tbuckley/cabot-search huggingface dataset:
Abstract 3988: Detection of novel t(12;17)(p12;p13) in treatment-refractory/relapsed acute myeloid leukemia by anchored multiplex PCR(AMP)-based next-generation sequencing
Authors: Laura Johnson, Katelyn Trifilo, Helen Wang, Brian Kudlow, Eric Padron, Peter R. Pappenhausen, Mohammad Hussaini
Journal: Cancer Research (2016)

Abstract Gene fusions are an important class of mutations and have been shown to drive many genetic diseases. While several technologies can be used to detect fusions, anchored multiplex PCR (AMP) next generation sequencing (NGS)-based detection offers the advantages of novel fusion detection and the ability to multiplex multitudinous genes. Here we report application of this technology in the evaluation of a 56-year-old man diagnosed with AML (2013). He was treated initially with Vidaza and later with CLAG-M induction (2014) with complete response and consolidation CLA (2015). He relapsed (4/2015) and was reinduced with 7+3 (Ida). He relapsed again and was reinduced with FCT but bone marrow biopsy showed persistent disease (75% blasts). Karyotype showed 46, XY, t(12;17)(p12;p13)[20]. It was postulated that ETV6 oncogene was involved based on 12p13 locus. The partner gene was unknown in this patient with multiply relapsed/refractory disease. AMP technology (Archer FusionPlex) confirmed involvement of the expected ETV6. However, more importantly, employing this technology lead to the discovery of a novel fusion partner, HIC1. The identity of the novel fusion partners was supported by the breakpoints originally observed by karyotype analysis. AMP promotes discovery of novel fusions by targeting one (known) of two genes involved in the fusion event. HIC1 regulates cellular growth and serves as a tumor suppressor gene. Inactivation of HIC1 has been associated with aggressive disease and poor survival in other cancer types. Interestingly, in vitro restoration of gene function by 5-aza-dC resulted in decreased cell proliferation and tumor aggressiveness in pancreatic cancer and head and neck squamous cell carcinoma suggesting the prospect of a therapeutic target. This discovery provides new insight into a possible leukemogenic pathway in AML and potential for targeted therapy. Citation Format: Laura Johnson, Katelyn Trifilo, Helen Wang, Brian Kudlow, Eric Padron, Peter R. Pappenhausen, Mohammad Hussaini. Detection of novel t(12;17)(p12;p13) in treatment-refractory/relapsed acute myeloid leukemia by anchored multiplex PCR(AMP)-based next-generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3988.
Presence of interstitial lung diseases (ILD) in patients diagnosed with myelodysplastic syndromes (MDS): Mayo Clinic experience.
Authors: Rama Nanah, Darci Zblewski, Mrinal M. Patnaik, Kebede Begna, Rhett P. Ketterling, Vivek Iyer, William J. Hogan, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2016)

