bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of MiR-32 on gastric carcinoma tumorigenesis by targeting Kruppel-like factor 4.
Authors: Yan Chao , Yu Jianchun , Kang Weiming
Published: February 2017

76

Background: Gastric cancer (GC) is a prevalent malignant cancer worldwide and is highly lethal because of its fast growth. Currently, the comprehensive treatment is the combination of surgery, chemotherapy and radiotherapy, which has made progress in the treatment of advanced GC. However, the accuracy of current diagnostic methods is not very satisfactory. To address these limitations and improve the survival rate and reduce mortality it is necessary to identify sensitive early diagnostic markers. MiR-32 has been reported as an oncogenic microRNA in many cancers, but its role in GC is unclear. Methods: We detected miR-32 expression in clinical gastric carcinoma tissue samples and adjacent normal tissue samples from the same patient. The expression of miR-32 was also detected in 40 gastric carcinoma patients’ plasma, as compared with the plasma of 40 healthy individuals. The proliferation ability of cells was monitored by the xCELLigence Real-Time Cell Analyzer (RTCA)-MP system. Transwell insert chambers with an 8 μm diameter porous membrane (Neuro Probe, MD, USA) were used for the migration/invasion assays. Also, the plasmid construction and luciferase reporter assay, western blotting analysis and immunofluorescence cell staining were performed. Data were analyzed with SPSS v.17.0 software. Results: We detected the expression level of miR-32 in two normal gastric tissue, the GES-1 cell line, and eight gastric carcinoma cell lines. The expression of miR-32 was significantly higher in tumor tissues as compared with normal tissues, p = 0.0016. The expression of miR-32 was significantly higher in 40 gastric carcinoma patients’ plasma, as compared with the plasma of 40 healthy individuals, p = 0.004.MiR-32 promotes the proliferation, migration and invasion of GC cells. The expression of KLF4 is negatively regulated by miR-32. Knockdown of KLF4 promotes cell proliferation, migration and invasion in GC cell-lines. Conclusions: In addition to identifying upregulated miR-32 as a diagnosis biomarker in clinical GC tissue and plasma, we have defined the biological functions of miR-32 as an oncogene in GC cells and explored the molecular mechanism of miR-32 in GC cells’ aggressive phenotype.
Relevance of CEA and LDH in relation to KRAS status in patients with unresectable colorectal liver metastases.
Authors: Connell Louise Catherine , Chou Joanne F. , Boucher Taryn Mary , Capanu Marinela , Kemeny Nancy E.
Published: February 2017

762

Background: While the significance of CEA, LDH and KRAS status as individual prognostic factors for patients (pts) with metastatic colorectal cancer (mCRC) has been addressed, the relationship and interdependence between these prognostic factors on overall survival (OS) is limited. Methods: A retrospective review of pts with unresectable liver metastases and no extrahepatic disease and known KRAS status and baseline CEA and LDH treated with hepatic arterial infusion (HAI) plus systemic therapy from 2002 to 2013. Baseline values were taken from start of HAI. OS was estimated using Kaplan-Meyer. Relationship between OS and markers were evaluated using Cox regression method. Results: A total of 75 pts were included: 54 pts were KRAS wildtype (WT) and 21 pts were KRAS mutant (MUT). Median follow-up was 88 months (mos) and median OS was 45.7 mos [95% CI: 32.1-68.8]. 27 pts (36%) underwent hepatic resection at 1-year, with 3-year OS of 85% [95% CI: 64%-94%] versus 31% [95% CI: 18%-44%] for pts who did not get to resection (p<0.01). Univariate analysis of factors associated with OS are shown in Table 1. On multivariate analysis, pts with CEA >200 ng/mL [HR 2.6, 95% CI: 1.2-6.0, p=0.018], KRAS MUT [HR 2.2, 95% CI: 1.1-4.3, p=0.018] and prior chemotherapy [HR 2.3, 95% CI: 1.1-4.5, p=0.017] had significantly lower OS. Pts who achieved hepatic resection had significant increase in OS [HR 0.4, 95% CI: 0.2-0.8, p=0.009]. Conclusions: This analysis verifies that high CEA, KRAS MUT, prior chemotherapy, and hepatic resection affect OS in pts with unresectable mCRC. This data also suggests that CEA is an independent predictor of survival. Although further investigation is needed, CEA is clinically relevant and should be included in standard laboratory testing. [Table: see text]
REOX: Effectiveness evaluation of re-exposure to oxaliplatin in patients with metastatic colorectal cancer.
Authors: Costa Talita Gonzaga , Felismino Tiago Cordeiro , Boente Leonardo de Azevedo , Mello Celso Lopes
Published: February 2017

