tbuckley/cabot-search huggingface dataset:
NCIC CTG BR.26: A phase III randomized, double blind, placebo controlled trial of dacomitinib versus placebo in patients with advanced/metastatic non-small cell lung cancer (NSCLC) who received prior chemotherapy and an EGFR TKI.
Authors: Peter Michael Ellis, Geoffrey Liu, Michael Millward, Francesco Perrone, Frances A. Shepherd, Sophie Sun, Byoung Chul Cho, Alessandro Morabito, Martin R. Stockler, Rafal Wierzbicki, Victor Cohen, Normand Blais, Randeep S. Sangha, Adolfo G. Favaretto, Jin Hyoung Kang, Carolyn F. Wilson, Joseph O'Connell, Keyue Ding, Glenwood D. Goss, Penelope Ann Bradbury
Journal: Journal of Clinical Oncology (2014)

8036^ Background: Dacomitinib (D) is an irreversible pan-HER inhibitor with evidence of activity in previously treated NSCLC patients (pts). Methods: BR26, a phase III randomized double blind placebo (P) controlled trial of D (45mg daily oral) vs P in NSCLC pts after one to three lines of chemotherapy and an EGFR TKI, randomized pts 2:1 to D or P. Response was assessed at 4, 8 then every 8 weeks during treatment. The primary endpoint was overall survival (OS). Secondary endpoints included OS in pts with KRAS wild type (WT) NSCLC, progression free survival (PFS), response rate (RR), toxicity, quality of life, biomarker analyses and resource utilization. Results: 720 pts were randomized: median age 64 yrs (range 32-90), male 51%, PS 0/1 75%, adenocarcinoma 73%, never smokers 36%. D did not improve OS compared with P (median OS 6.8m v 6.3m, HR 1.0, 95%CI 0.83-1.21, p=0.99). There was significant improvement in PFS favoring D (median PFS 2.7m v 1.4m, HR 0.66, 95%CI 0.55 – 0.79, p<0.0001). The RR was 7% v 1%, p=0.001. EGFR /KRAS status were known in 531/418 pts, respectively. The effect of D on OS was similar in pts with EGFR WT and EGFR mutation positive NSCLC (HR 0.93 vs 0.98, interaction p=0.69). The effect of D on OS appeared to differ by KRAS status: improving OS in pts with KRAS WT tumors (7.0m v 5.2m, HR 0.79, 95%CI 0.61 – 1.03), but worsening OS in pts with KRAS mutation positive NSCLC (5.8m v 8.3m, HR 2.1, 95%CI 1.05 – 4.22, interaction p=0.08). Pts on D had significantly longer time to deterioration of cough (p<0.0001), dyspnea (p=0.049) and pain (p=0.041). Pts treated with D vs. P [%] experienced more diarrhea (80 vs. 20), acneiform rash (60 vs. 10), oral mucositis (43 vs. 3), paronychia (30 vs. 0), dry skin (36 vs. 11), nausea/vomiting (36/28 vs. 25/16). Systemic therapy use after PD was 37% in pts. on D vs. 41% on P. Conclusions: D has activity in heavily pretreated pts with NSCLC. Although there was no improvement in OS, BR26 demonstrated a significant improvement in RR, PFS and time to symptom deterioration, and a trend to improved OS in pts with KRAS WT NSCLC. Further evaluation of D in biomarker defined subgroups appears warranted. Clinical trial information: NCT01000025.
Hepatitis B Virus (HBV) Reactivation In Anti-HB Core Antigen (anti-HBc) Positive Patients with Hematological Malignancies: A Prospective Multicenter Study
Authors: Maria Basso, Stefan Hohaus, Giulia Bosco, Antonio Grieco, Luca Laurenti, Giovanna Mansueto, Livio Pagano, G. Lodovico Rapaccini, Simona Sica, Giuliana Farina, Giovanna Valentini, Mariella D'Andrea, Aldo Morrone, Lorenzo Nosotti, A. Paviglianiti, Maria Concetta Petti, Luciana Annino, S. Cortese, Susanna Fenu, Giuseppe Leone, Maurizio Pompili
Journal: Blood (2010)
Sunitinib to upregulate IFNg-STAT1 signaling and to increase indoleamine 2,3-dioxygenase (IDO) expression in renal cell carcinoma (RCC).
Authors: Eric Jonasch, Anh Hoang, Mianen Sun, Lijun Zhou, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Nizar M. Tannir, Xiande Liu
Journal: Journal of Clinical Oncology (2016)