e18551 Background: MDS are a group of heterogeneous neoplasms defined by the presence of dysplasia and cytopenias with recurrent cytogenetic and molecular abnormalities. ILD are rare and have been reported in MDS patients. Possible culprits may include autoimmunity, prior drug therapy, and recurrent infections. Aim: To study the characteristics of MDS patients who had ILD. Methods: After due IRB approval, we searched MDS patients that were evaluated at Mayo Clinic between 1997 - 2010 for ILDs, Sweet’s syndrome and autoimmune diseases. ILD was considered present based on lung biopsy, pulmonary function tests and/or CT scan findings. Patients who had received a blood or marrow transplant were excluded. Results: Out of 827 MDS patients, 18 (2%) were found to have ILD. The median age was 73 years in ILD+ vs 71 years in those without ILD (ILD-). Males were comparable in both groups (72% vs 68% in ILD-). Cytogenetics were reported in 14 ILD+ patients; out of which 5 were diploid , 3 had 5q-, and 3 had a complex karyotype including 5q- and 3 had others. RAEB was found in 22% vs 29% in ILD- patients, and only 1 patient (5%) transformed into acute myelogenous leukemia vs 12% in ILD-. Median overall survival (OS) was 17 mo in ILD+ patients vs 29 mo in ILD- (p = 0.1). In ILD+ patients the pulmonary diagnoses were: usual interstitial pneumonia 22%, non-specific interstitial pneumonia 22%, bronchiolitis obliterans organizing pneumonia 22%, sarcoidosis 22%, and unclassified 11%. ILD diagnosis preceded MDS in 13 cases (72%) with median time to MDS diagnosis of 22.3 mo (range, 0-593), and followed MDS in 5 (28%) with a median time of 2 mo (range, 0-73). One patient had rheumatoid arthritis but no patient had Sweet’s syndrome. One patient received decitabine after an ILD diagnosis but none had lenalidomide. Only one patient was on amiodarone at the time of ILD diagnosis. Conclusions: Our study suggests that ILD are present in a higher percentage than anticipated ( < 1/1000 in general population) in the MDS population. Deletion 5q was found in 43% of cases. No statistical difference was found in CBC, bone marrow biopsy findings, IPSS/IPSS-R nor OS. Prior MDS treatment and autoimmunity seemed to play no significant role in ILD development.
Randomized phase III study of adjuvant chemotherapy for high-risk, node-negative breast cancer (BC) comparing FAC with FAC followed by weekly paclitaxel: First efficacy analysis of the GEICAM/2003-02 trial.
Authors: Miguel Martin, Ana Lluch, Amparo Ruiz, Manuel Ruiz Borrego, Agust Barnadas, Sonia Gonzalez, Lourdes Calvo, Mireia Margeli Vila, Antonio Anton, Alvaro Rodriguez-Lescure, Miguel Angel Seguí-Palmer, Montserrat Munoz-Mateu, Joan Dorca Ribugent, Jose Manuel Lopez-Vega, Cesar Mendiola Fernandez, Raquel Andres, Arrate Plazaola, Cesar Rodriguez, Maria Isabel Casas, Eva Maria Carrasco
Journal: Journal of Clinical Oncology (2012)

1001 Background: Adjuvant weekly paclitaxel (wP) sequential to anthracyclines improves the outcome of operable node-positive BC patients (pts) [Sparano NEJM 2008, Martin BCRT 2009]; however, most BC pts are currently node-negative at diagnosis. The role of wP in these pts is not well established yet. Methods: Pts aged 18-70, with T1-T3/N0 operable BC and at least one high-risk St Gallen 1998 criteria (size &gt;2 cm, hormone-receptor [HR] negative, grade 2/3, age &lt;35 years,) were eligible. HER2+ pts were allowed, after 792 entered the trial, the study was amended to exclude them. Pts were stratified by site, menopausal status, nodal status diagnostic method (sentinel-node biopsy versus lymphadenectomy) and HR status and randomized to receive FAC x6 (500/50/500 mg/m 2 every 3w) or FAC x4→wP x8 (paclitaxel 100 mg/m 2 weekly). The primary endpoint was DFS. The trial was designed to detect an absolute 5-y DFS increase of 5% (80% FAC, 85% FAC→wP); a sample size of 1812 evaluable patients (906 per arm) was required to detect this difference (α=0.05, β= 80%). Assuming a drop-out rate of 6%, 1929 pts were required. The first analysis of DFS was planned when a median follow-up of 5 years was reached. Results: Between September 2003 and October 2008, 1925 pts (FAC 974, FAC→wP 951) were randomized. Patient characteristics were well balanced between arms, median age was 50, 73% of pts were HR positive and 9% HER2 positive. 97% of pts with FAC and 85% of pts with FAC→wP completed all treatment as planned. The median dose intensity was 98% with FACx6, 99% with FACx4 and 98% with wP. The most frequent grade 3-4 toxicities (&gt;3% in either arm) with FAC vs FAC→wP were neutropenia (25% vs 22%) with 4% vs 3% of febrile neutropenia, fatigue (3% vs 8%), sensory neuropathy (0 vs 5%), and vomiting (4% in each arm). After a median follow-up of 5.3 years, the proportion of patients disease free is 93% and 90% with FAC→wP and FAC (HR for relapse 0.732, 95% CI: 0.542 to 0.990; log-rank p-value=0.0423). Conclusions: For pts with high-risk node-negative BC, adjuvant FAC→wP was associated with a small but significant improvement in DFS compared with FAC, with manageable toxicity.
Abstract 2332: Patient-derived tumor xenografts in humanized NSG-SGM3 mice: a new immuno-oncology platform
Authors: Li-Chin Yao, Mingshan Cheng, Minan Wang, Jacques Banchereau, Karolina Palucka, Leonard Shultz, Carol Bult, James G. Keck
Journal: Cancer Research (2016)