764

Background: Colorectal cancer has high incidence and mortality rates. Treatment of metastatic colorectal adenocarcinoma has evolved since the approval of irinotecan, oxaliplatin and monoclonal antibodies with survival surpassing 30 months in contemporary trials. Nevertheless there is paucity of effective options after failure of these protocols. Thus re-exposure to previously used drugs became a treatment strategy. We aimed to evaluate the efficacy of retreatment with oxaliplatin in mCRC and its correlation with clinicopathological features. Methods: We retrospectively analyzed 83 patients with mCRC who underwent REOX treated at a single cancer center in Brazil. REOX was defined as a second trial of an oxaliplatin containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF) after REOX. Results: Median age of our cohort was 53.5y. Female/Male: 51.8%/48.2%. Primary colon was found in 67.5% while 32.5% had primary rectal adenocarcinoma. KRAS status was wild type in 57.8% and mutated in 39.8%. Exclusive hepatic metastasis was found in 19.3%. Median follow-up after REOX was 31m. Main chemotherapy regimen was mFOLFOX6 (84.3%). Bevacizumab and Cetuximab were used in 42.2% and 6% respectively. Most patients underwent REOX in third and fourth lines, 48.2% and 25.3% respectively. Median time to treatment failure (mTTF) after REOX was 6.04m. Overall survival was 10.04m. Disease control (CR + PR + SD) was observed in 56.6%, while 42.2% had progressive disease (PD). Reasons for interruption were as follows: PD (68.7%), toxicity (19.3%) and metastasectomy (2.4%). Patients who attained disease control had better OS (14.5m) compared with patients who had PD (14.5m versus 6.24m, p < 0.0001). Patients with exclusive hepatic metastasis had a trend to a better TTF compared to other metastasis sites (8.96m X 6.01m, p = 0.2). Regarding KRAS status, there was no difference in mTTF (wt 6.68m, mut 6.04m, p = 0.14). Conclusions: In the setting of pretreated mCRC patients where there are few options available, REOX remains an effective treatment, with mTTF of 6.04m in our cohort. This could be related to progression of cell clones sensitive to the drug after a time lapse since the previous exposure.
Intravenous weekly high-dose infusion of 5-fluorouracil and folinic acid in previously heavily pretreated patients with metastatic colorectal cancer.
Authors: Piringer Gudrun , Huber Verena , Burgstaller Sonja , Weninger Martin , Karrer Andreas , Mayrbaeurl Beate , Thaler Josef
Published: February 2017

766

Background: Patients with metastatic colorectal cancer (CRC) usually receive multiple lines of treatment. Using a present day standard 1st line chemotherapy combination a progression free survival in the range of 8-12 months can be obtained. With consecutive treatment lines the median survival has now exceeded the 2-year landmark. In case of disease progression after two or more lines of treatment, the survival is about 4-6 months with best supportive care alone. However, some patients are still able and willing to receive further therapy. In the present retrospective analysis the efficacy of a weekly intravenous high-dose infusion of 5-Fluorouracil and folinic acid in heavily pretreated patients with metastatic CRC beyond the standard chemotherapy lines was evaluated. Methods: The Klinikum Wels-Grieskirchen collects data on all CRC patients since July 2006 in a clinical tumor registry. In this retrospective analysis pretreated CRC patients that were treated with the Ardalan-regimen (500mg/m2 folinic acid as 1 hour infusion followed by 2.600mg/m25-Fluorouracil as 24-hour infusion) have been evaluated. Results: A total of 23 evaluable patients with a median age of 66 years received the Ardalan-regimen as 2nd (4.4%), 3rd (13%), 4th (13%), 5th (52.2%), 6th (4.4%) or 7th (13%) line treatment. The median number of cycles received was 9 (range 2-18) and the Ardalan-regimen was started within 13-56 months (median 26 months) after the diagnosis of metastatic disease. Fourteen (60.9%) and nine (39.1%) out of these patients were women and men, respectively. 60.9% (14 patients) had a tumor located in the colon and 39.1% had rectal cancer. 17.4% of patients had stable disease and 65.2% of patients had progressive disease after 3 months of therapy. In 4 patients response according to RECIST criteria was not evaluable. Median overall survival since the start of the Ardalan-regimen was 6.7 months. Conclusions: Patients with advanced metastatic CRC can be candidates for multiple lines of therapy. In previously heavily pretreated patients, the Ardalan-regimen is able to control the disease in a limited proportion of patients.
Evaluation of state comprehensive cancer control plans for content related to stomach cancer.
Authors: Hillard James Randolph
Published: February 2017

8

Background: Since 1998, each US state, as well as some US territories and tribal groups, has had a written Comprehensive Cancer Control Program (CCCP). These plans are charged by the National CCCP with emphasizing “primary prevention of cancer”, supporting “early detection and treatment activities”, and promoting “health equity as it relates to cancer control.” Since stomach cancer still causes over 10,000 deaths a year in the US, since it is in many cases preventable, since its prognosis is highly related to timeliness of diagnosis, and since minority populations are disproportionately affected, it would appear to be an appropriate target for state CCCPs. In 2014, the World Health Organization recommended increased prevention efforts, in an extensive monograph titled “Helicobacter pylori as a Strategy for Preventing Gastric Cancer.” Methods: We reviewed the cancer control plans available on the CDC website, http://www.cdc.gov/cancer/ncccp/ccc_plans.htm as of July 1, 2015. These included those of all 50 states, the District of Columbia, 7 US territories, and 7 Native American/Alaskan Native Tribes. These plans were searched for the words “stomach,” “gastric,” “helicobacter,” and “pylori.” Results: 38 of 65 (58%) of CCCs mentioned the words “stomach” or “gastric” in their text, but only 5 (0.8%) had goals or strategies related to stomach cancer. Of plans which did mention stomach cancer, 19 (32%) mentioned it in the contest of smoking, 16 (25%) in terms of health disparities, and 15 (23%) in terms of diet. Only 5 states (10%), and 5 (36%) territories or tribes mentioned the terms “helicobacter” or “pylori”. Some of the identified risk factors were idiosyncratic (e.g. relating HPV infection to stomach cancer) or inaccurate (e.g. “there is no evidence that” eradication of H. pylori changes the course of disease after cancer has developed, or “fecal occult blood test should not be used for cancer screening,” since 99% of positives are caused by gastritis due to H. pylori). Conclusions: Stomach cancer currently receives little attention in State CCCPs. H. pylori infection as a target for prevention efforts receives far less attention still. Important opportunities for control of this cancer are being neglected.
A phase II study of neoadjuvant chemotherapy with a modified FOLFOX6 regimen for locally advanced gastric cancer.
Authors: Wang Xiang , Zhao Lin , Liu Hongfeng , Bai Chunmei , Li Xiaoyi
Published: February 2017

