bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of dementia diagnosis on receipt of postoperative colon cancer chemotherapy.
Authors: Chen Yingjia , Semrad Thomas John , Cress Rosemary Donaldson , Beckett Laurel A.
Published: February 2017

769

Background: Colon cancer and dementia have a high risk of co-occurrence. Prior studies found that patients with dementia have higher mortality than non-demented counterparts, mostly from non-cancer causes. We hypothesized that a dementia diagnosis using an improved algorithm would be associated with reduced use of postoperative therapy. Methods: In addition to the claims-based algorithm for dementia published by Centers for Medicare and Medicaid Services that uses SEER-Medicare Medicare Provider Analysis and Review, Carrier Claims, Home Health Agencies, and Outpatient files, we developed a medication-based algorithm using the part D file based on prescription for any of the five FDA-approved dementia drugs (donepezil, galantamine, memantine, rivastigmine, tacrine). We measured agreement between the two diagnostic algorithms with k-statistics. Using each algorithm and a final combined algorithm, we used multivariable logistic regression adjusting for demographics and disease characteristics to examine the effect of dementia on the use of post-operative colon cancer chemotherapy. Parallel analyses restricted the population to later-stage cancer patients (stage III/IV). Results: 46,126 patients diagnosed between 2007 and 2009 were identified. 20% had dementia by either of the algorithms. 9% of the dementia cases were identified through Part D data. The two algorithms showed moderate agreement (k>0.49, p=0.007). After surgery, those patients with dementia by the combined algorithm were less likely to receive chemotherapy (OR = 0.641, 95% CI: 0.597-0.688). Those with dementia identified by part D data were even less likely to receive chemotherapy than those identified by the claims algorithm (OR=0.617, 95% CI: 0.466-0.816 for medication; OR=0.767, 95% CI: 0.684-0.860 for claims). A similar pattern was detected when restricting to stage III/IV patients (OR=0.667, 95% CI: 0.457-0.973). Conclusions: Part D data increases the sensitivity for identifying dementia cases in SEER-Medicare. Patients with dementia are significantly less likely to receive post-operative chemotherapy. Thus, reduced postoperative colon cancer therapy among patients with dementia may contribute to higher cancer-related mortality.
Prophylactic use of oral dexamethasone (DEX) to alleviate fatigue during regorafenib (REG) treatment for patients with advanced colorectal cancer (aCRC).
Authors: Fukuoka Shota , Shitara Kohei , Noguchi Masaaki , Kawazoe Akihito , Kuboki Yasutoshi , Bando Hideaki , Okamoto Wataru , Kojima Takashi , Doi Toshihiko , Ohtsu Atsushi , Yoshino Takayuki
Published: February 2017

774

Background: Regorafenib (REG) is an oral multi-kinase inhibitor which demonstrated significant overall survival (OS) benefit for patient with advanced colorectal cancer (aCRC). Fatigue is the most common toxicity in all grade associated toxicity with REG, which is one of major reasons for early dose modification. On the other hand, recent study suggested that dexamethasone (DEX) improve the cancer associated fatigue. Methods: We retrospectively analyzed the effect of prophylactic use of oral DEX on fatigue during REG treatment for patients with aCRC. Ninety-three patients who received REG in our institution between May 2013 and June 2014 were divided into two groups according to use of oral DEX (2 mg per day; by investigator’s discretion). Outcomes measured in this study were a time to dose modification, incidences of toxicities, and anti-tumor effects. Results: Prophylactic DEX was administrated in 24 patients (DEX group) with regorafenib, and 69 patients received REG alone (no DEX). There were no significant differences in baselinepatient characteristics between 2 groups including starting dose of REG (79.1% in DEX and 84.1% in no DEX started with 160 mg/day). Time to dose modification was significantly longer in DEX than in no DEX (15 vs. 9 days; p=0.009). Incidence of fatigue (grade>1) was lower in DEX (25%) than no DEX (43%) by 18%, although the difference was not statistically significant (p=0.11). Fewer patients experienced decreased appetite (grade>1) with DEX than no DEX (4.2 vs. 33.3%; p=0.005) as well as hand foot skin reaction (grade>3; 0 vs. 27.5%, p=0.02). In contrast, the frequency of oral candidiasis, which was improved within 1 week, was higher in DEX group (14.3% and 0%; p=0.001). Disease control rate (45.8 vs. 36.2%), progression-free survival (median, 2.1 vs. 1.8 months) and OS (median, 7.6 vs. 6.0 months) were almost compatible between DEX group and no DEX. Conclusions: Although the incidence of fatigue was not significantly decreased by use of DEX, it prolonged time to dose modification of REG in our preliminary analysis. Decreased incidence of appetite loss and HFSR also suggest that concurrent DEX with REG warrants further investigation.
Efficacy and safety of capecitabine plus oxaliplatin (XELOX) as the perioperative treatment of patients with potentially resectable liver-only metastases from colorectal cancer: A single arm, open-label, multicenter phase II trial (ML22298; NCT00997685).
Authors: Lin Feng , Li Guoxin , Chu Zhonghua , Hao Chunyi , Chen Mingqing , Jiang Zhiwei , Chen Huanqiu , Lin Jianjiang , Li Dechuan , Hu Bing , Wang Xishan
Published: February 2017

