bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of primary and distant site surgery in patients with stage IV colorectal cancer.
Authors: Uyeno Lori , Nelson Rebecca A. , Singh Gagandeep , Garcia-Aguilar Julio , Kim Joseph 
Published: February 2017

499 Background: Operative management of primary tumor and distant metastases in stage IV colorectal cancer is highly variable and removal of asymptomatic primary tumors in the setting of distant disease remains controversial. The purpose of our study was to describe the patterns of surgery in stage IV colorectal cancer patients in a US population-based cohort and explore patient and tumor characteristics associated with treatment selection and survival. Methods: Stage IV colorectal cancer patients in Los Angeles County from 2000 to 2006 were identified using the LA County Cancer Surveillance Program registry. The cohort included 2,956 patients (2,211 stage IV colon and 745 stage IV rectal cancers). Cox proportional hazard models were used to estimate survival. Treatment was categorized as primary surgery, distant site surgery, or chemotherapy only. Multivariate logistic regression was used to identify patient and tumor variables associated with treatment. Results: Greater than 65% of the stage IV colorectal cohort had primary tumor surgery of which 51% had chemotherapy. Only 4.5% had surgery to remove distant disease. Patients who had chemotherapy only and no surgery was 15%. Median survival of primary surgery, distant surgery, or chemo only was 14, 21, and 11 months. Multivariate Cox regression revealed that primary surgery and distant surgery had a decreased risk of death compared to no surgery (HR= 0.4 p<.0001, HR=0.7 p<.004). Multivariate logistic regression was used to identify predictors associated with treatment selection. Patients >65 years (p<.003); low socioeconomic status (p<0.05); and rectal tumors (p<.0001) were less likely to have surgery of the primary tumor. Female gender (p<.0001) and primary tumor surgery (p<.0001) were predictors for distant site surgery whereas age>65 years (p<.0001) had a negative association. Conclusions: Our population-based study of stage IV colorectal cancer patients suggests that the majority of stage IV patients with distant disease have surgery, but less than 5% have surgery for distant disease. Although survival of stage IV colorectal patients is improved with surgery, increasing age, low socioeconomic status, and rectal tumors are negative predictors for undergoing surgery.
Establishment of primary gastric and gastroesophageal (GE) junction xenografts: A model for characterizing disease heterogeneity.
Authors: Janjigian Yelena Yuriy , Mazgaj Robert , Carbonetti Gregory , Tang Laura H. , Hefter Blake , Kelsen David Paul , de Stanchina Elisa , Strong Vivian E. 
Published: February 2017

51 Background: Gastric cancer is a heterogeneous disease that may be subdivided into distinct subtypes—proximal/gastroesophageal (GE) junction, diffuse/signet ring type, and distal gastric cancers—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology and gene expression. Human epidermal growth factor receptor (HER2) is a validated treatment target in gastric cancer. For patients with metastatic disease, the available cytotoxic agents are applied indiscriminately to all disease subtypes, and with only modest success. The purpose of this study is to establish xenograft models from gastric cancer subtypes to improve our understanding of disease heterogeneity and develop therapies geared for each subtype of gastric cancer. Methods: Fresh specimens obtained from resected primary or metastatic tumors under aseptic conditions. 1 g tumor samples injected SQ into flanks of NOD/SCID mice. Xenografts established after 5 passages and maintained by serial transplantation into new mice. Cell cultures established after 5 in vitro passages; cell lines after 15 passages. Results: To date 26 tumor samples have been implanted from which 8 xenografts have been established. Table below summarizes the results. Cell line established from HER2-positive, trastuzumab refractory tumor resected from brain metastasis. Conclusions: HER2-positive tumors have a favorable xenograft yield. Prior chemo or radiation therapy does not impact engraftment. Standard and experimental therapies are being tested on these xenografts to further validate difference in their biology and guide rational design of clinical trials. [Table: see text]
Impact of the gene expressions of thymidylate synthase and dihydropyrimidine dehydrogenase on survival in patients enrolled in the ACTS-GC study.
Authors: Sasako Mitsuru , Terashima Masanori , Ichikawa Wataru , Ochiai Atsushi , Kitada Koji , Kurahashi Issei , Sakuramoto Shinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi 
Published: February 2017

