bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in response to imatinib between gastrointestinal stromal tumors involving the liver and tumors that do not: Experience from Nairobi.
Authors: Othieno-Abinya Nicolas Anthony , Singh Riyat Malkit , Omollo Raymond , Gichuru Gladwell Wantiru 
Published: March 2020

e20504 Background: More than 60% of gastrointestinal stromal tumours (GISTs) arise from the stomach and about 20% from the small intestines. About 95% of GISTs express kit receptor tyrosine kinase (CD117) which is used for purposes of diagnosis and targeted treatment. However, kit expression alone is not specific for GIST, nor does it necessarily imply kinase activation. Poor prognostic features include involvement of the liver, and other bulky sites of disease. Methods: Patients with CD117-positive leiomyosarcomas arising in the abdomen and treated through the Glivec International Patient Assistance Program (GIPAP) clinics in Nairobi were studied. Details taken included sites involved by disease at diagnosis, stage, sites of metastases, whether the tumour had been resected or not, and outcome of treatment with imatinib. Data were summarized using proportions where the variables were categorical while mean (SD) or median (range) was used for continuous variables. Comparisons for categorical variables were done using chi square tests (or Fishers exact test for cell counts less than 5). The statistical level of significance was set to 5%. Results: In total 54 patients were included. Males were 36 (66.7%) and females 18 (33.3%). Age range was 25-86 years, median 50. Stomach was involved primarily in 22 of 47 cases evaluable (46.8%). The liver was primarily involved in 3 (6.4%) and liver metastases in 7 (15%). None of 8 patients (0%) with evaluable liver involvement regressed or stabilized on treatment for at least 6 months compared with 10 of 14 (71.4%) from the stomach, 7 of 7 (100%) from small bowel, and 7 of 13 (53.8%) with mesenteric/omental involvement. These differences were statistically significant (p = 0.001). Conclusions: Apparent lack of response by tumours involving the liver could suggest that the kit expression here may not be the factor activating the kit target in this subset of patients, or they could be of exon 9 mutation predominantly. Mutational analysis studies may shed more light in this issue.
Theranostic profiling of Ewing sarcoma (ES) and desmoplastic small round cell tumors (DSRCT).
Authors: Wen Wenhsiang , Chen Sting , Ghazalpour Anatole , Rhees Brian , McGinniss Matthew Jerome , Gatalica Zoran 
Published: March 2020

e20507 Background: Ewing Sarcoma (ES)/PNET and Desmoplastic Small Round Cell Tumor (DSRCT) are sarcomas with distinct chromosomal translocations involving the EWS gene (predominately EWS-FLI1 and EWS-WT1; respectively). Their diagnosis and treatment has been difficult due to the rarity, diverse clinical presentation, overlapping histologic features and genetic complexity (Taylor BS et al, 2011). Therefore, novel approaches in clinical management are warranted. Methods: Seventeen cases (9 ES and 8 DSRCT) were analyzed using a commercial molecular profiling service (CarisTargetNow, Caris Life Sciences, Phoenix, AZ). The whole genome transcriptome analysis (29285 transcripts) was performed using HumanHT-12 beadChip (Illuminia Inc, San Diego, CA) and comparison to pooled soft tissue reference sample. Additionally, a select number of chemotherapy-predictive (theranostic) biomarkers were evaluated using immunohistochemistry, FISH, and DNA sequencing. Results: We observed 160 commonly up and 357 commonly down regulated genes between ES and DSRCT in transcriptome analysis. Cell cycle signaling, DNA replication and E2F mediated pathway genes were most commonly up regulated. In addition, higher expression of SOX-2, a recently identified cancer stem cell marker (Riggi et al, 2010), were observed in DSRCT than in ES, suggesting EWS-WT1 translocation might result in reprogramming of DSRCT to express cancer stem cells. Above threshold expression of TOP2A and TOPO1was observed in approximately 50% of all cases. Additional theranostic biomarkers (ERCC1, TS, SPARC and MGMT) showed significant inter-individual variations. No KRAS mutations or EGFR gene amplification were observed in any case. Conclusions: 1. Our transcriptome analyses might provide future therapeutic targets in cell cycle regulation, DNA replication, receptor TKI pathways and stem cell reprogramming. 2. Using multimodality test approaches, we confirmed and refined the benefits in both tumor types of individualized therapeutic assessment including predicted susceptibilities to anthracycline, irinotecan, platinum analogs, fluorouracil, and temozolomide.
Treatment practice patterns and survival among patients with metastatic soft tissue sarcoma (mSTS) in a community setting in the United States.
Authors: Chen Clara , Borker Rohit , Dhanda Rahul , Nadler Eric 
Published: March 2020