777

Background: Surgical resection can improve survival of patients with resectable colorectal liver metastases (CLMs). Here, we investigatedthe efficacy and safety of XELOX as perioperative treatment for patients with potentially resectable CLM. Methods: Patients with potentially resectable liver-only metastases from CRC were enrolled. The primary endpoint of this study was progression-free survival (PFS); and the secondary endpoints included objective response rate (ORR), R0 resection rate, overall survival (OS) and safety profile of perioperative treatment of XELOX. Eligible patients were treated with XELOX (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 b.i.d. for 14 days every 3 weeks). Tumor remission was assessed by CT after 6 weeks (2 cycles) of chemotherapy. Resectability of CLM was assessed by CT after 12 weeks (4 cycles) of chemotherapy. Adjuvant chemotherapy using XELOX was started within 8 weeks after hepatectomy. Results: Thirty patients (17 males and 13 females) were enrolled from 10 medical sites between January 2010 and October 2011, with median age of 57.5 years (range: 32-77). Median PFS was 336 days (95% CI: 173~385), and median OS was 912 days (95% CI: 516~1332). The ORR was 40% (12/30). The conversion rate from unresectable to resectable was 43.3% (13/30). Among these 11 patients who had received surgery (2 had withdrawn consent), 10 (90.9%) had received R0 resection. Subgroup analysis shows that patients who had received hepatectomy had longer median PFS [95% CI] (382 days [210~518] vs. 173 days [111~337], p = 0.0268) and median OS [95% CI] (1332 [721~NA] vs. 516 [295~1046], p = 0.005). There were 4 patients with post-operation complications of ascites and/or hydrothorax, and 3 patients had early chemotherapy termination due to drug-related AEs, including leukopenia, hepatotoxicity and diarrhea. Conclusions: Perioperative chemotherapy of XELOX is an option for patients with potentially resectable CLM due to the effect in prolonging PFS and OS, as well as the manageable toxicities and post-operation complications. Clinical trial information: NCT00997685.
Management tips for the low incidence, of adverse events and well efficacy of regorafenib for metastatic colorectal cancer in Juntendo University Medical Hospital.
Authors: Higashihara Yoshie , Serizawa Nobuko , Kato Junko , Kodani Tomohiro , Osada Taro , Nagahara Akihito , Watanabe Sumio
Published: February 2017

778

Background: Regorafenib is an oral multi-kinase inhibitor that has demonstrated significant overall survival for metastatic colorectal cancer in CORRECT study. In the Japanese subset of CORRECT study, adverse events (AEs) such as hand-foot skin reaction (HFSR), anorexia, and liver dysfunction occurred at high frequency. Therefore, those AEs were one of the causes for treatment discontinuation. Methods: We retrospectively analyzed the safety and efficacy in 14 patients who received regorafenib monotherapy in our hospital between June 2013 and August 2014. Results: Among the 14 patients, median age was 64.5 years old (range 53-76). Median follows up time was 209 days (range 72-340), median PFS was 64 days (range 19-272), and median TTF was 66.5 days (range 18-280). There was no patient who had complete or partial response. The disease control rate was 36%. Nine patients initiated with 160 mg of regorafenib once daily, 4 patients with 120 mg, and one patient with 80 mg. The most common grade 3 or more AEs were HFSR, AST and ALT elevations and hypertension (2 patients, 14.2%, respectively). The frequency of HFSR was lower in our cohort the Japanese patients of CORRECT study. Treatment discontinuation due to drug related AEs occurred to 5 patients (35.7%). Dose reduction and interruption of regorafenib were required in 10 patients (71.4%) and 8 patients (57.1%), respectively. For prevention of HFSR, more than 90% of the patients were received proactive treatment including heparinoid and strong steroid from the start of the therapy. We carefully monitored their toxicities every week during the first cycle, and chose interruption if patients were had more grade 2 AEs. It is very important, we think to give the patients instructions on possible AEs and how to manage them using an illustrated book. Conclusions: Our cohort had lower HFSR in frequency than and similar efficacy to the Japanese subpopulation in CORRECT study. Enough explanation and instruction to patients might be important to decrease an incidence of AEs and treatment discontinuation due to drug- related AEs. We will increase the number of cases and examine in future.
Strategy for cStage4 colorectal cancer: Chemotherapy or resection of primary tumor?
Authors: Iwamoto Shigeyoshi , Hamada Madoka , Oishi Masaharu , Sakaguchi Tatsuma , Michiura Taku , Inoue Kentaro , Kwon A-Hon
Published: February 2017

779

Background: It is controversial that the primary tumor must be removed prior chemotherapy in cStage4 colorectal cancer, because some cases prognostic factor were metastatic sites. We report cases of cStage4 colorectal cancer which were underwent intrensive chemotherapy prior the primary tumor resection. Methods: 190 cases of metastatic colorectal cancer were treated by L-OHP based chemotherapy plus bevacizumab/cetuximab/panitumumab in September 2007 to June 2012. 56 cases were treated by intensive chemotherapy prior primary tumor resection, and 44 cases were underwent surgical resection of primary tumor after evaluation of chemotherapy response. Results: 38/10/8 cases were treated by bevacizumab/cetuximab/panitumumab with L-OHP combined therapy as intensive treatment. 30 patient with obstructed primary lesion were underwent stoma surgery (53.6%). Evaluable lesions except primary lesion were liver (50.0%), lung (12.5%), LNs (33.9%). Response rate of chemotherapy were 67.9% (PR/NC/PD: 38/14/4), and 44 cases were performed resection of primary lesion in PR and SD cases. Pathological G2 and G3 response in resected primary lesion were 18.4% (G1a/G1b/G2/G3:17/18/8/2). A GI perforation and bowel obstruction in chemotherapy and 3 cases of anastomotic leakage and 6 cases of SSI in perioperable period were observed respectively. Conclusions: It is seemed to contribute improvement of QOL and local control that start with systemic chemotherapy prior primary lesion resection, therefore some cStage4 cases were difficult to R0 resection also primary lesion and systemic chemotherapy could be reduced symptom with metastatic sites. Only 18.4% of the resected primary tumor were G2/3 pathological response by systemic chemotherapy, on the other hand preoperative chemo-radiation in rectal cancer accomplished 67.3% of G2/3 pathological response (in house data). The end-point of therapy in stage 4 colorectal cancer patient are QOL and prolong survival, and should be selected treatments depending on the patient condition.
Analysis of the GERCOR index in KRAS Exon2 WT patients with mCRC treated with salvage-line cetuximab-based chemotherapy: HGCSG0901.
Authors: Hosokawa Ayumu , Yuki Satoshi , Nakatsumi Hiroshi , Hatanaka Kazuteru , Tsuji Yasushi , Okuda Hiroyuki , Takahashi Yasuo , Konno Jun , Eto Kazunori , Kawamoto Yasuyuki , Sonoda Norikazu , Sato Yasushi , Saito Mayuko , Miyagishima Takuto , Ikeda Shinichiro , Yoshizaki Koji , Sasaki Takahide , Saitoh Soh , Sakata Yuh , Komatsu Yoshito
Published: February 2017