52 Background: The efficacy of 5-FU-based therapy is basically related to the expression of enzymes involved in pyrimidine metabolism, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT). Biomarker analysis was conducted to evaluate the influence of these expressions on the outcomes of patients enrolled in the ACTS-GC study, a randomized phase III trial, which demonstrated the efficacy of adjuvant treatment with S-1 after D2 dissection for stage II and III gastric cancer (Sakuramoto et al., NEJM 2007) Methods: Formalin-fixed paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3%) patients. Expressions of TS, DPD, TP and OPRT were measured by RT-PCR in macrodissected tumor specimens and normalized to β-actin expression as the reference gene. The expression levels of each gene were categorized as low or high at the 33.3rd or 66.7th percentile. If the p-value of the interaction was less than 0.1, statistical significance was assumed. Results: Expressions of the 4 genes were quantifiable in 97% of the 829 specimens and the distributions were balanced across the arms. The hazard ratio (HR) for overall survival (OS) of S-1 to surgery alone was smaller in the high-TS (highest one-third) (HR, 0.370; 95%CI, 0.221-0.619) than in the low-TS group (lower two-thirds) (HR, 0.757; 95%CI, 0.563-1.018). This interaction between TS expression and OS was statistically significant (p=0.015). Similarly, the HR for OS of S-1 to surgery alone was smaller in the high-DPD (higher two-thirds) (HR, 0.520; 95%CI, 0.376-0.720) than in the low-DPD group (lowest one-third) (HR, 0.848; 95%CI, 0.563-1.276). This interaction (p=0.065) was also statistically significant. There was no interaction between the TP or OPRT expression and OS. Conclusions: This large biomarker study showed that intratumoral TS and DPD gene expressions may be predictive markers of the efficacy of S-1 in gastric cancer patients receiving postoperative adjuvant chemotherapy with S-1.
Systematic survey of therapeutic trials for metastatic colorectal cancer.
Authors: Chen Zhiyu , Overman Michael J. , Garrett Chris R. , Jiang Zhi-Qin , Wolff Robert A. , Abbruzzese James L. , Eng Cathy , Kopetz Scott 
Published: February 2017

523 Background: The FDA’s 2004 “Critical Path Initiative” encouraged novel clinical trials and incorporation of biomarker-based enrichment studies to improve drug development. A survey of metastatic colorectal cancer (mCRC) trials from 2006 (Kopetz et al. JCO) demonstrated a very low utilization of novel therapies and minimal biomarker integration. The extent of change of mCRC clinical trials 5 years later is unknown. Methods: The NIH clinical trials database was searched for enrolling phase II or III treatment trials in mCRC, using previously published search strategies. Enrichment studies were defined by the presence of a tumor-based biomarker in the eligibility criteria. Trials were categorized according to FDA approval status and mechanism of action of the included agents, with novel agents being defined as ones not targeting the same protein or cellular mechanism as an existing agent that is FDA-approved for mCRC. Results: 162 trials were identified for mCRC pts with planned enrollment of 31,050 mCRC patients, representing a 58% and 45% increase from the 2006 survey, respectively. Fewer studies used only agents already FDA-approved for mCRC in 2011 compared to 2006 (39% vs 54%, respectively, P=0.02), with a substantial increase in the number of trials that included agents against novel therapeutic targets (n=49 vs 13, P=0.001). Enrichment trial designs were identified in 64 studies, compared with 13 in 2006 (P=0.0001). While the majority of these designs were for KRAS-wild type tumors and EGFR monoclonal antibodies, there has been a 5-fold increase in novel biomarker-directed trials (n=3 vs 15). However, 101 trials (62%) with an anticipated enrollment of over 21,000 mCRC pts, neither incorporate a novel agent nor biomarker in their trial design. Conclusions: Compared with trial in 2006, current mCRC trials are more likely to evaluate novel agents and incorporate enrichment designs with tumor-based biomarkers. Yet despite the rapid development of biomarker technology for pt enrichment and wider acceptance of innovative trial designs, most clinical trials are empiric in design and fail to integrate recommendations from the FDA Critical Path Initiative.
HLA-cw polypmorphism and killer cell immunoglobulin-like receptor (KIR) gene analysis in Korean patients with colorectal cancer.
Authors: Kim Hyung Jin , Lee In Kyu , Kang Won-Kyung , Kwon Jung Hyun , Oh Seong-Taek 
Published: February 2017