Abstract Humanized mice engrafted with tumors enable in vivo investigation of the interactions between the human immune system and human cancer. We have recently found that humanized NOD-scid IL2Rγnull (NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of check-point inhibitors. Next generation NSG strains include triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSG-SGM3). Here we provide a direct comparison of check-point inhibitors evaluation in NSG and NSG-SGM3 mice engrafted with CD34+ human hematopoietic progenitor cells (HPCs) from the same donor and implanted with PDX tumors. Corroborating earlier studies, reconstitution of human immune system in the blood was faster and more robust in NSG-SGM3 compared to NSG recipients throughout the course of the study (18 weeks). Human CD45+ cells reached 25% of total blood cells at week 4 in hu-NSG-SGM3 mice and at week 9 in hu-NSG mice. A majority of blood hCD45+ cells in hu-NSG-SGM3 at week 4 were CD33+ myeloid cells. Circulating hCD3+ T cells reached 10% at week 9 and included regulatory T cells (Tregs), consistent with earlier studies. Hu-NSG mice displayed comparable hCD3+ T cells in the blood only at 12-15 weeks and did not contain Tregs. PDX tumors were then engrafted into partially HLA-matched hu-NSG-SGM3 mice at 9 weeks post engraftment. Two PDX models previously shown to respond to anti-PD1 therapy in hu-NSG mice, BR1126 and LG1306, were used. Treatment with the anti-PD-1 receptor antibody pembrolizumab (Keytruda) significantly reduced tumor growth in both models. Thus, PDX-bearing hu-NSG-SGM3 mice might serve as a new and improved platform for preclinical immuno-oncology efficacy studies. Citation Format: Li-Chin Yao, Mingshan Cheng, Minan Wang, Jacques Banchereau, Karolina Palucka, Leonard Shultz, Carol Bult, James G. Keck. Patient-derived tumor xenografts in humanized NSG-SGM3 mice: a new immuno-oncology platform. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2332.
Abstract 1826: IMI's CANCER-ID: Status of liquid biopsy standardization
Authors: Klaus Pantel, Leon WMM Terstappen, Barbara Baggiani, Thomas Krahn, Thomas Schlange
Journal: Cancer Research (2016)

Abstract The CANCER-ID (www.cancer-id.eu) consortium was established in early 2015 with more than 30 partners as part of the Innovative Medicines Initiative (IMI), Europe's largest public-private partnership funded in equal parts by the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The goal is to develop standard operating procedures (SOPs) and qualify respective mature technologies for pre-analytical sample handling, enrichment, isolation and analysis of Circulating Tumor Cells (CTCs), circulating free tumor DNA (ctDNA) and microRNAs (miRNAs) as novel blood-based biomarkers in cancer liquid biopsy, with a particular focus on Non-Small Cell Lung Cancer (NSCLC) and HER2-treatment refractory breast cancer. Over the 5-year period of the project, CANCER-ID will evaluate different technologies in the field, testing their clinical utility in multicenter clinical studies in support of regulatory approval of these devices. During the first year of the project, a number of different technology platforms have been implemented at several partner sites to establish SOPs with standardized blood samples spiked with selected cancer cell lines as standards. An important outcome of these studies are pre-analytical sample handling procedures, e.g. using different fixatives and tube systems as well as biobanking protocols that allow shipment and standardized long-term storage of liquid biopsy material. Most importantly, the knowledge generated within IMI's CANCER-ID will be used to establish and validate SOPs for the analysis of patient blood samples using different technologies, which represents a promising diagnostic tool holding the potential for optimized treatment decisions and therapeutic monitoring of cancer patients. The international exchange of human patient samples for research purposes poses a number of regulatory challenges linked to the different legal and ethical environments. The diverse national regulations for clinical samples and data require coordinated monitoring of interactions and guidance of the different partner organizations. As close collaboration with regulatory authorities is crucial for CANCER-ID to achieve its objectives, the consortium has established a contact with CDER/FDA via a Critical Path Innovation Meeting (CPIM). We will discuss the CANCER-ID approach to meet these many requirements and will present a matrix for coordinating such international efforts with stakeholders from different organizations. Citation Format: Klaus Pantel, Leon WMM Terstappen, Barbara Baggiani, Thomas Krahn, Thomas Schlange. IMI's CANCER-ID: Status of liquid biopsy standardization. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1826.
Abstract 724: MicroRNA-100/mTOR/IL-1ra signaling maintains TAMs phenotype and enhances tumor cell stemness property in mouse breast cancer
Authors: Wei Wang, Yan Liu, Jian Guo, Huiwen He, Junling Xie, Chong Chen, Yunping Luo
Journal: Cancer Research (2016)