781

Background: The GERCOR index (GI) based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, in the salvage setting, the validity of the GI has not been reported in patients treated with cetuximab (Cmab)-based chemotherapy. Methods: 269 patients with mCRC treated with Cmab contained chemotherapy were retrospectively registered from 27 centers in Japan. This analysis was included in the KRAS Exon2 wild type patients who were refractory to or intolerant of 5-FU / irinotecan/ oxaliplatin and were never administered anti-EGFR-antibody. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 132 patients. Median OS and PFS were 9.8 and 4.3 months. The distribution and median OS / PFS for GI were as follows: low risk (L)(n = 28; 17.9/3.8 months), intermediate risk (I)(n = 52; 12.2/5.0 months), and high risk (H)(n = 52; 7.5/4.1 months). For OS, there was significant difference between L and H (p < 0.001) and between I and H (p < 0.001), but not between L and I (p = 0.076). For PFS, there was significant difference between I and H (p = 0.017), but not between L and I (p = 0.407), and between L and H (p = 0.222). In the Cox multivariate analysis, GI showed an independent prognostic impact (L vs. I ; HR 2.195, p=0.003 / L vs. H ; HR 4.028, p<0.001), but not predictive impact (L vs. I ; HR 0.987, p=0.958 / L vs. H ; HR 1.314, p=0.268). Conclusions: In this analysis, GI might be a prognostic factor in salvage treatment with Cmab-based chemotherapy.
Factors affecting chemotherapy use and delay (≥ 8 weeks) after colorectal cancer surgery and the impact of chemotherapy delay on survival.
Authors: Kim Ik Yong , Kim Young Wan
Published: February 2017

784

Background: To date, reasons for adjuvant chemotherapy (AC) omission and delay have not been extensively studies. This study aimed to evaluate factors affecting chemotherapy use and delay (≥8 weeks) after colorectal cancer surgery and their impact on survival. Methods: Between 2008 and 2013, consecutive 584 patients undergoing major resection for stage II and III colorectal cancer in a single tertiary referral center. Results: Among 584 patients with stage II and III diseases, AC was performed in 460 (78.8%) patients. Regimens included fluorouracil with folinic acid (n=257, 55.9%), FOLFOX (n=134, 29.1%), capecitabline (n=62, 13.5%), and tegafur-uracil (n=7, 1.5%). Factors affecting not receiving AC were older age (>80 years), American Society of Anesthesiologists score (≥3), presence of postoperative complication, and not receiving preoperative chemoradiation. Overall survival was 87.2% (AC +) and 58.5% (no AC, p<0.001) in stage II disease, and 79.5% (AC +) and 24.6% (no AC, p<0.001) in stage III disease, respectively. Recurrence-free survival was 83.7% (AC +) and 61.9% (no AC, p=0.003) in stage II disease, and 60.5%(AC +) and 21.8% (no AC, p<0.001) in stage III disease, respectively. Among 460 patients undergoing AC, AC was initiated within 8 weeks in 438 patients (95.2%) and after 8 weeks in 22 patients (4.8%). Factors affecting AC delay were male gender, rectal primary, intraoperative blood loss (>100ml), and presence of postoperative complications. Overall survival was 90.8% (AC +) and 40.0% (no AC, p=0.111) in stage II disease, and 82% (AC +) and 35.6% (no AC, p=0.275) in stage III disease, respectively. Recurrence-free survival 80.1% (AC +) and 54.5% (no AC, p=0.133) in stage II disease, and 64.4% (AC +) and 0.0% (no AC, p=0.014), respectively. Conclusions: In stage II, III patients, it appears that use of AC is more closely related patient’s survival rather than the time of AC initiation. To improve oncologic outcomes after curative resection, it is important to increase the proporation of AC use.
Oxaliplatin rechallenge in patients with metastatic colorectal cancer prior treatment with oxaliplatin.
Authors: Kim Jeong-Eun , Hong Yong Sang , Kim Kyu-Pyo , Park Seong Joon , Lee Jae-Lyun , Kim Tae Won
Published: February 2017

