bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of recurrence in stage I/II colorectal cancer: Analysis of a single institution’s experience for over 24 years.
Authors: Gonzalez Velez Miguel , Duma Narjust , Sanchez Larysa Jessica , Undamatla Ramya , Ruiz Mino Jose , Gutierrez Martin
Published: February 2017

534

Background: Surgical resection remains a mainstay of treatment for localized colorectal cancer (CRC). However, up to 35% of patients (pts) develop recurrence with a significant decrease in overall survival. The aim of this study was to evaluate clinical characteristics and specific predictors of recurrence for stage I/II CRC Methods: We performed a retrospective analysis of 2310 pts diagnosed with stage I/II CRC at our institution between 1990 and 2013, with a minimum follow up of 24 months. Tumor characteristics and recurrence data were studied. Cox regression was used for statistical analysis. Results: Of the 2310 pts, recurrence was identified in 276 (12%) pts, of which 88 (32%) pts had early recurrence ( < 1 year). Median time of recurrence was 625 days. 210 (76%) pts had local recurrence while 66 (24%) pts had distal recurrence, with liver being the main site of distant metastasis. Males had a higher recurrence rate than females (16% vs. 7%, p < 0.0001). When comparing recurrence pts (R) with non-recurrence (NR) pts, Hispanics were more prevalent in the R group (13% vs 8%, p < 0.01). R pts were more likely to have rectal and poorly differentiated tumors (33% vs. 13%, p < 0.0001; 23% vs. 14%, p < 0.0001, respectively). Mucinous adenocarcinomas were more prevalent in the R group (16% vs. 9%, p < 0.0005). In multivariate analysis: male sex (OR: 1.24, 95% CI: 1.21-1.56, p < 0.001), rectal tumors (OR: 4.2, 95% CI: 3.14-5.06, p < 0.001), tumor size (OR: 2.55, 95% CI: 1.31-4-51, p < 0.01), and positive margins (OR: 3.6, 95% CI: 2.13-5.21, p < 0.04) were independent predictors for recurrence. K-ras (+) status was a predictor of recurrence by univariate analysis. Age, race, and histologic grade were not predictors of recurrence. Pts with early recurrence had a lower median overall survival compared to pts that developed recurrence after 1 year, 37 months (95% CI: 26.6-49.6) vs. 59 months (95% CI: 42.4-74.3), p < 0.04. Conclusions: Pts with recurrence were more likely to have rectal and poorly differentiated tumors. Poorer survival was observed in pts with early recurrence. These findings could serve as important prognostic information and may help identify the pts that would benefit from aggressive surveillance after treatment.
Genotype-phenotype correlation of gastric cancer in familial adenomatous polyposis.
Authors: Ito Tatsuhiro , Iwaizumi Moriya , Tao Hong , Osawa Satoshi , Kurachi Kiyotaka , Hamaya Yasushi , Takagaki Kosuke , Furuta Takahisa , Sugimoto Ken , Sugimura Haruhiko , Maekawa Masato
Published: February 2017

535

Background: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colorectal tumor syndrome characterized by the formation of a number of adenomatous polyps throughout the entire colon. Clinically, a precise family history together with surveillance of the colon as well as extra-colonic organs for people at risk is important to prevent cancer progression because of an almost 100% lifetime risk of colorectal cancer if the colon is not removed. Although there are fascinating correlations between the location of the APC mutation and the clinical phenotype, none has reported about genotype-phenotype correlation of gastric cancer in FAP, which occupies 2.1-4.2% in East Asia. Methods: Peripheral blood samples were obtained from 29 probands that was clinically diagnosed with FAP and DNA was extracted from the peripheral blood. All the coding exons of APC and their boundary regions were amplified using PCR and were directly sequenced. For large deletion/insertion analysis, an MLPA was performed using MLPA kit (P043 APC, MRC-Holland). Using results from the APC mutation analysis, we examined correlation between location of APCgermline mutation and clinical phenotype including gastric cancer. Results: Among 16 probands (3 cases were severe FAP, 12 cases classical FAP, and one case attenuated FAP) that were identified APC germline mutation, correlation between density of colonic adenomatous polypsosis and distribution of the APC mutation donated the same tendency of previous report. Among the 16 probands, 11 had fundic gland polyposis (FGPs) of the stomach and three had gastric adenocarcinoma (one case with FGPs and others without FGPs). Interestingly, all the three cases did not have severe adenomatous polyposis of the colon and their APC mutations were distributed at the location that is reported to be correlated with attenuated FAP. Conclusions: Patients with gastric cancer in FAP clinically have a tendency of having non-severe adenomatous polyposis of the colon and their location of APC mutation may be correlated to the hot spot location of attenuated FAP, suggesting that patient with non-severe colonic adenomatous polyp should have upper GI screening for gastric cancer prevention.
Thromboembolism incidence in patients with gastrointestinal tract cancer receiving chemotherapy: A single-institutional retrospective cohort analysis.
Authors: Oba Ayane , Nakamura Michio , Murai Taichi , Matsuda Chika , Itaya Kazufumi , Koike Yuta , Endo Ayana , Tsukuda Yoko , Ono Yuji , Kudo Takahiko , Nagasaka Atsushi , Nishikawa Shuji
Published: February 2017

