bluuebunny/crossref_metadata_2025_split huggingface dataset:
The 12-gene colon cancer assay validation and utility: Summary of clinical evidence.
Authors: Burke Emily , Tezcan Haluk , Lopatin Margarita , Clark-Langone Kim Michelle , Lee Mark , Shak Steven , Sing Amy Pratt 
Published: February 2017

523 Background: The 12-gene colon cancer assay is the first commercially available molecular assay to predict the risk of recurrence in stage II/III colon and rectal cancer. Rigorous evidence for clinical validity and utility of an assay is imperative since the result is used for treatment decision-making. This summary outlines the studies that meet an established definition of clinical validation and additional studies that support the utility of the assay. Methods: Prospectively designed studies using archival tissue with pre-specified methods, clinical outcomes, and analysis plan were considered clinical validation studies (Simon et al. JNCI 2009). Additional studies that demonstrated the utility of the assay in a clinical setting were considered supportive. Results: The assay has been clinically validated in four independent studies with 3315 patients (2390 stage II/628 stage III colon and 130 stage II/167 stage III rectal). All four studies demonstrated a significant association (p<0.05) between the result and outcome (e.g. recurrence risk and cancer specific survival). The score was examined in the context of other variables, including T and N stage, MMR status, number of nodes examined, lymphovascular invasion, and tumor grade; across all studies, the result consistently contributed to risk stratification beyond these variables. Three clinical utility studies with 502 patients showed that 29-45% of initial treatment recommendations in stage IIA colon cancer were changed, with a net reduction in use of adjuvant chemotherapy. Conclusions: Clinical validation of the 12-gene assay followed a now-standard approach of using archived tissue from multiple large, prospectively-designed studies with documented long-term outcomes; the 12-gene colon assay meets level IB evidence criteria. Subsequent studies showed the assay has impact on clinical practice. The underlying tumor biology assessed by the score is relevant in both colon (stage II and III) and rectal cancer, providing information beyond conventional features, and can help guide treatment decisions regarding adjuvant chemotherapy.
Updated patient reported outcomes and survivorship care plan use by survivors of colorectal cancer (CRC).
Authors: Metz James M. , Hampshire Margaret K. , Vachani Carolyn , Di Lullo Gloria A. , Hill-Kayser Christine 
Published: February 2017

527 Background: Colorectal cancer patients may be at risk for late effects after treatment, the impact of which may difficult to evaluate using conventional methods. Here, we described patient reported outcomes after CRC, as well as use of survivorship care plans. Methods: Patient-reported data were gathered via a convenience sample frame from CRC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLinkwebsite, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, CRC survivors are queried regarding late effects associated with specific treatments, and asked to answer “yes,” “no,” or “I don’t know.” They are also asked to score GI toxicity using WHO criteria. All data have been maintained with IRB approval. Results: 657 CRC survivors utilized the care plan and answered queries regarding late effects; 64% were female and 82% Caucasian. Median diagnosis age was 50 (24 – 76) and median current age 54 (24 – 77). Many reported having had multimodality therapy - 97% surgery, 89% chemotherapy, and 37% radiation. Overall, 63% reported chronic changes in bowel patterns, 38% chronic diarrhea, 9% bowel obstruction, 18% hernia development, 8% radiation colitis, and 2% fistula formation. Of 249 survivors who graded GI toxicity, 23% reported 4-6 stools per day, and 18% > 6 stools per day or incontinence. When queried regarding sexual function, 35% of men reported worse erectile function than pre-treatment, and 42% of women reported sexual changes such as vaginal dryness. A follow-up survey was completed by 31 (5%) of users, who reported that care plans improved knowledge about late effects (90%) and potential related treatments and tests (83%). Conclusions: Survivors using this tool report significant toxicity after cancer treatment, mainly related to GI and sexual function. Survivors appear to gain knowledge from survivorship care plans. The data reported here may be of significant impact in future study of quality of life, as well as patient counseling and survivor care.
Association of radiation therapy with overall survival in patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum.
Authors: Marcus David Mitchell , Nickleach Dana , El-Rayes Bassel F. , Landry Jerome Carl 
Published: February 2017

