bluuebunny/crossref_metadata_2025_split huggingface dataset:
An observational study evaluating the expression of HER2 (1+, 2+, and 3+) with HLA A2/A3+ in gastric adenocarcinoma patients.
Authors: Patnaik Ashis , Parvatini Shyam , Sachdeva Shalabh , Choy Gavin S. , Sharma Akhilesh , Jagannath Palepu 
Published: February 2017

18 Background: Gastric cancer remains a major health issue and results in 800,000 annual deaths worldwide. Despite approximately 50% of the gastric and gastroesophageal (GE) junction adenocarcinomas are diagnosed with resectable disease, 40% of disease recurrence is observed in 24 months. While trastuzumab has shown to increase overall survival in HER2 IHC3+ metastatic disease, no current therapies are available for low expressing, or IHC 1+ or 2+ patients. NeuVax (nelipepimut-S) is an immunogenic peptide epitope derived from the extracellular domain of HER2/nu protein administered in combination with rhGM-CSF. NeuVax binds to HLA-A2 and A3 on tumor and antigen presenting cells (APC) and elicits a proliferation of CD8+ (cytotoxic) T-cell immune response against HER2 expressing cancer cells. A proof of concept clinical study will be conducted to assess the effectiveness of nelipepimut-S to prevent recurrence and increase disease free survival in gastric cancer patients with all levels of HER2 expression with HLA A2+/A3+. This prospective observational study was undertaken to estimate the HLA A2/A3+ and HER2 expression status in the Indian population. Methods: Tumor tissue samples from gastric or GE junction adenocarcinoma patients were collected from S. L. Raheja Hospital, Mumbai, India. A serum sample was collected for HLA testing by quantitative PCR. IHC (DAKO, 1:600 dilution) was employed for detection of HER2. All patients were consented for the study. Results: Of the 50 patients evaluated, 12 (24%) were positive for HER2 (1+, 2+, 3+) with HLA2/A3 alleles, meeting the defined projected clinical protocol population of all levels of expression of HER2 and HLA A2+ and/or A3+. Of the 12 patients, 9 (75%) and 3 (25%) expressed HLA A2 and A3, respectively, with no patient demonstrating HER2 3+ expression. Conclusions: Results from this prospective observational study suggest patients with gastric and GE junction adenocarcinoma have HLA A2+ and/or A3+ expressing tumors with mostly HER2 1+, 2+ expression. The estimated incidence of HER2 3+ expression in this population may be limited by size of current study. Results will inform the screen failure rate of the planned Phase 2 clinical study.
Resected pancreatic cancer (PC): Impact of adjuvant therapy (Rx) at a high-volume center (HVC) on overall survival (OS).
Authors: Mandelson Margaret T , Picozzi Vincent J. 
Published: February 2017

191 Background: Surgical outcomes for resected PC are known to be superior at HVCs. However, the impact of adjuvant (Rx) performed at HVCs is less studied. We examined the impact of site of adjuvant Rx administration on our resected patients (pts). Methods: Eligible pts were diagnosed 2003-2014 and resected at HVC. Pts were excluded for neoadjuvant Rx, synchronous cancer, death/lost to follow-up within 3 months or contraindications (e.g. morbidity) to adjuvant Rx.. Pts were also excluded if they refused adjuvant treatment or if a community oncologist (CC) was not identified in the medical record or in the western Washington population-based cancer registry. Pt and tumor characteristics were compared in univariate analysis and survival was calculated from date of diagnosis to death or last follow-up. Five year OS was estimated by the Kaplan Meier method and compared using Cox proportional hazards modeling to evaluate the impact of HVC adjuvant Rx on OS while adjusting for potential confounding factors. Results: 245 pts were eligible for study: 139 (57%) treated at HVC, 106 (43%) treated at CC. HVC and CC pts were similar with respect to stage and tumor size, nodal status, resection margins and average distance travelled to HVC. They differed by age (HVC: 63.1, CC: 68.2 p < 0.01). Median and 5-yr OS was 36 mos and 33%. Median OS for HVC vs CC was 44 mos vs. 28 mos (p < 0.01), and 5yr OS was 38.6% vs. 24.8% (p < 0.01), adjustment for age did not alter our findings. Conclusions: 1) With respect to adjuvant Rx for resected PC, HVC and CC pts differed with respect to age only. 2) Both median and 5- yr OS was statistically superior at HVC vs CC. 3) Our study supports the use of HVCs for all Rx components for PC treated with curative intent. 4) Ongoing investigation of patterns of care and their impact on OS in PC is warranted.
Clinical outcomes of patients enrolled in clinical trial compared with patients outside clinical trial in advanced gastric cancer.
Authors: Han Jaejoon , Kim Jin Won , Kim Se Hyun , Lee Jeong-Ok , Kim Yu Jung , Lee Keun-Wook , Kim Jee Hyun , Bang Soo-Mee , Lee Jong Seok 
Published: February 2017