e20510 Background: Although guidelines exist for use of chemotherapy in mSTS, a disease associated with extremely poor survival, data on real world treatment practice patterns and disease prognosis are lacking, especially in community settings. This study describes the treatment patterns and survival among patients with mSTS in a community setting. Methods: A retrospective cohort study using an oncology electronic medical record (EMR) database from 7/2008 to 12/2010 was conducted. Study subjects were aged ≥18 years, had mSTS, and received 1st and/or 2nd line chemotherapy during the study period. Treatment patterns were documented based on descriptive analysis of the EMR data. Kaplan-Meier estimates were calculated for reporting overall survival (OS) across lines of therapy. Results: The study sample consisted of 368 mSTS patients (mean age [SD]: 61 years [16 years]). Among those who received chemotherapy (179 patients), 178 patients (99%) received 1st line treatment while 43 patients (24%) received 2nd line treatment. Doxorubicin + ifosfamide (29%), docetaxel + gemcitabine (25%) and doxorubicin (13%) were more frequently used in 1st line treatments, while docetaxel + gemcitabine (58%) and doxorubicin liposomal (16%) were more frequently used in 2nd line treatments. The table reports the data on OS. Conclusions: There is a lack of standard of care in treatment of mSTS in the community setting in the US. The prognosis of metastatic disease, especially in the advanced lines of treatment, remains poor. [Table: see text]
Phase II study of adjuvant imatinib mesylate (IM) in patients after resection of primary gastrointestinal stromal tumor (GIST): Efficacy and safety at one year.
Authors: Yalcin Suayib , Buyukberber Suleyman , Yilmaz Ugur , Lee Po-Huang , Srimuninnimit Vichien , Lin Pin-Wen , Elserafy Mostafa M. , Manieh Moustafa , Sunpaweravong Patrapim , Istomin Yuriy , Sriuranpong Virote , Hwang Tsann-Long 
Published: March 2020

e20514 Background: The mainstay treatment of primary GIST is surgery, but GIST often recurs even after complete resection. This study assessed the safety and efficacy of adjuvant IM in patients (pts) with resected GIST at intermediate/high risk of tumor recurrence. Methods: This open-label, single arm, prospective Ph II study (NCT01172548) was conducted in Asia Pacific/Africa/Russia/Middle East/Europe in eligible pts: aged ≥18 years (yrs), having had complete gross resection of primary GIST within 70 days of enrollment, with CD117 +ve, WHO PS ≤1, and no other adjuvant therapy. The planned sample size was 150 pts. Pts were to receive IM (400 mg/day, po) for 2 yrs post surgery. Dose modifications were allowed for toxicity. The primary endpoint was recurrence-free survival (RFS) rate at 2 yrs (based on CT/MRI and survival) in ITT pts (all pts who received ≥1 dose of study drug); null hypothesis based on historic data controls treated with surgery alone: RFS rate at 2 yrs of 0.7 (1 yr rate 0.98) (NCT00041197). A protocol-planned analysis at 1 yr in all enrolled pts (mITT) included safety, RFS, and overall survival. The study was approved by IRB/IEC/REB; all pts provided written informed consent. Results: Pt accrual was complete with 127 pts in the mITT population. Most pts (n=94, 74%) were <65 yrs (median 56 [19–81] yrs); female (53%). Most common primary tumor sites: stomach (n=68, 54%), small intestine (n=48, 38%), colon/rectum (n=7, 6%). Main discontinuations (n=24, 18%): disease progression (n=8, 6%); withdrawal of consent (n=7, 5%); adverse events (AEs) and lost to follow-up (each n=3, 2%). Mean RFS rate at 1 yr was 0.95 (95% CI 0.907–0.993). Most AEs were mild or moderate (Table); no deaths occurred by 1 yr. Conclusions: Adjuvant IM 400 mg/day was efficacious and had a promising safety profile at 1 yr in pts after complete resection of primary GIST. [Table: see text]
Soluble HER2 (sHER2) as a prognostic serum biomarker of non-small cell lung cancer.
Authors: Wilson Bethany Cox , Cardenas Andres , Kimbler Kimberly D. , Gal Tamas , Witt Lisa A , Arnold Susanne M. , Branscum Adam J. , Baron Andre T. 
Published: March 2020