525 Background: Many kinds of genetic and environment factors are involved in colorectal cancer development. Natural killer cells (NK cells) play important roles to protect from viral infections and the early development of cancers, and it is activated or inhibited by killer cell immunoglobulin-like receptors (KIR) which bind to HLA class I. KIR genes are encoded on chromosome 19q13.4. And there are 7 kinds of activating KIRs, and another 7 kinds of inhibiting KIRs. The genetic polymorphisms of KIR genes effect the expression of KIR on NK cells, and there are ethnic differences. In this study, we were trying to investigate the KIR genotype of Korean colorectal cancer patients. Methods: DNAs were extracted from the peripheral bloods from normal populations and Korean colorectal cancer patients. KIR genes were amplified using PCR-SSP methods, and HLA-Cw genes were characterized using PCR methods. The results were analyzed between cancer patients and normal control group. Results: KIR2DL2 and KIR2DS2 were found at low rate and KIR2DL3 were found at high rate compare to the Eastern studies, but the rates were similar with Japan study. In this study, KIR2DS5 (33.2% vs. 20.8%, p-value<0.007) was increased in colorectal cancer group, and in rectal cancer subgroup, KIR3DL1 (93.2%, vs. 98.1%, p-value<0.05), KIR2DS2 (7.8% vs. 19.5%, p-value<0.01), KIR2DS4 (93.2% vs. 98.1%, p-value<0.05) were decreased significantly. HLA-Cw6 (9.1% vs. 15.7%, p-value<0.05) and HLA-Cw7 (17.4% vs. 27.7%, p-value<0.02) were decreased in colorectal cancer group, but no difference was found when they were classified to HLA-C1 and HLA-C2 group. Among the patients with HLA-C1 homozygote, KIR2DS2 was decreased significantly (5.8% vs. 14.5%, p-value<0.004). Conclusions: There are ethnic differences of KIR genotypes. KIR2DS5 is increased in Korean colorectal cancer patients, and in rectal cancer subgroup, KIR3DL1, KIR2DS2 and KIR2DS4 are decreased, so there are immunologic differences between colon and rectal cancers. And among the patients with HLA-C1 homozygote, KIR2DS2 is decreased. Therefore KIR2DS2 in presence of their ligand (HLA-C1 group) may have protective effect against colorectal cancer.
A phase II open-label trial of dacomitinib monotherapy in patients with HER2-positive advanced gastric cancer after failure of at least one prior chemotherapy regimen.
Authors: Oh Do-Youn , Lee Keun-Wook , Cho Jae Yong , Kang Won Ki , Rha Sun Young , Bang Yung-Jue 
Published: February 2017

54 Background: HER2 is a clinically relevant therapeutic target in gastric cancer. Trastuzumab plus chemotherapy has improved patients’ survival in HER2 (+) advanced gastric cancer (AGC). Pan-HER inhibitor shows significant antitumor effects in in vitro and xenograft model of HER2 (+) gastric cancer. The aim of this study was to find the efficacy/safety of dacomitinib, a irreversible pan-HER tyrosine kinase inhibitor by Pfizer, in HER2 (+) AGC patients. Methods: We enrolled AGC patients with HER2 FISH (+) or HER2 IHC 3+ who were treated with at least one prior palliative chemotherapy regimen and with ECOG PS 0-2, normal cardiac ejection fraction. Patients were treated with dacomitinib 45 mg once daily continuously every 4 weeks. Response was evaluated every 8 weeks using RECIST v1.1 and safety was assessed with CTCAE v4.0. The primary endpoint was 4 month-progression free survival rate (4m-PFS). PK and PD study were also conducted. Results: A total of 27 patients were enrolled. The median age was 61 (range: 43-80). Twenty two patients were male. The ECOG PS was 0 in 9 patients, 1 in 16, and 2 in 2. The number of prior palliative chemotherapy regimen was 1 in 7 patients (25.9%), 2 in 9 (33.3%), more than 3 in 11 (40.7%). Six patients received prior anti-HER2 therapy (trastuzumab 2, lapatinib 2, lapatinib or placebo in clinical trial 2) A total of 80 cycles were delivered (median 2 cycles per patient, range: 1-6). The 4m-PFS was 22.2 % and median progression-free survival was 2.1 months (95% CI: 2.3-3.4) There was 2 PR, 9 SD and 16 PD, resulting in 7.4 % response rate (95% CI: 0-17.5%) and 40.7 % disease control rate (95% CI: 21.9-59.6%). Median overall survival was 7.1 months (95% CI: 4.4-9.8). The most common toxicities were skin rash, diarrhea, and fatigue, but most of them were grade ½. Grade 3 skin rash was observed in 3 patients. There was no treatment-related death. Conclusions: Considering the heavily pretreated nature of enrolled patients, the dacomitinib is active and safe treatment option in HER2 (+) AGC patients. The results of PK and PD studies will be also presented at the meeting. (ClinicalTrials.gov: NCT01152853 )
A single-institution phase II trial of five fractions of radiotherapy followed by four courses of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma.
Authors: Myerson Robert J. , Parikh Parag J , Tan Benjamin , Hunt Steven , Fleshman James W , Birnbaum Elisa H , Mutch Matthew G , Kodner Ira J , Safar Bashar , Naughton Michael , Picus Joel , Sorscher Steven , Lockhart Albert Craig , Rigden Caron , Suresh Rama , Wang-Gillam Andrea , Hall Lannis 
Published: February 2017