21 Background: Participation in clinical trials gives patients with cancer a chance to receive potential benefits, such as experimental treatment, meticulous follow-up and toxicity managements. We aimed to assess the evidence that such an effect exists in patients with gastric cancer. Methods: Clinical characteristics and overall survival of patients with metastatic or recurrent gastric cancer who received fluoropyrimidine and platinum combination palliative chemotherapy within or outside clinical trials at tertiary referral hospital from January 2010 to December 2012 were retrospectively analyzed. Results: Of the 244 patients, 84 patients (34%) were enrolled in clinical trials. During the study period, 20 patients in four phase 3 trials, 54 patients in eight phase 2 trials and ten patients in two phase 1 trials were participated in clinical trials. Twenty patients (8%) at first-line and 64 patients (38%) at second-line or later were enrolled in clinical trials. Younger age (P = 0.014), metastatic disease (P = 0.015) and HER2 IHC status (P = 0.005) were correlated with participation in clinical trials. The median overall survival of patients who participated in clinical trials at first-line was better than those who did not participated in clinical trials, although it was not statistically significant (16 months and 11 months, respectively, P = 0.407). Number of participation in clinical trials was not associated with survival outcome (1 versus ≥ 2 trials: 15 months and 18 months, respectively, P = 0.545). Second-line chemotherapy was administered in 167 patients. The median overall survival of patients who participated in clinical trials at second-line or later was also better than those who did not participated in clinical trials, however, it was not statistically significant (9 months and 6 months, respectively, P = 0.101). Conclusions: Younger patients, metastatic disease, positive HER2 IHC status, and clinical setting of second-line or later were associated with more participation in clinical trials. The median overall survival was numerically longer in patients who were enrolled in the clinical trials although it was not statistically significant.
Irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): A single institution experience.
Authors: Bupathi Manojkumar , Ahn Daniel H. , Ciombor Kristen Keon , Wu Christina Sing-Ying , Mikhail Sameh , Goldberg Richard M. , Noonan Anne M. , Stephens Julie , Reardon Josh , Hays John L. , Bekaii-Saab Tanios S. 
Published: February 2017

215 Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer with a very dismal prognosis. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in progression free survival (PFS) and overall survival (OS) with acceptable toxicities when combined with 5-Fluorouracil (5FU)/ leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in APC. Methods: We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs) and Kaplan-Meier methods were used to calculate the median PFS and OS. Results: Forty patients were included in this analysis, 33% male. Patients had received 1 to 5 lines of prior therapy (27% with 1 prior and 25% with more than 3 lines of prior therapy). The mean age at diagnosis was 60 and 97% had ECOG of 1. The average CA 19-9 at the start of therapy was 33168 U/ml. The median PFS (from the start of FOLFIRI to disease progression or last follow up) was 2.59 months [95% confidence interval (CI); (1.90, 3.54)] and OS (from the start of FOLFIRI to death or least follow up) was 4.75 months [95% CI (3.14, 8.98)]. The most common AEs included fatigue (98%), neuropathy (83%), anorexia (68%), nausea (60%) and constipation (55%). Grade 3 toxicities included fatigue (13%) and rash (3%). There were no observed grade 4 toxicities that were observed. Conclusions: In this single institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in this heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC.
Impact of sarcopenia evaluated using the total psoas area (TPA) in patients undergoing Y-90 radioembolization for hepatocellular carcinoma (HCC).
Authors: Ioannides Pericles , Abuodeh Yazan , Jin Will , Hoffe Sarah E. , Frakes Jessica M. , Kim Richard D. , Choi Junsung , El-Hadda Ghassan E. , Biebel Benjamin , Kis Bela , Sweeney Jennifer , Friedman Mark , Kothari Nishi , Anaya Daniel A. , Latifi Kujtim 
Published: February 2017