541

Background: Although cancer and its treatments are well-recognized risk factors for thromboembolism (TE), such as venous and pulmonary TE, there are very few data of the incidence of cancer associated TE in the Asian population. So we conducted a retrospective cohort study to investigate the TE incidence of gastrointestinal tract cancer (GTC) patients (pts) receiving chemotherapy in a Japanese community hospital’s daily practice setting. Methods: All the patients received chemotherapy for GTC in our hospital from January 2008 to May 2015 were identified through medical records review extracted by our hospital data warehouse. We analyzed the incidences of TE by reviewing all the reports of contrast-enhanced computed tomography performed on each patient during chemotherapy and identified the association between several clinicopathological factors and TE incidence using chi-square tests and logistic regression. Results: Five hundred fourteen Japanese GTC pts were analyzed on this study. Patient characteristics were as follows; male/female 317/197, median age 69.1 (range 21.1 - 89.1), Gastric (GC)/Colorectal cancer (CRC) pts 213/301, non-adjuvant (non-Adj)/adjuvant (Adj) setting 314/200, tumor-bearing (TB)/non-TB pts 344/170, multiple primary (MP)/single primary (SP) pts 29/485. The incident rate with TE in GC and CRC pts was 10.3 % (n = 22) and 16.6 % (n = 50), respectively. In relation to the status of malignancy, the incidence of TE was 16.6 % (n = 52) and 10.0 % (n = 20) in non-Adj and Adj setting (p = 0.0367), 16.9 % (n = 59) and 7.9 % (n = 13) in TB and non-TB pts (p = 0.007), 31.0 % (n = 9) and 13.0 % (n = 63) in MP and SP pts (p = 0.007), respectively. Conclusions: We found that there were significantly higher incidences of TE in non-Adj, TB, and MP compared with Adj, non-TB, and SP pts, respectively. Although the ethnic differences of the TE incidence rate between Caucasian and Asian population were reported, the incidence of Asian population received cancer chemotherapy remains unclear yet. So further accumulation of data are necessary to establish a Guideline for Asian to prevent and manage TE occurred during cancer chemotherapy such as ESMO or ASCO guidelines. Clinical trial information: UMIN000018912.
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.
A prospective translational study investigating molecular predictors of resistance and response to regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (mCRC): Initial magnetic resonance imaging (MRI) sub-study result.
Authors: Khan Khurum Hayat , Rata Mihaela , Koh Dow-Mu , Tunariu Nina , Collins David J. , Chau Ian , Watkins David J. , Starling Naureen , Rao Sheela , Peckitt Clare , Fotiadis Nicos , Begum Ruwaida , Saffery Claire , Thomas Janet , Gerlinger Marco , Valeri Nicola , Cunningham David
Published: February 2017

580

Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (Ktrans) derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and Ktrans were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour Ktrans was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median Ktrans change (-36 to + 17%). Overall, the cohort average Ktrans decreased from 0.17 to 0.07 min-1(58%). No significant ADC changes were observed at day 15. Of the 4 pts with Ktrans reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no Ktrans change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with Ktrans reduction were classified as responders. Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings. Clinical trial information: EUDRACT No: 2014- 003579-51.
Tumor site, clinicopathological characteristics, and survival of patients undergoing primary elective colorectal cancer resection.
Authors: Park James Hugh , Edwards Joanne , Roxburgh Campbell S.D. , Mcmillan Donald C. , Horgan Paul G.
Published: February 2017