81

Background: The aim of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy with the mFOLFOX6 regimen in gastric cancer patients. Methods: This study was a single-arm phase II study. 73 patients with histologically confirmed locally advanced gastric cancer (T2-T4 or N+) were enrolled. The patients were administered the mFOLFOX6 regimen for 3 cycles. Surgery was scheduled 3-4 weeks after the completion of the chemotherapy. Postoperative chemotherapy began 4 weeks after surgery, and the program choice was based on the results of patients’ clinical/pathological evaluations. Perioperative efficacy, toxicity, effects of surgery, postoperative observation, and prognosis were studied. Survival analysis was performed to identify the relationship between the response and outcome and to identify factors predictive of OS. Results: 73 patients received the neoadjuvant chemotherapy, and 67 (91.8%) completed all of the preoperative cycles, with grade 3-4 toxicity arising in 33.0%. Surgery was performed in 71 (97.3%) patients, and radical resection was achieved in 67 (91.8%) patients. Postoperative chemotherapy started in 63 (88.7%) patients. The radiology response rate of chemotherapy was 45.8%. Among the patients who underwent radical surgery, pT downstaging was observed in 22 (32.8%) patients and pN downstaging was observed in 17 (25.4%) patients. All of the patients showed different levels of histological regression of the primary tumour, with a ≥ 50% regression rate of 49.2% and a pCR rate of 3.0%. Univariate analysis identified factors that were associated with OS, including local tumour infiltration, Lauren classification, pre-chemotherapy N stage, ypTNM stage, and pathologic regression rate (GHR)( ≥ 2/3/ < 2/3, ≥ 50%/ < 50%). Multivariate analysis identified both ypTNM stage and Lauren classification as independent predictors of survival. Conclusions: The mFOLFOX6 regimen was very effective and well-tolerated as a neoadjuvant chemotherapy for locally advanced gastric cancer. The ypTNM stage could serve as an independent predictor of survival. GHR ≥ 50% / < 50% could be used as a surrogate marker to guide the selection of a postoperative chemotherapy regimen. Clinical trial information: NCT02226380.
Surveillance strategy based on the incidence and patterns of recurrence after curative endoscopic submucosal dissection for early gastric cancer.
Authors: Kim Jae J.
Published: February 2017

87

Background: To suggest an appropriate surveillance strategy after curative endoscopic submucosal dissection (ESD) for early gastric cancers, based on incidence and patterns of local, metachronous, and extragastric recurrence. Methods: Between 2003 and 2011, 1497 consecutive patients with 1539 differentiated-type early gastric cancers meeting absolute or expanded indication criteria underwent curative ESD. They were followed up with esophagogastroduodenoscopy (EGD) and abdominal computed tomography (CT) under a standardized surveillance protocol. Long-term outcomes were analyzed for 1306 patients with at least 1 year’s follow-up. Results: Incidences of residual and synchronous lesions detected within 1 year were 0.13 % and 0.87 %, respectively. During median 47 months of follow-up, there was 1 local recurrence (0.08 %; early gastric cancer) and 47 cases of metachronous recurrence (3.6 %; 44 early gastric cancers, 3 pT2 advanced gastric cancers); all were curatively treated. During a 5-year surveillance, the cumulative incidence curve of metachronous recurrence increased linearly. Median time from ESD to metachronous recurrence was 30 months. There were 2 extragastric recurrences (0.15 %) in lymph nodes, at 5 and 4 years, respectively, after curative ESD for absolute and expanded indications. The patient with the expanded indications underwent a palliative operation and died of gastric cancer progression. Conclusions: There was a constant incidence rate of metachronous recurrence during a 5-year surveillance period and there was extragastric recurrence at least 4 years after ESD of early gastric cancer even for absolute indications. Therefore, annual or biannual surveillance EGD and abdominal CT might be necessary for at least 5 years after curative ESD for early gastric cancers, with absolute as well as expanded indications.
The ratio of major and minor axis by EUS as a possible predictive marker for the diagnosis of submucosal invasive gastric cancer.
Authors: Hwang Jae Jin , Park Young Soo , Lee Dong Ho , Jung Hyun chae
Published: February 2017