217 Background: Severe skeletal muscle depletion, or sarcopenia, is an independent predictor of clinical outcomes in multiple gastrointestinal cancers. This marker of nutritional status has been defined using the TPA which is measured on a single cross sectional CT image at the L4 vertebral body level. We sought to evaluate whether TPA was predictive of outcomes in those patients with unresectable HCC receiving Y-90 radioembolization. Methods: In an IRB approved database consisting of HCC patients treated with Y-90 radioembolization, 111 patients met our selection criteria of treatment from 2009-2014. To be eligible for the study, patients were included prior to their first injection of Y-90 if they had CT imaging available that included the L4 vertebral level that could be transferred to the treatment planning software system. Of these, 73 patients met criteria and were included in the final analysis. The L4 vertebra was identified on axial CT imaging and the psoas muscle was manually contoured bilaterally. Sarcopenia was defined by the presence of the psoas area in less than the median of the cohort. Results: Sarcopenia was associated with a significantly decreased overall survival (p = 0.013) The mean age of the cohort was 67.6 years (range, +/- 9.45) consisting of 84% male and 16% female patients. Difference in age or gender did not correlate significantly with survival. The median survival time in the “low” (sarcopenic) group was 10.46 months (range, +/- 1.21), whereas the median survival in the “high” group was 18.02 months (range, +/-4.26). The median survival for the entire cohort was 12.86 months. OS at 30 months was 15.4% in the sarcopenic group and 30.2 % in the “high” group. TPA in the upper quartile was associated with a survival benefit compared to the bottom quartiles. The presence of sarcopenia was associated with an increased risk of mortality (HR = 2.049; p = 0.015 CI: 01.150, 3.649). Conclusions: Measurement of the psoas area using TPA is a simple objective method to detect frailty and is predictive of overall survival outcome following Y-90 radioembolization
A multi-center study of 349 pancreatic mucinous cystic neoplasms: Preoperative risk factors for adenocarcinoma.
Authors: Postlewait Lauren McLendon , Ethun Cecilia G. , Merchant Nipun B. , Parikh Alexander A. , Idrees Kamran , Hawkins William G. , Fields Ryan C. , Weber Sharon M. , Cho Clifford Suhyun , Martin Robert C. G. , Scoggins Charles Raben , Bentrem David J. , Kim Hong Jin , Ahmad Syed A. , Abbott Daniel Erik , Kooby David A. , Maithel Shishir Kumar 
Published: February 2017

231 Background: Pancreatic mucinous cystic neoplasms (MCN) are defined by presence of ovarian stroma per WHO 2000 classification. Given their malignant potential, current guidelines recommend resection. However, there are limited data on preoperative risk factors for adenocarcinoma (AC) and high grade dysplasia (HGD) occurring in an MCN. Methods: MCN resections from 2000-2014 at the 8 institutions of the Central Pancreas Consortium were included. Patients with and without AC/HGD were compared. Primary aims were to determine preoperative risk factors for AC/HGD in an MCN and to assess outcomes of MCN-associated AC. Results: Of 1667 resections for pancreatic cystic lesions, 349 pts (21%) had an MCN with 52 (15%) having MCN-associated AC/HGD. Male gender (29 vs 8%; p<0.001), head/neck location (39 vs 13%; p<0.001), increased MCN size (7.2 vs 4.6 cm; p=0.004), radiographic presence of a solid component/mural nodule (54 vs 20%; p<0.001), and duct dilation (43 vs 12%; p<0.001) were associated with AC/HGD compared to benign MCN. All persisted as independent predictors of MCN-associated AC/HGD (Table). AC/HGD was not associated with presence of radiographic septations or preoperative cyst fluid analysis (CEA, amylase, or mucin). Median CA19-9 for patients with AC/HGD was 210 vs 15 U/ml for those without (p=0.001). In the 44 pts with AC, 41 (93%) had lymph nodes harvested with nodal metastases in only 14 (34%). Median FU for pts with AC was 27 mos. AC recurred in 12 pts (27%) with a 3-yr RFS of 59%. OS for pts with MCN-associated AC was 64% at 3 yrs. Conclusions: Adenocarcinoma or high grade dysplasia is present in 15% of resected pancreatic mucinous cystic neoplasms. Pre-operative factors associated with AC/HGD in an MCN include male gender, head/neck location, larger MCN, solid component/mural nodule, and duct dilation on imaging. MCN-associated AC appears to have decreased LN involvement and increased RFS and OS compared to typical pancreatic ductal adenocarcinoma. [Table: see text]
Effect of regorafenib on angiogenesis in neuroendocrine tumors in vitro.
Authors: Milosavljevic Tanja , Juge Elise , Reeks Adrianne , Owens Jennifer , Wang Yi-Zarn , Boudreaux J Philip , Woltering Eugene 
Published: February 2017