614 Background: Recently we reported that antiangiogenic therapy-treated primary RCC demonstrated increased infiltration of CD4 and CD8 T cells and higher expression of the immune checkpoint ligand PD-L1, all of which were associated with therapy resistance. IFNg-STAT1 signaling pathway drives the expression of both immunosuppressive and immunostimulatory molecules that are involved in lymphocyte trafficking, antigen presentation and immune checkpoints. The purpose of this study was to assess the impact of antiangiogenic therapy on IFNg signaling and on a broader tumor specific immune profile. Methods: We performed immunohistochemical staining of tissue microarrays (TMAs) generated from 40 sunitinib treated primary RCC from patients treated on clinical trial and compared stains to untreated control tumors. We used Vectra imaging to spectrally unmix antibody signal and to quantitate expression levels. We used immunoblot and real-time PCR to investigate the changes in protein and mRNA, respectively. We assessed for statistical significance using an unpaired Student t test. Results: We found that sunitinib treated RCC tissues demonstrated STAT1 phosphorylation (1.2% vs. 4.8%; P&lt;0.001) or nuclear localization (7.4% vs. 15.6%; P=0.005), which was inversely related to patient survival. Furthermore, sunitinib treatment magnified IFNg-induced STAT1 activity by increasing the activity of janus kinase 2 (JAK2) and decreasing the protein levels of inhibitors PIAS and SOCS. On the one hand, sunitinib increased the transcription of VCAM1, CCL4, HLA-B and CD80, which facilitate T cell infiltration or antigen presentation; on the other hand, sunitinib increased transcription of the T cell negative regulator IDO1 (1 vs. 3.2, P&lt;0.001) and CTLA4 (1 vs. 3.1, P=0.01). Conclusions: These results indicate that sunitinib both positively and negatively regulates the tumor immune microenvironment via modulation of STAT1 mediated signaling. IDO upregulation is a key driver of T-cell nutrient deprivation and can be targeted therapeutically. These findings will help us devise precise interventions to overcome tumor cell specific immunosuppressive signaling.
Roneparstat (SST0001), an Innovative Heparanase (HPSE) Inhibitor for Multiple Myeloma (MM) Therapy: First in Man Study
Authors: Monica Galli, Hila Magen, Hermann Einsele, Manik Chatterjee, Mariella Grasso, Giorgina Specchia, Paola Barbieri, David Paoletti, Silvia Pace, Ralph D Sanderson, Alessandro Rambaldi, Arnon Nagler
Journal: Blood (2015)
Ketoconazole improved fenretinide exposures and achieved clinical responses in recurrent neuroblastoma: a NANT study
Authors: Min H. Kang, Araz Marachelian, Julia Glade Bender, Judith Villablanca, Susan Groshen, Meaghan Granger, Brian D. Weiss, Katherine K. Matthay, Charles P. Reynolds, Barry J. Maurer
Journal: Annals of Oncology (2015)
Molecular characterization of normal karyotype acute myeloid leukemia in Korean patients.
Authors: Y. Choi, J. Lee, D. Kim, J. Ahn, S. Lim, S. Kim, E. Hur, M. Seol, K. Lee
Journal: Journal of Clinical Oncology (2010)

