bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER2 status in primary tumors and metastatic regional lymph nodes in patients with esophageal adenocarcinoma (EAC).
Authors: Yoon Harry H. , Shi Qian , Sukov William R. , Sattler Christopher A. , Vaidya Rakhee , Wiktor Anne E. , Diasio Robert B. , Wu Tsung-Teh , Jenkins Robert B. , Sinicrope Frank A. 
Published: March 2020

4071 Background: Selection of patients for HER2-targeted therapy is based on HER2 analysis in primary EACs. Since EACs metastasize via regional lymph nodes, concordance of HER2 gene amplification results between primary tumors and their metastatic lymph nodes (MLN) is a clinically important issue. Methods: Resected EACs (N = 103) having at least three distinct regional MLNs (total 508 MLNs; median 4 [range 3-11]) were sectioned using routine procedures and tested for HER2 amplification by fluorescence in situ hybridization (FISH). Primary tumors were also evaluated for HER2 protein expression by immunohistochemistry (IHC) and by FISH. Amplification was defined as HER2/CEP17 ≥ 2. IHC was scored as 0, 1+, 2+, or 3+. Primaries whose HER2 status was positive by both FISH and IHC (ie, amplified and IHC3+), or negative by both (ie, nonamplified and IHC0-1+), were selected. HER2 status was compared between primaries and their MLNs (kappa). Results: Concordant HER2 results between primaries and their MLNs were found in 92% (95/103) of EACs (Table; κ = .76 [95% CI .60 - .92]). However, among patients with HER2-positive primaries, 19% (4/21) had HER2-nonamplified MLNs; among these cases, either all MLNs were HER2-nonamplified (n = 2), or both HER2-nonamplified and –amplified MLNs were present (n = 2). Among HER2-negative primary EACs, 5% (4/82) of cases had MLNs that were all HER2-amplified (n = 3) or both HER2-nonamplified and -amplified (n = 1). Conclusions: A patient subset whose primary EACs were HER2-positive (by both FISH and IHC) were unexpectedly found to lack HER2 amplification in corresponding MLNs. Conversely, a subgroup with HER2-negative primaries had HER2-amplified MLNs, and would have been deemed ineligible for HER2-targeted therapy. These preliminary data suggest that evaluating MLNs in resected EACs has the potential to better identify patients who benefit from HER2-targeted therapy. [Table: see text]
Promoter polymorphisms of the SWI/SNF chromatin remodeling complex molecule, BRM, and esophageal adenocarcinoma outcome.
Authors: Korpanty Grzegorz , Qiu Xin , Eng Lawson , Faluyi Olusola Olusesan , Cheng Dangxiao , Renouf Daniel John , Knox Jennifer J. , Wong Rebecca , Darling Gail , Xu Wei , Dodbiba Lorin , Azad Abul Kalam , Reisman David , Cuffe Sinead , Liu Geoffrey 
Published: March 2020

4077 Background: Better understanding of the biology of esophageal cancer may help improve its treatment. The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development and outcome. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM -741 and BRM -1321) have been correlated with BRM loss and elevated cancer risk in upper aerodigestive cancers (Wang et al, Carcinogenesis, 2012) and more recently in lung cancer outcome (Cuffe et al, ESMO, 2012) by our research teams. Objectives: We evaluated BRM polymorphisms and their role in the survival of esophageal cancer patients. Methods: 223 histologically-confirmed esophageal adenocarcinoma patients of all stages were evaluated. The two BRM polymorphisms utilized Taqman genotyping. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 85% were male; the mean age was 63 years. 37% had stage IV advanced tumors. The median PFS was 1.03 years, while median OS was 1.82 years. After adjustment for known prognostic clinical variables, carrying homozygous variants of both BRM polymorphisms (double homozygotes) was associated with a worse outcome: aHR 1.84 (1.06-2.34, p=0.03) for OS and aHR 1.93 (1.10-2.48, p=0.02) for PFS. The direction and magnitude of associations were similar in subsets of patients by age, gender, smoking status, use of platinum agents, and disease stage. Non-significant trends in the same direction but of aHR magnitudes 1.34-1.54 were seen in the patients who carried one homozygous variant or who were double heterozygotes. Conclusions: We report the initial association of BRM polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.
A comparison of postoperative quality of life after open and laparoscopic gastrectomy for early gastric cancer: A multicenter, nonrandomized, controlled study (CCOG 0802).
Authors: Tanaka Chie , Misawa Kazunari , Fujiwara Michitaka , Ito Seiji , Mochizuki Yoshinari , Kobayashi Daisuke , Yamamura Yoshitaka , Ando Masahiko , Morita Satoshi , Kodera Yasuhiro 
Published: March 2020

