bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leptomeningeal carcinomatosis in BRCA-mutated pancreatic cancer.
Authors: Slostad Jessica Anne , Hallemeier Christopher Leigh , Bamlet William R , Couch Fergus , McWilliams Robert R. 
Published: January 2019

239 Background: Pancreatic adenocarcinoma is a rapidly fatal cancer with 5-year overall survival <5%. 5-10% of pancreatic cancers occur in patients with family history of disease, and 5-27% of these familial cancers are BRCA associated, with defects in Homologous Recombination Repair (HRR). In breast and ovarian cancer, BRCA mutations may be associated with increased risk for brain metastasis (BM). BM is rare in pancreatic cancer, but it is suggested HRR deficient pancreatic cancer patients may have an increased risk for BM/LC. Methods: We analyzed 3030 prospectively identified patients with pancreatic cancer and HHR mutation germline sequencing data (BRCA1/2, ATM, PALB2) from the Mayo Clinic Pancreatic Cancer SPORE Registry. We used clinical databases (2000-2018) to assess the presence of BM or leptomeningeal carcinomatosis (LC). Unconditional logistic regression analysis, with Odds Ratio (OR) and 95% Confidence Interval (CI), assessed the association between HRR gene germline mutation carrier status and any BM. Results: Of 3030 total pancreatic cancer patients, 8 were diagnosed with clinically evident BM/LC (0.26%), confirming the very low incidence of this metastasis site (Table). Of these, all had BM, and 4 also had LC present. No patients had LC diagnosed without BM present. 175/3030 (5.8%) patients had a germline HHR gene mutation. Of these, 1 patient was a BRCA2 carrier (0.57% of HRR deficient patients). 7 /2763 (0.25%) patients without germline HRR mutations had BM or LC (p = 0.44, OR 2.26; 95% CI: 0.27, 18.49). Conclusions: To our knowledge, this is the largest review of BRCA-associated pancreatic cancer patients with BM or LC. The incidence of BM is rare at 0.27%, with LC at 0.14%. Limitations include likely underdiagnosis given short clinical course and lack of availability of somatic HRR gene status. Our study suggests HRR germline carrier patients may have an increased risk of BM/LC development compared to non-carriers. Given rarity, larger studies should be explored. [Table: see text]
Insurance status and hepatocellular carcinoma: A NCDB analysis.
Authors: Ahmed Hibah , Ahmed Aabra , Wolfe Katrina , Silberstein Peter T. 
Published: January 2019

240 Background: Typically occurring in patients with chronic liver disease, hepatocellular carcinoma is the most common liver cancer. Our goal was to compare survival of patients with differing insurance types diagnosed with hepatocellular carcinoma identified in the National Cancer Database (NCDB). Methods: We identified 113,159 patients with hepatocellular carcinoma in the NCDB diagnosed between 2004-2014. Patients included were categorized as having no insurance, private insurance, Medicaid, or Medicare were included. Between-insurance survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Statistically significant survival differences were indicated between all insurance groups (all adjusted p < 0.05), such that privately insured patients had the highest median survival. The discrepancy in survival between uninsured and privately insured patients was the largest (4.6 months vs. 16.9 months, respectively). Medicaid patients on average had a survival of 9.8 months, while Medicare patients had a median survival of 10.0 months. 19% of uninsured patients presented with stage I hepatocellular carcinoma, whereas 30.3% of privately insured patients presented with stage I hepatocellular carcinoma. More uninsured patients did not have surgery of the primary site compared to privately insured patients (87.7% vs. 70.0%, respectively). Likewise, more privately insured patients had a transplant compared to those with Medicaid, Medicare, or those who were uninsured (13.0% vs. 5.7% vs. 5.0% vs. 1.6%, respectively). Conclusions: Our study shows the discrepancies in survival between patients with differing insurance statuses. Of all insurances, those privately insured had the largest median survival. Median survival and percentage surviving. [Table: see text]
Sorafenib versus transarterial chemoembolization as adjuvant therapies for patients with hepatocellular carcinoma and microvascular invasion.
Authors: Bi Xinyu , Gao Jie , Cai Jianqiang 
Published: January 2019