785

Background: With limited number of available cytotoxic agents for the treatment of metastatic colorectal cancer (mCRC) patients (pts), rechallenge of chemotherapy can be considered for continuum of treatment. We investigated the efficacy and feasibility of oxaliplatin rechallenge in mCRC pts who have been already exposed to prior oxaliplatin-based chemotherapy. Methods: mCRC pts, who were re-treated with oxaliplatin-based chemotherapy as second or later line treatment in the presence of evaluable disease, were retrospectively accrued. Only those who remained disease-free or progression-free at least 6 months after the last dose of prior oxaliplatin were included. Results: Between January 2009 and May 2014, 110 pts were retreated with oxaliplatin-based regimen; 42 (38.2%) patients received prior oxaliplatin as adjuvant chemotherapy and 68 (61.8%) as palliative chemotherapy. Median disease-free or progression-free duration after prior oxaliplatin was 15.4 months (range, 12.9-17.6 months). All of them received oxaliplatin rechallenge in combination with fluoropyrimidines. The overall response rate to the oxaliplatin rechallenge was 30.9% (34/110), and the disease-control rate was 68.2% (75/110) with 1 complete response, 33 partial responses, and 41 stable diseases. Median progression-free survival and overall survival with rechallenge of oxaliplatin-based therapy were 5.9 months (95% CI, 4.6-7.2 months) and 19.7 months (95% CI, 11.9-27.5 months), respectively. Grade 2 or 3 neuropathy was observed in 16 patients. Any grade hypersensitivity reaction was observed in 10 patients within 4 cycle of treatment. Among them, 6 patients stopped treatment due to grade 3 or 4 hypersensitivity reaction. Conclusions: Rechallenge of oxaliplatin-based therapy could be a treatment option in patients who achieved at least 6 months of disease-free or progression-free survival with prior oxaliplatin-based chemotherapy, especially in those who have lack of further treatment option with good performance status. However, neurotoxicity and hypersensitivity reaction should be cautiously monitored in this setting.
Identification of the gastric microbiome from endoscopic biopsy samples using whole genome sequencing.
Authors: Zhang Chao , Cleveland Kyle , Schnoll-Sussman Felice , McClure Bridget , Bigg Michelle , Thakkar Prashant , Schultz Nikolaus , Pamer Eric G. , Betel Doron , Shah Manish A.
Published: February 2017

8

Background: H. pylori is the primary risk factor for gastric cancer (GC). However, virtually all infected patients do not develop GC, and H. pylori eradication does not reduce GC risk. We established a whole genome sequencing (WGS) pipeline to detect the gastric microbiome from small endoscopic samples directly. With it, we are not only be able to accurately detect H. pylori infection in GC, but also examine the microbiome in samples from other malignancies. Methods: Patients (pts) undergoing upper endoscopy without chronic inflammatory disease or chronic NSAID use were eligible for participation, categorized as follows: (1) active infection (H. pylori identified on biopsy, or positive CLOtest), (2) prior infection (previous H. pylori treatment, or ELISA IgG positive), and (3) gastric cancer. Endoscopic biopsies from 3 locations in the antrum/body were freshly frozen for WGS on a HiSeq2500 platform at ~10X coverage. Our customized computational pipeline successively removes human sequences, with remaining un-mapped reads aligned to 1,400 unique bacteria genomes. Results: 16 biopsy samples taken from 10 pts were sequenced. All H. pylori positive samples detected by our pipeline have been successfully validated by qPCR. Surprisingly, H. pylori was identified in previously treated pts. We also applied our pipeline to control samples to evaluate the performance of bacterial identification. Negative sample are blood samples from HapMap projects with human DNA only. In contrast, positive samples are bacteria enriched samples from Human Microbiome Project. Our identifications matched the previously reported results. Finally, we profiled 37 gastric cancer tumors and matching normal WGS samples from TCGA and found that 40% of them are H. pylori positive. This result is a novel discovery that was not reported in the TCGA GC study. Conclusions: This is the first demonstration of detailed unbiased microbiome detection performed from gastric endoscopic biopsy samples using WGS. We found that standard treatment does not always eradicate H. pylori possibly explaining why H. pylori treatment fails to reduce cancer risk. We also found that ~40% of gastric cancers have evidence of persistent H. pylori bacterial content.
A phase II trial of cabozantinib (XL-184) in patients with advanced cholangiocarcinoma.
Authors: Goyal Lipika , Yurgelun Matthew B. , Abrams Thomas Adam , Kwak Eunice Lee , Cleary James M. , Knowles Michelle , Regan Eileen , Gisondi Amy , Sheehan Susan , Zheng Hui , Zhu Andrew X.
Published: February 2017

800

Background: Cholangiocarcinoma (CCA) carries a poor prognosis in advanced stages, and no standard treatment exists beyond the first line gemcitabine/platinum based combination regimen. Based on preclinical evidence of dysregulation of the VEGF and c-MET pathways in CCA, we performed a single arm phase II study of the dual VEGF receptor and c-MET small molecule inhibitor cabozantinib in patients with advanced CCA. Methods: All eligible pts had histologically confirmed unresectable or metastatic CCA and had progressed after 1 or 2 lines of systemic therapy. Pts were treated with cabozantinib 60mg orally daily continuously for 28 day cycles. Tumor assessments were obtained radiologically every 8 weeks. The primary endpoint was progression free survival (PFS). A Simon two stage design was used, and 9 of 20 pts had to be progression free at 16 weeks in order to proceed to the second stage. Results: Nineteen pts (male 32%; median age 67 years old; intrahepatic vs extrahepatic CCA, 95 vs 5%; 1 vs 2 previous lines of systemic therapy, 53% vs 47%%) were enrolled and all received at least one dose of study drug. After 12 pts failed to be progression free at 16 weeks, the study was terminated as it was determined that the criterion for proceeding to stage 2 could not be met. The median follow-up was 4.07 months (mos). No objective responses were seen. The median PFS was 1.77 mos (95% CI, 1.63-5.37), and the median overall survival was 5.20 mos (95% CI, 2.70-8.17). Eleven (58%) patients required dose reductions. Grade 3 and 4 adverse events occurred in 79% of pts and included neutropenia, epistaxis, hyperbilirubinemia, alkaline phosphatemia, AST/ALT elevation, anemia, lipasemia, and hypertension. One pt had a bowel perforation and another developed an enterocutaneous fistula while on the study drug. VEGF and c-MET pathway-related biomarker analysis is ongoing. Conclusions: Cabozantinib demonstrated limited antitumor activity in an unselected population of pts with advanced CCA. Despite close monitoring, a high rate of > grade 3 toxicities was observed at 60 mg daily dosing. This pt population may be more sensitive to drug doses tolerated by other solid tumor patient populations, and therefore, close monitoring remains critical for these pts in early phase clinical trials. Clinical trial information: NCT01954745.
Preoperative serum VEGF-A levels to predict survival for Caucasian and Asian patients undergoing resection for gastric adenocarcinoma.
Authors: Park Do Joong , Yoon Changhwan , Ku Geoffrey Yuyat , Coit Daniel G. , Strong Vivian E. , Yang Han-Kwang , Kim Hyung-Ho , Suh Yun-Suhk , Yoon Sam S.
Published: February 2017

