bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel solution to achieve “80% by 2018” Two-Man colonoscopy performed by primary care physicians with expert back-up: Compliance and capacity without diluting quality.
Authors: Lloyd Stephen Carroll 
Published: February 2017

544 Background: The American Cancer Society (ACS) supports 80% by 2018. We have an innovative solution to address barriers: compliance and capacity without diluting quality. Methods: The “gold standard” test is a high-quality colonoscopy. To improve compliancewe leverage the primary care physician (PCP) through navigators. The existing colonoscopists are saturated while screening only half. Quality, as reflected in the protective benefit, is called into question by large-scale studies. An estimated 7% of CRCs are diagnosed as “interval cancers.” occurring in patients compliant with screening. Results: First, when the PCP invites the patient, their “butts” show up! Compliance in our study more than doubled and exceeded the ACS 80% by 2018 goal. We present an update to the initial study (de Groen, NEJM 2014) adding 15,000 more consecutive cases and 4 years to the database; incidence dropped (83%) as did mortality (89%). This is the first large study to demonstrate no diminution of protection in the right colon! Our hypothesis is that the two-man technique simplifies visualizing the mucosal surface. The continual availability of an “expert” to “mentor and monitor” was sufficient to supervise 30 PCPs and thus augment capacity (4,000 cases rather than 1,000 cases per year per expert). With the average cost of $250,000 per case of advanced CRC, the savings are more than double the screening costs. Conclusions: The inclusion of the PCP in CRC screening addresses the barriers: enhanced compliance, augmented capacity without any diminution in quality. The PCP provides capacity needed to screen the underserved (more than half of the at risk population not “up to date” with screening colonoscopy). Rather than taking patients from traditional providers, the model has excelled in identifying the underserved. To achieve 80% by 2018 will require 6,000,000 additional annual screening colonoscopies but would prevent 100,000 cases of CRC and 25,000 deaths. At the current rate, 30,000 PCP colonoscopists could meet this demand. Utilizing PCPs using the team colonoscopy approach could one day result in near elimination of deaths from “the preventable cancer.”
Molecular profiling of TOPO1: A way to evaluate irinotecan treatment in colorectal cancer?
Authors: Cunningham Julia Marie , Prins Petra , Conkright Brian , Boca Simina , Rao Shruti , Gabrielson Andrew , Oseran Andrew , Beckman Robert , Al-hajeili Marwan , Madhaven Subha , Marshall John 
Published: February 2017

546 Background: Front-line chemotherapy for metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine backbone plus either oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI). Large, prospective trials enrolling chemotherapy-naïve patients (pts) show FOLFOX and FOLFIRI treatment to be equivalent with similar response rates. Methods: Irinotecan inhibits TOPO1, which is now a candidate marker for irinotecan treatment benefit. Thus, we retrospectively analyzed TOPO1 expression level in 49 pts with mCRC who were treated with irinotecan-containing regimens at the Lombardi Comprehensive Cancer Center between 2009 and 2014. Patient characteristics and outcomes were compiled through chart review and the effect of TOPO1 expression on clinical outcomes was assessed. TOPO1 expression in tumor tissue from each pt was analyzed using a commercially available molecular profiling (MP) service (Caris Life Sciences). Results: The median overall survival (OS) for all pts was 33.9 months (mo), defined as the time from metastasis to death or censorship. When grouped by “high” or “low” TOPO1 expression, as defined by Caris at the time of the testing, 29 pts were high-expressers and 20 were low-expressers. High TOPO1 expressers receiving irinotecan (n = 22) had a median OS of 27.2 mo, compared with median 41.5 mo for low-expressers (n = 14) (p = 0.27). Irinotecan is conventionally given as second-line therapy. The median OS of pts receiving second-line irinotecan was 38.2 mo for high-expressers [n = 11] vs. 68.5 mo for low-expressers [n = 5]) (p = 0.32). Conclusions: Our limited data do not support the use of TOPO1 expression levels as a predictive marker for irinotecan therapy in mCRC. However, our conclusions are limited by small sample size, lack of a control group to distinguish prognostic from predictive markers, and timing of TOPO1 measurement, which in many cases was after irinotecan therapy. Physicians currently lack an evidence-based way to choose between potentially efficacious regimens for mCRC. More rigorous studies are needed to assess the benefit of MP in mCRC care. We are currently planning a prospective study with the hope of validating the use of TOPO1 expression as a predictive marker for treatment of this disease.
IHC-based predictive biomarker for irinotecan response.
Authors: Ando Koji , Shah Ankur K. , Sachdeva Vibhu , Taylor-Parker Julian , Oki Eiji , Bharti Ajit 
Published: February 2017