9

Background: The aim of this study was to evaluate the efficacy of the ratio of major and minor axis by endoscopic ultrasonography (EUS) as a possible predictive marker for the diagnosis of submucosal invasive gastric cancer. Methods: Between March 2014 and December 2014, the medical records of 51 patients with unclear distinction between mucosal and submucosal gastric cancer were retrospectively reviewed. Patient and tumor characteristics, accuracy rate and factors associated with correct diagnosis of submucosal invasive tumor in Ratio for gastric cancer were analyzed. Results: The mean age was 62.0 ± 12.6 (range, 35-79 years) and the male to female ratio was 1:0.45. The mean tumor size was 25.8 ± 14.7 mm. The overall accuracy was 60.7% (31/51) using the EUS and 82.3% (42/51) using the EUS ratio index (p = 0.045). The sensitivity, specificity, positive predictive value and negative predictive value to submucosal gastric cancer were 68.1, 55.1, 53.5, 65.9% using the EUS and 81.8,82.7,78.2,85.7% using the EUS ratio index, respectively. In the multivariate analysis, differentiated (Odds ratio [OR]: 1.42, 95% confidence interval [CI]: 0.95-1.89), no ulceration (OR: 1.96, 95% CI: 1.49-2.43), and deep submucosal invasion ( > 500 μm, OR: 2.77, 95% CI: 2.16-3.34) were independent factors, associated with correct diagnosis of submucosal invasive tumor in Ratio for gastric cancer (p < 0.05) Conclusions: The ratio of major and minor axis by endoscopic ultrasonography (EUS ratio index) might be a possible predictive marker for the diagnosis of submucosal invasive gastric cancer.
Neoadjuvant chemoradiotherapy versus chemotherapy and surgery for patients with locally advanced esophageal squamous cell carcinoma.
Authors: Hao Daxuan , Li Xue , Yang Yuanyuan , Zhang Yougai , Wu Xiaoyuan , Chen Yongshun , He Chunyu , Wang Wen , Liu Jinsong , Wang Jianhua
Published: February 2017

91

Background: Neoadjuvant chemoradiotherapy (nCRT) combined with surgery has been recommended as the standard treatment for locally advanced esophageal cancer in western countries. However, in clinical practice, neoadjuvant chemotherapy (nCT), rather than nCRT, is preferred for a large cohort of patients with locally advanced esophageal squamous cell carcinoma (ESCC) for fear of increasing the odds of postoperative morbidity in China. The aim of this study is to compare the clinical efficacy of nCRT and nCT in terms of postoperative morbidity, tumor pathology and survival in patients with locally advanced ESCC. Methods: A total of 111 patients with locally advanced ESCC (T2-4N0-1M0) received neoadjuvant treatment at our institution from January 2009 through January 2014.Among these patients, 53 cases received one cycle of neoadjuvant chemotherapy with concurrent radiotherapy while the remaining 58 cases received two cycles of neoadjuvant chemotherapy only before surgery. Results: pCR was observed in 15 patients in nCRT group (28.3%) and 8 patients in nCT group (13.8%, P= 0.060). Postoperative morbidity was 32.1% in nCRT group and 37.9% in nCT group (P= 0.660). Disease-free survival rates at 1, 2, 3 years were 73.1%, 66.7%, 53.6% in nCRT group and 73.7%, 60.4%, 52.2% in nCT group (P= 0.848). Overall survival rates at 1, 2, 3 years were 88.5%, 78.0%, 59.5% in nCRT group and 89.5%,72.9% and 56.2% in nCT group(P= 0.749). No significant differences were found in recurrence rate between two groups (P= 0.836). Conclusions: Neoadjuvant CRT may achieve higher pCR rate than neoadjuvant CT without increasing the odds of postoperative morbidity. Both neoadjuvant CRT and CT can prolong survival in patients with locally advanced ESCC. Further study is needed to prove which one is better.
Multimodal analgesia combined with intravenous administration of acetaminophen in perioperative management of esophagectomy using modified ERAS protocol.
Authors: Ogata Takashi , Nakajima Tetsushi , Kano Kazuki , Segami Kenki , Maezawa Yukio , Sato Tsutomu , Cho Haruhiko , Yoshikawa Takaki
Published: February 2017

