bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and therapeutic impact of family with sequence similarity 83, member B in EGFR gene wild type-lung adenocarcinoma.
Authors: Yamaura Takumi , Okabe Naoyuki , Takagi Hironori , Owada Yuki , Inoue Takuya , Watanabe Yuzuru , Fukuhara Mitsuro , Muto Satoshi , Matsumura Yuki , Hasegawa Takeo , Hoshino Mika , Osugi Jun , Shio Yutaka , Ezaki Junji , Watanabe Shinya , Suzuki Hiroyuki 
Published: September 2018

e23136 Background: We have reported the usefulness of Family with sequence similarity 83, member B (FAM83B) as a novel biomarker for diagnosis and prognosis of lung squamous cell carcinoma. FAM83B expresses not only in lung cancer but also in several types of solid cancer. More recently, novel finding showing FAM83B involve to tumor growth, oncogenesis, and resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in breast cancer cell lines has been shown. EGFR signaling pathway also plays an important role in lung adenocarcinoma, therefore, we hypothesize that FAM83B associates with tumor proliferation in lung adenocarcinoma (ADC), results in resistance to EGFR-TKI and in a novel therapeutic target in a part of lung ADC. Here we show that correlation between FAM83B expression and clinicopathological features. Methods: This study was conducted with approval of ethics committee in our institute, and informed consent was obtained from all the participants. We identified 216 participants underwent for primary lung ADC between 2008 and 2015. Paired tumor and corresponding normal tissue samples obtained from patients were subjected. FAM83B mRNA expression were examined by cDNA microarray, and analyzed relationship between the level of FAM83B and clinicopathological variables including survival analysis. Further, FAM83B knock down study was performed in several types of cancer cell lines (H1975, HLC-1, H2347) to validate whether FAM83B involve to cell proliferation. Results: FAM83B highly expressed in male (p = 0.007), or smoker (p = 0.007), or EGFR wild type tumor (p<0.001). Multivariate analyses also showed that EGFR wild type-tumor correlate with FAM83B expression. In survival analysis, multivariate analysis showed FAM83B correlated with poor outcome in both disease free survival and overall survival (p = 0.011 and p = 0.001), especially stratified by EGFR wild type-tumor (p = 0.017, p = 0.008). Gene silencing with FAM83B siRNA showed growth suppression of HLC-1 and H1975 cell lines. Conclusions: FAM83B could involve to tumor proliferation of lung ADC in part, and expected to be the novel therapeutic target of EGFR wild type-ADC.
Copper chelation as targeted therapy in a genetic mouse model of oncogenic BRAF-driven thyroid cancer.
Authors: Xu Mengmeng , Range Danielle , Sosa Julie Ann , Counter Christopher 
Published: September 2018

e23148 Background: Over half of papillary thyroid cancers (PTC) contain the MAPK pathway activating, oncogenic BRAF V600E mutation. Early clinical trials using inhibitors to this mutant protein or its substrates, the MEK1/2 kinases, prolonged progression-free survival or stabilized disease in patients with advanced PTC. However, the toxicities of these inhibitors are uniquely highlighted in an indolent disease like PTC, which would require patients to endure toxicities long-term. Our goal was to determine if tetrathimoybdate (TM), a well-tolerated copper chelator we have previously shown to inhibit BRAF-mutated melanoma via MEK inhibition, can inhibit BRAF-driven PTC growth. Methods: We assessed TM in comparison to current standard of care (SOC), Lenvatinib and Sorafenib, and mutant BRAF inhibitor, Vemurafenib. Anchorage independent growth assays were used to test the inhibitory effect of these drugs on human BRAF-mutated PTC cell lines. We then confirmed these findings by treating a genetically engineered mouse model (GEMM) of aggressive BRAF-driven PTC. Results: TM inhibited 57.5% of colony growth in vitro, which was not significantly different from the 42.4% and 32.2% inhibition by Sorafenib and Lenvatinib, respectively. TM inhibition was less effective than the 70.3% inhibition by Vemurafenib ( p =0.04). We confirmed these results in vivo, where mice on the TM arm, on average, were observed to have 14.8% of their thyroid glands occupied by tumor, a statistically significant reduction from the mice in the control arm, whose tumor load averaged 23.6% ( p= 0.008). This 37.4% reduction in tumor burden was not statistically different from the 35.2% reduction measured in the Vemurafenib arm, where mice on average had 15.3% of their thyroid glands replaced by tumor. Conclusions: The copper chelator, TM, was as effective as the SOCs, Lenvatinib and Sorafenib, at inhibiting the growth of human PTC in vitro. Although TM was slightly less effective than Vemurafenib in vitro, TM was as effective as Vemurafenib at reducing tumor load in a GEMM of BRAF-driven PTC. Success of TTM in these PTC models may next inform a Phase I trial assessing TM in patients with advanced PTC.
Antitumor activity against GPR87-expressing non-small cell lung cancer cells in GPR87-suppressing adenoviral vector.
Authors: Nakano Takayuki , Liu Dage , Kita Yusuke , Tokunaga Yoshimasa , Nii Kazuhito , Matsuura Natsumi , Nakashima Nariyasu , Tarumi Shintaro , Zhang Xia , Go Tetsuhiko , Kakehi Yoshiyuki , Yokomise Hiroyasu 
Published: September 2018