548 Background: For gastro-intestinal cancers, irinotecan is used as first or second line, either as single agent or in combination therapy. The patient response rate is low and drug resistance mechanism is not understood. Irinotecan like other topoisomerase I inhibitors (camptothecin and their analogues, CPTs) are not MDR substrates, topoI mutations are rare and other potential mechanisms have not been validated. One of the most distinct cellular responses to CPT is the proteolytic degradation of topoI by the ubiquitin proteosomal pathways (UPP) and the rate of topoI degradation determines the drug response. Using a functional proteomic approach we have defined the mechanism of UPP mediated topoI degradation and have identified the molecular determinant of CPT resistance. We have demonstrated that higher basal level of topoI-pS10 drives rapid topoI ubiquitination and degradation in response to CPT. Methods: We have raised mouse monoclonal antibody that specifically binds with topoI-pS10 for immunohistochemistry (IHC) staining of the formalin fixed paraffin embedded (FFPE) slides. In our first cohort of retrospective study, 48 metastatic colorectal cancer tissues were immunostained with anti-topoI-pS10 and nuclear staining was quantitatively analyzed. Results: Data were summarized with descriptive statistics. ROC analysis was used to assess diagnostic characteristics across different thresholds. Mean and median positive nucleation values correlated strongly with drug response. Median nucleation level among non-responders was 69% compared to 9% for responders (Wilcoxon p = 0.0006). ROC analysis demonstrated an optimal threshold between 30-40% nucleation. Using a threshold of 35%, the estimated sensitivity was 82% (95% CI 56-95) and specificity was 77% (57-89). Estimated positive and negative predicted values were 67% (43-85) and 88% (69-97) respectively. We have also got similar results in 80 patient gastric cancer retrospective studies. Conclusions: Basal level of topoI-pS10 can be used as a predictive biomarker for topoI inhibitors. Our IHC based test can be adopted in clinical pathology settings to determine the topoI-pS10 level and stratify the patient population for CPT based therapy.
Intra-individual genetic heterogeneity among liver metastases in metastatic colorectal cancer.
Authors: Sveen Anita , Loes Inger Marie , Alagaratnam Sharmini , Nilsen Gro , Høland Maren , Lingjaerde Ole Christian , Sorbye Halfdan , Berg Kaja Christine Graue , Horn Arild , Angelsen Jon-Helge , Knappskog Stian , Lonning Per Eystein , Lothe Ragnhild A 
Published: February 2017

555 Background: Almost 50% of patients with colorectal cancer (CRC) develop liver metastases, often as multiple simultaneous metastatic deposits. Up to 25% of the patients are eligible for partial liver resection, but 70% will relapse after surgery and there are currently no good criteria to select patients who will benefit from the treatment. Genetic heterogeneity among metastatic deposits has great potential impact on disease progression, but has not been well described. Methods: Totally 134 liver metastatic deposits were collected from 45 patients undergoing partial liver resection for metastatic CRC according to a prospective study protocol. All deposits were analyzed for high-resolution DNA copy number variation using the Affymetrix SNP Array 6.0. A novel bioinformatic approach was used to measure intra-individual genetic heterogeneity among the metastatic deposits. Results: The patients showed a large variation in the level of intra-individual metastatic heterogeneity, and heterogeneity was independent of the number of liver metastases analyzed per patient. Heterogeneity was a strong and independent prognostic factor in multivariate analysis with known clinicopathological prognostic factors. Patients with a high level of heterogeneity (above the median) had a three-year overall survival rate of 18%, compared with 66% for patients with a low level (hazard ratio, HR = 3.7, P = 0.007). The corresponding survival rates for progression-free survival were 6% and 24% (HR = 2.6, P = 0.01). Conclusions: A high level of intra-individual genetic heterogeneity among liver metastatic deposits is associated with poor survival after partial liver resection in patients with metastatic CRC.
Association between cetuximab response and differential immunologic gene expression signatures in colorectal cancer metastases.
Authors: Lee Michael Sangmin , Vincent Benjamin Garrett , McRee Autumn Jackson , Sanoff Hanna Kelly 
Published: February 2017

