tbuckley/cabot-search huggingface dataset:
Randomized phase III trial of pemetrexed (Pem)+carboplatin (Cb)+bevacizumab (Bev) followed by maintenance Pem+Bev (Pem arm) versus paclitaxel (Pac)+Cb+Bev followed by maintenance Bev (Pac arm) in patients (pts) with stage IIIb/IV nonsquamous non-small cell lung cancer (nsNSCLC) (POINTBREAK): African American (AA) subset.
Authors: Craig H. Reynolds, Jyoti D. Patel, Edward B. Garon, Mark R. Olsen, Philip D. Bonomi, Ramaswamy Govindan, Coleman K. Obasaju, Eduardo J. Pennella, Jingyi Liu, Susan C. Guba, David R. Spigel, Robert C. Hermann, Mark A. Socinski
Journal: Journal of Clinical Oncology (2013)

e19150 Background: AAs with lung cancer (LC) have shorter survival than Caucasians (Cs). Despite a higher LC incidence among AAs than Cs (74.7 vs 64.4/100,000), AAs are underrepresented in clinical trials. There are no reports of randomized LC prospective trials reporting AA results. In POINTBREAK, we enrolled AAs at the same rate as the US incidence of NSCLC in AAs. We report efficacy/safety of AAs in both arms and efficacy/safety of AA and C within the Pem Arm. Methods: Data from AAs and Cs enrolled in POINTBREAK were analyzed. AAs in both arms were evaluated in a pre-specified analysis. Hazard ratio and p-values were derived from a multivariate Cox-PH model by adjusting stratification factors. Results: Of 939 randomized pts, 94 were AA and 805 were C. Demographics were comparable between AA/intent-to-treat populations (%): 56/53 male, 65/52 ≤65 years, 87/88 ever smoker, 86/90 stage IV, 43/44 Eastern Cooperative Oncology Group performance status 0. The table shows efficacy results. Among AAs, drug-related grade 3/4 adverse events (AEs) include (Pem Arm %/Pac Arm %): anemia (7.3/0), thrombocytopenia (9.8/4.0), fatigue (4.9/4.0), neutropenia (31.7/44.0), febrile neutropenia (0/4.0). Within Pem Arm, drug-related grade 3/4 AEs (AA%/ C%) were anemia (7.3/15.9), thrombocytopenia (9.8/25.5), fatigue (4.9/11.5), neutropenia (31.7/25.3), febrile neutropenia (0/1.6). Conclusions: Median OS for Pem Arm was not superior to Pac Arm in AAs. Within Pem Arm, there were no significant differences between AAs and Cs for efficacy outcomes. Both regimens were tolerable in AAs. Clinical trial information: NCT00762034. [Table: see text]
Phase I dose finding study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, alone or in combination with paclitaxel in Japanese patients.
Authors: Yasuhito Fujisaka, Takayasu Kurata, Junji Tsurutani, Wataru Okamoto, Hidetoshi Hayashi, Hisato Kawakami, Eisei Shin, Nobuya Hayashi, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2013)

e13501 Background: AZD8931 is an equipotent, reversible inhibitor of signaling by EGFR, HER2 and HER3. Methods: This open-label, multiple-dose cohort study (NCT01003158) was conducted in Japan to evaluate the safety, tolerability and PK of ascending doses of AZD8931 alone (starting dose 40 mg bd) in patients (pts) with advanced solid malignancies and AZD8931 in combination with paclitaxel (P; 90 mg/m 2 on days 1, 8 and 15 of a 28-day cycle) in pts with advanced breast cancer. Results: Between Jan 2010 and Apr 2012,17 pts were treated; 11 with AZD8931 monotherapy (40/60/80 mg bd [n=3/4/4]) and 6 with AZD8931 40 mg bd plus P. Median (range) duration of exposure to AZD8931 was 42.5 (22–238) and 79.5 (53–244) days for monotherapy and combination therapy, respectively. No DLTs were observed (in the DLT evaluation period) and therefore the MTD was not confirmed for AZD8931 alone or with P. The most frequent AEs (all grades) with AZD8931 monotherapy were diarrhea, paronychia, rash pustule and dry skin (each n=8) and with combination therapy were diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n=4). Throughout the study grade ≥3 AEs were reported for 1, 2 and 4 pts in the 40 mg, 60 mg and combination groups, respectively. One serious AE was reported each in the 40 mg (grade 3 intervertebral disc protrusion) and combination (grade 2 infectious pneumonia) groups; neither was considered related to study treatment. One pt in the combination therapy part discontinued due to an AE of grade 1 pneumonia. AZD8931 was rapidly absorbed (median t max 1–2 hours), well distributed, had moderate clearance (31–39 L/h) and a t ½ of 12 hours. There was no suggestion of a PK interaction between AZD8931 and P. One pt on AZD8931 80 mg bd (primary stomach cancer) and another receiving AZD8931 plus P (advanced breast cancer) had an unconfirmed and confirmed PR, respectively (duration of responses 42 and 172 days, respectively) demonstrating preliminary efficacy. Conclusions: Although a MTD was not confirmed for AZD8931, based on overall incidence of AEs of rash and diarrhea in the 80 mg group, doses up to 60 mg bd as monotherapy and 40 mg bd combined with P are the recommended doses for evaluation in Japanese pts. Clinical trial information: NCT01003158.
Clinical activity of antineoplastic drugs selected by tumor oligonucleotide expression microarrays (MP) in advanced and refractory cancer patients.
Authors: Joseba Rebollo, Manuel Sureda, Ramón González-Manzano, Francisco J. Fernández-Morejón, José Farré, Francisco Fernández-Latorre, Jesús Vegas, Elena Ma Martínez, Pedro Bretcha, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2014)