6592 Background: Recent advances in molecular characterization of AML have led to molecular classification of normal karyotype (NK) AML. Studies from the Western countries have shown favorable prognostic impact of NPM1 gene mutations. We investigated clinical implications of the NPM1 mutations as well as other gene alterations in Korean patients with NK AML. Methods: Patients included in this retrospective study had NK AML, received standard induction chemotherapy (‘7+3’ regimen), and had DNA samples from leukemic blasts at diagnosis. Polymorphisms of 4 genes (GSTT1, GSTM1, GSTA1, MDR1 [C3435T]) and mutations of 2 genes (FLT3, NPM1) were analyzed using PCR (GSTT1, GSTM1, FLT3- ITD), RFLP (GSTA1, MDR1[C3435T]), and direct sequencing (NPM1). Clinico-laboratory data were retrieved from the Asan Medical Center Leukemia Registry. Results: One hundred and two patients, 63 males and 39 females, were included. Median age was 44 years (range, 15-80). Null genotype of GSTM1 and GSTT1 was observed in 41.2% and 52.0% of the patients, respectively. Genotype of GSTA1 was CC in 75.3% and CT in 24.7%, and C3435T polymorphism of MDR1 gene was CC in 52.2%, CT in 39.1% and TT in 8.7%. FLT3-ITD was detected in 22.8% and NPM1 was mutated in 36.5%. For total patients, CR rate was 78.9%, and survival probabilities at 5-year were 39.9% for OS, 57.9% for RFS, and 42.5% for EFS. Multivariate analyses demonstrated independent prognostic factors for clinical outcomes of NK AML as followings: (1) for the induction of CR, no independently significant factor, (2) for OS, age (RR 2.710, p=0.003) and FLT3-ITD (RR 1.947, p = 0.025), (3) for RFS, age (RR 6.333, p < 0.001), FLT3-ITD (RR 3.658, p = 0.002), and uric acid level (RR 2.833, p = 0.027), and (4) for EFS, age (RR 3.422, p = 0.003), FLT3-ITD (RR 2.655, p = 0.005), and C3435T of MDR1 (RR 0.449, p = 0.013). Conclusions: Mutations of the NPM1 gene did not show significant impact on clinical outcomes in Korean patients with NK AML, whereas presence of a FLT3-ITD mutation was significantly associated with inferior survivals. Racial differences in clinical significance of genetic alterations should be considered before molecular classification is established in NK AML. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Janssen Korea, Novartis Korea
Abstract 884: NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler
Authors: Chen Shen, Jonathan J. Ipsaro, Junwei Shi, Christopher R. Vakoc
Journal: Cancer Research (2016)

Abstract The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by utilizing a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome and are each released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. Citation Format: Chen Shen, Jonathan J. Ipsaro, Junwei Shi, Christopher R. Vakoc. NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler. [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 884.
Third metal stent for revision of malignant hilar biliary strictures
Authors: Tae Lee, Jong Moon, Hyun Choi, Yun Lee, Moon Choi, Sang Cha, Young Cho, Sang-Heum Park, Sun-Joo Kim
Journal: Endoscopy (2016)

<b>Background and study aim: </b>Endoscopic stent-in-stent (SIS) placement of multiple metal stents is technically demanding. In the present study, we explored the technical feasibility and efficacy of endoscopic deployment of a third metal stent to create a triple SIS placement in patients with a bilateral SIS configuration for inoperable high grade malignant hilar biliary stricture (HBS) that had failed clinically. <b>Methods:</b> Eighteen patients with histologically proven inoperable HBS underwent deployment of an additional third metal stent as a revisionary method after early clinical failure following technically successful bilateral SIS placement using cross-wired metal stents. The main outcome measures were the technical and clinical success rates, and adverse events. <b>Results:</b> The overall technical and clinical success rates were 88.9 % (16/18) and 87.5 % (14/16), respectively. The early and late complications were cholangitis (n = 2) and cholecystitis (n = 1). Stent occlusion developed in 35.7 % (5/14) of patients in whom a third metal stent for revision of a bilateral SIS configuration was clinically successful. The median (range) times for stent patency and patient survival were 176 days (49 – 372) and 216 days (52 – 384), respectively. <b>Conclusions: </b>Endoscopic deployment of an additional third metal stent into a bilateral SIS configuration was technically feasible and effective in patients with inoperable high grade malignant HBS in whom bilateral SIS placement had failed clinically.
Primary Refractory Disease in Non-Hodgkin's Lymphoma: A Retrospective Study On 3,952 Newly Diagnosed Patients Undergoing First-Line Chemotherapy
Authors: Corrado Tarella, Angela Gueli, Federica Delaini, Andrea Rossi, Anna Maria Barbui, Giuseppe Gritti, Daniele Caracciolo, Huijing Hu, Daniela Gottardi, Roberto Passera, Alessandro Rambaldi
Journal: Blood (2012)
Endoscopic treatment of sporadic small duodenal and ampullary neuroendocrine tumors
Authors: Rodica Gincul, Thierry Ponchon, Bertrand Napoleon, Jean-Yves Scoazec, Olivier Guillaud, Jean-Christophe Saurin, Mihai Ciocirlan, Vincent Lepilliez, Mathieu Pioche, Christine Lefort, Mustapha Adham, Jean Pialat, Jean-Alain Chayvialle, Thomas Walter
Journal: Endoscopy (2016)