558 Background: Different immune cell infiltrates into colorectal cancer (CRC) tumors are associated with different prognoses. Tumor-associated macrophages contribute to immune evasion and accelerated tumor progression. Conversely, tumor infiltrating lymphocytes at the invasive margin of CRC liver metastases are associated with improved outcomes with chemotherapy. Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) and stimulates antibody-dependent cellular cytotoxicity (ADCC) in vitro. However, it is unclear in humans if response to cetuximab is modulated by the immune response. We hypothesized that different immune patterns detected in gene expression profiles of CRC metastases are associated with different responses to cetuximab. Methods: We retrieved gene expression data from biopsies of metastases from 80 refractory CRC patients treated with cetuximab monotherapy (GEO GSE5851). Samples were dichotomized by cetuximab response as having either disease control (DC) or progressive disease (PD). We performed gene set enrichment analysis (GSEA) with GenePattern 3.9.4 using gene sets of immunologic signatures obtained from the Molecular Signatures Database v5.0. Results: Among the 68 patients with response annotated, 25 had DC and 43 had PD. In the PD cohort, 59/1910 immunologic gene sets had false discovery rate (FDR) < 0.1. Notably, multiple gene sets upregulated in monocyte signatures were associated with PD. Also, gene sets consistent with PD1-ligated T cells compared to control activated T cells (FDR = 0.052) or IL4-treated CD4 T cells compared to controls (FDR = 0.087) were associated with PD. Conclusions: Cetuximab-resistant patients tended to have baseline increased expression of gene signatures reflective of monocytic infiltrates, consistent with also having increased expression of the IL4-treated T-cell signature. Cetuximab resistance was also associated with increased expression of the PD1-ligated T cell signature. These preliminary findings support further evaluation of the effect of differential immune infiltrates in prognosis of metastatic CRC treated with cetuximab.
Differences in gene-expression in mCRC tissue samples with regard to tumor location and used chemotherapeutic substances: Data of the FIRE-1 study.
Authors: Stintzing Sebastian , Modest Dominik Paul , Jung Andreas , Kirchner Thomas , Schäfer Reinhold , Sers Christine , Hildebrandt Bert , Daum Severin , Folprecht Gunnar , Schuler Martin H. , Kasper Stefan , Trojan Jorg , Jaeger Dirk , Schulze-Bergkamen Henning , Fischer von Weikersthal Ludwig , Schalhorn Alexander , Heinemann Volker 
Published: February 2017

562 Background: Colorectal cancer can be divided in different subgroups by their way of carcinogenesis. Clinically, right-sided (caecum, colon ascendens and transverse colon) and left-sided tumors (colon descendens, sigmoid and rectum) have different prognosis. The reasons behind the different prognosis remains unclear and can be found in both, anti-VEGF treated tumors and anti-EGFR treated tumors, with a more prominent effect for anti-EGFR treated patients. Until now, differences in efficacy of chemotherapeutic treatment between left-sided and right-sided colorectal cancer tumors have not been elucidated. Methods: 168 tumor samples of the FIRE-1 trial were investigated for RNA expression of the tumorous tissue. RNA was extracted of microdissected FFPE tissue and used for NanoString gene expression analysis. A total of 790 different RNAs were analyzed using the nCounter PanCancer Pathways Panel plus 20 RNA´s with key roles in the metabolism of substances commonly used in mCRC treatment. Using nSolver Software, normalization and quality control was done according to the manufacturer’s recommendations. Differences in expression between right- and left-sided tumors were calculated. P values were corrected using Benjamini-Yakutieli false discovery rate (FDR). Results: Data of 160 tumor samples passed QC and had sufficient data on location of the primary. Of the 790 tested RNA´s 70 showed significant differences in univariate analysis. Among those were EREG which has been reported to be of predictive value for anti-EGFR antibody treatment and ANGPT1 that has been reported to be of predictive value for anti-VEGF antibody treatment. Furthermore TS has been expressed differentially which has been reported to be predictive for the use of 5-FU. Conclusions: Patients with right-sided mCRC tumors have a worse prognosis when compared to left-sided tumors. Reasons for this are manifold. We are able to find significant differences in genes associated with 5-FU, anti-EGFR antibody, and anti-VEGF antibody treatment which may be able to explain some of the differences seen in clinical trials.
Clinical prognostic factors and genomic analysis of ovary metastases (mets) from colorectal cancer (CRC).
Authors: Ganesh Karuna , Shah Ronak , Vakiani Efsevia , Kemeny Nancy E. , Lincoln Anne , Tran Christina , Varghese Anna M. , Yaeger Rona D. , Cercek Andrea , Segal Neil Howard , Reidy Diane Lauren , Epstein Andrew S. , Weiser Martin R. , Garcia-Aguilar Julio , Berger Michael F. , Saltz Leonard , Stadler Zsofia Kinga 
Published: February 2017