Abstract Tumor-associated macrophages(TAMs),the main part of immune cells in tumor microenvironment(TME),play a potent role in promoting tumorigenesis. MicroRNAs (miRs) are considered to be crucial regulators in tumor progression. However, the role that miRs play in TAMs phenotype regulation still remains unclear. In this study, we demonstrated that miR-100 played an important role in maintaining TAMs phenotype and enhancing tumor stemness properties. First, miRNome of TAMs isolated from mouse breast tumor was performed. Compared with macrophages from normal spleen, 40 miRs candidates, in 150 TAMs-high and 169 TAMs-low expressed miRs which were selected from miRNome, were further identified by real-time PCR. Importantly, miR-100 was found with TAMs-high expression pattern(about 70 folds changes). Moreover, we found that miR-100 overexpressed RAW264.7 cells and peritoneal macrophages gained M2 phenotype such as CD206+ cells percentage. Mechanism study demonstrated that miR-100 up-regulated IL-1ra expression detected by cytokine array. Furthermore we found that IL-1ra could enhance 4T1 breast cancer cell stemness properties including increasing tumor cell sphere formation and drug resistance in vitro. Taken together, our results demonstrate that TAMs-high expressed miR-100 could function to maintain the phenotype of TAMs via targeting mTOR pathway, and promote tumorigenesis by enhancing IL-1ra secretion, which would also serve as a promising therapy target to remodel TME and tumor metastasis. Citation Format: Wei Wang, Yan Liu, Jian Guo, Huiwen He, Junling Xie, Chong Chen, Yunping Luo. MicroRNA-100/mTOR/IL-1ra signaling maintains TAMs phenotype and enhances tumor cell stemness property in mouse breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 724.
Abstract 3363: Resistin promotes tumor angiogenesis and lymphangiogenesis through c-Src/PI3K/AKT signaling pathway in human chondrosarcoma cells
Authors: Meng-Ju Chi, Hsiao-Chi Tsai, Chih-Hsin Tang
Journal: Cancer Research (2016)

Abstract Chondrosarcoma is a kind of commonly found bone malignant tumor. The development of distant metastasis often leads to a significant decline in overall survival, and there are no specific therapeutic methods for it until today. For tumors to metastasize, angiogenesis and lymphangiogenesis are both important steps in the early periods. Resistin was discovered as an adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. However, the role of resistin in the angiogenesis and lymphangiogenesis of human chondrosarcoma is largely unknown. In our lab, we found that the expression of resistin was higher in chondrosarcoma biopsy tissues than in normal cartilage. We also confirmed that treated cells with resistin increased VEGFA and VEGFC expression, promoting angiogenesis as well as lymphangiogenesis in human chondrosarcoma cells. Moreover, the inhibitors and siRNAs of c-Src, PI3K, and AKT reduced the resistin-increased cell angiogenesis and lymphangiogenesis. Our results indicate that resistin promotes chondrosarcoma angiogenesis and lymphangiogenesis by the increasing VEGFA and VEGFC expression through the activation of the c-Src/PI3K/AKT signaling pathway expression. Therefore, resistin may represent a potential novel molecular therapeutic target for chondrosarcoma therapeutic treatment. Citation Format: Meng-Ju Chi, Hsiao-Chi Tsai, Chih-Hsin Tang. Resistin promotes tumor angiogenesis and lymphangiogenesis through c-Src/PI3K/AKT signaling pathway in human chondrosarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3363.
The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Vassiliki Papadimitrakopoulou, J. Jack Lee, Ignacio I. Wistuba, Anne S. Tsao, Frank V. Fossella, Neda Kalhor, Sanjay Gupta, Lauren Averett Byers, Julie G. Izzo, Scott N. Gettinger, Sarah B. Goldberg, Ximing Tang, Vincent A. Miller, Ferdinandos Skoulidis, Don L. Gibbons, Li Shen, Caimiao Wei, Lixia Diao, S. Andrew Peng, Jing Wang, Alda L. Tam, Kevin R. Coombes, Ja Seok Koo, David J. Mauro, Eric H. Rubin, John V. Heymach, Waun Ki Hong, Roy S. Herbst
Journal: Journal of Clinical Oncology (2016)