232 Background: Regorafenib, a potent multikinase inhibitor, targets a broad range of receptor tyrosine kinases (RTKs), including but not limited to VEGFR, PDGFR, and FGFR, which play an integral role in angiogenesis. Human neuroendocrine tumors (NETs) rely on RTKs to mediate tumor neovascularization, development, and metastasis. Similar kinase inhibitors like PTK787 profoundly inhibit angiogenesis in human NETs. We hypothesized that Regorafenib would have antiangiogenic and antitumor effect on human NETs. This study demonstrates inhibitory activity of Regorafenib on pathologic angiogenesis in vitro using our human tumor angiogenesis model (HTAM). Methods: Human NETs were collected in cell culture media in the O.R. and transported to the laboratory at 4⁰C. Tumors were minced into 2 mm fragments, embedded in a fibrin-thrombin clot and supplemented with a nutrient culture media. Neovessels were visually scored and evaluated based on three parameters: percent initiation, angiogenic growth, and overall angiogenic response. An effective concentration was selected for all successive HTAM assays based on dose response experiments. Angiogenesis data was obtained for 77 patients and analyzed for significance using paired samples t-test (MedCalc). Results: Dose-dependent inhibition of angiogenesis was observed for all NETs (n = 77): primary tumors (n = 11), lymph nodes (n = 28) and organ (n = 38) metastases. Selected dose of Regorafenib [1100 nM] achieved statistically significant inhibition of angiogenic growth (59%) and overall angiogenic response (44.5%) in all NETs (p < 0.0001). However, there was no significant inhibition of percent initiation for all NETs except in primary tumors (p = 0.0260). Conclusions: Regorafenib is an effective antiangiogenic agent for NETs in-vitro. Regorafenib targets angiogenic growth in all NETs and inhibits initiation of angiogenesis exclusively in NET primary tumors. This suggests preferential use of Regorafenib for NET patients who have not yet developed metastases. Alternatively, Regorafenib could be an effective adjuvant treatment for advanced stage patients.
Radiosensitivity differences between liver metastases based on primary histology suggest implications for clinical outcomes following SBRT.
Authors: Ahmed Kamran A. , Caudell Jimmy J. , El-Haddad Ghassan , Berglund Anders E. , Hoffe Sarah E. , Frakes Jessica M. , Eschrich Steven A. , Torres-Roca Javier 
Published: February 2017

239 Background: Increasing evidence in the management of oligometastases with stereotactic body radiotherapy (SBRT) reveals differences in outcomes based on primary histology and dose selection. We have previously identified a multigene expression index for tumor radiosensitivity (RSI) with validation in multiple independent cohorts. In this study, we assessed RSI in liver metastases and our clinical outcomes following SBRT based on primary histology. Methods: Patients were identified from our institutional IRB approved prospective observational protocol. A total of 444 metastatic liver lesions were obtained from a de-identified meta-data pool. Gene expression was from Affymetrix Hu-RSTA-2a520709. The RSI 10 gene assay was run on tissue samples and calculated using the previously published algorithm. A cohort of 33 patients with 38 liver metastases treated with SBRT using 50 Gy or 60 Gy in 5 fractions was used for clinical correlation. Results: The median RSI for all liver lesions was 0.42 (Q1, 0.28; Q3, 0.49). The most common primary histology for liver metastases were colorectal (n = 374; 81%), pancreas (n = 18; 4%), and breast (n = 15; 3%). There were significant differences in RSI of liver metastases based on histology. The median RSIs for liver metastases in descending order of radioresistance were skin (0.54), colorectal (0.43), stomach (0.43), pancreas (0.42), lung (0.35), breast (0.34), small intestine (0.22), and anal (0.21); p = 0.0003. A total of 57 patients had multiple liver tissue samples. When averaging RSI values from the same patient, significant differences continued to be noted based on primary histology: colorectal (0.43), lung (0.43), breast (0.34), and anus (0.20); p = 0.008. The 12 and 24 month Kaplan-Meier rate of local control (LC) for colorectal lesions was 79% and 59% compared to 100% for non-colorectal lesions (p = 0.019), respectively. Conclusions: In this first analysis assessing the radiosensitivity of liver metastases, we find significant differences based on primary histology. As we move towards an era of personalized radiation delivery, this study suggests primary histology may be an important factor to consider in SBRT dose selection.
Clinical utility of circulating tumor DNA (ctDNA) in resectable pancreatic ductal adenocarcinoma (PDAC).
Authors: Wong Hui-Li , Bushell Kevin , Karasinska Joanna , Arthur Sarah , Morin Ryan , Schaeffer David F. , Renouf Daniel John 
Published: February 2017