e23152 Background: GPR87 is a newly deorphanized member of the G protein-coupled receptor family, it was suggested to contribute to the viability of human tumor cells, and overexpression of GPR87 was found in many malignant tumors including lung cancer. To explore effective gene therapies, we previously reported that adenoviral vector expressing short hairpin RNA targeting GPR87 (Ad-shGPR87) exerts a strong anti-proliferation activity against GPR87-overexprssing human bladder cancer cells. Here, the effect of Ad-shGPR87 was further examined in lung cancer cells. Methods: Human lung cancer cells of EBC, H358, LUDLU, MAC10 and RERF were investigated. Two cell of adenocarcinoma cell H358 (Ad) and squamous cell carcinoma cell LUDLU with an overexpression of GPR87 were selected for experiment. An adenoviral vector expressing short hairpin siRNA targeting GPR87 gene (Ad-shGPR87) was constructed by the COS-TPC method with Adenovirus Expression Vector kit (Takara Biomedicals). Real-time RT-PCR was performed to evaluate gene expressions. MTT assay was used to evaluate the cell viability. A human tumor xenograft model in nude mice was prepared by subcutaneously implanting tumors derived from H358 cells. Results: Transfection with Ad-shGPR87 effectively downregulated the GPR87 expression in both cells (more than 90% 3 days after transfection). MTT assay demonstrated the transfection of Ad-shGPR87 strongly suppressed the cell viability (less than 6.6 % for LUDLU cell and 20.0% for H358 cell at nine days after transfection). Furthermore, the treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-overexpressing H358 xenografts. Conclusions: The cancer gene therapy using Ad-shGPR87 has a strong anti-tumor effect both in vitro and in vivo against the GPR87-overexpressing lung cancer cells. GPR87 appear to be a promising target for cancer therapy.
Next-generation sequencing (NGS) for personalized therapy in metastatic breast cancer: Selection of therapy and outcomes.
Authors: Gomes Jessica Ribeiro , Moreira Raphael Brandao , Alessandretti Matheus Bongers , Cruz Marcelo Rocha De Sousa 
Published: September 2018

e23166 Background: Treatment for metastatic breast cancer (MBC) has been driven by hormone receptors, HER2 expressions or their absence. Resistance to therapy and progressive disease will occur and empirical chemotherapy lines usually are the next steps. We aim to analyze the role of next-generation sequencing (NGS) for a personalized therapy in metastatic breast cancer and its potential clinical benefit. Methods: We included patients diagnosed with MBC treated at Centro Oncologico Antonio Ermirio de Moraes – Brazil from April 2013 to December 2016. All patients had metastasis accessible for biopsy. The tumor tissue was stored in paraffin and then analyzed by NGS-based assay that identifies genomic alterations within 236 genes. Results: 19 patients with MBC were evaluated (10 triple-negative; 4 HER2-positive; 5 hormonal receptor positive/HER2-negative). The most frequent and relevant genomic alterations identified by NGS assay were in the following genes: 13 TP53 (68.4%); 4 ERBB2 (21%); 4 PTEN (21%); 4 FGFR (21%); 3 PIK3CA (15.8%); 2 BRCA (10.5%); 2 ATM (10.5%); 2 AKT (10.5%); 2 MYC (10.5%); 1 CCND1 (5.3%); and 1 KRAS (5.3%). The NGS assay was able to suggest further therapy in 16/19 patients (84%). The suggested therapies would not be an empirical option according to the cancer’s subtype in 12/16 patients (75%). Therapy could be personalized in nine patients, across multiple lines of therapies (median of 5th line, with a range of 1-14). Median PFS was 6 months, and 8/9 patients (90%) achieved an objective response with the treatment indicated by NGS. Therefore, the assay provided clinical benefit in 42% of patients. Conclusions: NGS panel identified potentially actionable alterations in the majority of patients with MBC (84%). The overall clinical benefit with use of NGS-based assay was 42%. Further studies are necessary to better evaluate the role of NGS for a personalized therapy in MBC.
Clinical applications of genetic sequencing in lymphoma: A retrospective review.
Authors: Shango Maryann , Devata Sumana , Wilcox Ryan A. , Phillips Tycel Jovelle 
Published: September 2018