By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers.Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers.Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02).Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.
Abstract 409: Immunofluorescent digital slide technology to evaluate correlation between Glypican-3 expression and response to codrituzumab
Authors: Takayoshi Tanaka, Yasuo Sugitani, Tokiya Abe, Miho Kawaida, Ken Yamazaki, Akinori Hashiguchi, Michiie Sakamoto, Toshihiko Ohtomo
Journal: Cancer Research (2016)

Abstract Background: Codrituzumab/GC33/RO5137382 is a recombinant humanized monoclonal antibody against Glypican-3 (GPC3) which is highly expressed in HCC cells. As part of phase I clinical trial, GC-002US study, evaluating escalating doses of codrituzumab plus sorafenib in HCC, immunofluorescent staining of GPC3 were applied in addition to GPC3 immunohistochemistry (IHC) with conventional DAB staining. The objectives of this work were to compare GPC3 expression levels by different staining methods and evaluate the correlation between these GPC3 scores and codrituzumab activities. Methods: Biopsies specimens (n = 34) collected at baseline in the phase I trial were evaluated by GPC3-IHC and immunofluorescent quantification digital slide (IQD) methods. GPC3-IHC were conducted using mouse anti-human GPC3 antibody, mouse GC33 (Ventana Medical Systems) as reported previously (Ikeda M. et al., Cancer Sci. 2014: 105; 455-462) and H scores were derived by two pathologists. For IQD, biopsy specimens were stained with same primary antibody, and were incubated with Qdot 655-conjugated secondary antibody. Fluorescent images of whole slides were obtained with the Nano-Zoomer (Hamamatsu Photonics K. K.). The IQD intensity score (immunofluorescent intensity per pixel) and cell score (immunofluorescent intensity per cell) were calculated respectively using MatLab (MathWorks Inc.). Results: There was a statistically significant correlation between GPC3 H scores and IQD scores. Among GPC3 scores, only the IQD cell score was correlated with serum GPC3 C-terminus increase by treatment (p = 0.032), whereas in the patients treated with higher dose of GC33 (≥ 10 mg/kg/week) the cytoplasmic H and the IQD intensity score were also correlated with serum GPC3 C-terminus increase by treatment. Interestingly, increasing cut-off values of IQD cell score levels led to lower HR and longer PFS. Best HR with lowest p value was observed at a cut-off value of 66,183 (HR = 0.24, p = 0.038). Conclusion: This study suggested that higher GPC3 expression on HCC cells quantified by IQD method was superior to other scores to predict codrituzumab activity, though this analysis was conducted only with limited number of subjects assessed. Further assessment and validation in clinical study of codrituzumab would be necessary to make a final conclusion on the clinical application of GPC3 IQD. Citation Format: Takayoshi Tanaka, Yasuo Sugitani, Tokiya Abe, Miho Kawaida, Ken Yamazaki, Akinori Hashiguchi, Michiie Sakamoto, Toshihiko Ohtomo. Immunofluorescent digital slide technology to evaluate correlation between Glypican-3 expression and response to codrituzumab. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 409.