bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors influencing the number of retrieved lymph nodes (LNs) in patients with stage II colon cancer: LN size and areas of B cells and T cells.
Authors: Okada Kazutake , Sadahiro Sotaro , Saito Gota , Tanaka Akira , Suzuki Toshiyuki , Kamijo Akemi 
Published: February 2017

577 Background: In patients with stage II colon cancer, a high number of retrieved LNs has been reported to be associated with better outcomes. We examined the association between a high number of retrieved LNs and the presence of large mesenteric LNs and we evaluated the areas occupied by the T-cell and B-cell fields in LNs with large diameters. Methods: The study group comprised 320 patients with stage II colon cancer who underwent R0 resection from 1991 to 2003. The long- and short-axis diameters of 4,745 LNs were measured with a digitizer on specimens stained with hematoxylin and eosin. A LN with the largest long-axis diameter was selected for each patient and stained immunohistochemically using CD3 as a marker of T cells and CD20 as a marker of B cells. The CD3-positive and CD20-positive area ratios were evaluated, respectively. Results: The mean number of retrieved LNs was 15±10 per case. The correlation coefficients between the numbers and the long-axis diameters of LNs were as follows: mean 0.23, median 0.16, maximum 0.59, and minimum -0.29. The correlation coefficients between the numbers and short-axis diameters were 0.18, 0.13, 0.54, and -0.33, respectively. The correlation coefficient was highest for the maximum long-axis diameter. When the maximum diameter was divided at 5-mm intervals, the number of LNs significantly increased in parallel to an increase in the maximum long-axis diameter (p<0.001). The median follow-up was 119 months. Fifty-six patients (18%) had recurrence, 110 (34%) died of all causes, and 48 (15%) died of colon cancer. On survival analysis, age, T stage, and maximum long axis diameter of LNs were independent prognostic factors. The CD20 area ratio was significantly higher in LNs with a long-axis diameter of 10 mm or greater (0.44±0.09) than in LNs with a long-axis diameter of less than 10 mm (0.41±0.10, p=0.018). There were no differences in the CD3 area ratio. Conclusions: In stage II colon cancer, the number of retrieved LNs correlated with the maximum long-axis diameter of LNs. The long-axis diameter as well as age and T stage were independent prognostic factors. LNs with a larger long-axis diameter had a significantly increased intranodal B-cell area ratio.
A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer.
Authors: Janjigian Yelena Yuriy , Ku Geoffrey Yuyat , Ilson David H. , Boyar Michelle S. , Capanu Marinela , Chou Joanne F. , Kelsen David Paul , Imtiaz Tooba , Berger Michael F. , Vakiani Efsevia 
Published: February 2017

59 Background: Trastuzumab combined with chemotherapy is the standard of care for pts with HER2+ EG cancer. Resistance to trastuzumab clearly emerges in this population. Afatinib, a potent ErbB Family Blocker, induced tumor regression in MSKCC HER2+ patient derived xenografts (PDX). This study assesses safety and preliminary efficacy of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma, after progression on trastuzumab, received oral afatinib 40 mg daily. Archival pre-trastuzumab tissue, tumor biopsy after progression on trastuzumab and after 1 week on afatinib is mandated on protocol for next generation sequencing (NGS), proteomics and establishment of PDX. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 20 pts treated with afatinib; median age 61, KPS 80; median 2 (1 to 4) prior trastuzumab regimens, 67% of tumors IHC3+; 33% IHC2+/FISH>2.0. Common adverse events included: rash or dry skin (Grade 1/2:80%), diarrhea (Grade 1/2:60%), nausea/vomiting (grade 1/2:40%) fatigue (grade1/2: 25%). To date, 19 pts evaluable for response, 2 PRs and 6 SD, 42% disease stabilization rate (PR+SD) at 4months (4 to 13 mos). PDXs established from biopsies of 7 pts. EGFR amplification was detected in the tumor of 2 pts with PRs and 1 of 6 pts with SD. Recurrent PIK3CA, ERBB3 and MTORmutations were observed. Conclusions: Afatinib shows clinical efficacy and is well tolerated in patients with trastuzumab refractory, heavily pretreated EG cancer. Enrollment has now begun in an afatinib + trastuzumab cohort. Efforts to elucidate the mechanisms of trastuzumab resistance including validation of potential drivers of trastuzumab resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.
Comprehensive analysis of predictive biomarkers for patients with curative colorectal cancer patients and high risk of recurrence.
Authors: Mori Koichiro , Toiyama Yuji , Saigusa Susumu , Noguchi Tomofumi , Ide Shozo , Imaoka Hiroki , Uratani Ryo , Oki Satoshi , Fujikawa Hiroyuki , Hiro Junichiro , Kobayashi Minako , Ohi Masaki , Araki Toshimitsu , Inoue Yasuhiro , Tanaka Koji , Mohri Yasuhiko , Kusunoki Masato 
Published: February 2017