564 Background: Ovary mets constitute 5-10% of CRC mets, are associated with poor prognosis, cause morbidity due to disproportionately rapid growth compared with other mets and are less responsive to chemotherapy. The optimal management of ovary mets and the molecular basis of their unique growth pattern is unknown. Methods: 505 MSKCC patients with CRC (ICD-9 153, 154) and ovary mets (ICD-9 198.6) were identified. Patients without available pathology, with appendix cancer or only serosal ovary mets were excluded. Regression models were used to identify predictors of progression-free survival (PFS) and overall survival (OS) after surgery. Targeted exome sequencing of 341 cancer-associated genes was performed on 34 CRC ovary mets, including 20 matched pairs or trios of primary tumors, ovary mets and other mets from the same patient. Results: 184 patients with surgically resected CRC ovary mets were evaluated (median age 50 (17-86); OS 40 months (0.8-218) from CRC diagnosis, 23 months (0.2-199) from oophorectomy). 93/116 (80.2%) evaluable patients had concurrent growth of ovary mets on chemotherapy but shrinkage of other mets. In multivariate analysis, optimal surgical debulking was associated with improved PFS (HR = 0.11 (0.04-0.36)) and OS (HR = 0.42 (0.28-0.63)). Discordant ovary therapy response was associated with early progression (HR = 20.8 (1.59-274), and post-oophorectomy chemotherapy with reduced mortality (HR = 0.53 (0.33-0.84)). Ovary mets had increased KRAS (61.7% vs. 45.2%, p= 0.05) and SMAD4 (29.4% vs. 15.5%, p= 0.04) mutations compared to a 453 CRC cohort without ovary mets. In matched trios, mutations were largely concordant across tumor sites and no recurrent ovary met-specific mutations were found. However, 3/14 cases had identical mutations in the ovary mets and primary tumors, but additional private mutations in other mets. Conclusions: CRC ovary mets have frequent KRAS and SMAD4 mutations. Matched trios show clonal similarities between primary tumors and ovary mets, and divergence from other mets. Complete surgical resection of ovary mets is associated with substantially improved PFS and OS, similar to outcomes for localized CRC.
Whole exome sequencing and gene expression profiling of neuroendocrine carcinoma in the stomach.
Authors: Makuuchi Rie , Terashima Masanori , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Hatakeyama Keiichi , Kusuhara Masatoshi , Yamaguchi Ken , Oshima Keiichi , Urakami Kennichi , Hikage Makoto 
Published: February 2017

57 Background: Neuroendocrine carcinoma (NEC) in the stomach is a rare disease with the incidence of about 0.6 % of all gastric cancer and is well known as a highly malignant tumor with poor survival. Despite the malignant phenotype of this disease, the global gene expression profiling of gastric NEC has not yet been elucidated. We have started a comprehensive molecular profiling project that analyzes genome and transcriptome of tumor obtained from cancer patients admitted to Shizuoka Cancer Center from January 2014, setting a goal to get 3,000 samples in 3 years. We had already evaluated more than 1,500 samples from various types of malignancies, including 111 samples from gastric cancer. Here, we performed deep sequencing of 409 cancer-related genes for gastric NEC patients, adding whole-exome sequencing and gene expression profiling, to identify a gene variant of gastric NEC. Methods: Surgically-resected fresh tumor samples and peripheral blood were analyzed by whole-exome sequencing (Ion Proton, Life Technologies) and gene expression profiling (DNA microarray, Agilent Technologies). A total of 111 patients with gastric cancer were evaluated until August 2015, including 6 gastric NEC (5.4 %). We compared single nucleotide variants (SNVs) and gene expression profiles between gastric NEC and gastric adenocarcinoma. Results: All the gastric NEC patients were male with median age of 69 years (59–79 years). According to classification of TNM 7th, there were two patients with stage IA, one with IIA, one with IIIB and two with IIIC. Three of them had adenocarcinoma components constituted > 30% of the respective tumors, fulfilling the criteria for mixed adenoneuroendocrine carcinoma (MANEC), as defined by the WHO classification. There was no specific SNV for NEC. However, gene expression profiling identified several specific genes expressing in NEC; most of the highly expressed genes were also known to be expressed in neuroendocrine cells. Furthermore, CPLX2 and SCG3, which had been reported to be expressed in various neuroendocrine tumors, were included. Conclusions: Gastric NEC could be characterized by specific gene expression including those expressed in neuroendocrine cells and neuroendocrine tumors.
Molecular profiling of appendix-derived pseudomyxoma peritonei (PMP).
Authors: Gleeson Elizabeth , Feldman Rebecca , Millis Sherri Z. , Mapow Beth , Mackovick Lynn , Reddy Sandeep K. , Bowne Wilbur B. 
Published: February 2017