e23169 Background: Personalized therapy through the identification of targetable mutations within individual tumors has increasingly become a focus in the management of patients (pts) with relapsed/refractory malignancy. To better understand how this is clinically applied, we reviewed 29 cases of B- and T-cell lymphomas that had genetic sequencing of their tumor. Methods: The electronic medical records of 29 pts who underwent Michigan Oncology Sequencing (MI-ONCOSEQ) testing at the University of Michigan from 2013-2016 were reviewed for disease and treatment history. Reports from whole-genome tumor sequencing were obtained for each patient to identify putative molecular targets. Results: Sixteen male and 13 female pts had a median age of 59 years (range 30-80 years) and median disease stage of IV at diagnosis. Five had CTCL, 5 PTCL, 11 follicular, 1 CLL/ mantle cell (MC), 1 MC, 1 marginal zone, 1 Waldenstrom’s (WM) and 4 DLBCL. Pts received a median of 2 therapies prior to MI-ONCOSEQ biopsy. Targetable mutations were identified in 15 pts and a total of 5 pts underwent MI-ONCOSEQ-based treatments. Bosutinib was given for FYB-FGR fusion, imatinib for FLI1-PDGFRB fusion, and everolimus for activating mTOR mutation with an avg. treatment duration of 3.6 weeks due to progressive disease. Bosutinib and imatinib were 3rd line therapies and everolimus was 5th. Another 2 pts were treated with ibrutinib for transformed WM with MYD88 mutation and bortezomib after classification of DLBCL as ABC-type based on MI-ONCOSEQ results, with CR in both. Other targetable mutations identified include BRAF, CDK, BCL2, EZH2 and NOTCH. Of the remaining 12 pts with targetable mutations, 8 pursued clinical trials, 2 responded to standard therapy, 1 died shortly after genetic analysis and 1 declined further therapy. About 50% of these pts remain alive. Conclusions: Our results demonstrate that targeted therapy is favored after standard therapy or clinical trial options are exhausted. Barriers to its use include the availability of clinical trials, off-label drug access and our incomplete knowledge of driver mutations. With further understanding of disease pathogenesis, we expect personalized therapy will be possible for all patients.
Association of hypoxia-induced centrosome amplification with clinical outcomes in triple-negative breast cancer.
Authors: Mittal Karuna , Choi Da Hoon , Ogden Angela , Melton Brian D , Gupta Meenakshi Vij , Reid Michelle D. , Jonsdottir Kristin , Janssen Emiel A. , Aleskandarany Mohammad A. , Ellis Ian O. , Rakha Emad A. , Rida Padmashree C.G. , Aneja Ritu 
Published: September 2018

e23170 Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p < 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p < 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.
Correlation between mutation burden of tumor and immunological/clinical parameters in considering biomarkers of immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).
Authors: Owada Yuki , Muto Satoshi , Takagi Hironori , Inoue Takuya , Watanabe Yuzuru , Yamaura Takumi , Fukuhara Mitsuro , Okabe Naoyuki , Matsumura Yuki , Hasegawa Takeo , Ohsugi Jun , Tanaka Daisuke , Ito Emi , Nanamiya Hideaki , Imai Jun-ichi , Isogai Takao , Watanabe Shinya , Suzuki Hiroyuki 
Published: September 2018

