorafenib until 1st PD, followed by soafenib until 2nd PD. The primary endpoint of the study was the safety after 1st PD until 2nd PD. Secondary endpoints of the study were response rate (RR), disease control rate (DCR), time to first PD (TTP1), time to second PD during continued treatment (TTP2), overall survival (OS), and safety throughout the treatment period. Adverse event was evaluated as per The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tumor response was evaluated as per Modified Response Evaluation in Solid Tumors (mRECIST) criteria. The Kaplan–Meier method was used to determine TTP and OS. Results: Of 30 patients enrolled from 6 sites in Japan, 29 patients received sorafenib treatment, and one patient refused chemotherapy. Twenty patients continued sorafenib beyond PD. Grade 3/4 adverse events occurred less frequently during TTP2 than during TTP1. No critical events related to sorafenib were reported during TTP2. In the first-line therapy, 29 patients treated with sorafenib showed RR of 10.3%, DCR of 60.7% and median TTP1 of 102 days. Twenty patients who received continued sorafenib beyond PD and showed RR of 0%, DCR of 45%, and median TTP2 of 77 days. Median survival time was 306 days. Conclusions: Sorafenib beyond PD had acceptable tolerability and considerable efficacy. In the present conditions without second line treatment, sorafenib beyond PD might be one of the treatment options. Clinical trial information: UMIN000005818.
Video-assisted thoracoscopic transdiaphragmatic liver resection for malignant tumors located in the posterosuperior segments.
Authors: Sunahara Masao , Kurauchi Nobuaki , Tsunetoshi Yusuke , Sawano Takeyuki , Kasajima Hiroyuki , Hara Yutaka , Suzuki Shinsaku , Toyama Shigeru , Kimura Jun
Published: February 2017

469

Background: Laparoscopic liver resection has recently become more common. However, it is difficult to resect laparoscopically the liver tumor located in the posterosuperior segments (IVa, VII and VIII), especillay for patients with liver cirrhosis. Compared to laparoscopy, gaining access to tumors in the dome of the liver may be more easily obtained via thoracoscopy.Therefore, we describe the technique and outcome of a video-assisted thoracoscopic transdiaphragmatic liver resection in patients with a malignant tumor of the liver. Methods: Five female patients underwent video-assisted thoracoscopic transdiaphragmatic partial hepatectomy. The tumors were located at segment VIII in 4 patients and segment VII in 1. Three patients were preoparatively diagnosed with hepatocellular carcinoma, and two were metastatic tumor of the colorectal cancer. Underlying cirrhosis was staged as Child-Pugh B in 2 cases and Child-Pugh A in 1. Thoracoscopic transdiaphragmatic partial hepatic resection was chosen due to the tumor’s location and impaired liver function. The patient was placed in an oblique position with her left side on the table. The ports were placed around the tumor at three levels, the ninth (3cm mini-thoracotomy), the seventh (two ports, 5mm and 12mm), and the fifth (12mm) intercostals spaces. Using thoracoscopic ultrasonography, the portion of the diaphragm located just above the tumor was cut and opened using electric cautery. The partial liver resection was performed using coagulating shears and electric cautery. Results: No conversion to laparotomy occurred. The median blood loss was 200 g (20-500g), and median operating time was 220 min (135-347 min). There were no perioperative deaths, and no patients underwent reoperation. Conclusions: Thoracoscopic hepatic resection can be safely performed in patients with subdiaphragmatic tumors, especially with cirrhosis or previous upper abdominal surgery.
A phase III clinical trial of intra-arterial yttrium-90 glass microspheres in the treatment of patients with unresectable hepatocellular carcinoma.
Authors: Karpf Maria Angela
Published: February 2017

477

Background: Primary liver cancer is the fifth most commonly diagnosed cancer in men and eight most common in women. Currently, sorafenib is SOC treatment for pts with advanced hepatocellular carcinoma (HCC); however, it is associated with only modest improvement in median survival compared with best supportive care. Sorafenib is associated with significant toxicity. Yttrium 90 glass microspheres (TheraSphere; 90Y) have an HDE in the US for use in radiation treatment or as a neoadjuvant to surgery or transplantation in pts with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters. The purpose of this study is to evaluate treatment with 90Y in HCC pts who will then receive SOC sorafenib and to compare survival outcomes with those of pts receiving only sorafenib. The primary objective is to evaluate 90Y in pts with unresectable HCC where SOC sorafenib is planned. Methods: This Phase 3, open-label, multi-center, randomized study will evaluate 90Y treatment in ~390 pts with unresectable HCC. Eligible pts (where SOC sorafenib therapy is already planned) will be randomized 1:1 to control and treatment. Control patients will receive SOC sorafenib according to label. The treatment group will receive 90Y prior to SOC sorafenib. Primary outcome is overall survival from time of randomization. Secondary endpoints include time to progression/untreatable progression/symptomatic progression, tumor response, quality of life, and adverse events. Sorafenib pts will have study visits every 8 wks for as long as the patient remains in study. Pts randomized to 90Y will have pre-treatment evaluations and treatment to the first lobe during wks 3-4; patients with bilobar disease will have pre-treatment evaluations and treatment to the second lobe during wks 5-8. After 90Y treatment, study visits will occur every 8 wks as long as the pts remain in study. Follow-up visits will occur every 8 wks from randomization until disease progression. Results: This study is ongoing. Conclusions: This Phase 3 study will evaluate use of 90Y in advanced HCC patients given its potential to enhance survival with less toxicity than the current SOC. Clinical trial information: NCT01556490.
Management of chemotherapy‐induced anemia (CIA) with biosimilar epoetin alfa (Binocrit) in patients with pancreatic cancer (PC): An interim analysis of an ongoing French national observational study (The OncoBOS study).
Authors: Metges Jean Philippe , Desramé Jérôme , Bourgeois Vincent , Stamerra Otilia , Mouysset Jean-Loup , Aubron-Olivier Camille , Fernet Domitille , Boschetti Gilles
Published: February 2017

