bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burden of carcinoid heart disease in patients initiating treatment for carcinoid syndrome.
Authors: Joish Vijay N , Perez-Olle Raul , Lapuerta Pablo , Dharba Sam , Zacks Jerome 
Published: January 2019

262 Background: Carcinoid heart disease (CaHD) develops as a complication of uncontrolled carcinoid syndrome (CS) due to overproduction of serotonin. Delayed diagnosis or control of CS may result in a greater prevalence of cardiac involvement. The objective of this study was to determine the burden of CaHD in patients initiating somatostatin analogs (SSA) for CS. Methods: This retrospective study investigated claims for commercially insured adults receiving SSA for CS between 2010 and 2016. Claims were evaluated for markers of CaHD such as tricuspid or pulmonary valve-related disease. Eligible patients had ≥ 1 medical claim for CS, had initiated SSA treatment, were continuously enrolled in their health plan for 30 days prior to SSA initiation and for ≥ 1 year, had no sign of acromegaly, and did not participate in a clinical trial during the study period. Patients were followed as long as they were observed in the dataset. Descriptive statistics examined demographic and treatment characteristics and costs for patients with (cases) and without (controls) a marker for CaHD during the study period. Results: A total of 654 patients with CS met the study criteria, of which 38% (n = 248) already had ≥ 1 marker for CaHD prior to initiating SSA treatment. At least 1 CaHD marker was identified in 46% (n = 185) of patients (cases) during the follow-up period. Except for age, all demographic characteristics were similar between cases and controls (n = 221). Cases were significantly older than controls (mean 67 vs. 64 years, p = 0.004). Average follow-up was 26 months (SD 22.0) for cases and 35 months (SD 24.8) for controls. Average time to observation of first CaHD marker for cases was 16 months (SD 16.7) after SSA initiation; most (84%) had ≥ 2 CaHD markers. Markers of right heart involvement were present in 20% of cases, and aortic or mitral valve involvement in 15% and 24%, respectively. Annual per patient expenditures were significantly higher for cases versus controls (mean [SD]: $51,825 [$70,423] vs $29,068 [$56,454], respectively). Conclusions: This study revealed that CaHD is common among patients with CS both before and after initiating SSA treatment. Early diagnosis and control of CS is necessary to reduce the burden of CaHD.
Randomized phase II trial of the carboxylesterase (CES)-converted novel drug EDO-S7.1 in patients (pts) with advanced biliary tract cancers (BTC).
Authors: Pape Ulrich-Frank , Kasper Stefan , Meiler Johannes , Sinn Marianne , Vogel Arndt , Mueller Lothar , Burkhard Oswald , Caca Karel , Heeg Steffen , Laval Victor Rodriguez , Kühl Anya A , Arsenic Ruza , Jansen Holger , Utku Nalan 
Published: January 2019

264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to EDO-S7.1, and one pt (10%) PR (total: 40.0% [12.2, 73.8]) vs two pts with SD following BSC (20.0% [2.5, 55.6]; treatment difference –0.17, 0.57; p=0.0786). Median PFS was 103d with EDO-S7.1 vs 39d with BSC (p=0.006), and median TTF 92d vs 39d, respectively (p=0.006). Median OS was 227d with EDO-S7.1 vs 162d with BSC (p=0.088), and estimated 1-year OS 44% vs 11.3%, respectively. EDO-S7.1 had significant efficacy in pts with metastatic disease (p=0.029) or without prior surgery (p=0.032). Seven pts were eligible for exploratory analysis of tumor CES via immunohistochemistry. 4/7 pts had CES+ tumors and longer median PFS (195d [163, 233]) and OS (302d [214, 838]) vs pts with CES– tumors (46d [46, 83] and 83d [43, 319], respectively). The most common drug-related adverse events (G3–4) (%) were leukopenia 65 (26.1), neutropenia 78.3 (56.5), thrombocytopenia 56.5 (17.4), anemia 52.2 (17.4), alopecia 34.4 (0), fatigue 26.1 (0), and abdominal pain 30.4 (0). Conclusions: EDO-S7.1 demonstrated efficacy in pts with advanced BTC and may provide a new biomarker-guided therapeutic option with stratification by intra-tumor CES assessment. These findings will be explored in a larger patient cohort. Clinical trial information: NCT02094560.
Deleterious alterations in DNA-damage repair (daDDR) genes as a predictive biomarker for platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Palacio Sofia , Stowe McMurry Hannah , Ali Robert , Donenberg Talia , Silva-Smith Rachel , Wideroff Gina , Sussman Daniel A. , Rocha Lima Caio Max Sao Pedro , Hosein Peter Joel 
Published: January 2019