4088 Background: The aim of this study was to compare the postoperative health-related quality of life (HRQoL) between open and laparoscopic distal gastrectomy. Methods: A multi-institutional non-randomized study was conducted, and early gastric cancer patients were prospectively enrolled and underwent distal gastrectomy either by the open or laparoscopic approach. HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Cancer (QLQ-C30) and the site-specific module for gastric cancer (QLQ-STO22). Questionnaires were completed at baseline and at 1, 3, 6 and 12 months postoperatively. Clinicopathological characteristics and short term outcome including postoperative morbidity and HRQoL were compared between the approaches. Results: A total of 159 patients with clinical T1 tumors were enrolled between September 2008 and January 2011. Those who were found upon pathologic examination to have ≥aStage II disease (n=14) were excluded, and the remaining 145 patients (open: n=72, laparoscopic: n=73) were analyzed. There were no significant differences between the two groups regarding age, gender, macroscopic type, depth of invasion, lymph node metastasis, and pathologic type. Laparoscopic approach was associated with longer operating time, smaller blood loss, and similar incidence of postoperative complications. At each time point, the questionnaires were sent to the data center from >90% of the patients. The worst scores for most of the items were observed at 1 month postoperatively and improved thereafter. The role, emotional, cognitive, and social functioning scores were superior in the laparoscopic group at 6 and 12 months postoperatively. Symptom scales including fatigue, pain, anxiety, eating restriction, and taste problem were better in the laparoscopic group before 6 months but not at 12 months. Conclusions: Patients treated by the laparoscopic approach benefitted from better HRQoL in terms of symptoms scores during the first 6 months, while the superiority in several functioning scores lasted for 12 months.
A comparison of immunohistochemistry (IHC) and dual-color silver in situ hybridization (SISH) with a novel method combining both gene and protein platforms on a unique slide for testing the HER2 in gastric carcinoma.
Authors: Werner Dominique , Battmann Achim , Steinmetz Kristina , Jones Tobin , Martinez Michele , Lamb Tiffany , Al-Batran Salah-Eddin 
Published: March 2020