247 Background: ctDNA is emerging as a promising biomarker, with potential utility in screening, detecting minimal residual disease after curative resection and monitoring treatment response or resistance in advanced disease. Most PDAC studies to date have focused on identifying mutant KRAS ctDNA in metastatic disease. Here we perform sequential ctDNA quantification in patients (pts) with resectable PDAC using a novel and highly sensitive multiplex technology to explore the clinical utility of ctDNA as a diagnostic and prognostic biomarker. Methods: Banked plasma and tumor samples from 18 pts with resected PDAC were retrieved. Plasma samples were collected 0-28 days before, and 28-70 days after surgery. DNA was extracted using standard protocols and analyzed using the OnTarget system, which enriches for DNA molecules containing hot spot mutations prior to sequencing. A 96-plex panel that includes the most prevalent mutations in KRAS, PIK3CA and TP53 was used. Results: 16 pts (89%) had at least 1 mutation detected by OnTarget in the tumor sample, most frequently in KRAS codon 12 (n = 14). ctDNA was detected in the pre-operative blood sample in 7/16 pts with tumor mutations (sensitivity 44%) and 0/2 pts without detectable tumor mutations (specificity 100%). Of the 10 pts with available post-operative blood samples, 1 did not have a tumor mutation. 4 pts had detectable ctDNA, 3 of whom have recurred. In contrast, 0 of the 5 pts without detectable post-operative ctDNA have recurred. At median follow-up of 37 weeks, recurrence-free survival (RFS) was significantly longer in pts without detectable ctDNA after surgery (median not reached vs 9 weeks, p = 0.022). Of 11 plasma samples with detectable ctDNA, 3 harbored mutations that were not detected in the primary tumor, including 2 non-KRAS mutations (GNAS R201H and PIK3CA E542K). Conclusions: Pre-operative ctDNA has low sensitivity, suggesting limited utility in PDAC screening. RFS was significantly longer in pts without detectable post-operative ctDNA; however this analysis is limited by small numbers and short follow-up. Discordance in hot spot mutations detected in tumor and matched plasma was observed in 27% of samples, possibly related to intratumoral heterogeneity.
Association of long-term survival in pancreatic cancer (PDAC) with increased proliferative and anti-apoptotic protein activation.
Authors: Picozzi Vincent J. , Ramos Corinne , Hoke Nicholas N , Hoke Glenn D. 
Published: February 2017

254 Background: 5 year (yr) overall survival (OS) for resected PDAC is typically 20%. To test the potential for molecular prediction of > 5 yr OS in such patients (pts), we analyzed proteomic activation (phosphorylation) patterns in both cancer and stromal cells from initial surgical specimens prior to adjuvant therapy (Rx). Methods: Formalin-fixed, paraffin-embedded tissue from 40 pts (20 pts each with long-term actual disease-free OS [median 65 mo, range 26-137 mo] [LTS] and with early relapse/death < 2 yrs [STS]) with de novo resected PDAC formed the test cohort. All pts received adjuvant Rx (chemo Rx with/without chemoradiation). Laser Capture Microdissection enabled directed cancer and stromal cell isolation. Retrospective blinded protein activation analysis for both was performed via Reverse Phase Protein Array (RPPA). Differences in baseline protein signaling of LTS vs. STS were evaluated via two-way ANOVA analysis. Results: Analysis of > 50 signal transduction proteins (STPs) for activation (phosphorylation) showed these significant differences for LTS vs. STS in cancer cells: 1) Activation of proliferation markers Sox2/ Ki 67 were higher (p<0.0001). 2) Activation of anti-apoptotic signal transducer and activator of transcription 3 (p-STAT 3) ( p=0.047) and p-SRC kinase (p=0.039) were higher. 3) Activated p-m-TOR expression was higher (p=0.021). 4) Activation of mitotic marker histone H3S10 was lower (p=0.03). In stromal cells, activation of the survival marker Mek S298 was lower (p=0.021). For other STPs, differences for LTS vs. STS (e.g. Livin, PCNA) were not seen. Conclusions: 1) LTS and STS of de novo resected PDAC show clear differences in cancer cell protein activation re key markers of proliferation and apoptosis (Sox2, Ki67, STAT3, SRC kinase, H3S10). 2) For stromal cells, protein activation was largely similar, but a difference in activation of one stromal protein (Mek S298) was seen. 3) For these pts, differences in protein activation prior to adjuvant Rx could enhance current prognostic models and/or identify new pharmacological targets designed to improve OS. 4) These findings require further validation: a second 60 sample validation cohort is now under anaylsis.