553 Background: Preoperative radiotherapy (RT) with 5FU chemotherapy (CT) is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents have resulted in increased morbidity with little benefit. We evaluate a template that seeks to (1) include the known benefits of preoperative RT on local response/control, (2) provide for preoperative multi-drug CT, (3) avoid the morbidity of concurrent RT and multi-drug CT. Methods: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for surgery, provided the response was sufficient. Preoperative treatment was 5 fractions RT (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of mFOLFOX6. Postoperative CT was at the discretion of the medical oncologist. The principal objectives are to demonstrate that this regimen can achieve T stage down staging (ypT < cT) and acute grade 3+ gastrointestinal (GI) morbidity equal to or better than historical controls. Results: Accrual opened late 2009, with 60 patients enrolled through 8/2011. Forty-six have had sufficient time to proceed to surgery with 4 having grade 3 preoperative GI morbidity. Two cases are inevaluable for response: one withdrew consent prior to CT and one received no surgery due to progression of cM1 disease (with local response). The 44 evaluable cases included 4 cT4 and 40 cT3; 32 (73%) cN+, 4 cM1. At surgery 33 (75%) had ypT0-2 residual disease including 13 (30%) ypT0, 14 (32%) were ypN+. Cases were sub-analyzed by whether disease was too advanced for the upcoming ACOSOG preoperative FOLFOX vs. 5FU-RT trial. By ACOSOG eligibility, response rates were (eligible first, ineligible second) ypT0: 10/22 (45%) vs. 3/22 (14%) (p = 0.05), ypT0-2: 19/22 (86%) vs. 14/22 (64%) (p = NS). Conclusions: This regimen achieves high response rates with acceptable morbidity. The response for ACOSOG eligible cases meets pre-determined stopping criteria for proceeding to a randomized trial. Our successor study will randomize to this regimen vs. FOLFOX alone for ACOSOG eligible cases, while initially continuing as a single arm trial for ACOSOG ineligible cases.
A phase I/II trial of the multipeptide cancer vaccine IMA910 in patients with advanced colorectal cancer (CRC).
Authors: Mayer Frank , Mayer-Mokler Andrea , Nowara Elzbieta , Torday Laszlo , Ludwig Joerg , Kuttruff Sabrina , Weinschenk Toni , Walter Steffen , Singh Harpreet , Reinhardt Carsten 
Published: February 2017

555 Background: Treatment interruption after 12 weeks of oxaliplatin-based therapy followed by re-introduction upon signs of progression results in better overall tolerability and quality of life compared to continuous therapy while survival rates are only modestly impaired. Specific immunotherapy may provide a safe and tolerable intervention to prolong time to re-introduction and eventually overall survival. IMA910 is a novel peptide-based cancer vaccine consisting of 13 tumor-associated peptides (TUMAPs), which are naturally presented on MHC molecules of colorectal tumors. Methods: HLA-A*02+ advanced CRC patients being at least clinically stable after 12 weeks of first-line oxaliplatin-based therapy were enrolled. After immunomodulation with a single low dose of cyclophosphamide (300 mg/m2), patients were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF (cohort 1; n=66) or IMA910 with GM-CSF plus topically applied imiquimod (cohort 2; n=26). T-cell responses to individual IMA910 peptides were analyzed by HLA-multimer and intra-cellular cytokine assay. Analysis of disease control rates (DCR) and progression-free survival (PFS) was based on RECIST-centrally reviewed CT/ MRI scans. Results: IMA910 was overall well tolerated with most AEs being mild and transient local site reactions. Three patients presented with systemic hypersensitivity reactions, all of which were observed after ≥10 vaccinations and were confirmed to have an in vitro reaction against GM-CSF in all cases. IMA910 induced immune responses in 71% and 72% of patients in the two cohorts, respectively. Interestingly, patients developing CD8 T-cell responses against multiple TUMAPs had a better clinical outcome compared to others, in terms of DCR (18% vs. 2% at 6 months; p=0.012) and PFS (HR: 0.652; p=0.039). OS data will be shown at the meeting. Conclusions: Vaccination with IMA910 is safe, well tolerated, and immunogenic. Significantly better clinical outcome of multi-TUMAP responders in comparison to patients with one/no TUMAP response indicates clinical activity of IMA910 in 1st line advanced CRC patients.
Adjuvant chemoradiation therapy with 5-FU/LV (INT-0116) versus S-1 chemotherapy in completely resected gastric cancer: Practice pattern and feasibility at a single institution.
Authors: Hwang Deok Won , Lee Su Jin , Lee Jeeyun , Park Se Hoon , Park Joonoh , Park YoungSuk , Lim Hoyeong , Kang WonKi 
Published: February 2017