4100 Background: Amplification and/or protein overexpression of HER2 in gastric cancer is a prerequisite to establish an adequate treatment strategy. The European standard defined HER2 positivity by IHC as first evaluation assay followed by ISH in 2+ cases. Gastric tumors are heterogeneous and separate evaluations lead to uncertainties and in localizing distinct clones and are time consuming. The aim of this study was to evaluate the feasibility of gene-protein platform in comparison to single staining methods. Methods: IHC plus SISH and gene-protein platform (IHC/SISH, protein/gene) method for HER2 were performed in randomly collected 100 cases of gastric carcinoma. Results of IHC and SISH were compared with IHC/SISH staining. Rüschoff criteria were applied. Tumors were HER2 positive when expression 3+ or 2+ plus gene amplification (EU-Norm) was found. In Second definition (US-Norm), tumors showing HER2 expression 3+ or amplification were considered HER2 positive. Results: 96 of 100 samples were eligible. Amplification was observed in 14.6% and 15.6% by SISH and IHC/SISH. 71.9% by IHC vs. 75.0% by IHC/SISH had no expression (0) and 10.4% (IHC vs. IHC/SISH) had weak (1+) HER2 expression. Moderate expression (2+) and overexpression (3+) were observed in IHC 6.3%/11.5% and IHC/SISH 6.3%/8.3%, respectively. There were high concordances in IHC assessment of cases with score 0 (94.8%; κ=0.87) and 3+ (96.9%; κ=0.83) and moderate concordances in 1+/2+ cases (89.6%; κ= 0.44 vs. 93.8%; κ=0.47). Rate of HER2 positivity was similar in standard or novel method. In EU Definition 14.6% vs. 10.4% (p=0.52) were positive, respectively, with very good concordance (95.8%; κ=0.81).Concordance between HER2 positivity in standard or novel method was very good (99.0%; κ=0.96) in US definition with no significant differences (17.7% vs. 16.7%; p=1). Conclusions: Gene-protein platform has been tested for first time in gastric carcinoma. Results showed that this novel platform can be a feasible alternative to single methods. Discrepancies in cases with weak or moderate HER2 expression can be a result of observer variability.
Effect of the revised AJCC staging (7th edition) on prognostic stratification in patients with surgically resected esophageal squamous cell carcinoma.
Authors: Minella Gloria Terase , Luketich James D. , Davison Jon M. , Winger Dan , Levy Ryan M. , Gibson Michael K. , Pennathur Arjun , Nason Katie Sue 
Published: March 2020

4103 Background: Historically, the AJCC esophageal staging system separated patients into prognostic groups based on tumor, node, and metastasis (TNM) classifications. In 2010, the 7th edition (AJCC 7) significantly modified esophageal squamous cell cancer (ESCC) staging by separating ESCC from adenocarcinoma, incorporating tumor grade and location for node negative cancers, and stratifying by the number of involved regional nodes for node positive cancers. Our study aim was to determine whether AJCC 7 stage groupings provide improved survival prognostication compared to 6th edition (AJCC 6). Methods: We abstracted pathology and survival for 150 consecutive ESCC patients who underwent esophagectomy (1994-2012); 44 patients received induction therapy. AJCC 6 and AJCC 7 stages were assigned and overall survival analyzed from esophagectomy to death or most recent alive contact and censored at 60 months. Discriminatory ability and homogeneity within subgroups was assessed with Kaplan-Meier curves and monotonicity comparisons were evaluated with linear trend chi-squared tests. Overall survival was compared using Cox regression and Akaike Information Criterion (AIC) used to assess model fit. Results: Compared to AJCC 6, AJCC 7 upstaged 32 patients from IIa to IIb and 1 patient from IIb to IIIa and downstaged 3 patients from stage IIa to Ib. AJCC 7 subclassified 42 AJCC 6 stage III patients (17 IIIa, 10 IIIb and 15 IIIC). Median overall survival was 19 months. Kaplan-Meier log-rank statistic indicated stronger differentiation in AJCC 7 (19.8 vs 29.7). Cox regression likelihood (19.5 vs 26.1), AIC (618.1 vs 611.6), and linear trend chi-squared at 24- (17.5 vs 24.3) and 60-months (13.3 vs 17.3), were all superior for AJCC 7 stage groupings (AJCC 6 vs AJCC 7, respectively). Conclusions: AJCC 7 stage groupings demonstrate superior homogeneity, discriminatory ability and monotonicity compared to AJCC 6. Incorporating the extent of nodal disease, tumor location and tumor grade into the revised AJCC 7 stage classification improves prognostic stratification of surgically resected ESCC patients, including patients who received induction therapy.
Evaluation of serum HER2 extracellular domain in in metastatic gastric or gastroesophageal junction cancer: Correlation with HER2 status by immunohistochemistry and fluorescence in situ hybridization and clinicopathologic parameters.
Authors: An Xin , Dai Shuqin , Wang Fang , Shao Qiong , Chen Cui , Chen Yongchang , Kong Yanan , Li Cong , Luo Huiyan , Liang Ying , Wang Feng-Hua , Xu Rui-hua , Li Yu-hong 
Published: March 2020