585

Background: Cancers arising in the proximal and distal colorectum differ in embryological origin, predisposing genetic and epigenetic mutations, clinicopathological characteristics and survival. However, the effect of tumor site on the prognostic value of clinicopathological characteristics and systemic inflammatory responses (SIR) is not known. The present study aims to examine the relationship between tumor site, clinicopathological characteristics and cancer-specific survival (CSS) in patients undergoing elective colorectal cancer (CRC) resection. Methods: Patients who had undergone elective, primary resection of stage I-III CRC (1997-2013) were included. Tumors were categorized as proximal (cecum to splenic flexure) or distal (splenic flexure to rectum) based on pathological reports. SIR was assessed using modified Glasgow Prognostic Score (mGPS; 0-CRP < 10mg/L, 1-CRP > 10mg/L, 2-CRP > 10mg/L and albumin < 35g/L). Results: 796 patients were included; 302 tumors were proximal and 494 were distal to the splenic flexure. Proximal location was associated with advanced age, T stage, poor differentiation, greater lymph node yield, peritoneal involvement and an increased mGPS (all P< 0.01). In all patients, on multivariate survival analysis, distal tumor site, advanced age, T stage, N stage, venous invasion, margin involvement and mGPS were independently associated with reduced CSS (all P< 0.05). In patients with proximal cancer, only age (HR 1.8, P= 0.001), T stage (HR 1.9, P= 0.009), N stage (HR 1.9, P< 0.001) and mGPS (HR 1.6, P= 0.004) were associated with CSS, whereas in patients with distal CRC, T stage (HR 1.4, P= 0.024), N stage (HR 1.5, P= 0.001), venous invasion (HR 1.5, P= 0.038), margin involvement (HR 4.1, P< 0.001) and mGPS (HR 1.5, P= 0.003) were associated with survival. Conclusions: In the present study, tumor site was associated with distinct clinicopathological characteristics. Furthermore, the prognostic value of pathological characteristics currently employed in tumor staging, such as venous invasion and margin involvement, differed with tumor site, whereas evaluation of the SIR was similarly prognostic in patients with proximal and distal CRC.
Palliative treatment of obstructive esophageal cancer by vascular targeted photodynamic therapy (VTP): Preclinical study in orthotopic rat model.
Authors: Uzana Ronny , Preise Dina , Agemy Lilach , Elmoalem Rachel , Belkin Varda , Sasson Keren , Yechezkel Tamar , Salomon Yoram , Scherz Avigdor Joshua
Published: February 2017

59

Background: Vascular targeted photodynamic therapy (VTP) based on local sensitization of circulating WST11 (Pd-bacteriochlorophyll), enables effective focal ablation of solid tumors. WST11 clears from the circulation with t1/2 ~40 min (in humans) and does not accumulate in tissues which assures high level of safety and minimal adverse effects. Here we evaluate WST11-VTP for the treatment of obstructive esophageal cancer aiming at developing clinically relevant protocol. Methods: Using endoscopy guided procedure rat esophageal cancer cells (JA) were implanted in the mid esophagus. Following intravenous infusion of WST11, established tumors were illuminated by cylindrical fiber using the same endoscope sleeve. Safety and efficacy were evaluated by monitoring animal weight shift and histology of treated esophageal tissues. Treated animals included control (light/no WST11 or WST11/no light), WST11-VTP and WST11-VTP following treatment with bevacizumab at day -3. Results: WST11-VTP on esophageal tissues resulted in coagulative necrosis of the tumor graft and prolonged survival as evident by Kaplan—Meyer curves. The impact was confined to the illuminated site without signs of perforation or death. Following Bevacizumab, WST11-VTP showed similar results while control groups showed no effect. All treated animals started to regain weight at day 7 after VTP. Esophageal tissue and function was completely restored. Conclusions: WST11-VTP could be safely applied for the treatment of esophageal tumors, with only transient and mild adverse effect that are not affected by previous, clinically relevant treatment such as Bevacizumab application. Importantly, VTP effectively eradicated established esophageal tumors and could be translated into a clinical treatment protocol.
Assessing intratumor heterogeneity and evolutionary distance in exome sequencing of colon cancer.
Authors: Popper Ulrich , Rumpold Holger
Published: February 2017