e23184 Background: There has been reported that mutation burden of solid tumor might probably be a predictive biomarker of efficacy of immune check point inhibitors, and the number of researches are still ongoing. Although the correlation of mutation burden between by whole exome sequence and by large targeted panel sequence has also been reported, neither method can be said to have solved technical and economical difficulty of using in clinical practice. Here we describe more convenient factors that can be used instead of mutation burden. Methods: 92 NSCLC patients with surgery during 2013-2015 in our institution were subjected for this study. Mutation burden in tumor samples was analyzed by whole exome sequence using Next Generation Sequencer. The major gene alteration was also analyzed by small targeted panel sequence. As immunological parameters, tumor infiltrating lymphocyte and PD-L1 expression in tumor were assessed by immunohistochemistry test using anti-CD8 antibody and anti-PD-L1 antibody. Statistical analysis was performed on mutation burden and the result of major gene alternation, immunohistochemistry, and clinical parameters. Results: There were 64 adenocarcinomas and 28 squamous cell carcinomas. The median value of mutation burden was 60 genes (10-502). The factors including squamous cell carcinoma, male, smoking history, EGFR-mutation negative, and TP53 alteration positive indicated close connection with higher mutation burden (p < 0.001) There were no significant difference in PD-L1 expression of tumor and tumor infiltrating lymphocyte. Multiple regression analysis showed that negative EGFR-mutation and positive TP53 alteration contribute to higher mutation burden (p < 0.05). Conclusions: Mutation burden in NSCLC tumor could be associated with EGFR-mutation and TP53 alteration status. These findings suggest that some major gene alteration make it possible to predict mutation burden, and could potentially be more simple predictive biomarkers of immune check point inhibitors.
Impact of 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 fluorescent in situ hybridization (FISH) testing in breast cancers: Experience from a national reference laboratory.
Authors: Johnson Eric , Gulbahce Evin H 
Published: September 2018

e23188 Background: Accurate HER2 testing is expected to identify patients who will benefit from HER2 directed therapy (HDT) minimizing false positive and negatives. Like many biologic processes, HER2 protein expression and gene copy numbers are a continuum, however these tests are expected to be reported dichotomously. In 2013, ASCO/CAP revised the guidelines in an attempt to decrease false negative results and reverted to FDA approved ratio of ≥ 2.0 for HER2 positivity. We reviewed HER2 FISH testing results after the implementation of 2013 ASCO/CAP guidelines to determine the effects on HER2 reporting from our national reference laboratory. Methods: HER2 FISH testing performed between 5/2015-4/2016 at ARUP Labs following current 2013 ASCO/CAP guidelines was included. HER2 to control probe ratios, mean HER2 and control probe copy numbers were used to reassign HER2 status using 2007 ASCO/CAP, and FDA guidelines for each case. Results: HER2 FISH results were available in 2,017 cases. 342 (17.0%) cases were amplified, 301 (14.9%) were equivocal, and 1374 (68.1%) were non-amplified. After additional testing with alternate probe, 93 (31.2%) of the equivocal cases were reclassified as amplified increasing amplified cases to 21.6%. All of the equivocal cases which were reinterpreted as amplified with alternate probe showed low level amplification (range: 2.0-3.6; mean: 2.3). HER2 positivity rates following 2013 ASCO/CAP guidelines, both at initial testing and after additional testing to resolve equivocal results were significantly higher compared to 2007 ASCO/CAP guidelines and FDA criteria. Conclusions: 2013 ASCO/CAP guidelines lead to higher number of HER2 FISH positive and equivocal cases. In a reference laboratory setting where alternative control probe was used to resolves equivocal FISH cases, 31.2% of patients with initial equivocal results become HER2 positive. However, it is not known if these patients benefit from targeted therapies as they would not be included in the original adjuvant or metastatic trials.
Hyaluronan assessment in tumor microenvironment using new affinity histochemistry assay and scoring method.
Authors: Pu Jie , Aldrich Carrie , Zhu Junming , Jiang Ping , Wu Xionghua W. , Müller Thomas , Delgado Paco , Quiroz Michelle , Khelifa Sihem 
Published: September 2018