4107 Background: To explore the association between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and impact on overall survival (OS) in metastatic gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. Methods: A total of 219 histologically confirmed inoperable locally advanced, recurrent, or metastatic gastric or GEJ adenocarcinoma were included. Serum HER2 ECD was measured by chemiluminescent assay. Tissue HER2 status was accessed by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) assay. Results: The median serum ECD level was 9.3 ng/ml (range 3.0 to >350). Tissue HER2 status was positive (IHC3+ or 2+ with FISH amplification) in 37 patients (16.9%) and negative in 182 patients (83.1%). Statistically significant associations were found between serum HER2 ECD level and HER2 status assessed by IHC and FISH. The ROC-analysis suggested the cutoff of 16.35 ng/ml (24 of 219 patients had HER2 ECD >16.35 ng/ml ) could produce a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER2 status. If the cutoff value was increaseed to 22 ng/ml, then all 12 patients with serum HER2 ECD >22 ng/ml were HER 2 positive in primary tumor, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER2 ECD levels were strongly associated with liver metastasis (P < 0.001), the intestinal histologic type (Lauren's classification) (P =0.003), large number of metastais (>2) (P=0.012) and increased LDH level (P < 0.001) . High serum HER2 ECD levels were more common in GEJ adenocarcinoma although the difference had no stastical significance. HER2 ECD levels did not show a significant impact on OS. Conclusions: A significant association was observed between serum HER2 ECD levels and tissue HER2 status in metastasis gastric or GEJ adenocarcinoma. The high specificity of serum HER2 ECD assay to predict tissue HER2 status suggests its potential use as a surrogate marker of the HER2 status in gastric cancer.
Phase I study of PF-03446962 (anti-ALK-1 mAb) in hepatocellular carcinoma (HCC).
Authors: Simonelli Matteo , Zucali Paolo A. , Thomas Melanie B. , Brisendine Alan , Berlin Jordan , Noberasco Cristina , Denlinger Crystal Shereen , Kim Tae-You , Santoro Armando , Gallo-Stampino Corrado , Carpentieri Marina , Wang Erjian , Williams James Andrew , De Braud Filippo G. 
Published: March 2020

4121 Background: PF-03446962, a fully human IgG2 mAb against ALK-1 (Activin-Receptor Like Kinase-1, a specific TGF-β receptor) with anti-angiogenesis activity, showed a favourable safety profile and early signs of efficacy in a dose escalation study in patients (pts) with solid tumors. While the interplay between ALK-1 and VEGF-A is not fully elucidated, the clinical benefit observed in VEGF-TKI pre-treated pts supports ALK-1 acting as an escape mechanism after failure of VEGF blockade. Herein we report preliminary efficacy, safety and PK results from an expansion cohort in HCC pts who progressed after receiving at minimum sorafenib. Methods: Child-Pugh A HCC pts progressed on/intolerant to sorafenib. Tumor specimens (diagnostic and pre-PF-03446962) collected for IHC assessment of CD31, TGF-β, ALK-1 and cMET. Pts treated with 7 mg/kg PF-03446962 on Day 1, 29 and then q2 wks. Efficacy endpoints: Objective Tumor Response (OR) by RECIST, Disease Control Rate (DCR) at 12 wks, and Time To Progression (TTP). Secondary objectives: safety, PK and PD. Results: 24 pts with advanced HCC pre-treated at minimum with sorafenib (12/24 with ≥ 2 prior therapies) have been enrolled; 19 males and 5 females (median age: 64 y). Pts’ characteristics were: ECOG PS = 0 in 10 and = 1 in 14 pts; Child-Pugh = A5 in 16 and = A6 in 8 pts. The PK profiles from the HCC cohort were consistent with those of the dose escalation cohorts. Safety profile was manageable and mainly characterized by Gr 1-2 events. Gr 3-4 events were represented by thrombocytopenia (12.5%) and lipase increase, AST increase and abdominal pain (4.2% each). Telangiectasia, an anti-ALK-1 mediated toxicity, was also observed (8.3%, Gr 1). There were 3 treatment-related serious AEs (one tumor necrosis and two abdominal pain). No CRs or PRs were reported; DCR was 29.2% and mTTP was 3.0 months. In 7 pts, PF-03446962 was associated with stable disease for ≥ 12 weeks, suggesting that anti-ALK-1 treatment may be an effective strategy in the post-VEGFi setting. Correlation data of target tumor protein expression with efficacy will be presented at the Conference. Conclusions: PF-03446962 is a first in class mAb anti ALK-1. Preliminary clinical activity observed in this HCC expansion cohort warrants further investigations. Clinical trial information: NCT00557856.
Gene expression profiling (GEP) to predict the primary site of metastatic neuroendocrine tumors (NETs) presenting with an unknown primary.
Authors: Woltering Eugene , Anthony Lowell Brian , Diebold Anne E. , Boudreaux J Philip , Wang Yi-Zarn 
Published: March 2020