266 Background: Germline genetic testing and somatic genomic profiling using commercial multigene panels are now routine in mPDAC. A subset of these patients have deleterious alterations in genes involved with DDR. Herein we investigate the role of daDDR as a predictive biomarker for response to first-line platinum-based chemotherapy. Methods: Utilizing the IRB-approved pancreas cancer and genetics clinic databases at the University of Miami, we identified all patients with mPDAC who had germline and/or somatic mutation testing. We performed a retrospective chart review to extract demographic and clinical characteristics including treatments received, response and survival. Results: Between 2012 and 2018, 116 patients with mPDAC underwent germline (using Invitae, Ambry Counsyl or Myriad) and/or somatic testing (using FoundationOne CDx). Among these, 40 received first-line therapy with FOLFIRINOX (95%) or gemcitabine/cisplatin (5%). The median age was 59 years and 15 (38%) were female. The majority (70%) were Hispanic and 63% had de-novo mPDAC (treatment-naïve). Germline testing revealed daDDR in 5 patients and somatic NGS found an additional 4 patients with daDDR (total of 9 (23%), including 5 with BRCA2, one each with BRCA1, RAD51C, ATM and MUTYH). The median progression-free survival (PFS) was significantly longer in patients with daDDR than without (17.3 vs 7.8 months, log-rank p = 0.01). The median overall survival (OS) was not statistically different between the two groups. Three patients with daDDR had complete or near-complete radiological and tumor marker responses to FOLFIRINOX and were treated with olaparib (a PARP inhibitor) as maintenance and remain progression-free after 7, 12.4 and 13.6 months respectively. Conclusions: daDDR appears to define a subset of patients with mPDAC who may be more sensitive to platinum agents. There are currently no biomarkers for selection of first-line therapy in patients with mPDAC and we demonstrate that this composite biomarker which is easily done via commercially available assays may be able to inform treatment selection.
Mutational landscape by targeted next-generation sequencing in EBV-associated lymphoepithelioma-like cholangiocarcinoma.
Authors: Chiang Nai-Jung , Chen Ming-Huang , Chen Li-Tzong , Yanshen Shan 
Published: January 2019

269 Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma, which is highly associated with EBV infection and abundant lymphoplasmacytic cell infiltration. However, there’s limited data of genetic background in LELCC. Therefore, we want to explore the mutation profiles of LELCC, as well as copy number variations. Methods: Five patients’ tumor tissues diagnosed as LELCC, with positive EBER expression were retrospectively collected and microscopically dissected. Of them, two patients’ peripheral blood mononuclear cell served as background of germline mutations. Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes for analysis of tumor tissue and blood. PDL1 immunohistochemistry staining with 22C3 antibody pharmDx was applied. Results: All EBV-associated LELCC showed positive expression of PDL1 staining, with combined positive score from 5% to 30%. Both somatic and germline mutations can be detected in LELCC tissue because diffuse infiltration of lymphocytes over tumor. After adjusting for background germline mutation frequency from peripheral blood, only mutations with allele frequency less than or around 10% were considered as somatic mutations. Overall, 10 nonsynonymous somatic mutations were detected in 4 (80%) patients with a range of 1-5 mutations per sample. Mutations were identified including BARD1, EPHA5, MUC16, TNFAIP3, CD19, PTEN, TET1, RECQL4, CD79B, and KDM5A. Copy number changes were rare in this special population. Interesting, one patient who failed to gemcitabine plus cisplatin got partial response after anti-PD1 inhibitor treatment. Conclusions: LELCC is highly correlated with PDL1 expression in tumor and immune cells. It’s necessary to have both tumor tissue and peripheral blood for next-generation sequencing to identify truly somatic mutations in LELCC.
Prognosis of gastric dysplasia after complete resection with endoscopic procedures.
Authors: Park Junseok , Lee Joon Seong , Kim Jin-Oh , Jeon Seong Ran , Kim Hyun Gun , Lee Tae Hee , Cho Jun-Hyung 
Published: January 2019