528 Background: The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiation followed by surgery, but many physicians question the benefit of multimodality therapy in patients with stage T3N0M0 disease. We aimed to determine the impact of radiation therapy (RT) on overall survival (OS) in this group of patients. Methods: We used the Surveillance, Epidemiology, and End Results database to identify patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum from 2004 to 2010. The Kaplan-Meier method was used to compare OS for patients receiving RT vs. no RT, along with for pre-op vs. post-op RT among patients that received RT. Multivariable analysis (MVA) using a Cox proportional hazards model was performed to assess the association of RT with OS after adjusting for patient age, gender, race, tumor grade, carcinoembryonic antigen, type of surgery, and circumferential margin status. The analysis was repeated separately on patients that underwent total colectomy (TC) vs. sphincter-sparing surgery. Results: The cohort included 8,679 patients, including 4,705 who received RT and 3,974 who did not. Median age was 66 years. Five year OS was 76.5% in patients who received RT, compared to 60.0% in patients who did not receive RT (p <0.001). Five year OS was 76.9% for patients receiving pre-op RT vs. 75.7% in patients receiving post-op RT (p = 0.247). In patients undergoing TC, five year OS was 74.7% for patients receiving RT, compared to 47.5% in patients not receiving RT (p <0.001). In patients undergoing sphincter-sparing surgery, five year OS was 77.7% in patients receiving RT, compared to 62.9% in patients not receiving RT (p <0.001). Use of RT was significantly associated with OS on MVA, both in the entire cohort (HR 0.70 [95% CI 0.60-0.81]; p<0.001) and in subsets of patients undergoing TC (HR 0.55 [95% CI 0.38-0.79]; p=0.001) and sphincter-sparing surgery (HR 0.70 [95% CI 0.59-0.84]; p<0.001). Conclusions: The use of RT is associated with superior OS in patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum. This benefit is demonstrated in both the pre-op and post-op settings and applies to patients undergoing both TC and sphincter-sparing surgery.
Correlation of tumor-associated macrophages with clinicopathologic factors and angiogenesis in gastric cancer.
Authors: Lim Sung-Jig , Choi Sung Il , Park Jae 
Published: February 2017

54 Background: Tumor associated macrophages (TAMs) are major components of tumor environment, and polarized into M1 and M2 type. M1 has been known as antitumorigenic, whereas M2 as protumorigenic. M2 have a significant role in tumor progression by promoting tumor cell invasion, migration and angiogenesis. We evaluated the M2 macrophages to investigate its importance in predicting clinical outcome or prognosis, and the relationship between M2 and angiogenesis in patients with gastric cancer. Methods: Formalin-fixed, paraffin-embedded blocks were obtained from the 88 patients with gastric cancer. CD163+ TAMs and CD105+ vessels were evaluated by immunohistochemical staining and the extent of CD163+ TAMs in tumor were divided into three groups: (A) infiltrated TAMs in cancer cell nest (nest TAMs); (B) infiltrated TAMs in tumor stroma (stroma TAMs); and (C) infiltrated TAMs along the invasive margin of a tumor (margin TAMs). Results: The increased stroma and margin TAMs (>72 and >102, respectively) were closely correlated with lymph node metastasis, TNM stage and lymphatic invasion (p<0.05 in 3 factors) and positive correlation existed between the stroma and margin TAMs (p<0.001). Disease-free survival rate analyzed using the Kaplan– Meier method was significantly lower in patient with high stroma and margin TMAs than patient with low stroma and margin TAMs (p=0.0039 and 0.0499, respectively). CD105+ vessels showed significant correlation with lymph node metastasis and lymphatic invasion.(p=0.006 and p<0.0001, respectively) Stromal, marginal and nest TAMs were positively correlated with CD105+ vessels (p=0.001). Conclusions: M2 infiltration in tumor stroma and tumor margin in gastric cancer showed relationship with aggressive phenotypes such as lymph node metastasis, TNM stage and lymphatic invasion and was correlated with angiogenesis. This study supports the view that the adverse prognostic impact of M2 involves tumor angiogenesis in gastric cancer.
Phase II study of capecitabine in substitution of 5-FU in the chemoradiotherapy regimen for patients with squamous cell carcinoma of the anal canal.
Authors: Ribeiro Suilane Coelho , Moniz Camila Motta Venchiarutti , Riechelmann Rachel , Bariani Giovanni Mendonca , Braghiroli Maria Ignez , Nahas Caio , Coudry Renata , Alex Alexandra Khichfy , Carneiro Allyne Q. , Nebuloni Daniela R. , Glasberg Joao , Hoff Paulo 
Published: February 2017