e21000 Background: The human epidermal growth factor receptor (EGFR/HER) gene family encodes four homologous tyrosine kinases that regulate cell growth and proliferation, survival, motility, and adhesion. HER2 gene amplification and receptor overexpression have been observed in < 20% of non-small cell lung cancers (NSCLC). Serum concentrations of soluble HER2 (sHER2), a proteolytic fragment of the receptor’s extracellular domain, have been associated with tumor HER2 overexpression, advanced stage, and high grade. This study evaluated serum sHER2 as a prognostic biomarker of NSCLC. Methods: Patients with primary NSCLC (n=149) were recruited at the University of Kentucky prospectively between 2002 and 2008 by the Markey Cancer Center Biospecimen Core Program and linked to the Kentucky Cancer Registry - a population-based cancer registry of the NCI Surveillance, Epidemiology and End Results (SEER) Program - to obtain clinicopathological data. Serum samples were collected prior to surgery and quantified to determine sHER2 concentrations by sp185HER-2 ELISA (Bender MedSystems Diagnostics GmbH). Non-parametric tests were performed to assess whether sHER2 concentrations differed between NSCLC patients stratified by gender, stage, histology, and grade. Cox regression analyses were performed to assess whether sHER2 concentrations, age, gender, stage, histology, and grade are associated with progression free and overall survival. Results: Mean patient age in this case series is 62 years (SD = 10.84 years) and median overall survival is 30 months. Over 97% of patients are smokers. Although serum concentrations do not differ between males and females (p = 0.12), high sHER2 concentrations portend a 72% lower relative risk of death (H.R. = 0.283, p = 0.009) and longer overall survival among men, but not among women (H.R. = 1.012, p = 0.965) adjusted for stage. Conclusions: The results show that low serum sHER2 concentration is an adverse prognosticator of overall survival in males, but not females, and suggest that low serum sHER2 could be useful for stratifying male NSCLC patients for HER2-targeted therapy. Further investigation is warranted to assess sHER2 as a gender dependent prognostic (and potential theragnostic) biomarker of NSCLC.
Modulation of regulatory dendritic cell polarization in cancer by paclitaxel.
Authors: Zhong Hua , Zhong Runbo , Han Baohui , Shurin Galina , Shurin Michael 
Published: March 2020

e21001 Background: Tumors are dynamic organs, in which active processes of cell differentiation affect disease course by regulating the composition of cells at the tumor site. we hypothesize that regDC form the premalignant niche in the lung to support lung cancer development and sustain lung cancer growth and progression. Furthermore, we evaluated if paclitaxel affected regDC and paclitaxel in noncytotoxic concentrations prevents polarization of cDC into regDC.Methods: Bone marrow-derived cDC were treated with tumor conditioned media from 3LL lung cancer cell lines for 48 h, washed, depleted of GR1+ cells and added to ConA-stimulated syngeneic T cells. 3LL-induced regDC were isolated by cell sorting from the in vitro generated cultures or from lungs harvested from 3LL-bearing mice. Analysis of immunosuppressive DC revealed them as CD11clowCD11bhigh CD80lowCD86lowMHC-IIlowPDCA1negGR1neg cells. For the in vivo evaluation of the potential protumorigenic properties of regDC, sorted CD11clowCD11bhigh (regDC) and CD11chighCD11blow/neg (cDC) subsets were injected (5x105cells i.p.) into mice together with 1/15 of the minimum tumorigenic dose of 3LL tumor cells (2x104cells, i.v.). As expected, no tumor nodules were detected in lungs in mice treated with saline or cDC (0/6 mice).However, >30% of mice injected with regDC developed lung tumors, suggesting that regDC exhibit a potent protumorigenic activity in vivo. Next, we asked if paclitaxel could alter regDC formation in vivo. Paclitaxel was administered in 3LL lung metastasis bearing mice. Lymphoid and non-lymphoid tissues were harvested 3 weeks later and analyzed for regDC subsets by flow cytometry.Results: The addition of tumor conditioned converts immunostimulatory cDC into regDC that can suppress proliferation of T cells. Paclitaxel in ultra low noncytotoxic concentrations in vitro could prevent tumor-induced polarization of conventional cDC into regDC. Furthermore, administration of paclitaxel prevented formation of regDC in the lung and significantly inhibited formation of metastases .Conclusions: These data suggest that paclitaxel in ultra low nontoxic doses is able to module the tumor immunoenvironment and support the anti-cancer efficacy of cancer vaccine.
Prognostic value of post-induction PET/CT in untreated multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT).
Authors: Kostakoglu Lale , Dingli David , Beksac Meral , Zamagni Elena , Mark Tomer Martin , Chari Ajai , Elliott Brian M , Lowe Val J. , Ozkan Elgin , Nanni Cristina , Kucuk Ozlem , Fanti Stefano , Coleman Morton , Jagannath Sundar 
Published: March 2020