<b>Background and study aim: </b>As duodenal neuroendocrine tumors (NETs) are rare, their optimal management has not been clearly established. The aim of this study was to evaluate the feasibility and outcome of endoscopic treatment of duodenal NETs. <b>Patients and methods: </b>We reviewed the files of all patients who underwent endoscopic resection of a sporadic duodenal or ampullary NET between 1996 and 2014 at two centers. <b>Results:</b> A total of 29 patients with 32 uT1N0M0 NETs < 20 mm were included. Treatment consisted of endoscopic mucosal resection in 19 cases, and cap aspiration in 13 cases. Prior submucosal saline injection was used in 15 cases. Mortality was 3 % (one severe bleeding). Morbidity was 38 % (11/29). At post-resection analysis, mean tumor size was 8.9 mm (range 3 – 17 mm), 29 lesions were stage pT1, one was pT2, and 2 were pTx because of piecemeal resection. All NETs were well differentiated. A total of 27 lesions were classified as grade 1 and 5 were grade 2. The resection was R0, R1, and Rx for 16, 14, and 2 lesions, respectively. Three R1 patients underwent additional surgical treatment, with no residual tumor on the surgical specimen but with positive metastatic lymph nodes in two cases. One patient was lost to follow-up. Finally, 24 patients were included in the follow-up analysis. The median follow-up period was 56 months (range 6 – 175 months). Two patients presented a tumor recurrence during the follow-up period. <b>Conclusions: </b>Endoscopic treatment of small duodenal NETs was associated with significant morbidity, a difficulty in obtaining an R0 specimen, and the risk of lymph node metastasis. Nevertheless, it represents an interesting alternative in small grade 1 duodenal lesions and in patients at high surgical risk.
Abstract 3831: Oncogenic BRAF and concomitant RAS or PTEN/PI3K mutations determine together the response to RAS/RAF/PI3K signaling network inhibition
Authors: Tamas M. Garay, Eszter Molnar, Dominika Rittler, Walter Berger, Balazs Döme, Jozsef Timar, Balazs Hegedus
Journal: Cancer Research (2016)

Abstract Background: BRAF is key component in the growth factor signaling cascade that is often impaired in tumors. Although oncogenic BRAF mutation is considered to be the driver mutation in a variety of malignancies, the response to RAS/RAF/PI3K signaling network inhibition is not uniform among BRAF mutant tumors. Accordingly, we investigated the in vitro effect of RAS/RAF/PI3K signaling network inhibitors (panRAF, mutant BRAF specific, MEK and PI3K/mTOR inhibitors) in relation with BRAF concomitant RAS or PTEN/PI3K mutations in a panel of human cancer cell lines. Methods: Altogether 12 human cancer cell lines were investigated in vitro to assess the effect of inhibitors acting at the different levels of the RAS/RAF signaling network. The seven melanoma, two colon, two lung and one breast cancer cell lines were divided into 3 groups according to their mutational status: BRAF-mutant with no PTEN/PI3K/RAS mutations (A375, WM35, SK-MEL-28, CRL5885), BRAF + PTEN-PI3K (A2058, WM239, HT29, SW1417) and BRAF + RAS double mutant (WM3629, WM3670, MDA-MB-231, CRL5922). Effect of inhibitors on proliferation, clonogenic potential and migration were investigated SRB and clonogenic assays and videomicroscopy measurements, respectively. Both single agent and combination treatments were applied. Results: In single agent treatments panRAF and PI3K/mTOR inhibitors did not show mutation dependent differences in proliferation, however, mutant-BRAF and MEK specific inhibitors were more effective in cells without concomitant PTEN/PI3K or RAS mutations. Interestingly, not only the combination of BRAF and MEK inhibitors but the combination of PI3K/mTOR and MEK inhibition showed additive inhibitory effect on proliferation in all subgroups. Importantly, a distinct pattern emerged for the mutational subgroup specific migration inhibitory effects in comparison to the inhibition of proliferation. Conclusion: BRAF mutant cells carrying various concomitant PTEN/PI3K/RAS alterations display distinct response to RAS/RAF/PI3K network inhibition in terms of proliferation as well as migration. Our data suggests that combination treatments acting concurrently on different targets of the RAS/RAF/PI3K network can be more effective as single therapies. Citation Format: Tamas M. Garay, Eszter Molnar, Dominika Rittler, Walter Berger, Balazs Döme, Jozsef Timar, Balazs Hegedus. Oncogenic BRAF and concomitant RAS or PTEN/PI3K mutations determine together the response to RAS/RAF/PI3K signaling network inhibition. [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 3831.
Abstract 1894: Understanding the role of microRNA-206 in breast cancer
Authors: Valery Adorno-Cruz, Huiping Liu
Journal: Cancer Research (2016)

