bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-transcript blood signature for detection and assessment of gut neuroendocrine tumors.
Authors: Kidd Mark S. , Alaimo Daniele , Callahan Stephen , Texeira Nancy Smith , Drozdov Ignat , Modlin Irvin Mark 
Published: February 2017

216 Background: Gut neuroendocrine tumors (NETs or “carcinoids”) are difficult to manage since they present with advanced disease and limited treatment options are available. Imaging is relatively insensitive in identifying treatment efficacy and the current biomarker, a neurosecretory peptide, Chromogranin A (CgA), has limited value. There is a lack of specific blood biomarker tests both to detect tumors and measure treatment responsiveness. We report the utility of a 51 marker peripheral blood signature (NETest) in comparison to CgA. Methods: The signature was validated using a 2-step qPCR method for detecting NETs in two sets (n=115; n=120) and for measuring treatment responses in a third set (n=133, including complete remission: n=4, clinically stable disease: n=82 and non-responders/clinically progressive disease: n=47). Comparison with CgA (DAKO-ELISA) was undertaken. The confounding effects of PPIs, age, sex and race were also determined for the PCR test. Results: The PCR NETest detected NETs with high sensitivity (85-98%) and specificity (93-97%). It identified pancreatic and gastrointestinal NETs with similar efficacy (>85%) as well as metastatic and non-metastatic lesions. NETest score was significantly reduced (p<0.004) following surgery or RFA and significantly higher in clinically progressive disease compared to stable disease (5.8±0.3 versus 0.6±0.1, p<0.002). The performance metrics for differentiating stable and progressive disease were sensitivity: 91% and specificity: 91%. The score was robust (reproducibility: Coefficient of Variation<2%).Long-term PPI use (>1yr), did not alter the NETest values, neither did age, sex or ethnicity. The PCR score was significantly (p<0.0005) more accurate than CgA for identifying NETs and was elevated in 91% of NETs when CgA was normal. Conclusions: This study demonstrates that a multi (51)-gene NET panel is both sensitive and specific for detecting NETs and is capable of differentiating clinically stable from progressive disease. The test is robust and significantly more sensitive and specific (accurate) than CgA. The NETest thus facilitates both accurate disease detection, and disease progress thereby permitting assessment of treatment efficacy.
Measurement of circulating tumor DNA as a cancer biomarker in gastrointestinal malignancies using a novel next-generation sequencing method.
Authors: James Edward Samuel , Narayan Azeet , Stein Stacey , Lacy Jill , Patel Abhijit , Hochster Howard S. 
Published: February 2017

217 Background: Circulating tumor DNA (ctDNA) holds promise as a highly specific cancer biomarker. The presence of mutant tumor-derived DNA fragments in the blood provides an opportunity to non-invasively assess tumor mutation profiles and to quantify changes in tumor DNA levels over time. Methods: After obtaining informed consent, plasma samples were collected prospectively at multiple time points in a cohort of patients (pts) with various gastrointestinal (GI) malignancies in the locally advanced, metastatic and adjuvant settings. Hotspot regions of genes known to be commonly mutated in GI tumors were amplified by multiplexed PCR, and the resultant amplicons were subjected to next-generation ultra-deep sequencing. Suppression of sequencer and PCR errors allowed mutations to be identified and quantified with a sensitivity of approximately 1 variant in 5,000 molecules. Sample-specific barcoding allowed simultaneous analysis of up to 96 samples. Results: 29 out of 74 available samples from 17 pts were analyzed for the presence of ctDNA. 3 pts had KRAS mutations exclusively. 2 pts had mutations in two of the evaluated genes: KRAS plus PIK3CA and KRAS plus TP53. 2 pts with measurable mutant ctDNA had samples analyzed at multiple time points. One of these patients with locally advanced pancreatic cancer initially had a KRAS G12D mutation which disappeared after treatment with chemo-radiation therapy, but then he developed significantly rising levels of a different KRAS G12L mutation just preceding the diagnosis of liver metastases by imaging. A second pt with metastatic colon cancer had high levels of ctDNA prior to treatment that decreased dramatically after initiation of mFOLFOX and bevacizumab therapy. Conclusions: Our initial analysis indicates that our technique is able to quantify multiple mutations at very low copy numbers accurately in this cohort of pts with GI cancers. Moreover, we were able to monitor changes in mutation type and quantity using this non-invasive “liquid biopsy” approach. Analysis of remaining samples is ongoing, and additional longitudinal data will be presented.
Changing patterns in presentation and therapy of esophagogastric junction cancers in the United States.
Authors: Schwarz Roderich , Smith David D. , Nelson Rebecca A. 
Published: February 2017