94

Background: In perioperative management of esophagectomy, we have performed modified ERAS protocol including preoperative oral rehydration, early enteral nutrition, early mobilization, intestinal peristalsis promotion, pain control, and so on. We think these elements are related closely and useful in reducing complication and early recovery after surgery in case of high invasive surgery such as esophagectomy with 3 field lymph node dissection. And we think pain control is particularly close relationship with early mobilization, so multimodal analgesia is very important for postoperative pain control. Methods: We evaluated whether it is possible to reduce postoperative breakthrough pain by using postoperative pain control combined with acetaminophen IV. 124 patients were treated by esophagectomy with 3-field LN dissection from January 2013 to June 2015. Before May 2014, 49 patients were treated without acetaminophen IV protocol (Group A), and after May 2014, 75 patients were treated with acetaminophen IV protocol (Group B). We compared the number of analgesic drug until postoperative day 7, and compared the ratio of liver dysfunction in both groups. Both groups were used epidural anesthesia as postoperative pain management, and intravenous administration of acetaminophen 1000mg/day has been added between day3 to day 7 in Group B. Results: The number of analgesic drug use due to breakthrough pain(Group A / Group B) were day3:1.12/0.55, day4:1.58/0.83, day5:1.76/0.57, day6:1.24/0.49, and it was reduced significantly in Group B (p < 0.01). And liver damage as a side effect by acetaminophen IV, the rise of ALT(Group A / Group B) were seen 32.7%/66.7% in day6, and seen 20.4%/62.7% in day 8, and it was significantly higher in Group B at day6 and day8 (p < 0.01), but was no significant difference in day 30 between both groups. Conclusions: In perioperative management of esophagectomy, pain control combined with acetaminophen IV was useful as multimodal analgesia. Also was ALT rise is seen by liver damage, but it was the minor change in the acceptable range for natural healing.
Avelumab (MSB0010718C), an anti-PD-L1 antibody, as a third-line treatment in patients with advanced gastric or gastroesophageal junction cancer: A phase Ib JAVELIN Solid Tumor trial.
Authors: Oh Do-Youn , Lockhart Albert C. , Wong Deborah Jean Lee , Taylor Matthew Hiram , Bajars Marcis , von Heydebreck Anja , Moehler Markus H. , Safran Howard
Published: February 2017

TPS188

Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel-group expansion trial in patients (pts) with locally advanced or metastatic (LA/M) solid tumors that includes a heavily pretreated cohort of pts with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJ) to evaluate safety and efficacy of avelumab in the 3rd-line setting. Prior to adding this 3rd-line cohort, this trial had enrolled a separate cohort with advanced GC/GEJ who had received prior 1st-line chemotherapy (Chung et al, ECC 2015). Methods: This trial cohort is enrolling pts with histologically confirmed unresectable LA/M GC/GEJ who have been previously treated with 1st-line combination chemotherapy and 2nd-line ramucirumab, alone or in combination, and whose disease has progressed during or after ramucirumab treatment. Pts who have received prior treatment with trastuzumab and pts with HER2+ status are allowed. Eligible pts also must have tumor archival material or fresh biopsy, an ECOG performance status of 0 or 1 at the time of trial entry, and disease with ≥ 1 measurable lesion according to RECIST 1.1. Exclusions include prior therapy with immune checkpoint drugs or history of autoimmune disease. Up to 150 eligible pts will receive avelumab at 10 mg/kg as an IV infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Primary endpoint is confirmed best overall response (RECIST 1.1) as adjudicated by an IERC. Secondary objectives include assessment of progression-free survival, overall survival, and immune-related efficacy assessments. Association between tumor PD-L1 expression and efficacy will be evaluated. Adverse events will be assessed and graded according to NCI-CTCAE v4.0. Tumor evaluation will be performed every 6 wks until progression. Enrollment in this cohort began in June 2015. *Proposed INN Clinical trial information: NCT01772004.
Cell-free DNA genotyping using digital PCR for early detection of pancreatic neoplasm.
Authors: Karasaki Hidenori , Ono Yusuke , Koizumi Kazuya , Andoh Kiyohiro , Asahara Shingo , Yokochi Tomoki , Takahashi Kuniyuki , Maguchi Hiroyuki , Yamada Masataka , Ogata Munehiko , Sugitani Ayumu , Kono Toru , Nagashima Kazuo , Mizukami Yusuke
Published: February 2017

TPS464

Background: Pancreatic ductal adenocarcinoma (PDA) is still a dismal disease, and there is an urgent need to establish novel tool for early diagnosis of the tumor. There are two main types of pathologically and genetically distinct precursors for PDA — pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). Non-invasive markers for these precursor lesions have the potential to predict subsequent invasive tumor. Methods: Circulating cell-free DNA (cfDNA) released from tumor cells into the blood has been intensively studied as a novel way to monitor the genetic changes. To detect the cfDNA representing for the initiation and progression of PDA could be of the candidate for them. The role of cfDNA genotyping targeting the major driver mutations in these precursors, such as KRAS and GNAS, are currently under investigation in Japanese patients who have pancreatic tumors (UMIN000012810). The major technical challenge is to specifically detect the small fraction of tumor-derived DNA in patient plasma and urine. Since sequencing of target mutant alleles in cfDNA has a limitation to detect very low frequency variants, we sought to establish protocols for super-sensitive and absolute quantification of the “key drivers” for pancreatic tumor using a droplet digital PCR platform (Bio-Rad; QX200). The primary endpoint of this multi-center prospective analysis is to evaluate whether such an approach can appropriately monitor the risk of IPMN progression and detect localized early-stage PDA. Thirty cases of PDA and 90 cases of IPMN have been enrolled thus far. Detailed protocol for the study and improved technical points to quantify low-frequency variants will be discussed.
A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma.
Authors: Teague Andrea S. , Amin Manik A. , Lim Kian-Huat , Lockhart Albert C. , Masood Ashiq , Picus Joel , Singh Preet Paul , Suresh Rama , Tan Benjamin R. , Wang-Gillam Andrea
Published: February 2017

TPS471

Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.
A randomized, double-blind, placebo-controlled phase III study of ramucirumab versus placebo as second-line treatment in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein following first-line sorafenib (REACH-2).
Authors: Zhu Andrew X. , Galle Peter R. , Kudo Masatoshi , Finn Richard S. , Yang Ling , Abada Paolo , Chang Shao-Chun , Llovet Josep M.
Published: February 2017