27 Background: Gastric adenomas are considered premalignant, and some can be interpreted as cancer according to different pathologic guidelines. The dysplastic lesions share histologic characteristics including mucin phenotype that are related prognosis. The prognosis of the lesions has been studied but tends to be researched separately. Moreover, the proposed prognostic factors are mostly derived from the study of surgical specimens, and most of them did not consider the anatomical changes after surgery. Previously researched prognostic factors of gastric dysplasia were evaluated on the recurrence after complete resection with endoscopic procedure. Methods: From 2005 to 2016, 1678 gastric dysplasia were endoscopically removed in Soonchunhyang university hospital, Seoul. They were followed up with endoscopy under a standardized protocol. For the 716 lesions were histologically evaluated including mucin phenotype with immunohistochemical stain of MUC5AC, MUC6, MUC2, and CD10. Recurrence of dysplastic lesions were analyzed for the 688 lesions with at least 1 year’s follow-up. Results: Five-hundred and forty-three malignant lesions including in situ lesions were completely resected with endoscopic procedures. Endoscopic submucosal dissection was performed on 603 lesions and other lesions were removed with endoscopic mucosal resection. Submucosal invasion was on 83 lesions of carcinoma. The mucin phenotype of lesions was immunohistochemically evaluated. During median 40 months of follow-up, there was 89 cases of recurrence (12.9%). Kaplan-Meier analysis of the recurrence-free survival were estimated and the elderly over 65 years of age showed statistical significance (p = 0.039). Conclusions: Completely resected early stage of gastric dysplasia showed relatively low recurrence rate. Previously proposed histologic features did not affect prognosis. However, the age of patient showed statistical significance on recurrence-free survival. Regular surveillance on elderly patients is important to improve the clinical outcome of gastric dysplasia.
A pilot study of galunisertib (LY2157299 monohydrate) plus stereotactic body radiotherapy (SBRT) in advanced hepatocellular carcinoma (HCC).
Authors: Reiss Kim Anna , Ben-Josef Edgar , Damjanov Nevena , Hoteit Maarouf , Karasic Thomas Benjamin , Carpenter Erica , DiCicco Lisa , Garcia-Marcano Luis Anna , Mick Rosemarie , Vonderheide Robert H 
Published: January 2019