22 Background: Esophagogastric junction cancer (EGJC) has recently been included within the esophageal cancer (EC) AJCC TNM staging criteria. Trends in clinical presentation, therapeutic approach and outcomes are of interest. Methods: We identified EGJCs from the U.S. population SEER database and examined incidence, demographic, therapeutic and outcomes information. Siewert classification-related EGJC subtype-associated findings were also examined. Results: EGJC age-adjusted incidence rates (x10-5) have increased from 3.3 in 1973 to 7.5 in 2009. While the incidence rate for females has remained around 2, rates in males have increased from 6 to 13. Among 30,710 EGJC patients diagnosed between 1992 and 2009, potentially curative resection increased from 31% to 36% and radiation increased from 32% to 41% (p<0.0001). For resected EGJCs, significant trends over time include: increased total LN count (mean: 15.5 vs. 12.3), fewer positive LNs (3.1 vs. 4), smaller tumor size (29% vs. 36% >5 cm), lower T category (39% vs. 29% T1/2), lower N category (42% vs. 35% N0), lower stage group (29% vs. 38% stage 3/4), increased preoperative radiation (26% vs. 3%), decreased 90-day mortality (6.5 vs. 14.1%), longer overall survival (OS, median: 2.9 vs. 1.7 years) and longer disease-specific survival (median: 3.9 vs. 2.0 years) (all at p<0.0001). Multivariate predictors of OS include TNM categories, age, ethnicity, radiation, and total LN count (all at p<0.0001). There were significant differences in stage-for-stage OS between EC subtypes based on histology and primary tumor location, and in DSS between EGJC subtypes (Siewert I, II or III) as well. Conclusions: EGJC incidence rates, diagnosis and treatment have undergone significant changes within the U.S. population. The regional dissection extent remains an area of importance as it is associated with OS. Comparisons of various survival outcomes do not support using the same staging criteria for EGJC as for EC.
Mouse models of pancreatic cancer induced by chronic pancreatitis and smoking.
Authors: Edderkaoui M. , Grippo Paul J. , Ouhaddi Y. , Benhaddou H. , Xu S. , Pinkerton K. , Tsukamoto H. , Knudsen Beatrice , Gukovskaya A. S. , Pandol Stephen 
Published: February 2017

229 Background: Chronic pancreatitis (CP) and smoking are two major risk factors for pancreatic cancer (PaCa). Here we developed mouse models of PaCa by exposing mice to CP and/or smoking. Methods: Wild type (WT) and Pdx1-Cre;LSL-Kras transgenic mice were subjected to 7-hourly cerulein injections (50µg/kg) twice a week for 3 weeks to induce CP. Another group of mice was exposed to tobacco smoke (80mg/m3) in chambers for 5days/week during 6 weeks. A third group was exposed to both treatments. Mice were then sacrificed and pancreatic tissue analyzed. Pancreatic lesions, proliferation, fibrosis, inflammation, EMT and stem cell markers were analyzed by immunohistochemistry and Western. Results: CP significantly increased the number and stage of pancreatic neoplastic (PanIN) lesions with fibrosis, stellate cell activation and inflammation in transgenic mice. These changes were significantly less in WT mice. EMT markers (decrease in E-Cadherin and increase in vimentin protein levels) were stimulated by CP in both WT and transgenic mice. Similarly, smoking stimulated PanIN lesion formation, fibrosis and inflammation in transgenic mice, but to a lesser extent than CP model. Expression of EMT and stem cell markers was greater in the smoking model compared to CP. Combination of CP and smoking induced greater stimulation of PanIN lesion formation, fibrosis and inflammation compared to either treatment alone in transgenic mice. Conclusions: The results indicate that both CP and tobacco smoke promote PaCa progression in transgenic mice. The combination of CP and smoking has greater effects than either treatment alone. EMT and stem cell markers developed in WT as well as in transgenic mice with smoking suggesting that smoking has effects independent of Kras on cell transformation.
Searching for CDH1 gene mutations in early-onset diffuse gastric cancer in Chinese patients.
Authors: Yanjun Xu , Wenming Cao , Qi Xu , Jianmin Guo , Xinbao Wang , Xiangdong Cheng , Jieer Ying 
Published: February 2017