479

Background: OncoBOS is a prospective, non-interventional study describing Binocrit use in routine practice in France in patients receiving chemotherapy treatment (CT) for solid tumors, lymphoma or myeloma. This interim sub-analysis focuses on patients with PC. Methods: Patients ≥18 years with PC, CIA and eligible for treatment with Binocrit were included in this analysis. Patients characteristics, data on CIA and its management and predominant factors considered by the physician in prescribing Binocrit were recorded at baseline (BL), 3-4 weeks and 12 (± 1) weeks later. Hemoglobin (Hb) outcomes assessed included the proportion of patients achieving a Hb increase ≥1 and ≥2 g/dL, and the mean Hb change from BL. Results: 59 patients with PC (32 females (54.2%), mean age 68.3 years) from 22 sites were recruited from September 2011 to April 2014. Mean and median BL Hb levels were both 10 g/dL. The mean increase in Hb level was 1.1 g/dL after 1 month and 1.2 g/dL after 3 months (p<0.001 vs BL) of Binocrit treatment. A Hb increase ≥1 g/dL was achieved by 48.3% of patients at week 3-4 and 54.2% at week 12; a Hb increase ≥2 g/dL was achieved by 25.9% and 35.4% of patients at the same time points. Patients received a median dose of 30,000 IU Binocrit once weekly. Three of the 59 patients (5.1%) required a dose increase. Transfusion rates remained stable at 11.9% and 15.1% at week 3-4 and week 12, respectively. Oral and intravenous (IV) iron supplementation rates were low: oral iron was received by 1.7% and 0% of patients at week 3-4 and week 12, respectively; 20.3% and 13.2% of patients received IV supplementation at the same time points. Of note, iron status was assessed in only 11.9% of subjects at BL. Physicians considered quality of life (37.3%), fatigue (25.4%) and avoidance of blood transfusion (10.2%) as predominant factors in the rationale for CIA management. Over the treatment period, three treatment-related adverse reactions (non-serious) were recorded. Conclusions: This sub-analysis indicates that Binocrit, used in routine practice, is effective and well tolerated for the treatment of CIA in patients with PC.
Retrospective analysis of prognostic and predictive markers in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nabpaclitaxel: Influence of the presence of stent.
Authors: Montes Ana Fernandez , Gonzalez Villarroel Paula , Valladares Ayerbes Manuel , Gómez Juan Cruz De la Cámara , Quintero Guillermo , TuÃ±as Lidia Vazquez , Fernández Mercedes Salgado , Jorge Fernández Mónica
Published: February 2017

483

Background: Placement of a biliary stent is a standard measure for patients (pts) with pancreatic cancer. We evaluated prognostic/predictive factors that could predict the benefit of gemcitabine/nabpaclitaxel in pts with locally advanced unresectable and metastatic pancreatic adenocarcinoma and whether the presence of a biliary stent reduced the treatment efficacy Methods: We retrospectively analyzed 39 pts with locally advanced and metastatic pancreatic cancer treated with gemcitabine/nabpaclitaxel. Data included lactate dehydrogenase (LDH) level, alkaline phosphatase, neutrophil/lymphocyte ratio (NLR), performance status (PS), weight loss, presence of stent, analgesics use and CA 19.9 level. The correlation with response rate, progression-free survival (PFS) and overall survival (OS) was analyzed. Objective toxicities were assessed. Results: 30 pts (77%) had metastatic disease and 9 (23%) locally advanced pancreatic cancer. 46% had liver metastases and 41% lung metastases. Mean age of pts: 62 years (62% male). 20% had PS:0, 67% PS:1 and 13% PS:2. Stents were placed in 30% of pts, 69% had weight loss and 64% used analgesics at diagnosis. At the time of analysis 14 pts had died (25 alive). 56% had progressed, 3% were lost to follow-up and 41% had not progressed. A total of 54% disease stabilizations, 21% partial responses and 18% progressions were achieved (deaths: 7%). 43% required dose reduction. The main toxicity was hematologic (grade 1 anemia). Median PFS: 6 months (95%CI 4.4-7.6). Median OS: 15 months (95%CI 10.4-19.6). There was a statistically significant relationship between LDH level, NLR and PS and OS: LDH level higher than 363 increased the risk of death, NLR above 3.1 increased 1.8 times the risk of death and mean OS of pts with ECOG:0,1 was greater than that of pts with ECOG:2. No relationship between the presence of stent and PFS or OS was found, as well as with any of the other variables. Conclusions: The presence of stent did not reduce the efficacy of gemcitabine/nabpaclitaxel. Univariate analysis showed PS as a prognostic factor while multivariate showed LDH and NLR.
Histological evaluation of tumor response in metastatic lymph node after preoperative chemotherapy for gastric cancer.
Authors: Honda Shinsaku , Miki Yuichiro , Tanizawa Yutaka , Takagi Wataru , Hirata Fumiko , Omori Hayato , Tatsubayashi Taichi , Makuuchi Rie , Tokunaga Masanori , Bando Etsuro , Kawamura Taiichi , Nakajima Takashi , Terashima Masanori
Published: February 2017