560 Background: Squamous cell carcinoma (SCC) of the anal canal is an uncommon malignancy accounting for 1-5% of intestinal tumors; however, its incidence has been increasing. Treatment for stage II and III anal canal SCC is infusional 5-fluorouracil associated with mitomycin and radiotherapy, since 1974. More convenient treatments for patients are needed. Methods:Patients with SCC of anal cancer T2-4N0M0 or T (any) N1-3M0, with good performance status, normal blood, and renal function were treated with capecitabine 825 mg/m2 12/12hs during radiotherapy associated with a single dose of mitomycin 15 mg/m2 on day 1. Primary objective was local control rate at 6 months determined by clinical examination and radiological assessment. Sample size was calculated using Fleming single stage design. Results: From November/2010 to August/2013 42 patients were initially included, however 36 patients were assessed. Fifteen patients (41.7%) were stage II, 8 patients (22.2%) stage IIIA, and 13 patients (36.1%) stage IIIB. Four patients (11.1%) were HIV-positive, while 32 (88.9%) were HIV-negative. Thirty-two patients finished the treatment, 4 patients are still in treatment. Median follow-up was 18.7 months. Among patients who finished the treatment and were reevaluated at 6 months 4 patients (13.3%) presented partial response, 25 patients (83.3%) had complete response, and 1 patient developed liver metastasis (3.3%). Regarding grade 3-4 toxicities, 7 patients (21.8%) had grade 3 radiodermitis, 1 patient (3.1%) had grade 3 diarrhea, 2 patients (6.2%) had grade 3-4 thrombocytopenia, 3 (9.3%) had lymphopenia and one patient had grade 3 leukopenia. One HIV+ patient had septic shock, pneumonia, herpetic encephalitis and macrophage activation syndrome. Colostomy was required in 2 patients before the beginning of the treatment and 2 patients after the treatment because of local failure, corresponding to a colostomy rate of 12.5%. Conclusions: Capecitabine and mytomicin with radiotherapy seem to be a safe treatment for SCC of the anal cancer.
A UGT1A1 genotype-guided dosing study of irinotecan in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI plus bevacizumab (BEV).
Authors: Sharma Manish , Toffoli Giuseppe , Buonadonna Angela , Marangon Elena , Polite Blase N. , Frustaci Sergio , Innocenti Federico 
Published: February 2017

562 Background: Dosing based on UGT1A1*28 genotyping has been demonstrated to reduce irinotecan-related adverse events. Previous data (Toffoli et al. JCO, 2010) showed that mCRC pts treated with first-line FOLFIRI tolerated higher doses (310 mg/m2 for *1/*28; 370 mg/m2 for *1/*1) of irinotecan than the standard 180 mg/m2. The aims of this study (NCT01183494; supported by Eudract 2009-012227-28) were to define the maximally-tolerated dose (MTD) of irinotecan in FOLFIRI plus BEV as first-line therapy in mCRC pts and to determine whether BEV alters irinotecan pharmacokinetics (PK). Methods: Pts were accrued at 3 sites: Chicago (USA), Aviano (Italy), Rome (Italy). In *1/*28 and *1/*1 pts (*28/*28 pts were excluded), irinotecan was administered at an initial dose of 260 mg/m2 IV every 2 weeks. The dose was escalated to 310 and 370 mg/m2 if 0/3, <2/6, or <3/10 pts had a DLT (grade 3-4 non-hematologic or grade 4 hematologic toxicity during the first 28-day cycle). MTD was defined as the highest dose at which <4/10 pts had a DLT. 5-FU was administered as a 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, plus 200 mg/m2leucovorin. BEV was administered at 5 mg/kg IV on day 3 (2 days after irinotecan) and on day 15 (before irinotecan), then every 2 weeks. Irinotecan PK were collected on days 1-3 (in absence of BEV) and on days 15-17 (in presence of BEV). Results: 44 pts (23 *1/*28; 21 *1/*1) were enrolled and 43 were evaluable for DLTs during cycle 1 (Table). Neutropenia and diarrhea were the most common DLTs and were each observed in 5 of 11 (45%) pts with DLTs. The MTD is 260 mg/m2 in the *1/*28 cohort and at least 310 mg/m2in the *1/*1 cohort. In a preliminary analysis of 22 pts, BEV decreased the AUC of SN-38, the active metabolite of irinotecan (p = 0.026 by Wilcoxon matched pairs signed rank test). Conclusions: In first-line therapy of mCRC with FOLFIRI plus BEV, irinotecan doses higher than the standard dose can be safely administered based on UGT1A1 genotype. The impact of this genotype-guided dosing approach on survival will be established in future trials. Clinical trial information: NCT01183494. [Table: see text]
Reduced expression of DENND2D through promoter hypermethylation as an adverse prognostic factor in squamous cell carcinoma of the esophagus.
Authors: Hibino Soki , Kanda Mitsuro , Oya Hisaharu , Takami Hideki , Shimizu Dai , Nomoto Shuji , Koike Masahiko , Yamada Suguru , Nakayama Goro , Fujii Tsutomu , Sugimoto Hiroyuki , Fujiwara Michitaka , Kodera Yasuhiro 
Published: February 2017