23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.
MicroRNA-21 ISH analysis to predict DFS in pancreatic cancer patients undergoing adjuvant gemcitabine after curative surgery.
Authors: Morinaga Soichiro , Nakamura Yoshiyasu , Katayama Yusuke , Sawazaki Sho , Numata Koji , Higuchi Kosei , Godai Teni , Shiozawa Manabu , Miyagi Yohei , Ohkawa Shinichi , Yoichi Kameda , Akaike Makoto 
Published: February 2017

234 Background: Overexpression of microRNA-21(miR-21) in pancreatic cancer has been reported to be associated with tumor cell proliferation, invasion, and also resistance to gemcitabine (GEM) chemotherapy. The aim of this study was to evaluate whether miR-21 expression, determined by microRNA ISH, was associated with clinical outcomes of pancreatic cancer patients who underwent adjuvant gemcitabine chemotherapy after curative surgery. Methods: Expression levels of miR-21 were semi quantitatively analyzed for staining intensity and distribution of positive tumor cells, by microRNA ISH in formalin-fixed paraffin embedded tissue arrays from 41 pancreatic cancer patients who underwent adjuvant GEM chemotherapy after curative resection at Kanagawa Cancer Center. The staining intensity for the miR-21 was assigned a score from 1 to 3 based on staining with1+: weakly, 2+: moderately, and 3+: strongly positive. The percentage of positive tumor cells was scored as follows, 1+: < 50% positive cells, 2+: 50-80% positive cells, and 3+: ³a 81% positive cells. A composite score was obtained by calculating the sum of these two scores. Results: 27 patients were assigned to low miR-21 expression group (score <4) and 14 patients to high miR-21 group (score 4,5,6). High miR-21 expression group had a significantly shorter DFS (P = 0.039, by log-rank test). The median DFS was 9.8 months (95% CI, 6.9-12.6) in the low miR-21 group, and 7.9 months (95% CI, 6.1-9.8) in the high miR-21 group. The median OS was 19.6 months (95% CI, 6.3-32.8) in the low miR-21 group, and 15.1 months (95% CI, 11.7-18.5) in the high miR-21 group, but was not significant. Multivariate analysis including miR-21 expression, microscopic lymphatic invasion and microscopic perineural invasion, indicated that miR-21 expression (p = 0.024) and microscopic lymphatic invasion (p = 0.035) were the independent predictor for DFS. Conclusions: A high level of miR-21 expression in pancreatic cancer was significantly associated with shorter DFS in patients who received adjuvant GEM after curative resection. miR-21 ISH analysis may serve as a significant predictor for GEM resistance in adjuvant setting.
Phase II clinical trial of pasireotide LAR in patients with metastatic neuroendocrine tumors.
Authors: Strosberg Jonathan R. , Jump Helen , Valone Tiffany , Weber Jill , Khandelwal Vilay H. , Kunz Pamela L. 
Published: February 2017