607 Background: Preoperative serum systemic inflammatory response (SIR) has been reported in patients with various cancers including colorectal cancer (CRC) as predictive biomarker of early recurrence. Molecular phenotypes of CRC including microsatellite instability (MSI) status and tumor infiltrating lymphocytes (TILs) have also known to be associated with recurrence in curative CRC patients. We comprehensively evaluated SIR status, MSI status and TILs in curative CRC patients and investigated which can be promising as high risk markers of recurrence in these patients. Methods: This retrospective study enrolled 157 CRC patients with stage I-III undergoing curative operation for whom preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and CRP were available as indicators of SIR status. For analysis of molecular phenotypes, we evaluated TILs by counting the number of intra-tumor Foxp3 and CD8 positive T cells by IHC analysis. Next, MSI status was determined in using 5 mononucleotide repeat microsatellite markers. Finally, we investigated the impact of SIR status, TILs and MSI status on the recurrence of these patients. Results: This study included a total of 90 males and 67 females, with an average age of 66.9 years. Twenty-nine patients (18.4%) developed recurrence. Kaplan-Meier analysis using SIR indicators revealed that patients with high CRP, NLR and PLR levels were significantly poorer disease free survival (DFS) than those with low levels. Low infiltrating CD8-positive T cells were significantly predictive factors for poor DFS, but there was no correlation between MSI status and recurrence, In univariate analysis, low infiltrating CD8-positive T cells, high CEA, CRP, NLR and PLR levels in serum were significantly predictive factors for poor DFS, respectively. Multivariate analysis showed that low infiltrating CD8-positive T cells and high serum CRP levels were independent predictive markers for recurrence in curative CRC patients. Conclusions: We demonstrated that evaluation of both CRP levels in preoperative serum and tumor infiltrating CD8 lymphocytes in CRC tissues are useful to predict the curative CRC patients with early relapse.
Recurrence score distributions in stage II colon cancers of African American (AA) and Caucasian (CA) patients.
Authors: Govindarajan Rangaswamy , Posey James , Chao Calvin Y. , Lu Ruixiao , Jadhav Trafina , Javed Ahmed Y. , Javed Awais , Mahmoud Fade A. , Osarogiagbon Raymond U. , Manne Upender 
Published: February 2017

613 Background: The 12-gene colon cancer assay (Oncotype DX) can identify groups of stage II colon cancer patients with lower or higher recurrence risk, but distribution of scores based on race/ethnicity has not been assessed. This study compared the distribution of Recurrence Score results and gene expression profiles between African American (AA) and Caucasian (CA) stage II colon cancer patients. Methods: Stage II colon cancer patients were identified from tumor registry data from four institutions: University of Arkansas for Medical Sciences, Little Rock; Veterans Administration Medical Center, Little Rock; Baptist Medical Center, Memphis, and University of Alabama at Birmingham. The 12-gene assay and mismatch repair (MMR) status were performed on formalin-fixed paraffin-embedded tissues by Genomic Health (Redwood City, CA). T-test and Wilcoxon test were used to compare data from the two groups (SAS Enterprise Guide 5.1). Results: Of the 244 subjects, there were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median ages (years) were 66 for AAs and 68 for CAs. Age, gender, surgery year, pathologic T-Stage, tumor location, number of nodes examined, lympho-vascular invasion, and MMR status were not significantly different between groups (p>0.05). Recurrence Score results between AAs (mean 27.9; SD 12.8) and CAs (mean 28.1; SD 11.8) were not statistically different (p>0.05). The proportion of patients with high Recurrence Score values (≥41) was similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups, (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC3 and GADD45B) was significantly different between the racial groups (p>0.05). After controlling for clinical and pathologic covariates, means and distributions of Recurrence Score and gene expression profiles still showed no statistical significance between racial groups (p>0.05). Conclusions: In a cohort of AA and CA stage II colon cancer patients with similar clinical characteristics, the distribution of Recurrence Score results and gene expression data were similar between AA and CA patients.
The role of inflammatory monocytes in human metastatic colorectal cancer.
Authors: Grossman Julie G. , Nywening Timothy M. , Belt Brian , Pittman Elizabeth , Giorgi Andrew , Michael Ahlers , Hawkins William G. , Strasberg Steven M. , Goedegebuure Peter S. , Fields Ryan C. , Linehan David 
Published: February 2017