e21006 Background: Induction with novel biological agents has significantly improved progression free survival (PFS) of MM pts. However, role and timing of ASCT is unclear and there remains a need for a practical means to predict post-ASCT outcome. Our goal was to determine the prognostic value of FDG PET/CT (PET) after induction therapy (IT) in comparison with other prognostic factors and International Myeloma Working Group (IMWG) response criteria. Methods: Prospective, multicenter study of 113 newly diagnosed MM pts undergoing IT+ASCT. IT was not controlled and consisted of 2 or 3 novel agent combinations. The tested variables to predict PFS are shown in table. Two PET scoring systems were used: Score1, positive>marrow uptake; Score2, positive>liver uptake. ROC analysis determined the SUV cut-off. Results: With a median follow-up of 29.5 mo 56 (49.6%) pts relapsed (median PFS: 24.3 mo). Results are displayed in table. Post-IT, when a "+" PET (Score2) was associated with less than a VGPR response, relapses occurred in 83% of pts vs. in only 30% when PET was "-" and pts were in CR or VGPR. Multivariate analysis revealed only ISS to be an independent predictor of PFS (p=0.014). Conclusions: Post-IT a "-" PET associated with CR+VGPR suggests a durable response. Qualitative PET evaluation using a more liberal threshold (liver) to define positivity can be used to accurately assess response in MM. These data failed to prove the post-IT IMWG and PET response to be independent prognosticators while ISS was a superior predictor. This may be attributed to inadequate sample size, nonuniform pre- and post-ASCT treatments, varying follow-up times. Further analyses with stratifying various prognostic indicators and therapy schemes in a larger population are underway to determine a definitive role for PET as a predictor of post-ASCT outcome. [Table: see text]
Sensitivity of microcavity array system for circulating tumor cells in lung cancer patients.
Authors: Kenmotsu Hirotsugu , Hosokawa Masahito , Koh Yasuhiro , Yoshino Tomoko , Yoshikawa Takayuki , Naito Tateaki , Takahashi Toshiaki , Murakami Haruyasu , Nakamura Yukiko , Tsuya Asuka , Shukuya Takehito , Ono Akira , Akamatsu Hiroaki , Watanabe Reiko , Ono Sachiyo , Endo Masahiro , Kikuhara Yoshihito , Kanbara Hisashige , Matsunaga Tadashi , Yamamoto Nobuyuki 
Published: March 2020

e21007 Background: Epithelial Cell Adhesion Molecule (EpCAM)-based enumeration of circulating tumor cells (CTCs) has prognostic value in solid tumors such as advanced breast, colon and prostate cancers. However, poor sensitivity has been reported in non-small cell lung cancer (NSCLC). We have developed a microcavity array (MCA) system integrated with a microfluidic device for recovery and enumeration of CTsC, regardless of EpCAM expression level. This system can isolate tumor cells on the basis of differences in size and deformability between tumor and hematologic cells. Methods: Paired peripheral blood samples were collected from metastatic lung cancer patients. CTCs were enumerated by EpCAM-based immunomagnetic capture (CellSearch, Veridex) and by the MCA system. In the MCA system, trapped cells were stained with Hoechst 33342, FITC-labeled anti-pan cytokeratin antibodies and PE-labeled anti-CD45 antibodies for subsequent imaging analysis. CTCs were defined as cells with round to oval morphology, a visible nucleus, positive staining for pan-cytokeratin and negative staining for CD45. We evaluated the sensitivity of the MCA system for detecting CTCs in lung cancer patients compared with the CellSearch system. Results: Twenty-two metastatic NSCLC patients and 13 small-cell lung cancer (SCLC) patients were enrolled into this study between April 2011 and January 2012. CTCs were detected using the MCA system in 17 of 22 NSCLC patients (count ≥1 per 7.5 ml) compared with 9 of 22 patients using CellSearch (p=0.013). On the other hand, CTCs were detected using MCA in all 13 SCLC patients compared with just 9 of 13 patients using CellSearch (p=0.012). More CTCs from NSCLC patients were detected by the MCA system (median 13, range 0-313 cells/7.5ml) than by the CellSearch system (median 0, range 0-37 cells/7.5ml) demonstrating statistical superiority (p=0.002, Wilcoxon test). Conclusions: Our results suggest that the MCA system is potentially superior to the CellSearch system for detecting CTCs in lung cancer patients and further clinical development should be considered.
Exposing the criminal record of every blood sample: Use of SOMAmer technology and sample mapping vectors to mitigate false biomarker discoveries in lung cancer.
Authors: Gill Rosalynn D , Williams Steve , Ostroff Rachel , Brody Ed , Stewart Alex , Pass Harvey , Rom William , Weissfeld Joel L. , Siegfried Jill , Mehan Mike 
Published: March 2020