241 Background: Pasireotide LAR is a novel somatostatin analog (SSA) with avid binding to somatostatin receptor subtypes (SSTR) 1, 2, 3 and 5. It has been studied in patients who are refractory to SSAs, but has not yet been investigated in treatment naïve patients. Methods: We performed a phase II trial of first-line pasireotide LAR 60mg q4 weeks in patients with metastatic low and intermediate grade NETs. Prior systemic therapy, including octreotide and lanreotide, was not permitted. The primary endpoint was PFS. Immunohistochemical SSTR subtype analysis was performed on archival tissue. Results: 29 patients were enrolled of whom 28 patients were assessable for response. Primary sites included small intestine (14 pts), pancreas (6), rectal (2), unknown (4) and other sites (3). 13 patients had low-grade and 16 patients had intermediate-grade tumors. Best radiographic response was stable disease in 17 patients (60%), progressive disease in 10 patients (36%) and partial response in 1 patient (4%). Median PFS was 12.2 months (95% CI 7.7-17.5). The 1 year OS rate was 92% (CI 72%-98%). Although generally well tolerated, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia. 4 patients (14%) developed grade 3 hyperglycemia. 6 patients were started on insulin during the trial period, and at least 2 have remained on long-term insulin therapy despite discontinuation of pasireotide. Conclusions: Although the median PFS of 12.2 months in a heterogeneous population of NET patients is encouraging, the high rate of hyperglycemia requiring intervention represents a significant concern. Future studies of pasireotide should explore specific populations such as octreotide refractory patients. Clinical trial information: NCT01253161.
Clinical impact of reflection to expression of EMT marker in intraductal papillary mucinous neoplasm.
Authors: Ikemoto Tetsuya , Shimada Mitsuo , Utsunomiya Toru , Imura Satoru , Morine Yuji , Arakawa Yusuke , Mori Hiroki , Kanamoto Mami , Iwahashi Shuichi , Saito Yu 
Published: February 2017

244 Background: We have already reported that regulatory Tcells (Treg) reflects the aggressiveness of intraductal papillary mucinous neoplasms (IPMN) (Pancreas 2013), Notch signaling is related to agressiveness of IPMN (DDW 2012). Notch signaling, important pathway of expansion of Tregs, is considered to be one of the important factors which cause cancer progression especially through epithelial-mesenchymal transition (EMT). It still remains unclear whether EMT leads to pathological agressiveness in IPMN. Therefore, we evaluated that peripheral Treg reflected the expression of EMT-promoting transcriptional factors, Twist1 and Bmi1 in IPMN. Methods: The patients who received resections at out institute were enrolled in this study (from 2000 to 2012, n=35). Twist1, Bmi1 and E-cadherin protein expressions were investigated by immunohistochemistry. These protein expressions were compared to clinicopathological factors and peripheral Treg population. Results: Positive expression of Twist1 and Bmi1 was observed in 40.0% and 34.3%, respectively. Twist1 and Bmi1 expression were significantly higher in IPMNs with high-grade dysplasia and invasive carcinoma than IPMNs with low to moderate-grade dysplasia (p<0.05). High Twist1 expression was correlated with Jagged1 expression and inversely correlated with expression of E-cadherin (p<0.05). IPMN aggressiveness correlated to Jagged1 expression and Treg (p<0.05) Higher expression of Twist1 and Bmi1 simultaneously were correlated with an poor disease-free-survival (p<0.05). Conclusions: Twist1 and Bmi1 may cause the progression of IPMN through EMT promotion which is induced by Notch signaling. High expression of both Twist1 and Bmi1 is associated with a worse clinical outcome and Treg population may be a marker to reflect these EMT status.
Prognostic impact of pancreatic intraepithelial neoplasia (PanIN)-III accompanying chronic pancreatitis in patients who underwent R0 resection for pancreatic adenocarcinoma.
Authors: Hwang In kyeom , Kang Bong Kyun , Lee Yoon Suk , Kim Jaihwan , Hwang Jin-Hyeok 
Published: February 2017