58 Background: Esophageal cancer ranks sixth in cancer mortality worldwide and patients with ESCC have a poor prognosis with a 5-year survival rate of less than 10%. Elucidation of the mechanisms of carcinogenesis and tumor progression in esophageal cancer is urgently needed to develop targets for therapy and prognostic biomarkers. In the present study, the expression and regulatory mechanism of the Differentially Expressed in Normal and Neoplastic cells Domain containing 2D (DENND2D), which is a regulator of Rab GTPases, were investigated to explore its potential as a tumor suppressor gene for esophageal squamous cell carcinoma (ESCC). Methods: The level of DENND2D mRNA expression in ESCC cell lines and surgical specimens was determined using a quantitative real-time reverse transcription-polymerase chain reaction assay, and the relationship between the expression level of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanism of DENND2D expression in ESCC. Results: The level of DENND2D mRNA expression was reduced in 8/9 ESCC cell lines and in 59/65 surgical specimens, and the mean expression level was significantly lower in cancerous tissues than in corresponding normal tissues (p<0.001). The expression pattern of DENND2D protein and mRNA was consistent. Downregulation of DENND2D mRNA in ESCC tissues was identified as an independent prognostic factor in multivariate analysis (hazard ratio: 2.194; p=0.039). The DENND2D promoter was methylated in five out of nine ESCC cell lines, and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in ESCC tissues (64.6%) and was significantly associated with downregulation of DENND2D mRNA expression (P = 0.008). Conclusions: Our data suggest that DENND2D is a candidate tumor suppressor gene that was inactivated by promoter hypermethylation in patients with ESCC and may serve as a novel biomarker of ESCC.
Long-term quality of life (QoL) for stage II/III rectal cancer survivors in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS).
Authors: Charlton Mary E. , Stitzenberg Karyn Beth , Lin Chi , Juarez Grelda Yazmin , Halfdanarson Thorvardur Ragnar , Pendergast Jane F. , Chrischilles Elizabeth A. , Wallace Robert B. 
Published: February 2017

584 Background: Standard therapy for stage II/III rectal cancer includes surgery, radiation, and chemotherapy. Multiple trials demonstrated neoadjuvant chemoradiation (CRT) provides better local control and decreased morbidity compared to adjuvant CRT, though differences in overall survival and long-term QoL have not been demonstrated. We examined impact of treatment (pre-op CRT/post-op CRT/no CRT) on long-term QoL. Methods: CanCORS patients with survey/medical record data diagnosed in 2003-2005 with stage II/III rectal (non-rectosigmoid) cancer had resection and survived > 7 years were included. QoL (SF-36, EQ-5D) measures and defecation problems were derived from surveys at 14 months and 7 years post-diagnosis. Mean scores were adjusted for the following when significant: age, gender, stage, sphincter preservation, comorbidities, and baseline self-reported health status and QoL scores. Results: Of 119 patients, 53% received pre-op CRT, 23% post-op CRT, and 24% no CRT. Of 114 patients with 14-month follow-up, Pre-op CRT and No CRT groups had better EQ-5D adjusted mean scores but worse defecation scale (DS) scores compared to the Post-op CRT group. Of 49 disease-free survivors with 7 years follow-up, there were no differences among groups in QoL scores, but the No CRT group had better DS scores than other groups. Conclusions: No major differences were detected in long-term QoL based on treatment aside from the DS, though sample sizes became small. Regardless of treatment, long term (7y) mental health and vitality were generally comparable to U.S. norms, while physical health and overall health status (EQ-5D) were somewhat lower. [Table: see text]
Does up-front definitive surgical resection with delayed chemotherapy in patients with stage IV rectal cancer compromise overall survival?
Authors: Manyam Bindu V. , Koyfman Shlomo A. , Sohal Davendra , Mallick Ismail , Reddy Chandana A. , Remzi Feza H. , Kalady Matthew F. , Lavery Ian C. , Kiran Ravi P. , Abdel-Wahab May 
Published: February 2017