TPS478

Background: Ramucirumab (Ram) is a human IgG1 monoclonal antibody that inhibits ligand activation of the vascular endothelial growth factor receptor 2 (VEGFR2). The Phase 3 REACH study assessed Ram in the treatment of patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib. Ram was well tolerated. A significant improvement in overall survival (OS) in the overall population (N = 565) was not demonstrated (Hazard Ratio [HR] = 0.866; p = 0.1391). However, a meaningful improvement in OS was observed in the pre-specified subgroup of patients with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL (N = 250)(HR = 0.674; p = 0.0059) and warrants confirmation. Methods: REACH-2 is a randomized, double-blind, placebo-controlled phase III study of Ram and best supportive care (BSC) versus placebo and BSC in patients with HCC and elevated baseline AFP following prior therapy with sorafenib. Eligible patients will be randomized 2:1 to receive Ram (8mg/kg, IV) or placebo on Day 1 of each 14-day cycle until disease progression or other discontinuation criteria. Eligible patients must have a diagnosis of HCC (tissue or tumor with classical imaging characteristics); prior sorafenib; Child-Pugh score < 7; Barcelona Clinic Liver Cancer Stage C or Stage B disease not amenable/refractory to locoregional therapy; AFP ≥ 400 ng/mL; ECOG performance status < 2. Patients with history of encephalopathy, ongoing clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after sorafenib are not eligible. The primary objective is to assess the OS for patients treated with Ram versus placebo, and assumes an OS HR of 0.7 (85% power; 2 sided type I error 0.05). Target enrollment is 399 patients with the primary analysis at 318 events (20% censoring). Secondary objectives include progression free survival, objective response rate, safety, and patient focused outcomes. Additional objectives include assessment of biomarkers relevant to angiogenesis and HCC. Clinical trial information: NCT02435433.
Prospective phase I study of nab-paclitaxel plus gemcitabine with concurrent MR-guided IMRT in patients with locally advanced or borderline resectable pancreatic cancer.
Authors: Olsen Jeffrey R. , Parikh Parag J. , DeWees Todd A. , Olsen Lindsey , Hawkins William G. , Strasberg Steven M. , Lim Kian-Huat , Singh Preet Paul , Suresh Rama , Tan Benjamin R. , Ratner Lee , Fields Ryan C. , Amin Manik A. , Wang-Gillam Andrea
Published: February 2017

TPS480

Background: Radiotherapy (RT) for locally advanced and borderline resectable pancreatic cancer (LABPC) is controversial as potential local control benefits are often obscured by high rates of distant progression. However, local failure remains a significant cause of morbidity among patients without distant progression after initial chemotherapy, although toxicity concerns may limit delivery of optimal systemic therapy concurrent with RT. Given known systemic efficacy and radiosensitization effects of nab-paclitaxel (A) with gemcitabine (G), we initiated a phase I study of nab-paclitaxel with gemcitabine (AG) and concurrent intensity modulated radiation therapy with magnetic resonance guidance (MR-IMRT) for LABPC. Methods: A planned 24 patients with LABPC will be enrolled to a phase I dose escalation trial using the Time-to-Event Continual Reassessment Method (TITE-CRM) design. Following one lead-in cycle of GA, MR-IMRT is administered daily with concurrent weekly GA for a total of 25 fractions in 5 weeks. The initial dose levels for RT and AG, respectively, are: 40 Gy MR-IMRT, 75 mg/m2 A and 600mg/m2 G. The maximum possible dose level is 60 Gy MR-IMRT, 100mg/m2 A and 1000mg/m2 G. To reduce toxicity risk, MR-IMRT volumes include the primary tumor only, with cine-MR used for intra-fraction tumor tracking in place of fiducial markers. The primary endpoint is determination of the maximum tolerated dose level, with secondary endpoints including rate of conversion to resectable disease, progression- free survival, overall survival, and patient reported quality of life. Clinical trial information: NCT02283372.
Cisplatin plus irinotecan in the treatment of gallbladder or biliary tract cancer: A randomized phase II trial (NCT01859728).
Authors: dos Santos Lucas Vieira , Ferraz MauriÂcio Wagner Souto , Lima Joao Paulo , Abdalla Kathia Cristina
Published: February 2017