246 Background: The clinical significance of pancreatic intraepithelial neoplasia (PanIN)-III, known as carcinoma in situ of pancreatic ductal adenocarcinoma (PDAC), remains unclear yet. Recent research showed inflammation enhanced early cellular invasion of PanIN-III by facilitating epithelial to mesenchymal transition (EMT), even before frank malignancy in experimental model. Therefore we decided to investigate whether PanIN-III accompanying chronic pancreatitis (CP) might have an important prognostic impact in patient who underwent curative resection for PDAC. Methods: Medical records of 199 PDAC patients with R0 resection were reviewed. Presence and grade of PanIN and CP in resected specimen were determined based on College of American Pathologists protocol. Overall survival (OS) and disease free survival (DFS) were analyzed according to PanIN-III and CP. Results: CP was observed in 19.6% (39/199) of resected specimen and PanIN-III in 21.1% (42/199). In the group with CP, PanIN-III was associated with poor prognosis in univariate analysis (16.6 months vs. 32.0 months, P=0.001 for OS and 7.5 months vs. 15.1 months, p=0.012 for DFS), whereas PanIN-III was not a prognostic factor in the group without CP. When we divided into two groups [PanIN-III accompanying CP (n=12) vs. the others (n=187)], it showed that median DFS and OS were significantly shorter in PanIN-III and CP group than those of the others (7.5 months and 16.6 months vs. 12.4 months and 26.0 months, p=0.017 and p=0.003, respectively). In multivariate analysis, PanIN-III accompanying CP remained a statistically significant poor prognostic factor (HR: 2.06; 95% CI: 1.008 to 4.221; p=0.048 for OS, HR: 2.6; 95% CI: 1.267 to 5.462; P=0.009 for DFS using Cox proportional hazard ratio). Conclusions: PanIN-III accompanying CP might influence on poor long-term outcomes in patients who underwent R0 resection for PDAC. Therefore, it would support that chronic inflammation could enhance the dissemination of carcinoma in situ.
GATA6 expression in Barrett’s metaplasia development and malignant progression.
Authors: Pavlov Kirill , Honing Judith , Meijer Coby , Boersma-van Ek Wytske , Peters Frans , van den Berg Anke , Karrenbeld Arend , Plukker John Theodorus , Kruyt Frank , Kleibeuker Jan 
Published: February 2017

26 Background: Barrett’s metaplasia is characterized by the presence of a columnar metaplastic epithelium in the esophagus. Barrett’s metaplasia can show malignant progression towards esophageal adenocarcinoma by a metaplasia-dysplasia-carcinoma sequence. The underlying mechanisms of Barrett’s metaplasia development and malignant progression are poorly understood. The transcription factor GATA-6 is known to be involved in columnar differentiation and carcinogenesis. GATA6 gene amplification was recently linked with aggressiveness in esophageal adenocarcinoma. Here, we studied GATA6 protein expression in normal squamous, metaplastic, dysplastic and esophageal adenocarcinoma tissues in order to identify a possible role of GATA-6 in the development and malignant progression of Barrett’s metaplasia. Methods: Samples of squamous epithelium (N=37), Barrett’s non-intestinal metaplasia (N=16), Barrett’s intestinal metaplasia (N=29), high-grade dysplasia (N= 39), in situ esophageal adenocarcinoma (N=29) and an esophageal adenocarcinoma tissue microarray (N=95) were stained with a polyclonal antibody against GATA6. Staining intensity was categorized as absent, weak, normal or strong. Scoring was performed by two independent observers and validated by a pathologist. Results: GATA6 expression was absent in squamous epithelium but expressed in all samples of Barrett’s metaplasia, preferentially in the lower half of the crypt. Expansion of GATA6-positive cells throughout the crypt was observed in high-grade dysplasia. While all cases of in situ esophageal adenocarcinoma showed GATA6 expression we observed complete loss of GATA6 expression in 17% of esophageal adenocarcinoma samples. Conclusions: GATA6 is absent in squamous epithelium but its expression increases along the metaplasia-dysplasia carcinoma sequence. GATA6 expression remains predominantly present in esophageal adenocarcinoma, however, its expression is lost in a subset of samples. Analysis of the relation between GATA6 expression and clinicopathological characteristics in esophageal adenocarcinoma is pending.