81

Background: Clinical trials in gastric adenocarcinoma (GC) patients of vascular endothelial growth factor A (VEGF-A) targeted therapies have suggested these therapies may be more effective in Caucasians (CA) than in Asians (AS). Methods: Levels of VEGF-A in serum were measured in CA and AS treated at two institutions prior to potentially curative surgical resection for GC, and levels were correlated with overall survival (OS). Results: There were significant differences in CA (n=118) and AS (n=115) in terms of age (median 66 vs. 59), use of neoadjuvant (52% vs. 14%) and adjuvant therapy (27% vs. 18%), tumor location (58% upper/GE junction vs. 80% distal/middle), Lauren classification (57% vs. 46% intestinal), and TNM status (65% stage II or III vs. 55% stage I). CA had a median VEGF-A levels that was 95% higher than that of AS as well as a much higher standard deviation (88.1 + 6206 vs. 45.2 + 76.3 pg/ml, p<0.001). CA with proximal/nondiffuse tumors had significantly higher VEGF-A levels than those with distal/nondiffuse or diffuse tumors (median 120 vs. 71 and 50 pg/ml; p=0.016). The 5-year OS for CA with low vs. high VEGF-A levels was 72.4% vs. 43.4% (p=0.001). In AS, there was no significant difference in 5-year OS according to VEGF-A level (77.4%% vs.85.6%, p=0.236). On multivariate analysis, tumor size, location, grade, N stage, and serum VEGF-A level were independent predictors of OS in CA. Conclusions: In patients with resectable GC, higher circulating VEGF-A levels are independently associated with decreased OS in CA but AS, suggesting varying importance of this angiogenic factor in GC progression among different races.
Her2 expression in gastroesophageal cancer (GEC) FFPE tissue using mass spectrometry (MS) and correlation with HER2 gene amplification.
Authors: Catenacci Daniel Virgil Thomas , Zhao Lei , Whitcomb Emma , Henderson Les , O'Day Emily , Xu Peng , Xiao Shu-Yuan , Lee Sang Mee , Liao Wei-Li , Thyparambil Sheeno P , Uzzell Jamar , Darfler Marlene , Krizman David , Burrows Jon , Hembrough Todd A.
Published: February 2017

82

Background: HER2+ GEC derived benefit from trastuzumab. Her2 IHC is semi-quantitative, subjective, and sensitive to antigen instability; HER2 FISH is laborious, expensive, and subjective. False positivity/negativity have been described. Also, these are low throughput assays; there is known molecular heterogeneity, with several putative biomarkers, and only scarce tissue to assess for each. We sought to evaluate the association of Her2 MS expression with HER2 FISH, along with other markers within the ‘GEC-plex’. Methods: We utilized a previously described unique Her2 peptide and quantification method (Hembrough et al J Clin Oncol 32,2014(suppl 3;abstr17)). The assay was run on 27 cell lines, in parallel with HER2:CEP17 FISH. Her2 expression thresholds were established for HER2 amplification using ROC curves. We adjusted for Her3, Egfr, and Met MS expression levels and sample HER2:CEP17 ratio heterogeneity in a multiple linear regression model. The model/cut-offs were then validated prospectively on GEC tissues (n=142). Results: Her2 MS on cell lines revealed concordance with FISH (HER2:CEP17) ratio (R2=0.75), which improved by adjusting for Her3 MS, Egfr MS, Met MS and HER2:CEP17 heterogeneity (R2>0.98), with significant interactions. IHC correlation with HER2:CEP17 ratio was poor (R2=0.12). A wide range of expression was noted within IHC3+ patients (<150-24671amol/ug). Her2 MS expression (>150 amol/ug) was seen in 72.9% (102/142) of tissues (range <150-24671amol/ug); 9.9% (14/142) had Her2 > 750 amol/ug - all were HER2 FISH amplified. 6/142 (4%) cases <500 amol/ug were clinically ‘HER2amplified’. IHC/FISH results for cases with 550-750 amol/ug demonstrated an ‘equivocal’ zone, not unlike ‘IHC 2+’, but less frequent (8/142, 5.6% vs 46/142 32.4%). Conclusions: The MS HER2 assay can be multiplexed with other GEC biomarkers. A robust model was developed that showed strong correlation of Her2 MS with HER2:CEP17 ratio, particularly when adjusting for covariates Egfr MS, Met MS, Her3 MS, and HER2 FISH heterogeneity. Future analysis will assess the established model as a tool for better prediction of therapeutic benefit from anti-Her2 therapy compared to current methods.
Frequency of c-Met, HGF, and HER-2 expression and evaluation of their association with clinicopathologic and prognostic factors in gastric cancer.
Authors: Yalcin Suayib , Yildiz Yetkin , Sokmensuer Cenk
Published: February 2017