4141 Background: NETs often present as liver metastasis with an unknown primary. Accurate subtyping of NETs has important clinical implications for staging and site-specific targeted therapy. Traditionally, the work-up to identify a primary NET as being lung, pancreatic or gut-based can be challenging and time-consuming. Methods: GEP was performed on formalin-fixed, paraffin-embedded tumor samples using a 92-gene RT-PCR assay (CancerTYPE ID, bioTheranostics Inc.) as part of the clinical work-up for patients diagnosed with NETs and unknown primaries. Results: Results were categorized by level of agreement (Table). Of the 39 patients tested with the assay, 82% presented with liver metastasis. Assay results from those patients with adequate work-up were concordant with clinical data in 77% (23/30) of cases. Surgery was performed in 12 of these cases and 100% accuracy of the molecular assay was confirmed, resulting in 75% of primary tumors being found in the gut and 25% in the pancreas or duodenum. Assay predictions were clinically plausible but inconsistent in 13% (4/30) of cases and were discordant with histology, IHC, imaging/radiological findings, and clinical impression in 10% of the cases. Conclusions: The 92-gene assay accurately predicted tumor subtype in patients presenting with NETs and an unknown primary. These findings have clinical utility for appropriate treatment selection, particularly where targeted therapies are available (everolimus, sunitinib). We believe the 92-gene assay can be useful in clinical management, and that our approach will lead to effective diagnosis and treatment algorithms to streamline extensive pre-operative work-up. [Table: see text]
Dosing patterns for octreotide LAR in neuroendocrine tumor (NET) patients: NCCN NET outcomes database.
Authors: Strosberg Jonathan R. , Bobiak Sarah , Zornosa Carrie C. , Choti Michael A. , Bergsland Emily K. , Benson Al Bowen , Bloomston Mark , Kulke Matthew , Shah Manisha H. , Yao James C. 
Published: March 2020

4142 Background: Among patients (pts) with neuroendocrine histology, 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks is FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration is often prescribed for pts who experience refractory symptoms (e.g., flushing and/or diarrhea) on the maximal labeled dose. Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations, clinical characteristics, reasons for dose increase, and maximal dose. Results: Among 1,886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n=82) and 23% of pNET pts (n=15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. The primary tumor sites among carcinoid pts receiving above label dosing were small bowel (n=40), colorectal (n=4), and unknown (n=34). Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n=53, 65%), tumor progression (n=21, 25%), high urine 5-HIAA (n=1, 1%) and unknown (n=7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%), 40 mg every 3 weeks (15 pts, 18%), and 30 mg every 2 weeks (14 pts 17%). Among pNET pts, reasons for change included uncontrolled symptoms (n=5, 33%), tumor progression (n=9, 60%), and unknown (n=1, 7%). The most common maximal dose/frequency combinations among pNET pts were 40mg every 4 weeks (n=5, 33%), 30mg every 2 weeks (n=4, 27%), and 60 mg every 4 weeks (n=4, 27). Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.