244 Background: Microvascular invasion (MVI) is a risk factor for poor prognosis following curative resection in hepatocellular carcinoma (HCC). Currently, there is no standard of care for patients with HCC and MVI. The present study compared the effectiveness of sorafenib and transarterial chemoembolization (TACE) as adjuvant therapies following hepatic resection in patients with early and intermediate-stage HCC and MVI. Methods: This bi-center retrospective study examined 70 patients with HCC and MVI treated by hepatic resection between June 2009 and March 2018. Twenty-four patients received no postoperative adjuvant therapy (control), 19 received TACE and 27 received sorafenib. Recurrence-free survival (RFS) and overall survival (OS) were compared by the log-rank test. Results: Subjects consisted of 62 males and 8 females, with a median age of 53.5 (range, 28-82) years. The median follow-up was 26.0 (range, 4.1-103.1) months. RFS in the sorafenib group was significantly improved compared with the TACE group (P=0.048), but not with the control group. OS in the sorafenib group was significantly improved compared with both TACE (P=0.015; 2-year OS: 100% vs. 78.6%) and control (P=0.023; 2-year OS: 100% vs. 80.0%) groups. Conclusions: Adjuvant sorafenib following hepatic resection improved OS in patients with HCC and MVI and might be a better choice than adjuvant TACE.
Sunitinib in patients with pancreatic neuroendocrine tumors (panNETs): Exploratory pharmacogenomic analyses.
Authors: Fazio Nicola , Martini Jean-Francois , Croitoru Adina-Emilia , Schenker Michael , Li Sherry , Rosbrook Brad , Fernandez Kathrine C. , Tomasek Jiri , Thiis-Evensen Espen , Kulke Matthew H. , Raymond Eric 
Published: January 2019

255 Background: In a phase IV trial (NCT01525550), median progression-free survival (PFS) was 13.2 mo in sunitinib-treated patients (pts) with well-differentiated panNETs. Objective response rate (ORR) was 24.5% and median overall survival (OS) was 37.8 mo. Exploratory analyses evaluated potential associations between single nucleotide polymorphisms (SNP) in genes involved in angiogenesis, protein transport or inflammatory response and clinical outcomes. Methods: Blood samples were genotyped using TaqMan assays for 12 SNPs previously associated with panNET risk, prognosis or drug effect. Associations between SNP and PFS or OS were assessed by comparing genotypes within treatment-naïve (TN), previously treated (PT) and combined groups, and within a genotype between treatment groups, using Kaplan-Meier analysis and Cox proportional hazards models. Fisher’s exact test was used for association between ORR and genotype. PFS and ORR were investigator-assessed. P values displayed are unadjusted and Bonferroni method was used for multiplicity adjustment. Results: 56 pts were genotyped: 25 TN and 31 PT. There were no significant associations between genotype and PFS or OS but there was a trend toward shorter PFS in pts with VEGFR1 rs9554320 C/A versus C/C (hazard ratio [HR] 1.78; 95% confidence interval [CI] 0.83–3.82; p = 0.117) and VEGFR1 rs9582036 A/C versus A/A (HR 1.88; 95% CI 0.9–3.93; p = 0.102). The genotypes G/G of VEGFA rs2010963 (p = 0.041) , G/G of VEGFA rs833068 (p = 0.041) and A/C of VEGFR1 rs9582036 (p = 0.046) showed a trend toward a higher ORR in the PT versus TN group. Genotype T/T of VEGFR2 rs7692791 (p = 0.103) showed a trend toward to a lower ORR in the TN versus PT group. Higher ORR was associated with IL1B rs16944 G/A versus G/G (46.4% vs 4.5%; p = 0.001) in the combined group. Conclusions: Potential associations between ORR and VEGFA rs2010963 and rs833068, VEGFR1 rs9582036 and VEGFR2 rs7692791 were observed. IL1B rs16944 was significantly associated with ORR, consistent with the role of IL1B in panNET etiology and development. Most correlations were not significant after adjustment for multiplicity. Clinical trial information: NCT01525550.
Growth factor signaling in pancreatic neuroendocrine tumor metastases.
Authors: Rheinheimer Brenna , Heimark Ronald , Jie Tun 
Published: January 2019