624 Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. 60% of CRC patients are diagnosed with metastatic (m) CRC and the 5-year survival is <20%. Myeloid cells, particularly inflammatory monocytes (IM), are recruited from the bone marrow to the tumor microenvironment where they become tumor associated macrophages and play a crucial role in tumor progression, metastasis, and chemoresistance. While the importance of IM have been shown in other malignancies, little is known about their role in human CRC. Methods: Human tissue was collected under an IRB approved protocol at Washington University. Flow cytometry was performed on PBMCs and single cell suspensions of normal tissue and tumor samples. Qualitative RT-PCR and confocal microscopy were performed for CCL2. T-cell suppression assays were performed using CD14+ IM isolated from patient peripheral blood and tumor samples. Results: Analysis of pre-operative blood revealed that monocyte levels correlate with the extent of disease burden. Monocytes were elevated in CRC patients compared with controls (p<0.0001), additionally patients with liver metastasis had further elevation in monocytes compared with patient’s with primary disease (p=0.01). In metastatic patients, monocyte levels also correlate with survival following resection of hepatic metastasis (p=0.0002). FACS analysis confirmed these findings and demonstrated that the circulating CD11b+/CD14+/CCR2+ subset of IM was responsible for the increase. Both primary CRC and liver mCRC had increased expression of CCL2 compared to uninvolved tissue (p=0.008 and p=0.03, respectively). Production of CCL2 was localized to CRC cells. FACS analysis showed CCR2+ tumor infiltrating macrophages were elevated in CRC liver metastasis compared to adjacent normal liver and a paucity of effector T-cells. CD14+ TAMs isolated from mCRC inhibited T-cell proliferation, illustrating the immune suppressive phenotype of these cells. Conclusions: Inflammatory monocytes correlate to prognosis in mCRC. Therefore, targeting CCR2+ myeloid cells may improve anti-tumor immunity and patient survival in metastatic disease.
Phase II pharmacodynamic trial of palbociclib in patients with KRAS mutant colorectal cancer.
Authors: O'Hara Mark H. , Edmonds Christine , Farwell Michael , Perini Rodolfo F. , Pryma Daniel A. , Teitelbaum Ursina R. , Giantonio Bruce J. , Damjanov Nevena , Lal Priti , Feldman Michael D , Zhang Paul J. , Mankoff David A. , Gallagher Maryann , DeMichele Angela , Vaughn David J. , O'Dwyer Peter J. 
Published: February 2017