TPS485

Background: Gallbladder and biliary tract cancer (GBTC) have an aggressive behavior and gemcitabine-platinum chemotherapy emerged as the new standard of care for advanced or metastatic GBTC. Despite optimal management, prognosis is still poor. This randomized trial aims to compare irinotecan plus cisplatin versus gembitabine plus cisplatin in advanced or metastatic GBTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic carcinoma of GBTC (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent are stratified by ECOG (0 or 1 vs 2) and hematogenic metastases (yes vs no) and randomized to receive Irinotecan 65mg/m² D1 and D8 q21 days plus Cisplatin 60mg/m² D1 q 21 days (IP) or Gemcitabine 1000mg/m² D1 and D8 every 21 days plus cisplatin 25mg/m² D1 and D8 every 21 days (GC), until disease progression or unacceptable toxicity, with standard hydration and antiemetics. Computed tomography for response evaluation is undertaken every 6 weeks. The primary end-point is overall response rate (ORR). Assuming p0 = 25%, p1 = 50%, alpha = 5% and beta = 20% in an optimal Simon’s two stage design, 24 patients per arm will be recruited (N1 = 9; R1 = 2; Ntot = 24; Rtot = 9). The sample size for each arm was calculated separately. Secondary end-points are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), quality of life and safety. This clinical trial was activated in January 2013 and the accrual period is expected to end by December 2017. This protocol was approved by institutional review board. Clinical trial information: NCT01859728.
Regorafenib in metastatic colorectal cancer: An exploratory biomarker trial.
Authors: Salem Mohamed E. , Petricoin Emanuel , Wellstein Anton , Pierobon Mariaelena , Wang Hongkun , Mikhail Sameh , Hartley Marion L. , Smaglo Brandon George , Lou Emil , Alistar Angela Tatiana , Dorsch-Vogel Karen , Pishvaian Michael J. , He Aiwu Ruth , Kim Alexander Y. , Shivapurkar Narayan , Reddy Sandeep K. , Marshall John
Published: February 2017

TPS773

Background: Treatment with Regorafenib (REGO) has shown significant clinical benefits in metastatic colorectal cancer (mCRC) patients (pts) as demonstrated in the CORRECT and CONCUR trials. Results from both studies suggest that subgroups have differential responses. Further research to identify these subgroups through the identification of molecular biomarkers is needed. Methods: Forty pts with refractory mCRC are being enrolled in this study. The primary objective is to prospectively identify tissue and serum-based biomarkers that can predict response to REGO. Secondary objectives are to determine molecular mechanisms by which REGO controls refractory mCRC, as well as molecular pathways involved in the acquisition of resistance. Tumor and blood samples are obtained prior to and 2 weeks after starting REGO. Blood samples are collected on day 1 of each cycle thereafter. Pts will receive 160 mg REGO daily for 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Multi-omic based biomarker discovery approaches will be used to uncover predictive marker candidates with special attention to the tumor microenvironment. Laser capture microdissection will be used on tumor tissue to procure highly enriched populations of pt-matched epithelial and stromal/immune cell infiltrates. Each of these entities will be analyzed for RNA expression changes and protein signaling/drug target activation mapping. Protein signaling analysis will be performed by reverse phase protein array of key REGO-related proteins and phosphoproteins (e.g. phosphoVEGFR, Tie2, phosphoRET), as well as broad-scale mapping of mitogenic, survival, autophagy, inflammatory, motility, and signaling networks. Tumor profiling will include next-generation sequencing for 592 genes with 53 selected gene fusions, and IHC and FISH/CISH for selected biomarkers, including PDL1, HER2, MSI, TS, ERCC1, and TOPO1. Blood samples will undergo protein, miRNA, and mutated DNA analysis, as well as exosomal signature study via a proprietary synthetic polyligand multiplexed aptamer-based assay. Exploratory analysis of biomarkers will be used to determine correlations between the presence of, or change in, biomarker levels and clinical response. Clinical trial information: NCT01949194.
Capecitabine maintenance therapy after adjuvant chemotherapy of FOLFOX (or XELOX) in patients with stage IIIC or R0 resected stage IV colorectal cancer (CAMCO study).
Authors: Ling Jiayu , Wang Wenjing , Li Shanshan , Cai Yue , Hu Huabin , Deng Yanhong
Published: February 2017

TPS781

Background: Surgical resection and adjuvant therapy has become the main treatment for resectable colorectal cancer (CRC). Treatment with current strategies, however, recurrent rate is high for stage IIIc or R0 resected stage IV CRC (high risk-CRC). For some other maglinancies with high risk of recurrence, such as gastric cancer or high-risk gastrointestinal stromal tumor, longer period of postoperative chemotherapy was applied. The effectiveness of maintenance therapy following standard adjuvant chemotherapy in high risk-CRC has not been verified in clinical trial. Capecitabine is is an orally-administered chemotherapeutic agent used in the treatment of CRC, either as neoadjuvant therapy with radiation, adjuvant therapy or for metastatic cases. This study is exploring the efficacy and safety of strategy of surgical resection and adjuvant chemotherapy followed by maintenance capecitabine for stage IIIC or R0 resected stage IV CRC. Methods: The study was designed as an open-label phase II trial with 200 patients assigned to two thearapy group: experimental arm A (Adjuvant chemotherapy with mFOLFOX6 or XELOX for more than four months + oral capecitabine 1000mg/m2 twice daily days1-14 every 3 weeks for 12 months maintenance) or standard arm B (Adjuvant chemotherapy with mFOLFOX6 or XELOX for more than four months + observation). Eligibility included patients of 18-80 years of age, diagnosis of adenocarcinoma of the colon or rectum, received curative resection when diagnosed, with postoperative stage of IIIC OR IV(R0 resected), PS 0-1 and adequate organ function. Doses were modified for hand-foot syndrome, diarrhea and other grade 3 toxicities. The primary aim is to evaluate the 3 year disease free survival of the patients. Secondary aims inclued overall survival, safety, quality of life and an assessment of predictive molecular markers of maintenance strategy. After completion of adjuvant treatment, patients are followed every 3 months for 2 years, and then every 6 months for 3rd-5th years. This study is now open to accrual in The Sixth Affiliated Hospital of Sun Yat-sen University. Clinical trial information: NCT01880658. Clinical trial information: NCT01880658.
Addressing patient needs through compilation of self-reported verbatim comments.
Authors: Hartman Scott , Denny Diane , Hizon Sarah , Kendrick Danielle , Markman Maurie
Published: February 2017