256 Background: Pancreatic neuroendocrine tumors (PanNETs) are among one of the fastest growing cancer diagnoses, yet clinical management for patients with metastatic disease is largely empirically based. Currently, surgical resection remains the only curative option; however, surgical resection of metastatic disease may not be feasible. Preliminary genomic analysis of primary PanNETs revealed a complex mutational landscape with four common oncogenic events; but, critical activation pathways of metastatic lesions have yet to be elucidated. Therefore, pan-genomic analysis of metastatic PanNETs is necessary to understand which genes/pathways are deregulated in PanNET metastases for potential therapeutic exploitation. Methods: We initiated a preliminary genomic sequencing study to evaluate mutations in a set of matched primary and metastatic PanNETs to determine genetic variants involved in metastasis to the liver. De-identified FFPE tumor samples were analyzed from patients who underwent surgical resection without receiving preoperative therapy. DNA was isolated and whole exome sequencing was performed using the Nextera Rapid Capture Exome Kit by Illumina on an Illumina HiSeq 2000/2500. The following criteria were used to define genetic variants: bidirectional, non-synonymous, clean mapping in IGV, ≥ 15X coverage, and an alternate allele frequency of 0.3 ≤ x ≤ 0.7. Results: All metastatic PanNETs were classified as WHO grade G2/G3 based on their KI-67 proliferation index. Each primary PanNET contained an average of 102 genetic variants while liver metastases showed an average of 124 genetic variants. MUFFINN and string analysis revealed that primary PanNETs contained enrichment for mutations involved in the PI3K/Akt and Ras signaling pathways while liver metastases showed enrichment for mutations involved in the MAPK and ErbB signaling pathways. Additionally, two-thirds of liver metastases contained somatic mutations in FGFR3. Conclusions: We have discovered novel pathways that have the potential to regulate pancreatic neuroendocrine tumor metastasis along with an innovative signaling pathway that may sustain metastatic growth and survival as well as exploitation for therapeutic potential.
Whole-exome sequencing in unresectable pancreatic cancer patients with long-term survival.
Authors: Sudo Kentaro , Yokoi Sana , Ohara Osamu , Nakamura Kazuyoshi , Tsujimoto Akiko , Kita Emiri , Hasegawa Yoshinori , Nakayama Manabu , Ishii Hiroshi , Denda Tadamichi , Yamaguchi Taketo 
Published: January 2019

260 Background: Advances in technology of genomic sequencing have revealed the mutational landscape of pancreatic cancer. However, little is known with regard to molecular mechanisms underlying clinical diversity in “unresectable” advanced pancreatic cancer. Methods: We performed whole-exome sequencing using frozen cancer tissues prospectively obtained by EUS-FNA from primary tumors before chemotherapy in patients with metastatic or locally advanced pancreatic cancer (n = 35). All patients had pathological confirmation (adenocarcinoma, n = 34; carcinoma, n = 1). Somatic alterations in the cancer genome were compared with clinical outcomes. Results: Seventeen patients had metastatic disease and 18 had locally advanced disease. Thirty-four patients received chemotherapy with or without radiotherapy and one patient was treated with supportive care alone because of rapidly progressive disease. With a median follow-up time of 60.6 months (range 41.9–94.0) for censored cases, the median survival for all patients was 10.8 months. Nine patients survived more than 2 years ( > 6 years, n = 2; > 3 years, n = 3; > 2 years, n = 4), while 11 patients died within 4 months. We show mutational landscape of unresectable advanced pancreatic cancer and identified somatic mutations in known cancer related genes including KRAS (89%), TP53 (71%), SMAD4 (20%), CDKN2A (17%) and ARID1A (14%). We found that ARID1A mutation was mutually exclusive with TP53 mutation except for one tumor and had a significant correlation with survival outcomes. Among 9 patients who survived more than 2 years, 5 patients (56%) had ARID1A somatic mutation, whereas none (0%) had mutations in the remaining 26 patients who died within 2 years ( P = 0.0004). The median overall survival was 47.7 months for 5 patients with ARID1A-mutated tumors and 8.9 months for 30 patients with ARID1A wild-type tumors ( P = 0.0101). Conclusions: This is the first study to perform whole-exome sequencing in unresectable pancreatic cancer patients including very long-term survivors. We found that ARID1A mutations were associated with longer survival.
The effect of hepatic stellate cells on hepatocellular carcinoma progression.
Authors: Iwahashi Shuichi , Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Saito Yu , Yamada Shinichiro , Rui Feng 
Published: January 2019