88

Background: Met and HER-2 are protoonkogenes encoding receptor tyrosin kinases c-Met and HER-2 respectively. HGF is c-Met’s ligand. We aimed to determine the frequency of c-Met, HGF and HER-2 overexpression in gastric cancer and investigated their association with clinicopathological factors and prognosis. Methods: Patients withstage 1-4 disease were analyzed. Overexpressions of c-Met, HGF and HER-2 were carried out with immunohistochemistry. Results: A total of 143 patients, 97 male 46 female were enrolled. C-Met score was 3(+) in 31.5%, 2(+) in 27.3% and 1 (+) in 10.5% of the patients. There was no statistically significant difference in age, sex, tumor location, differentiation, Lauren classification, TNM staging, presence of distant metastasis, depth of tumor invasion (T), lymphovascular invasion, and survival between c-Met subgroups. HGF positivity was 20.6%. HER-2 was 3(+) in 9.1%, 2(+) in 9.8%, and 1(+) in 16.1% of the patients. HER-2 overexpression was associated with better differentiation, intestinal subtype and advanced stage. C-Met overexpression was 84.6% in HER-2 overexpression positive group and 56,2% in HER-2 overexpression negative group. There was no statistically significant difference in survival between the c-Met overexpression positive and negative stage 3 and 4 patients and there was no statistically significant differences in survival between the HGF positive and negative groups. The median survival was 11.6±6.3 months in HER-2 overexpression positive stage 4 group and 11.9±6.8 months in HER-2 overexpression negative stage 4 group. There was no statistically significant differences in survival between the two groups. Conclusions: C-Met was not associated with any negative prognostic factors in gastric cancer. HER2 was associated with better differentiation, intestinal subtype, advanced stage and c-met overexpression. HGF expression was not asscociated with any clinicopathological factor.
INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG), first results.
Authors: Pavlakis Nick , Sjoquist Katrin Marie , Tsobanis Eric , Martin Andrew , Kang Yoon-Koo , Bang Yung-Jue , O'Callaghan Christopher J. , Tebbutt Niall C. , Rha Sun Young , Lee Jeeyun , Cho Jae Yong , Lipton Lara Rachel , Burnell Margot J. , Alcindor Thierry , Strickland Andrew , Wong Mark , Kim Jin Won , Simes John , Zalcberg John Raymond , Goldstein David
Published: February 2017

9

Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has limited options following failure of first or second line chemotherapy (CT). Regorafenib (REG) is an oral multi-kinase inhibitor of kinases involved in angiogenesis, tumor microenvironment, and oncogenesis. This study examined whether REG has sufficient activity and safety for further evaluation. Methods: International (Australia & New Zealand (ANZ), Korea, Canada (NCIC CTG)) randomised phase II trial with 2:1 randomisation and stratification by: (1) Lines of prior CT for advanced disease (1 vs. 2) and (2) Region. Eligible patients received best supportive care plus 160mg REG or matching PBO orally on days 1-21 each 28-day cycle until disease progression or prohibitive adverse events. Primary endpoint was progression free survival (PFS) in the REG arm, assuming median 8 weeks (wks) in PBO arm, aiming for 13.2 wks with REG to be of interest. Results: From Nov 2012 to Feb 2014, 152 patients were enrolled, 147 evaluable [pre-specified primary analysis population]: (REG n=97: PBO n=50); well matched for key baseline prognostic indicators; male:female (118:29); primary location: OG Junction (56), stomach (85); lines of prior therapy: 1 (63), 2 (84); ECOG 0 (62): 1 (85). Time on treatment: Median: 7.9 (REG) v 4 (PBO) wks. In the evaluable population median PFS was 11.1 wks (95% CI: 7.7 - 12.3) (REG) and 3.9 wks (95% CI: 3.7 - 4.0) (PBO), log-rank p <0.0001; HR 0.41 (95% CI: 0.28 to 0.59). PFS results were maintained for secondary analysis including all randomized patients (n = 152). REG was well tolerated, with the spectrum of toxicity in keeping with previous reports. Conclusions: PFS was clearly significantly longer with REG than PBO, though PBO PFS was less than anticipated. The pre-specified exploratory comparisons provide compelling evidence that REG has sufficient activity with acceptable tolerability in refractory AOGC to warrant phase III evaluation. Mature OS results will be presented at the meeting. Clinical trial information: 12612000239864.
Effect of renal function on continuation of S-1 adjuvant chemotherapy in gastric cancer patients.
Authors: Makihara Katsuya , Azuma Sayaka , Ueno Hiroyuki , Nakata Izumi , Yamamoto Kazuyoshi , Nishikawa Kazuhiro , Hirao Motohiro , Fujitani Kazumasa , Tsujinaka Toshimasa
Published: February 2017

90

Background: The results of ACTS-GC study showed that postoperative adjuvant chemotherapy with S-1 is the standard treatment for patients with stage II and stage III gastric cancer (GC) in Japan. In addition, completion of 12 months of S-1 treatment and a high relative performance (RP) value were reported to be related to improved survival. The plasma 5-fluorouracil concentration in patients receiving S-1 treatment is known to be significantly higher in patients with 50 ≤ Ccr < 80 mL/ min than in those with Ccr ≥ 80 mL/ min. The aim of this study was to investigate the association of the dose of S-1 based on renal function and compliance with S-1 treatment. Methods: This study is retrospective cohort study, included GC patients who were administered S-1 adjuvant chemotherapy at the Osaka National Hospital in Japan between August 2006 and August 2013. Cohort A comprised patients with Ccr ≥ 80 mL/min, those with 50 ≤ Ccr < 80 mL/min and dose reduction by one level, and those with Ccr < 50 mL/min and dose reduction by two levels. Cohort B included patients with Ccr < 50mL and dose reduction by one level. We compared the completion rate of 12 months of S-1 treatment and the RP value between cohorts A and B. Results: In total, 103 patients were included in this study: cohort A included 53 patients, and cohort B included 50 patients. The completion rate of 12 months of S-1 treatment was significantly higher in cohort A at 83% than in cohort B at 56% (OR: 3.8 [95% CI: 1.6–9.9], p = 0.003). The median RP value was significantly higher in cohort A at 93.8% than in cohort B at 74% (p = 0.007). In the subgroup analysis, no difference was found in the completion rate among patients with S-1 dose < 65 mg/m². Conclusions: Renal function was found to be an important factor for compliance with S-1 treatment as adjuvant chemotherapy for GC. The results of the present study suggest the need for dose reduction by one level in patients with Ccr < 80 mL/min.
The treatment of esophageal cancer by vascular-targeted photodynamic therapy (VTP) using orthotopic rat model.
Authors: Uzana Ronny , Preise Dina , Agemy Lilach , Elmoalem Rachel , Brandis Alexander , Belkin Varda , Salomon Yoram , Scherz Avigdor
Published: February 2017