626 Background: Cell cycle dysregulation is a hallmark of most cancers. At the G1/S transition, cyclin dependent kinase (CDK) 4 and CDK 6 proteins associate with cyclin D proteins to allow cell cycle progression. Tumor cells that are driven by abnormalities of the cell cycle through activation of the cdk4/6-cyclin D axis showed increased phosphorylation of retinoblastoma protein (Rb), the major substrate for CDKs at the G1/S transition. Palbociclib is a potent specific inhibitor of cdk 4/6, with preclinical data showing G1 arrest in Rb-positive cells. Since activation of the MAP kinase pathway impacts directly on cdk-cyclin activation, we performed a phase II trial of palbociclib in patients with metastatic, KRAS-mutant colorectal cancer (mCRC). Methods: We screened 36 patients with KRAS mutant mCRC for Rb expression and 35 (97%) were Rb positive. We enrolled 15 patients, 9 (60%) of which were male and 6 (40%) female, median age was 62, 10 (67%) colon, 4 (27%) rectal (27%) rectal, and 1 (7%) appendiceal malignancy. Patients received 125mg daily of palbociclib for 21 days of a 28-day cycle, the recommended phase II dose. Results: Six patients (33%) experienced grade 3 neutropenia, 1 patient had grade 3 neutropenic fever (6%), and 2 patients (11%) had grade 3 AST/ALT elevation. There were no responses, but 5 patients (33%) had stable disease by RECIST criteria after 2 cycles of treatment, and 1 patient had stable disease for 8 cycles. The median number of cycles was two. As a pharmacodynamic marker of activity, 9 patients underwent FLT-PET at baseline and after 1 cycle of therapy. FLT-PET uses the tracer 3’-deoxy-3’[18F]-fluorothymidine, uptake of which is proportional to cellular proliferation. Six of the 9 patients (67%) had a decrease in uptake in target lesions, with an average 20% decrease in uptake in target lesions. FLT uptake in the bone marrow decreased by an average 4.85% and this correlated with a decrease in absolute neutrophil count of 62.3% (r2 0.59). Conclusions: While palbociclib has limited activity in KRAS mutant mCRC as a single agent, there is a clear pharmacodynamic effect as determined by FLT-PET imaging. Given the limited toxicity profile, combinations with non-myelosuppressive agents hold great promise. Clinical trial information: NCT01037790.
Colorectal cancer (CRC) cohort analysis of patients treated with buparlisib in a distinctive tissue-agnostic trial model for molecularly preselected tumors.
Authors: Piha-Paul Sarina Anne , Knost James A. , Nikolinakos Petros , Schwartzberg Lee Steven , Yardley Denise A. , Slosberg Eric Daniel , Kang Barinder , White Theresa , Lebedinsky Claudia 
Published: February 2017

644 Background: This is a CRC cohort analysis from the novel Novartis “Signature” program of tissue-agnostic, genetic alteration specific signal-finding protocols. Potential patients are identified via standard-of-care profiling; we bring the ‘Protocol to the Patient’, with rapid start-up process. Buparlisib (BKM120) is an oral pan-PI3K inhibitor evaluated in this program. Methods: Patients had progressive/relapsed CRC harboring PI3K pathway activated tumors, measurable disease, ECOG PS ≤1, and adequate organ function. A local CLIA-certified test is sufficient for eligibility. Central post hoc broad tumor molecular profiling of genetic alteration is performed. BKM120 was given orally (100 mg) qd. The primary objective is to assess clinical benefit (SD or better at 16 weeks). Statistical design adaptively clusters patients into cohorts for independent analysis for early futility or efficacy. Results: 18 CRC patients were dosed: 10 females, 15 Caucasian, median age 58 years (40-80), all had ECOG PS ≤1. Median prior therapies: 4 (1-13). Actionable alterations present at baseline (local): 10 (55.6%) PIK3CA mutation, 4 (22.2%) PTEN loss (IHC), 3 (16.7%) each PTEN mutated and PIK3R1 mutated. Median time on study was 5.1 weeks (1-16). Frequently observed AEs: nausea (67%), fatigue (39%), vomiting (33%), diarrhea (33%), anxiety (28%) and decreased appetite (28%). Three patients discontinued due to AEs. At week 16: 13 patients did not meet clinical benefit criteria and 5 patients were non-evaluable. Two patients had SD at week 8. Central genomic profiling: DNA from 14 patients was assessed covering a panel of 288 cancer genes. All patients had a mutation in APC, 10 (71%) also had KRAS mutations and 11 (79%) had mutations in TP53. Three patients with the lowest PFS exhibited mutations in ERBB2 and ERBB4. Concordance between local and central lab results was 73%. Conclusions: This program facilitated the enrollment of molecularly profiled CRC patients with PI3K pathway alterations. In this cohort, BKM120 had a manageable safety profile with negligible activity as single agent. Further evaluation can determine the effect of BKM120 in combination with other agents. NCT01833169 Clinical trial information: NCT01833169.
Irinotecan (Iri) and buparlisib (B) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Baranda Joaquina Celebre , Reed Greg , Williamson Stephen K. , Perez Raymond P. , Stoltz Maxine L. , Mackay Chris , Madan Rashna , Pessetto Ziyan Y. , Godwin Andrew K. 
Published: February 2017