270 Background: TGF-β, the strongest known immunosuppressive cytokine, modulates the hepatic immune response to various antigens and to ionizing radiation. When activated, TGF-β blocks the effector T-cell response to cellular destruction and the release of tumor-specific antigens. Preclinical data demonstrate that neutralizing TGF-β during radiation effectively generates a CD8+ T-cell response to multiple endogenous tumor antigens, thereby generating an in-situ vaccine against a tumor. We hypothesized that the combination of TGF-β receptor inhibition plus SBRT would produce a potent and clinically effective antitumor immune response against HCC. Methods: Patients received galunisertib (LY2157299 monohydrate) on days 1-14 of each 28 day cycle. SBRT was delivered in a single fraction of 18 Gy between days 15-28 of C1. Pre-treatment and on-treatment biopsies were obtained, as well as serial blood collections for CTCs, ctDNA and PBMCs. Results: 15 patients with advanced HCC and Child’s Pugh A cirrhosis were treated. 9/15 (60%) had a prior history of infectious hepatitis, three of whom had active viremia at time of enrollment. 6/15 (40%) had received prior systemic therapy for HCC and 12/15 (80%) had received prior liver directed therapy. The most common treatment-related toxicities were: fatigue (53%), nausea (47%), increased alkaline phosphatase (33%), abdominal pain (33%), vomiting (20%), decreased white blood cell count (20%). All drug-related toxicities were grade 1 or 2, with the exception of one patient who had grade 3 achalasia, thought possibly to be related to study drug. Median PFS was 3.68mo. There were two confirmed partial responses (PRs) and six additional patients had stable disease (SD) for at least four months, resulting in a disease control rate (DCR) of 53%. Both PRs included shrinkage of lesions that had not been radiated. Translational studies are currently underway. Conclusions: The combination of galunisertib with SBRT in patients with advanced HCC is a well-tolerated regimen. In this small pilot study, we observe a DCR of 53% including two PRs. These results warrant further study of this therapeutic combination in advanced HCC. Clinical trial information: NCT02906397.
The feasibility of hepatectomy for the super-elderly patients with HCC.
Authors: Ohta Shogo , Iwahashi Shuichi , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Saito Yu , Yamada Shinichiro , Shimada Mitsuo 
Published: January 2019

274 Background: We previously reported the feasibility of hepatectomy for HCC patients who were above 80 years old (Yamada S, Shimada M, et al. Hepatology Res. 2012). However, there was the manuscript that it was important to assess the preoperative co-morbidity on hepatectomy in elderly patients. The aim of this study is to investigate the feasibility of hepatectomy in super-elderly patients over 85 years old focused on the postoperative complications. Methods: Two hundred twenty-nine patients with HCC who underwent primary hepatectomy from April 2004 to October 2016 were enrolled in this study. Patients were divided into three groups; above 85 years old (super-elderly, n=6), between 75 and 85 years old (elderly, n=54) and below 75 years old (non-elderly, n=169). All of patients in this study did not underwent neither preoperative treatment nor additional splenectomy. Clinicopathological data and outcomes after hepatectomy were compared between three groups. Results: There were no significant differences between the super-elderly group and other two groups in the patients’ backgrounds and tumor factors. Regarding as the rate of total postoperative complications, there was no difference between three groups However, in super-elderly group, the mortality was higher compared with other two groups (super-elderly 16.7%, elderly 0%, non-elderly 1.2%: p<0.01 One-way ANOVA, Turkey’s test). There was the one patient of liver failure in the super-elderly group, and he died due to the liver and respiratory failure. In long-term outcomes, there was no significant difference between the super-elderly group and other two groups. Conclusions: The long-term outcome of super-elderly patients was similar to that of non super-elderly, however, the careful attention to the liver failure might be paid on super-elderly hepatectomy patients. Therefore, hepatectomy might be justified for selected super-elderly patients.
Frequency and feasibility of detecting FGFR mRNA expression in archival samples of patients with cholangiocarcinoma (CCA).
Authors: Chougule Abhijit , Lennerz Jochen K , Zhu Andrew X. , Bardeesy Nabeel , Ting David Tsai , Deshpande Vikram , Goyal Lipika 
Published: January 2019