265 Background: The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Some manuscripts mentioned that activated HSCs predicted prognoses of hepatocellular carcinoma. The aim of this study is to investigate the effect of HSCs and the role of IL-6 / Stat3 pathway on HCC progression. Methods: HCC cells (Hep G2 and Huh 7) were co-cultured with HSC (LX2 and Li90). The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44), TGF-b and p-STAT3 of cancer cells were evaluated. Then the IL-6 neutralization was performed during HCC cells and HSCs co-culture. The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44) and p-STAT3 of cancer cells were evaluated. Results: Co-culture with hepatic stellate cell increased cancer cell viability and migration ability. The expression of E-cadherin, EpCAM and CD44 of cancer cells also increased after co-culture with HSCs. The IL-6 expression and secretion of HSCs were elevated by cancer cell stimulation. The over-expressed IL-6 activated STAT3 of cancer cell showed as the level of phosphorylated STAT3 increased. Neutralized IL-6 during co-culture significantly decrease the viability and migration ability of cancer cells. Also, the expression of E-cadherin, EpCAM and CD44 of cancer cells decreased. Conclusions: HSCs might promote HCC progression through IL-6 / STAT3 pathway.
Comprehensive characterization of single circulating rare cells through automated picking and high-throughput mRNA profiling in patients with pancreatic cancer.
Authors: Kim Dong Uk , Lim Min Ji , Cho Yoonkyoung 
Published: January 2019

271 Background: Circulating rare cells (CRCs) such as circulating tumor cells (CTCs), tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression. However, there are limited reports characterizing single CRCs comprehensively because of technical limitations including isolation and analysis of rare cells. We aimed to test the feasibility of the automated picking and mRNA profiling platforms of CRCs for evaluating the phenotypic heterogeneity of CRCs and the relationship between clinical outcomes and CRCs in patients with pancreatic cancer. Methods: CRCs were collected from 3ml of whole blood in 4 patients with pancreatic cancer using filter-based lab-on-a-disc platform. The filter membrane was transferred to ALS CellCelector (ALS, Germany) which is picking single nucleated CD45 negative cells to 96-well plate. The single cells were analyzed with the BioMark HD (Fluidigm, USA) which is digital PCR-based mRNA profiling for 48 markers such as epithelial, mesenchymal, stem-like, macrophage, fibroblast, oncogenic and immunogenic markers. Results: CRCs were detected in 3 of 4 patients (75%). Sixty-six-year-old female who had large pancreatic cancer with liver and lung metastasis presented 13 single rare cells including 7 epithelial CTCs with hematopoietic features (CD45 and CD14 positive), 3 mesenchymal CTCs, 2 stem-like CTCs, and 1 CAF. One epithelial CTC with hematopoietic features and one stem-like CTC were detected in 51-year-old male and 61-year-old female with metastatic pancreatic cancer, respectively. There was no CTC in 80-year-old male with localized pancreatic cancer. Conclusions: The automated picking and mRNA profiling platforms showed the feasibility of showing tumor heterogeneity and predicting clinical outcomes in patients with pancreatic cancer.
Thermal safety and effectiveness of tumor treating fields’ delivery to the abdomen as determined by computational simulations.
Authors: Weinberg Uri , Bomzon Zeev , Naveh Ariel , Yesharim Ofir , Farber Ori , Kirson Eilon 
Published: January 2019