590

Background: Carcinogenesis is considered to be an evolutionary process by natural selection of cell clones which have acquired advantageous heritable characteristics. This adaption process, which resembles Darwin’s evolutionary theory, has also been suggested as a potential mechanism promoting resistance to anti-cancer treatment. Methods: We performed whole exome sequencing of four colon cancers at five morphologically different loci of the primary tumor tissue. To investigate intratumor heterogeneity we conducted structural variant analysis, copy number analysis and ploidy profiling. We propose an evolutionary distance of the tumor samples based on a distance function in copy number space. Results: Copy number and phylogenetic analysis demonstrated substantial intratumor heterogeneity, with all 20 samples (5 loci for 4 tumors) possessing a unique copy number profile. Our analysis further revealed cancer-specific, tumor-specific and locus-specific copy number variants. We found that at least one copy of 18q, including the genes DCC and SMAD4, as well as 8p, carrying the CSMD1 gene, was missing in all tumors. Additionally, gains of chromosome 7,8q, 13q, 20q and losses of 4q and 21q were frequent. Using our distance measure in copy number space, phylogenetic analysis grouped together the five loci of one tumor and showed their evolutionary branching. We found that our distance measure in copy number space is superior to a distance measure in SNV space for colon cancer. Conclusions: Our analysis reveals that the landscape of the tumor genome cannot be captured by single tumor-biopsy, which is one of the challenges to personalized-medicine as heterogeneity can lead to therapeutic failures. However, there can be characteristics of the tumor genomes that are stable across samples which can potentially be used as biomarkers. Nonetheless variability of copy number profiles of colorectal cancers might suggest a personalized therapy.
Long-term effect of Wnt/β-catenin small molecule inhibitor CWP232291 on intestinal carcinogenesis in novel GEM model deficient in Smad4 and p53.
Authors: Park Jun Won , Park Jung Min , Green Jeffrey E. , Kim Hark K.
Published: February 2017

594

Background: We have established and characterized a novel genetically-engineered mouse (GEM) model for colorectal cancer by performing intestinal epithelium-specific knockout of Smad4 and p53 under Villin promoter. CWP232291 (JW Pharmaceutical Corporation, Seoul, Korea) is a potent Wnt/ β-catenin small molecule inhibitor currently tested in several Phase I trials. We evaluated chemopreventive efficacy of long-term CWP232291 treatment for intestinal carcinogenesis in our novel GEM model. Methods: Three-week-old GEM mice were intraperitoneally injected BIW for 17 weeks with 100 mg/kg CWP232291 (n = 19) or vehicle normal saline (n = 27) and then sacrificed. Results: All Villin-Cre;Smad4F/F;Trp53F/F mice developed multiple spontaneous intestinal tumors with the high proliferative activity and the activation of Wnt signaling pathway (median adenocarcinoma-free survival, 5.4 months; incidence of adenocarcinoma, 75.9 %). Whereas, Villin-Cre;Smad4F/F or Villin-Cre;Trp53F/F micedidn’t develop any intestinal tumors until 20 weeks. A histological assessment showed that tumor-bearing mice were significantly reduced after CWP232291 treatment (CWP232291, 50.0% vs vehicle, 84.0%; P < 0.01). More importantly, CWP232291 showed significant decrease in the incidence of malignant tumors (CWP232291, 37.5% vs vehicle, 78.3%; P < 0.05). In addition, tumor multiplicity is significantly decreased in CWP232291-treated mice (CWP232291, 1.2 ± 0.4 vs vehicle, 2.8 ± 0.4, P < 0.01). Immunohistochemistry showed that CWP232291 treatment reduced β-catenin, myc and cyclin D1 levels in tumors. In-vivo limiting dilution assay using primary mouse cancer cells showed that the frequency of cancer stem cells (CSCs) was 1/3,223 for the untreated group and 1/48,069 for the CWP291-treated group (p < 0.001). Conclusions: These results showed that CWP232291 inhibited Wnt signaling and reduced the CSCs through down-regulation of β-catenin and Wnt target genes and exerted a chemopreventive effect in our GEM model. This suggests that CWP232291 may be a promising candidate for colorecal cancer chemoprevention and maintenance.
Serum leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennaryN-glycan as a novel tumor marker for colorectal cancer.
Authors: Shinozaki Eiji , Tanabe Kazuhiro , Akiyoshi Takashi , Tsuchida Tomohiro , Miyazaki Yuko , Kojima Nozomi , Igarashi Masahiro , Ueno Masashi , Suenaga Mitsukuni , Mizunuma Nobuyuki , Nakayama Konosuke , Iijima Sadayo , Yamaguchi Toshiharu
Published: February 2017