571 Background: PMP is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. Cytoreductive surgery and intraperitoneal chemotherapy offers optimal outcomes for most patients; however, for patients that progress, there are few treatment options. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy. Methods: 54 patients with appendix-derived PMP were included in the study and tested centrally at Caris Life Sciences (Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: Targeted sequencing of 47 genes detected variants in KRAS (79%), GNAS (73%) and SMAD4 (18%). Mutations were found at low frequencies (n = 1-2) in APC, ATM, BRAF, PIK3CA, MLH1 and TP53. GNAS and KRAS co-occurrence was found in 38%. High rates of protein overexpression were found in EGFR (83%), cMET (59%), cKIT (58%) and PDGFRA (58%), respectively. Immune checkpoint expression was found in 36% (PD1-positive tumor infiltrating lymphocytes) and 9% (PDL1 tumor expression). Expression of surrogate markers of cell proliferation were found at low rates (TLE3 27%, TOP2A 22%), consistent with the slow-growing biology of PMP. PTEN was intact (wild type [100%] and positive IHC [80%]) in the majority of PMP. Patients exhibit stable microsatellite status and mismatch repair proficiency in 93% of patients. Importantly, multidrug resistance protein expression was found at high levels (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1) and irinotecan (TOPO1) chemo-sensitivities were found to be favorable in 93%, 87%, 77% and 65%, respectively. Conclusions: Molecular profiling by multiple platforms identified potential therapy options in the non-targetable setting of a KRAS-mutated population. The role of cMET-targeted therapies and immune checkpoint inhibitors merit further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate responses to systemic treatment.
Whether mCRC patients with other RAS mutations benefit from the addition of bevacizumab as first-line therapy.
Authors: Zhou Mingyi , Yu Ping , Hou Kezuo , Qu Xiujuan , Liu Yunpeng , Chen Ying , Qu Jinglei , Zhang Jingdong 
Published: February 2017

579 Background: It is not clear whether Bevacizumab plus chemotherapy could improve the prognosis of mCRC patients with other RAS mutations beyond KRAS exon 2. Methods: The MEDLINE, EMBASE, Cochrane databases, and Clinical Trials databases were reviewed to September 2015. The data of patients with KRAS exon 2 mutations was only available in FIRE3 study. So we could not perform the meta-analysis by KRAS exon 2 mutations. The data of patients with other RAS mutations beyond KRAS exon 2 were available in PEAK and FIRE3 studies. Hazard ratio (HR) was used to analyze the progressive-free survival (PFS) and overall survival (OS). Relative risk (RR) was used to analyze overall response rate (ORR). Results: Patients with other RAS mutations beyond KRAS exon 2 benefited from the addition of Bevacizumab. Bevacizumab + chemotherapy significantly improved the PFS compared with anti-EGFR moAb + chemotherapy (HR: 1.82, CI: 1.20–2.77, P =.005). The addition of Bevacizumab tended to improve ORR, though there is no significant difference (RR: 0.83, CI: 0.58–1.18, P =.288). But the OS tended to be shorter in Bevacizumab + chemotherapy arm than anti-EGFR moAb + chemotherapy arm without significant difference (HR: 0.72, CI: 0.25–2.05, P =.534). Conclusions: Patients with other RAS mutations beyond KRAS exon 2 could choose Bevacizumab plus chemotherapy as first-line therapy. But there is still no adequate evidence to reject or support the predictive value of RAS status in the effect of the addition of Bevacizumab. Moreover, which is the better primary endpoint, PFS or OS? Which is the better consequence of strategy, anti-EGFR moAb followed by Bevacizumab or Bevacizumab followed by anti-EGFR moAb? RCTs with large sample size comparing the efficacy of anti-VEGF moAb + chemotherapy and chemotherapy alone by RAS status as the first-line therapy in mCRC patients are required in the future.