655 Background: The PIK3CA pathway has oncogenic role in mCRC. Buparlisib is an oral pan-class PIK3CA inhibitor. It is currently being studied in combination trials for various malignancies. The primary objective of this phase I trial was to identify the maximum tolerated dose (MTD) for Iri plus B in pts with previously treated mCRC, with or without previous Iri therapy. We also performed PK analysis of each drug alone and in combination, determined clinical response to the combination, and evaluated achieval FFPE samples for somatic mutations in a panel of cancer associated genes, including PIK3CA for clinical correlation. Methods: A 3+3 dose titration method was used. Iri was administered intravenously every 14 days (one cycle) and B orally daily. Pts received the first dose of Iri on Cycle1 Day1. B was started 24 hours after the first dose of Iri. Safety and toxicity assessments were performed every cycle. Results: Twenty patients were enrolled: 4 in cohort 0 (Iri 120 mg/m2 + B 50 mg/d), 11 in cohort 1 (Iri 150 mg/m2 + B 50 mg/d), 5 in cohort 2 (Iri 150 mg/m2 + B 80 mg/d). The most common Grades 3/4 adverse events were neutropenia and abdominal pain. The MTD was Iri 150 mg/m2 + B 50 mg/d. The DLTs include male genital mucositis, grade 3 diarrhea, and asymptomatic grade 3 hyponatremia. In cohort 1, one pt experienced grade 2 delirium and a pt in cohort 2 had grade 3 psychosis. Of the 4 pts who received 4 cycles of therapy 2 had stable and 2 had progressive disease. No objective responses were seen. There is no significant change in the PK of Iri between Cycles 1 and 2. B at 50 mg had no consistent effect on the disposition of Iri given at 120 mg/m2 and 150 mg/m2. The Cmax and AUC for B show clear dose proportionality. Using targeted re-sequencing, a 48-gene panel that included AKT1, BRAF, KRAS, and PTEN was performed. The complete analysis of the correlative study will be presented in the meeting. Conclusions: This first human trial established that Buparlisib (50 mg qd) and Iri (150 mg/m2 q14d) are tolerable in combination. However, it is too early to determine the activity of this combination in the treatment of mCRC. Clinical trial information: NCT01304602.
Nomograms for overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer (mCRC): Construction from 19,678 ARCAD patients.
Authors: Sjoquist Katrin Marie , Renfro Lindsay A. , Simes John , Tebbutt Niall C. , Clarke Stephen John , Meyers Jeffrey P. , Gonsalves Wilson I. , Adams Richard , Seymour Matthew T. , Saltz Leonard , Schmoll Hans , Sargent Daniel J. , De Gramont Aimery , Zalcberg John Raymond ,   on behalf of the Fondation Aide et Recherche en Cancérologie Digestive (ARCAD) Group
Published: February 2017

659 Background: Prospective survival prediction of patients with metastatic colorectal cancer is difficult. Prognosis estimation based on readily available clinicopathologic factors has the potential to inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for OS and PFS in mCRC using the multi-trial ARCAD database. Methods: Data from 19,678 mCRC pts accrued to 24 first line randomized phase III clinical trials since 1997 were used to construct and validate Cox models for PFS and OS, stratified by treatment arm within each study. Candidate variables included age, gender, BMI, performance status, colon vs. rectal cancer, prior chemotherapy, number of metastatic sites, sites of metastases (liver, lung, lymph nodes), and baseline bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil:lymphocyte ratio (dNLR). Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions considered if p<0.001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated using a 10% holdout sample from each trial. Results: Nomograms for OS and PFS including remaining variables were well calibrated with C-indices of 0.66 and 0.60, respectively. Evaluation of external validity revealed good concordance; 71% and 67% respectively between predicted (> vs. <50% probability) and actual (yes/no) 1-year OS and 6-month PFS, and median 1-year OS and 6-month PFS predictions fell within the actual 95% Kaplan-Meier intervals. Gender, liver and lung metastases, and dNLR were not prognostic for OS; prior chemo, colon vs. rectum, dNLR, liver and lymph node metastases, and gender did not predict for PFS. No clinically relevant pairwise interactions were identified. Conclusions: The proposed nomograms are well calibrated and internally and externally valid. These tools have the potential to aid prognostication and patient/physician communication, and balance risk in randomized trials in mCRC.