51

Background: Preoperative chemotherapy is thought to be an option for treatment of advanced gastric cancer. However, optimal predictive marker for survival of preoperative chemotherapy had not yet been established. Histological response is thought to be a good candidate of predictive marker, however, it had been determined only in primary tumor, not in the metastatic lymph node. The aim of this study is to evaluate the role of histological response in metastatic lymph node on the survival in patients received preoperative chemotherapy for advanced gastric cancer. Methods: A total of 38 patients who underwent curative resection after preoperative chemotherapy from were included. For histological evaluation in lymph node, we determined it as positive if remaining viable tumor cells are less than 30% of the tumor area at one or more of the resected metastatic lymph nodes. We also evaluated histological response in primary tumor according to the Japanese Gastric Cancer Classification. Results: 21 patients received preoperative chemotherapy as planned neo-adjuvant chemotherapy and remaining 17 received chemotherapy as palliative intent and then converted to surgery. Pathological TNM stage was 0 in 2, I in 5, II in 13, III in 11, and IV in 7, respectively. In lymph node, histological response was able to evaluate in 31 of 38 patients. Among them, positive response was observed in 15 patients. Histological tumor response in primary tumor was grade 0 in 2, grade 1a in 10, grade 1b in 7, grade 2 in 10, and grade 3 in 2. The 3-year relapse-free survival (RFS) rate was significantly better in patients with positive histological response in lymph node (71 %) than in those without response (21 %) (p = 0.003). Similarly, 3-year RFS rate was significantly better in patients with histological response in primary tumor (grade 2, 3) (73 %) than in those without response (grade 0, 1a, 1b) (30 %) (p=0.007). Three-year RFS in patients who demonstrate histological response both in primary tumor and lymph node was as high as 89 %. Conclusions: Histological responses in lymph nodes, as well as primary tumor, appear to be a useful predictive marker for survival in patients underwent curative resection after preoperative chemotherapy.
Expanded KRAS and NRAS assays increase detection of mutations that predict for resistance to therapy in colorectal cancer patients.
Authors: Larson Garrett , Israyelyan Anna , Lenz Heinz-Josef , Astrow Stephanie H.
Published: February 2017

519

Background: The selection of targeted therapies is guided by the analysis of somatic mutations. The identification of RAS activating mutations can be used to examine tyrosine kinase inhibitor therapeutic eligibility and prognosis. Beyond known mutations in RAS exon 2 (codons 12 and 13), the identification of additional mutations in RAS exons 3 and 4 (codons 61, 117 and 146) also predict for resistance to EGFR therapy in colorectal cancer (CRC). Meta-analysis supports screening for these additional mutations in any screening strategy prior to administration of EGFR mAb therapy in metastatic CRC patients (Sorich, MJ, et al., Ann Oncol, Aug 12, 2014). Methods: We expanded our existing allele-specific KRAS and sequencing-based NRAS assays to include codons 61, 117, and 146 and analytically validated these assays to CAP/CLIA standards. DNA, from microdissected colon tumor tissue that was wild-type for RAS exon 2, was tested for exon 3 and 4 mutations and included over 15 additional mutations. Results: Forty-two (9.1%) samples were identified as bearing either an exon 3 or 4 KRAS mutation amongst 461 colon cancer specimens. Exon 4 codon 146 mutations were more prevalent than three of the commonly screened exon 2 mutations: G12A, G12R, and G12S. Five (1.8%) of samples were identified as carrying exon 3 or 4 NRAS mutations amongst 272 colon cancer specimens. This included a single codon 146 mutation in exon 4. As is seen with exon 2, RAS mutations at exons 3 and 4 were mutually exclusive of activating BRAF mutations with ~10% of patients harboring V600E. The collection of additional data studying KRAS and NRAS mutation status is currently ongoing. Conclusions: The KRAS expanded coverage contributed an additional 5.5% to overall burden of specimens bearing mutations. The NRAS expanded coverage contributed an additional 1.8% to the mutational burden. These analyses in clinical cohorts support the observations made in a trial population (Douillard JV, et al. NEJM 369:1023-34, 2013). The expanded RAS coverage identifies additional patients unlikely to respond to EGFR-targeted therapies that would otherwise have been assessed as “no mutation detected” in using assays restricted to RAS exon 2.