e21012 Background: Biomarker discovery studies may fail to translate to the clinic because the study population does not match the intended clinical use or because hidden preanalytic variability in the discovery samples contaminates the apparent disease specific information in the biomarkers. This can arise from differences in blood sample processing between study sites or in samples collected differently at the same study site. Methods: To better understand the effect of different blood sample processing procedures, we evaluated protein measurement bias in a large multi-center lung cancer study using the >1000 protein SOMAscan™ assay. These analyses revealed that perturbations in serum collection and processing result in changes to families of proteins from known biological pathways. We subsequently developed protein biomarker signatures of cell lysis, platelet activation and complement activation and assembled these preanalytic signatures into quantitative multi-dimensional Sample Mapping Vector (SMV) scores. Results: The SMV score provides critical evaluation of the quality of every blood-based sample used in discovery and also enables the evaluation of candidate protein biomarkers for resistance to preanalytic variability. Despite uniform processing protocols for each clinic, the SMV analysis revealed unexpected case/control bias arising from collecting case and control serum from different clinics at the same academic centers, an effect that created false or bias-contaminated disease markers. We therefore used the SMV score to remove bias-susceptible analytes and to define a well-collected, unbiased training set. An improved classifier was developed, resistant to common artifacts in serum processing. Conclusions: . The performance of this classifier to detect lung cancer in a high-risk population is more likely to represent real-world diagnostic results. We believe this approach is generally applicable to clinical investigations in all fields of biomarker discovery and translational medicine.
Correlation of markers of oxidative damage and circulating IL6 levels with survival following treatment with bevacizumab in metastatic colorectal cancer patients.
Authors: Noonan Sinead , Martin Petra , Maguire Aoife , Biniecka Monika , Tosetto Miriam , Hyland John , Sheahan Kieran , O'Donoghue Diarmuid , Mulcahy Hugh , Fennelly David , O'Sullivan Jacintha 
Published: March 2020

e21024 Background: Angiogenesis drives cancer growth, tumour progression and metastases. Hypoxic tumours initiate recruitment of their own blood supply and enhance expression of vascular endothelial growth factor (VEGF). Bevacizumab is a recombinant humanised monoclonal anti-VEGF antibody which prevents VEGF binding to its receptors and improves overall survival in metastatic colorectal cancer patients when combined with cytotoxic chemotherapy. Currently, Bevacizumab is indicated as a first line treatment in all metastatic colorectal cancer patients, however only 38-44% of these patients will have a response to treatment. There is no good marker to predict treatment response. The role of inflammation and oxidative damage in driving angiogenesis and clinical response to bevacizumab is poorly understood. The aim of this study was to investigate the levels of oxidative damage and inflammation in the tissue and in the circulation of patients receiving Bevacizumab. Methods: Tissue from 80 patients was constructed into tissue microarrays (TMAs) and screened by immunohistochemistry for the levels of a DNA adduct marker 8oxodG and a lipid peroxidation marker 4HNE in addition to Ki67 status. Serum was screened for 8oxodG, 4HNE and the inflammatory cytokines; IL1β, IL6, IL8, TNFα and pro-angiogenic factors; Ang 2, TGFβ, VEGF using ELISA. Data was correlated with patient survival following Bevacizumab treatment. Results: 8oxodG stromal nuclear positivity significantly correlated with survival following bevacizumab (p=0.035) and this was independent of cell proliferation status. Following multivariate analysis, circulating IL6 levels also significantly correlated with survival following bevacizumab treatment (p=0.01). Using linear regression, circulating levels of 8oxodG correlated with IL6 levels (p=0.016). Circulating Ang 2 levels correlated with IL6 (p=0.006). Conclusions: We have shown for the first time that levels of a DNA adduct marker 8oxodG and circulating levels of IL6 correlate with survival in metastatic patients receiving Bevacizumab.