281 Background: Fibroblast growth factor receptor (FGFR) inhibitors show promising activity in patients with intrahepatic CCA harboring FGFR2 fusions, but these alterations have a modest frequency of 15-20%. FGFR mRNA expression has shown preliminary potential as a predictive biomarker for FGFR inhibition in advanced urothelial cancer and is currently being used for patient selection in clinical trials. To assess if we can increase the number of patients with CCA eligible for FGFR inhibitor trials, we evaluated the frequency and feasibility of detecting FGFR mRNA overexpression in archival CCA tissue. Methods: Patients with intrahepatic and extrahepatic CCA who received treatment at the MGH between 1/2004 and 12/2013 were included. Tissue microarrays of archival specimens were stained using the FGFR1-3 pooled, FGFR1, and FGFR2 RNA in situ hybridization probes (RNAscope 2.5 assay). Clinicopathologic data were obtained from the medical record. CCA cell lines were assessed for sensitivity to the FGFR selective inhibitor BGJ398 and also for FGFR expression by qPCR. Results: 90/111 (81%) TMA specimens were evaluable: median age 62.6 years, female 63%, median tumor size 5.1cm, intrahepatic/extrahepatic 71%/29%%. Among the 90 samples, 14% samples stained negative for the pooled FGFR1-3 probe, and 23%, 32%, and 30% stained 1+, 2+, and 3+ positive, respectively. Of note, majority of the samples stained 3+ for FGFR2. Examination of 11 ICC cell lines lacking FGFR gene abnormalities revealed that the single line with marked overexpression of FGFR1 exhibited hypersensitivity to BGJ398. Conclusions: Selection of patients with CCA for treatment with FGFR inhibitors based on mRNA expression levels is feasible on archival tissue with the FGFR RNA ISH probes, and this technique may identify a subpopulation of patients without FGFR genetic abnormalities who may benefit from FGFR inhibitors. [Table: see text]
Sequential gemcitabine (G), oxaliplatin (O), and irinotecan (I) based weekly metronomic chemotherapy (MC) regimens for the treatment of metastatic pancreatic cancer (mPC): A community cancer clinic experience.
Authors: Chue Ben M. , La Course Bryce D. 
Published: January 2019

284 Background: mPC has a poor prognosis with a median overall survival (mOS) ranging from 8.5 to 11.1 months (mo) with standard treatment, outlining the need for new innovative treatments. MC regimens utilize lower doses of chemotherapy that are administered more frequently which can maintain dose intensity while reducing toxicity. MC with paclitaxel (P) or nab-paclitaxel (N) may have effects on the tumor microenvironment. Methods: A retrospective analysis of treatment regimens and survival of patients (pts) with biopsy proven mPC who received treatment between August 2004 and August 2018 was performed. Results: 30 pts with biopsy proven mPC were identified. 14 pts received prior chemotherapy. mOS of this cohort was 18.9 mo after diagnosis and 14.2 mo after beginning MC. 70% of pts (21/30) survived longer than 12 mo, 37% (11/30) greater than 24 mo, and 27% (8/30) greater than 30 mo. All MC regimens were given on a weekly basis and included: P 60 mg/m² and G 600 mg/m² (PaG); P 60 mg/m², O 50 mg/m², folinic acid (L) 20 mg/m², and 5-fluorouracil (F) 425 mg/m² (POLF); P 60 mg/m², I 100 mg/m², and cisplatin (C) 20 mg/m² (PIC) or P 60 mg/m², I 100 mg/m², L 20 mg/m², and F 425 mg/m² (PILF). 21 pts received N instead of P at some point during their treatment. PaG, POLF, and PIC or PILF were purposely switched before disease progression after a median length of 13, 11 and 13 weeks respectively. 16 pts received PaG as their first regimen. 12 of these 16 pts then received POLF as their second regimen, and 7 of these 12 pts subsequently received PIC or PILF as their third regimen. These 7 pts had a mOS of 21.7 mo after diagnosis and 19.1 mo after beginning MC. 10 pts were successfully able to receive PaG, POLF, or PIC/PILF more than once. Conclusions: Weekly MC regimens such as PaG, POLF, and PIC/PILF that are given sequentially are an effective treatment for mPC. Switching regimens may prevent the development of chemotherapy resistance, allowing for chemotherapy regimens to be used again in the future. There are limitations of retrospective studies so further investigation of this treatment strategy should be done with a large randomized clinical trial.
Landscape of circulating tumor DNA profiling of advanced pancreatic cancer (PDAC).
Authors: Mody Kabir , Kasi Pashtoon Murtaza , Surapaneni Phani Keerthi , Borad Mitesh J. , Ahn Daniel H. , Mahipal Amit , Starr Jason Scott , Ritter Ashton , McMillan Jessica , Wylie Natasha , Roberts Ali , Nagy Rebecca J , Bekaii-Saab Tanios S. 
Published: January 2019

289 Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA), which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.