111

Background: Cancer Treatment Centers of America, Inc. (CTCA) is a national network of five hospitals that specialize in the treatment of patients fighting complex or advanced-stage cancer. The Symptom Inventory Tool (SIT) is an assessment that captures the patients’ perceived symptom burden, from baseline and every 21 days thereafter. The SIT is comprised of questions utilizing the M.D. Anderson Symptom Inventory tool, with eight questions and a free text box added by CTCA. Patient comments are provided in approximately 5% of all assessments (representing 3,700 comments) since initiation of the SIT. Methods: Patients answer the question, “Is there anything else that you would like to tell us or are there additional concerns you would like addressed?” within a free text field. In addition to availability to the care team to address any identified urgent need, each comment is classified into 15 defined categories to allow trending. The report is disseminated monthly to a multi-disciplinary team for follow-up on service delivery and consideration in program development. Results: The table represents the top five patient comment categories along with “other”. In addition, a sample of last quarter's data revealed that 84% of comments required immediate follow-up that may have otherwise been missed without text data mining. Conclusions: Verbatim comments are of significant value and can be best managed via dual processes to ensure timely follow-up and to support programmatic alignment, continuously analyzing data for areas of improvement. [Table: see text]
An approach to implementing meaningful change in a provincial health care system.
Authors: Ang Michelle , Lockhart Elizabeth , Brundage Michael Donald , Hart Margaret , Hartman Mark , Foxcroft Sophie , Reddeman Lindsay Elizabeth , Simniceanu Carina , Mendelsohn Marissa , Favell Lisa , Wang Jonathan , Meertens Elaine , Gutierrez Eric , Warde Padraig Richard
Published: February 2017

120

Background: Radiation treatment (RT) is essential to cancer management, contributing to cure and symptom control. With increasing cancer incidence and treatment complexity, health systems must adapt to ensure patients (pts) receive the highest quality of care. Methods: With the objective of ensuring equitable access to high-quality, safe care, Cancer Care Ontario (CCO), a provincial government agency, identified provincial variability in RT activities. As a result, CCO prioritized 3 quality initiatives over the past 7 years: 1) Access to Intensity Modulated RT (IMRT) (2008-2013); 2) Peer Review of RT plans due to increasing RT planning complexity and the existence of high-profile RT errors (2012-present); and 3) Ensuring equitable access to RT (RT Utilization) (2014-present). Strategic plans were developed using change management framework adapted from the Kotter process for leading change (Kotter, JP. Harvard Bus Rev 73:59-67, 1995). In each initiative, CCO created a climate for change, engaged the provincial RT community to move priorities forward, and worked to sustain achieved gains. Results: CCO found that building a project team, communicating a clear understanding of goals and objectives, providing sufficient resources to cancer centres, and public reporting of results were key contributing success factors. IMRT project: Currently in sustainability phase. IMRT rates increased from 20% in 2008/09 - full implementation and target attainment in 2012/13. Public reporting continues. Peer Review of RT plans: Currently moving from engagement to implementation phase. Increase from 44% of RT cases undergoing peer review in 2013/14 to 68% in 2014/15. RT Utilization Project: Currently in engagement phase. Provincial shortfall of 11% in annual RT rates correlates to roughly 2500 pts who do not receive RT as needed. Engaging data experts and consulting with regional administrators, RT utilization is the current change priority for CCO’s RT program. Conclusions: These projects demonstrate the possibility of using change management practices to achieve quality improvement in healthcare. Ongoing work continues to ensure that pts in Ontario receive the highest quality cancer care.
Choosing Wisely: Opportunities for improving value of cancer care in the Deep South.
Authors: Pisu Maria , Rocque Gabrielle Betty , Kenzik Kelly , Jackson Bradford E. , Li Yufeng , Acemgil Aras , Taylor Richard A. , Salter Terri , Partridge Edward E.
Published: February 2017

13

Background: Under the Choosing Wisely (CW) Campaign, the American Society of Clinical Oncology (ASCO) and the American Society of Therapeutic Radiology and Oncology (ASTRO) recommend against non-evidence-based costly medications, tests, and procedures. CW recommendation adherence in the Deep South is largely unknown, and opportunities to reduce overuse and costs may exist. Methods: Analysis of administrative claims and tumor registry data from 12 cancer centers of the University of Alabama Health System Cancer Community Network, for Medicare beneficiaries ≥65 years old with cancer. Main outcome: percent of beneficiaries adhering to 9 CW recommendations. Results: 2012-2015 (Q1) adherence varied across CW recommendations and cancer centers, and increased over time for CW 2 and 7, decreased for 3, 5, and 6, and did not change for others. Conclusions: Opportunities to improve quality and value of cancer care exist in the Deep South. Research should understand how to minimize use of non-evidence based medications, tests, and procedures. [Table: see text]