Abstract MicroRNAs are short non-coding RNA sequences that that can modify genes in post transcriptional manner and are often de-regulated in cancer. Cancer stem cells, a subset of cancer cells with stem cell properties, are considered the root of tumorigenesis and seeds of metastasis. In this study we are interested in elucidating the role of miR-206 in breast cancer stem cell-mediated tumorigenesis and metastasis. We have observed that microRNA-206 (miR-206) regulate the metastatic traits of breast cancer cells, both in vitro and in vivo. Our studies have elucidated a signaling cascade that culminates in the silencing of cytokine (such as interleukin) and integrin expression. Knockdown of the interleukin and integrin genes by siRNAs mimics the phenotype of miR-206 expression in breast cancer cells. DNA content analysis using propidium iodide staining revealed that knockdown of miR-206 targets as well as over-expression of miR-206 in MDA-MB-231 cells regulates cell cycle arrest. Our results indicate that miR-206 mediates its regulatory effects through inhibiting multiple targets. MiR-206 may serve as a new therapeutic candidate for the future treatment of breast cancer. Citation Format: Valery Adorno-Cruz, Huiping Liu. Understanding the role of microRNA-206 in 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 1894.
Abstract 5112: Galactose probes hit neuroblastoma cells through a specific galactose-galectin association
Authors: Giuseppina Simone, Mirco Ponzoni, Fabio Pastorino
Journal: Cancer Research (2016)

Abstract Galectins are a family of proteins that decorate the cell membrane and form extracellular molecular associations with β-galactoside sugars. In order to mimic multivalent molecular recognitions, galactoside moieties have been immobilized on microbeads and used in cytofluorimetric analysis and in microfluidic assay to study the molecular association between carbohydrates and proteins in neuroblastoma (NB) cells. The hypothesis behind this investigation was that the molecular mechanisms by which glycans modulate neural metastatic cells involve protein-carbohydrate association. To evaluate the binding between microbeads and tumor cells, two human NB cell lines were used in cellular association experiments. GI-LI-N cells, derived from the peripheral blood of a bone marrow-infiltrated, high risk, stage IV NB patient, were chosen for metastatic characteristics; IMR-32 cells were chosen because derived from the primary tumor in the abdominal site of an unknown-stage NB patient. In vitro experiments have revealed molecular binding preferences of the metastatic NB cells. This result underscores that the efficiency of the cellular association might be related to the differences in the expression of the galectins between the two cell lines (GI-LI-N cells &amp;gt;&amp;gt; IMR-32 cells) and that the formation of the molecular association galectin-galactose could discriminate the tumor stages. Ex vivo investigations have supported in vitro results; indeed, galactose moieties mostly recognized GI-LI-N cells derived from orthotopic tumor-bearing mice respect to explanted IMR-32 cells. This molecular association was tumor cells specific because it discriminated healthy tissues. The understanding of this mechanism of recognition, and of possible cellular discrimination, can be relevant for the diagnostic monitoring of metastatic NB cells, and for producing probes tailored to interfere with galectin activities associated with the malignant phenotype. Citation Format: Giuseppina Simone, Mirco Ponzoni, Fabio Pastorino. Galactose probes hit neuroblastoma cells through a specific galactose-galectin association. [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 5112.
P1317 : Efficacy of ursodeoxycholic acid as a volume reducing treatment for symptomatic polycystic liver disease: An international, multicenter, randomized controlled trial
Authors: H.M. D’Agnolo, T.J. Gevers, I. Riaño, L. Bujanda, B. Takkenberg, U. Beuers, J.M. Banales, J.P. Drenth
Journal: Journal of Hepatology (2015)