91

Background: Vascular targeted photodynamic therapy (VTP) based on local sensitization of circulating WST11, a water-soluble derivative of Pd-bacteriochlorophyll, enables effective focal ablation of solid tumors. Highly toxic oxygen radicals are produced in the vascular lumen upon illumination with near infra-red light (755nm), leading to irreversible occlusion of tumor feeding arteries and veins. WST11 clears rapidly from the circulation and does not accumulate in the body, providing high level of safety and minimizing adverse effects. WST11-VTP completed Phase II clinical trials in USA and Phase III in Europe for the treatment of early localized prostate cancer as a first line monotherapy with above 80% complete response rate. Here we evaluate its’ safety and efficacy for the treatment of esophageal cancer aiming at development of clinically translatable treatment protocol. Methods: We developed an orthotopic model in which esophageal cancer cells are implanted in the mid esophagus using endoscopy guided procedure. Established tumors are illuminated with cylindrical diffuser deployed through the custom built endoscopy guided system following infusion of WST11. For assessment of treatment safety and tissue recovery normal esophagus tissue was subjected to WST11-VTP using the same treatment set up. Selectivity and efficacy were evaluated histologically by examining sections of treated tumors and normal esophageal tissues under various treatment conditions. Results: Safety control VTP procedures on healthy esophageal tissues have shown a confined destruction only at the illuminated zone while collateral damage to neighboring tissues was not observed. The impact runs as deep as the muscularis propria without signs of perforation or death as a result of the procedure. The VTP protocol was able to ablate implanted and established tumors as opposed to the control group with light illumination alone without the sensitizer (WST11). Conclusions: VTP could be safely applied to treat esophageal tumors, with transient and mild adverse effects. Importantly, VTP effectively eradicated established esophageal tumors in tested set up that could be translated into a clinical treatment protocol.
Association between intratumoral HER2 heterogeneity (IHH) and trastuzumab (T-mab) efficacy in HER2 positive–gastric cancer (GC).
Authors: Wakatsuki Takeru , Yamamoto Noriko , Chin Keisho , Ogura Mariko , Shinozaki Eiji , Suenaga Mitsukuni , Ozaka Masato , Matsusaka Satoshi , Takahari Daisuke , Ichimura Takashi , Kumekawa Yosuke , Nakayama Izuma , MATSUSHIMA TOMOHIRO , Mizunuma Nobuyuki , Sano Takeshi , Yamaguchi Toshiharu , Ishikawa Yuichi
Published: February 2017

92

Background: ToGA study showed superiority of adding T-mab to standard chemotherapy and a positive correlation between HER2 expression levels and the T-mab efficacy. In gastric cancer IHH is frequently recognized but its clinical impact on T-mab efficacy is unclear. Methods: Patients who were treated with T-mab and had surgical specimens available for IHC test were retrospectively examined. When all tumor cells overexpressed HER2 protein by IHC, the tumor was defined as non-HER2-heterogeneous. The others were defined as HER2-heterogeneous. Progression-free survival (PFS) and overall survival (OS) were estimated using by Kaplan-Meier methods and compared by the log-rank test. The level of significance was set to p<0.05 and all statistical tests were two-sided. Results: 23 patients were enrolled. Their median age was 68 years and 83% were male. PS 0, GEJ cancer, intestinal type histology, visceral metastasis (lung or liver), and previous chemotherapy were found in 57%, 35%, 83%, 57%, and 57% of them, respectively. After a median follow-up of 11.3 months, the median OS, PFS, and overall response rate were 14.4 months, 10.8 months, and 62.5%, respectively. All tumors were IHC3+, and 13 were non-HER2-heterogeneous and 10 were HER2-heterogeneous. There was no significant difference in clinicopathological features between the two groups. Median PFS in non-HER2-heterogeneous group (21.9 months) was significantly longer than that in HER2-heterogeneous group (8.6 months), (HR: 0.24 [0.06-0.91], P=0.024). Median OS in non-HER2-heterogeneous group was not reached while that in HER2-heterogeneous group was 12.9 months (HR: 0.29 [0.06-1.42], P=0.102). A higher rate of response to T-mab was seen in non-HER2-heterogeneous group than in HER2-heterogeneous group, though the difference was not statistically significant (75% vs. 50%, p=0.608). Conclusions: IHH might have robust clinical impact on T-mab efficacy for HER2 positive GC. These findings should be validated by independent large cohorts and further molecular correlative analyses are warranted.
Potential of PAR1 to be involved in the acquisition of drug resistance in human gastric cancer cell.
Authors: Fujimoto Daisuke , Ueda Yuki , Hirono Yasuo , Goi Takanori , Yamaguchi Akio
Published: February 2017