e23196 Background: Enzymatic degradation of hyaluronan (HA) by PEGylated recombinant human hyaluronidase PH20 (PEGPH20) induces a remodeling of the tumor microenvironment that impacts tumor behavior and response to therapy. Ventana Medical Systems, Inc., (VMSI) and Halozyme Therapeutics co-developed the VENTANA HA RxDx Assay and a scoring method to evaluate HA in solid tumors to potentially predict which patients might better respond to the addition of PEGPH20 to cancer treatments. Methods: Using Halozyme’s novel recombinant HA binding probe altered to include a rabbit Fc region, VMSI developed a highly specific and sensitive affinity histochemistry assay that binds to HA in tissues. Histological features and staining patterns of 106 samples from Halozyme’s 109-202 Phase 2 study of PEGPH20 combined with nab-paclitaxel plus gemcitabine (AG) vs. AG alone in patients with previously untreated stage IV pancreatic ductal adenocarcinoma (PDA) with clinical outcome data were analyzed to develop a scoring method evaluating HA accumulation. Results: A novel scoring algorithm focused solely on the extracellular matrix (ECM) was developed. An ECM HA staining ≥ 50% of the entire tumor surface at any intensity defines an HA-High PDA. We recommend that a 0.05 cm x 0.2 cm uninterrupted fragment of tumor cells and associated stroma obtained using needle gauges of 16 to 20 G as the minimally required amount of tissue to assess HA in PDA. Based on verification studies performed by VMSI, including an inter-reader precision study with a 94% agreement rate, VMSI scoring method proved to be trainable, reproducible, and transferable to pathologists, supporting an IDE approval for selecting patients in the Phase 3 HALO 109-301 study. Conclusions: Performance of the VENTANA HA RxDx Assay, a robust affinity histochemical assay, has been successfully verified in PDA. Two Halozyme clinical studies in PDA (Phase 2 HALO 109-202 Stage 2 & ongoing Phase 3 HALO 109-301) are expected to validate the VMSI HA scoring method in selecting patients who might better respond to the addition of PEGPH20 to cancer treatments. Current Phase 1/2 studies are exploring the utility of the VENTANA HA RxDx Assay and the pantumor potential of PEGPH20.
Measuring functional HER2-driven signaling status ex vivo to predict response to HER2 therapy: Results from a mouse breast tumor xenograft study.
Authors: Laing Lance G. , Burns David J , Huang Yao , MacNeil Ian A. , Rich Benjamin E. , Soltani Sajjad , Myhre Samantha , Sullivan Brian 
Published: September 2018

e23203 Background: Clinical trials indicate a weak correlation between HER2 expression levels and HER2 targeted therapy benefit. Other biological factors, such as HER2 signaling activity, may be important to measure when identifying patients for treatment with HER2 therapies. To measure the HER2 signaling activity of a patient’s live tumor cells, a new assay using an impedance biosensor, the CELx HER2 Signaling Function (CELx HSF) Test, was developed. In this study, we evaluated whether functional HER2 signaling status was more predictive of response to a dual-HER2 kinase inhibitor than HER2 receptor or gene amplification status, using breast tumor xenograft in vivo models. Methods: Two breast cancer cell lines were studied: HCC1954, a HER2+ cell line with normal HER2 signaling according to the CELx HSF Test, and BT483, a HER2- cell line with abnormally high HER2 signaling according to the CELx HSF Test. Thus, the HER2 receptor status of each cell line was opposite its HER2 signaling status. For each cell line, twenty 4-5 week old female NSG mice were injected with two million cells. Mice were randomly assigned to either a control group that received Captisol or a treatment group that received lapatinib at a dose of 20mg/kg daily for 16 days. Results: There was no significant difference in tumor volume between the control and lapatinib-treated groups in the mice injected with the HCC1954 (HER2+, normal HER2 signaling) cells. Average tumor sizes reached 1028.7 ± 166.9 mm3 for the control group and 893.8 ± 111.5 mm3 for the lapatinib-treated group (P = 0.285) by the end of the study. With the BT483 (HER2-, abnormal HER2 signaling) cells, lapatinib treatment significantly slowed down the increase in tumor size. Average tumor sizes reached 328.3 ± 54.9 mm3 for the control group and 192.4 ± 19.4 mm3 for the lapatinib-treated group (P = 0.0049). Conclusions: The results demonstrate that functional HER2-driven signaling status in live tumor cells is more correlative to response to lapatinib in mouse xenograft tumors than HER2 expression level. These findings provide strong evidence that HER2- breast cancer patients with abnormal HER2 signaling may respond to anti-HER2 therapies.