595

Background: CEA and CA19-9 are measured widely in daily practice for colorectal cancer to monitor the condition of treatment, though its specificity and sensitivity is not satisfied enough. While, the innovation of mass spectrometry in this decade is dramatically. The revolutionized approach for the screening of glycomarkers provides a chance to discover more desirable tumor markers. We focused on glycan alterations of serum glycoproteins and tried to find new markers which are more specific and sensitive than the current markers. Methods: Sera of 80 CRC patients and 50 healthy volunteers were analyzed in this study. Glycopeptides were prepared from serum proteins by trypsin digestion, enriched by filtration and aleuria aurantia lectin(AAL), and then applied to liquid chromatography time-of flight mass spectrometry* (*LC-TOF-MS). Data was analyzed with our newly developed software, which calculates all of peak intensities and positions (m/z and elution time), aligns all peaks for all samples, and finally screens markers from a million of candidates. Results: Leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan (LRG-FTG) was discovered as a new CRC marker from over 100,000 candidate glycopeptide peaks. The level of LRG-FTG in CRC patients (1.25 ± 0.973 U/ml) was much higher than that of healthy parsons (0.496 ± 0.433 U/ml, p < 10-10). Its sensitivity and specificity exceeded those of CA19-9. CEA and LRG-FTG levels were moderately correlated (r = 0.61), however their relation was independent and complementary. Combination marker of LRG-FTG and CEA showed 84% of sensitivity, 90% of specificity and 0.91 of AUC (ROC analysis), and responded well to the efficacy of chemotherapy. Conclusions: Serum LRG-FTG was significantly elevated in CRC patients compared to healthy volunteers. The combination with CEA is expected to be an alternative diagnostic marker which distinguishes CRC from healthy persons and a sensitive monitoring marker for evaluation of efficacy during chemotherapy. Further validation study is warranted to evaluate serum LRG-FTG combination test compared with conventional tumor markers.
Does pre-operative aspirin and statin prescription modulate the post-operative systemic inflammatory response following surgery for colorectal cancer?
Authors: Watt David G. , Park James Hugh , Ng Shoukee K , Horgan Paul G. , McMillan Donald C
Published: February 2017

596

Background: Aspirin use has been reported to reduce the pre-op systemic inflammatory response (SIR) in patients with colorectal cancer (CRC). Moreover, an exaggerated post-op SIR, evidenced by C-reactive protein (CRP) concentrations, is associated with poorer short and long term outcomes, highlighting the importance of CRP as a potential therapeutic target for improving outcomes following surgery for CRC. Drugs such as corticosteroids, aspirin and statins may modulate the post-op SIR, but there is little current evidence supporting this hypothesis. Therefore, the aim of the present study was to determine whether pre-op prescription of aspirin or statins modulated the post-op SIR in patients undergoing surgery for CRC. Methods: Included patients were obtained from a prospectively maintained database of CRC resections from a single institution (2010-2014). The relationship between pre-op aspirin and statin prescription and post-op CRP concentrations was examined. Results: 446 patients were included. The majority of patients were > 65 yrs (64%), male (57%) and underwent elective surgery (91%). 120 patients were prescribed aspirin and 187 prescribed statins with 100 patients prescribed both. Patients prescribed aspirin had a reduced post-op SIR particularly on day 3 (p = 0.009), 4 (p = 0.003) and 5 (p = 0.005). This effect was also observed following elective surgery (n = 402) on day 3 (p = 0.014), day 4 (p = 0.009) and day 5 (p = 0.019). Patients prescribed a statin also had a reduced post-op SIR, particularly on days 3 (p = 0.010), 4 (p = 0.006) and 5 (p = 0.017) and also following elective surgery on day 3 (p = 0.039) and day 4 (p = 0.039). The combination of aspirin and statin, compared with none or each on its own, resulted in the lowest post-op SIR, particularly on day 3 (p = 0.015), day 4 (p = 0.006) and day 5 (p = 0.023). Conclusions: Pre-op prescription of aspirin or statins resulted in a reduced post-op SIR following surgery for CRC. Therefore, pre-op use of these medications may be of benefit in improving outcomes, by reducing the post-op SIR – a reported predictor of both long and short term outcomes, following surgery for CRC.