272 Background: Tumor Treating Fields (TTFields), an antimitotic cancer treatment, utilizes low intensity (1-3 V/cm), intermediate frequency (100-300 kHz), alternating electric fields delivered non-invasively by transducer arrays placed on skin over tumor region. Safety of TTFields has been established in pancreatic cancer (Phase II study; PANOVA; NCT01971281). A Phase 3 study in locally-advanced pancreatic cancer (PANOVA-3) and a phase 2 study in hepatocellular cancer are ongoing. Preclinical studies suggest that TTFields’ intensity correlates with treatment efficacy. Simulations can determine the thermal safety of TTFields by evaluating tissue heating due to field absorption and resultant risk of thermal damage. We used computational simulations to study the effectiveness of field distribution and associated heating in realistic phantoms during TTFields delivery to the abdomen. Methods: Delivery of TTFields to computational phantoms of a male (DUKE 3.0), a female (ELLA 3.0) and an obese male (FATS 3.0) was simulated. For each phantom, 6-8 different transducer array layouts to the abdomen were tested. Specific Absorption Rate (SAR) levels were calculated to assess the risk of thermal damage to tissues, and compared to the SAR control level of 10 W/kg per International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines for occupational exposure (Health Physics 74 (4) 494; 1998). The field intensities were measured to determine the effectiveness of treatment delivery. Results: Altering the size and position of the arrays facilitates field intensities above the therapeutic threshold of 1 V/cm. Within the abdominal internal organs, the SAR values were generally below the ICNIRP recommended level of 10 W/kg. The maximum SAR levels did not exceed 20 W/kg. Conclusions: TTFields could be delivered at intensities above therapeutic threshold of 1 V/cm by strategizing the array size and placement. TTFields to the abdomen can be delivered to target gastrointestinal cancers without causing thermal damage to abdominal tissues. These results also indicate that TTFields delivery can be optimized in gastrointestinal cancers.
Patient reported abdominal pain as a surrogate of the clinical benefit of tipifarnib in pancreatic cancer patients.
Authors: Gualberto Antonio , Scholz Catherine Rose , Van Cutsem Eric 
Published: January 2019

275 Background: Tumor CXCL12 expression identifies patients who may benefit from tipifarnib therapy. In pancreatic cancer, CXCL12 is known to decrease abdominal pain by inducing the migration of pain suppressing Schwann cells to tumor lesions. Given the association between CXCL12 and pain suppression, we investigated whether the absence of patient reported abdominal pain could be a surrogate of clinical benefit from tipifarnib in pancreatic cancer patients. Methods: We conducted a retrospective analysis of a randomized placebo-controlled trial comparing gemcitabine plus tipifarnib (GT) versus gemcitabine plus placebo (GP) in pancreatic adenocarcinoma patients. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine at standard dosing. Primary study end point was overall survival. Results: 688 patients were enrolled of whom 155 (22.5%) reported no abdominal pain at study entry, 81 received GT and 74 GP. Baseline characteristics were balanced in the subset of patients with no reported abdominal pain (GT,GP): median age (63,59), female gender (35%,43%), ECOG 0-1 (89%,90%), metastatic disease (64%,70%), 6-month weight loss >10% (48%,39%), 6-month jaundice history (51%,45%), and prior Whipple surgery (16%,13%). Subjects receiving GT who did not report abdominal pain at study entry had higher frequency of locally advanced disease (36% vs 24%) and 6-month jaundice (51% vs 38%), and lower frequency of lung (6% vs 14%) and peritoneum (4% vs 13%) metastases than those reporting pain. No differences in survival were observed in the overall study. Median overall survival for GT was 193 vs 182 days for GP. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 305 vs 176 days, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 184 vs 182 days. A trend for better survival with GT was observed in subset of patients with no abdominal pain at study entry (GT,GP): 305 vs 184 days, p=0.058. Conclusions: Absence of abdominal pain may serve as a surrogate of clinical benefit from tipifarnib in pancreatic cancer. (Van Cutsem et al. JCO 2004;22:1430-8; NCT00005648; Trial Sponsor: J&J PRD). Clinical trial information: NCT00005648.