94

Background: Side Population (SP) is a FCM term to define cell clusters with strong ability to efflux DNA dye Hoechst 33342 by ABC transporters. In some cases, cancer stem-like cells (CSLCs) were identified using the FCM-based SP technique and SP cells had ability of drug resistance because SP cells were expressed ABC transporter. CSLCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. We had showed PAR1 had an intimate involved in gastric cancer metastasis. And PAR1 contributed to leukemic stem cell maintenance. So we studied PAR1 induced SP cells acquired the ability of drug resistance in gastric cancer. Methods: MKN45 cells stably expressing PAR1 (45-PAR1) were generated in our laboratory. siRNA against PAR1 was synthesized. We studied the change in fraction of SP cell, when PAR1-expressing cell (45-PAR1 and MKN74), PAR1-null expressing cell MKN45 and inhibited PAR1-expressing MKN74 by PAR1 siRNA (74-PAR1siRNA) were treated with PAR1 agonist TFLLR-NH2 or TFLLR-NH2 plus PAR1 selective antagonist SCH79797. And, we compared the drug resistance using paclitaxel, cisplatin and 5-FU and researched ABC transporter expression in MKN45, 45-PAR1 and MKN74 with TFLLR-NH2 or SCH79797 or PAR1 siRNA. Results: We showed the fraction of SP cells in 45-PAR1 and MKN74 achieved dramatic increases by TFLLR-NH2. But, the fraction of SP cells in MKN45 and 74-PAR1siRNA remained about the same by TFLLR-NH2. When treated with SCH79797, the fraction of SP cells remained about the same, too. As for drug resistance assay, 45-PAR1 and MKN74 achieved the same strong resistance of the SP cells by TFLLR-NH2. But, MKN45 and 74-PAR1siRNA were not able to obtain the drug resistance. When treated with TFLLR-NH2, 45-PAR1 and MKN74 showed the high expression of ABCG1 and MRP1, that proteins are ABC transporters, compared to MKN45 and 74-PAR1siRNA. These expression levels in 45-PAR1 and MKN74 with TFLLR-NH2 were equal to the SP cells. Conclusions: PAR1 is closely-involved in that gastric cancer cells achieved the drug resistance and were led to SP enriched in CSLCs.
Multiomics profiling for gastric cancer using high-tech omics-based patient evaluation (HOPE).
Authors: Terashima Masanori , Oshima Keiichi , Kusuhara Masatoshi , Urakami Kennichi , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Makuuchi Rie , Miki Yuichiro , Hatakeyama Keiichi , Yamaguchi Ken
Published: February 2017

95

Background: The Project HOPE (High-tech Omics-based Patient Evaluation) is an ongoing comprehensive platform that analyzes genome and transcriptome of fresh surgical specimens and blood samples obtained from cancer patients using whole-exome sequencing (WES, AmpliSeq Exome kit, Life Technology) and gene expression profiling (GEP, DNA microarray, Agilent Technologies). The research plan was approved by institutional review board (IRB) in Shizuoka Cancer Center, and total number of patients evaluated in this plan was about 3000 during the 3-year period of the research. Here, we focused on gastric cancer to investigate its characteristic profile. Methods: Tumor sample and peripheral blood was obtained from a total of 19 gastric cancer patients. At the initial stage of the study, the known mutation sites were analyzed by the WES, and expression level of cancer-related genes was evaluated by GEP. Results: Fourteen patients out of 19 patients (74 %) were categorized as advanced gastric cancer. The patients with single nucleotide variations (SNVs) in tumor protein P53 (TP53) accounted for 37% (7/19), and 21% (4/19) of patients had multiple SNVs in the known mutation sites. Furthermore, in two patients with gene amplification of ERBB2 or EGFR, mRNA expression corresponding these genes was markedly up-regulated. Conclusions: WES and GEP analyses may play an important role in interpretation of genetic changes of cancer tissues and personalized medicine.
Non-invasive volatile organic compound analysis from exhaled breath for the diagnosis of gastroesophageal cancer.
Authors: Markar Sheraz , Hanna George
Published: February 2017

TPS225

Background: The work carried out in our laboratory using Selective Ion Flow-Tube Mass Spectrometry (SIFT-MS) analysis of volatile organic compounds (VOCs) in exhaled breath has identified compounds that can differentiate gastro-esophageal cancer from non-cancer patients. A model has been developed based on 220 patients with upper gastrointestinal pathology (81 cancer, 88 positive control and 51 patients with endoscopically normal gastrointestinal tract). Methods: Clinical trial registry number: 14/LO/1136. Study 1: Refinement of VOC exhaled breath model. Exhaled breath from 120 patients undergoing diagnostic lower endoscopy for the investigation of gastrointestinal symptoms will be used to refine the existing model by studying the influence of lower gastrointestinal diseases and in particular colorectal cancer, upon VOC analysis. To date 94 patients have been recruited. Study 2: Blinded validation multi-centre study for the use of exhaled Breath SIFT-MS analysis to predict gastro-esophageal cancer. This study will be conducted across four centers and will utilize SIFT-MS exhaled breath analysis, for comparison of predicted cancer risk based upon the VOC exhaled breath model compared to endoscopic findings and histology biopsies in order to determine the overall diagnostic accuracy for this non-invasive test. Sample Size – Based upon a prevalence of cancer of 50% in the study population and maintaining a sensitivity and specificity of 80% for the diagnostic model derived from our previous research, the sample size estimated is 325 patients. Inclusion criteria:Patients with upper gastrointestinal symptoms attending for endoscopy or surgery. Exclusion criteria: Patients with a documented active infection or liver disease. Statistical methods: Comparison of predicted cancer risk and actual OGD findings or histology from endoscopic biopsies will then be made, and the overall diagnostic accuracy (sensitivity, specificity, positive and negative predictive value, ROC curve analysis) for this non-invasive diagnostic investigation will be determined. Deliverables: The diagnostic accuracy of the exhaled breath test for the prediction of oesophago-gastric cancer. Clinical trial information: 14/LO/1136.