57 Background: Considering the high incidence of gastric cancer worldwide, large-scaled phase III adjuvant trials have been relatively scarcely reported. Until 2010, there have been two large-scaled adjuvant trials in gastric cancer that showed survival benefit from adjuvant chemotherapy +/- radiotherapy: S-1 monotherapy and chemoradiation therapy (CRT) with 5-FU/LV. There has been no direct comparison between S-1 monotherapy and CRT. We analyzed the practice pattern of adjuvant treatment at single institution in Korea in terms of patient’s preference, compliance rate, adverse events between CRT and S-1. Methods: From January 2008 to July 2009, 405 gastric cancer patients who had received adjuvant therapy after curative resection were included for the study. The CRT regimen was INT 0116 protocol. The S-1 monotherapy was to administer 40-60 mg bid, for 28 days, every 6 weeks (8 cycles). Results: Of the total 405 patients, 244 (60.3%) patients had CRT and 161 (39.7%) patients had S-1 monotherapy. The median age was 54 years (range, 24-80) and most of the patients were ECOG PS 0-1. S-1 group was more common than CRT group in Stage II (52.2% for S-1 vs. 47.8% for CCRT) and CRT group was more common in stage III-IV (72.4% for CCRT vs. 27.6% for S-1, p<0.001). The patients’ compliance for the planned treatment was significantly higher in CRT group (95.1% vs. 72.8%, p<0.001). Most common reason for cessation of S-1 therapy was patients’ refusal. For severe adverse events, grade 3-4 neutropenia was substantially more frequent in CRT group (40.2% vs. 8.7%, p<0.001) and GI toxicities of nausea and mucositis were frequent in CRT group when compared with S-1 group (CRT vs S-1; nausea, 5.7% vs <1%; p=0.002; mucositis, 7.4% vs 2.5%; p=0.034). Conclusions: Patients with advanced stage (III–IV) preferred CRT to S-1. The compliance was significantly higher for the CRT group despite of higher incidence of adverse events.
MRI-based selection of patients with metastatic extramesorectal rectal cancer nodes for preoperative chemoradation.
Authors: Maas Monique , Lambregts Doenja MJ , Gillissen Freek , Engelen Sanne ME , Lahaye Max J , Buijsen Jeroen , Beets-Tan Regina GH , Beets Geerard L 
Published: February 2017

570 Background: 20% of rectal cancer patients have metastatic lymph nodes outside the mesorectum (EMRs). These EMR node positives are associated with poor prognosis. Accurate selection would help to tailor treatment and improve prognosis for these patients. Methods: Rectal cancer patients were included in a study in which treatment was based on (contrast-enhanced) MRI. EMR-status was predicted by an expert radiologist. Based on this prediction patients underwent chemoradiation (CRT) of the EMRs. 6-8 weeks after CRT EMRs were restaged. If still involved, the EMRs were resected. When the EMRs were sterilised by the CRT, they were not resected. Patients were followed 3 to 6-monthly after surgery by a combination of modalities. 3-year outcome was estimated with Kaplan-Meier curves. Results: 50 patients with suspected EMRs were included. Median follow-up was 26(0-50) months. In 13 patients EMRs were resected after CRT and in only 2/13 positive nodes were found. Of the remaining 37 patients 5 had a local recurrence (LR). In total 32+11=43 patients (86%) had no involved EMRs after CRT. Five patients had metastasis of whom 2 also had a LR. 3-year LR was 2.3%, 3-year DFS was 86% and 3-year OS was 90%. Conclusions: MRI-based selection of patients with EMRs for CRT provides adequate local control. Distant metastasis is the main cause of poor prognosis in these patients. When MRI is used for EMR identification and thus for identification of patients who need CRT also on the obturator regions, patients can be spared an extensive resection with associated morbidity.