586 Background: Definitive resection of the primary is frequently part of the management of patients (pts) with stage IV rectal cancer with good performance status and low volume of systemic metastases. It is unclear whether delaying systemic therapy for up front surgical management of the primary compromises overall survival (OS). Methods: Pts with metastatic rectal adenocarcinoma who received definitive surgical resection between 1998-2011 were identified in an IRB approved registry. The sequencing of CT and surgery, and the use of perioperative radiation therapy (RT), was at the discretion of treating physicians. Preoperative chemotherapy (Pre-CT) regimens included 5-fluorouracil (5-FU) +/- leukovorin (LV), capecitabine, 5-FU/LV/oxaliplatin +/- avastin, or 5-FU/LV/irinocetan. RT dose was typically 50.4 Gy. OS was measured from the date of diagnosis. Baseline variables were compared using the Chi-square and unpaired t-tests. OS was calculated using the Kaplan Meier method. Univariate (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazards regression to identify variables associated with OS. Results: In this study of 115 pts, 75 (65%) were treated with pre-CT, while 40 (35%) were treated with up front surgery. Of the pts who received surgery up front, 3 (8%) received RT and of the pts who received pre-CT, 62 (83%) received RT. The cohort was predominantly male (70%) with a median age of 57, median KPS of 80, and median follow-up of 24.1 months. 94% of pts had T3/T4 tumors, 80% had N+ disease, and 33% had poorly differentiated tumors. Liver directed therapy (LDT) was performed in 61% of pts. There was no significant difference in OS (32.3 vs. 32 months; p = 0.24) between pts treated with pre-CT and those who received surgery up front, respectively. UVA demonstrated that pre-CT was not associated with OS (HR 1.26; p = 0.544). MVA demonstrated that pts with poorly differentiated tumors (HR 2.04; p = 0.007) and those that did not undergo LDT (HR 2.45; p = 0.001) had inferior survival. Conclusions: Delaying systemic chemotherapy in order to achieve local control with surgical resection up front does not appear to impact OS in pts with stage IV rectal cancer.
Phase II study of 5-FU dose-adjusted mFOLFOX7 plus bevacizumab in patients with metastatic colorectal cancer (AJUST study).
Authors: Yakabe Tomomi , Denda Tadamichi , Morita Yoshitaka , Matsuda Chu , Kim Ho Min , Fujieda Shinji , Fukunaga Mutsumi , Oba Koji , Sakamoto Junichi , Mishima Hideyuki 
Published: February 2017

592 Background: Individual fluorouracil dose adjustment improved efficacy and toxicity in patients with colorectal cancer receiving FOLFOX. But the usefulness has not been studied in Japan. Methods: To evaluate the efficacy and toxicity of 5-FU dose-adjusted mFOLFOX7 plus bevecizumab, we conducted a multi-center phase II study of 5-FU dose-adjusted mFOLFOX7 plus bevacizumab as first line treatment in patients with metastatic colorectal cancer (AJUST study UMIN000007194). Blood samples were collected from patients receiving 46 hours continuous infusion of 5-FU therapy ( 2400mg/m2). 5-FU measurement were performed using my 5FUR assay. 5FU dose were adjusted according to the AUC. The results were compared with previously reported data. Results: A total of 48 patients were registered between April 2012 to June 2013 from 11 institutions in Japan. They had a wide range of AUC from 14 to 37 mg.h/L . The AUC of 5FU were 22.58 ± 5.33 mg.h/L. 29 patients (60.4%) receiving mFOLFOX7 were in the AUC target range of 20-24 mg/h/L. 16 patients (33.3%) were below the target range, and only 3 patients (6.2%) were above the target range. Past reports showed the AUC of 5FU 20.35 ± 9.87 mg.h/L. Our results of AUC, patients below the target range, and within the target range did not show significant difference from previously reported data (p= 0.12, 0.76, 0.82 respectively), except patients above the target range (p=0.047). Conclusions: This is the first report of individual fluorouracil dose adjustment of mFOLFOX7 plus bevacizumab in Japan. The mean AUC and the percentage of patients below the target range were comparable with previously reported data. These results suggested that 5FU dose monitoring is also useful for Japanese patients. The efficacy and toxicity will be presented in the meeting. Clinical trial information: 000007194.