e22173 Background: MP is potentially useful for the sensitivity and resistance prediction to conventional and targeted drugs, although the wide number of platforms and algorithms used makes validation difficult. It’s important to confirm the prediction of response for selected drugs. Methods: RNA from fresh-frozen tumor biopsies from advanced and pretreated cancer patients (pts) was hybridized to a whole human genome oligonucleotide microarray. Selected genes related to the sensitivity and resistance profile for the most frequently used drugs were studied in tumor and normal tissue of origin to evaluate the differential expression associated with the malignant phenotype. The core set of predictive genes included 48 genes for the commonest drugs as well as roughly 100 genes of other therapeutic targets and activated pathways. This genes were identified from literature review. The results were used to guide experimental treatment selecting each drug given according to the MP results. RECIST (v1.1) criteria were used to define clinical response. All patients signed informed consent both for treatment and bioanalysis. Results: A total of 62 evaluable pts with a variety of advanced and refractory solid tumors were treated according to MP recommendations. Median age was 55 years and median number of previous systemic therapies were 2 (range 1 to 9). When chemotherapy drugs were selected by MP, 19 pts (30.6%) had Partial Response (PR) and 24 pts (38.7%) Stabilization (Clinical Benefit Rate (CBR) of 69.4%). According to the drug used, response rate (and CBR) with 5FU (19 pts) was 47% (84%), CPT (14 pts) 71% (86%), TEM/DTIC (11 pts) 36% (54%), MMC (10 pts) 10% (60%), Alkylatings (9 pts) 33.3% (78%), Taxanes (8 pts) 25% (62%), Gemcitabine (8 pts) 37.5% (100%), Antifolates (8 pts) 37% (75%), Platinums (7 pts) 71% (86%) and Anthracyclines (4 pts) 25% (75%). Conclusions: Although the number of patients is low with a heterogeneous clinical characteristics to draw definitive conclusions, gene expression tumor molecular profiling-based drug selection of drugs is feasible and seems to be predictive of a higher than expected drug activity in a set of advanced and refractory cancer patients.
Translational correlates, including outcome for patients with ER-/PR-/HER2- (triple negative (TNeg)) disease from N0234, a phase II trial of gemcitabine and erlotinib for pts with previously treated metastatic breast cancer (MBC)
Authors: S. Thome, T. Hobday, D. Hillman, M. Aubry, W. Lingle, M. Reinholz, D. Graham, P. Flynn, A. Moreno, E. Perez
Journal: Journal of Clinical Oncology (2007)

1071 Background: N0234 is a phase II trial of gemcitabine at 1000 mg/m 2 days 1 and 8 of a 21 day cycle and erlotinib at 150 mg daily in patients with previous therapy with either an anthracycline or a taxane for MBC. A partial response (PR) rate of 17% has been reported (ASCO 2005). Recent information suggests that over-expression of the EGFR pathway is frequent in patients with TNeg MBC. Methods: Tissue and serum were obtained for translational studies of ER, PR, HER2, and proteins related to EGFR pathway on tissue using immunohistochemistry; CK19, mammoglobin, and TTK on circulating tumor cells (CTCs). Markers were evaluated centrally, blinded to patient outcome. Complete data were available in 57 of 59 eligible patients; 20/57 patients (pts) were TNeg. Results: A PR rate of 25% and clinical benefit rate (PR + stable disease &gt; 6 months)of 25% was observed in TNeg pts as compared to a PR rate of 14% (p = 0.30) and clinical benefit rate 22% (p= 0.75) for non-TNeg pts. Median progression free survival 72 days vs 98 days (p=0.13) and overall survival 227 days vs 738 days (p&lt;0.001) were shorter for TNeg pts. Translational results for the EGFR pathway proteins and CTC analysis is forthcoming. Conclusions: The combination of gemcitabine and erlotinib appears to be as active in the non-TNeg and TNeg subset of patients on this trial. TNeg patients had an inferior clinical result, confirming the poor outcome seen in these patients. Data for the remaining biomarkers potentially predictive of activity will be presented. Supported by CA-25224, CA-37404. [Table: see text]
CLINICAL EFFICACY OF SOFTSEAL-STF HEMOSTATIC PAD WITH SHORT HOLD TIME COMPARED TO TRADITIONAL MANUAL COMPRESSION AFTER TRANSFEMORAL CATHETERIZATION
Authors: Nolan Machernis, Tadele Mengesha, Robyn Shearer, Louie Kostopoulos, Yoseph Shalev, Tonga Nfor, Jayant Khitha, M. Fuad Jan, Tanvir Bajwa, Suhail Allaqaband
Journal: Journal of the American College of Cardiology (2017)
SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis
Authors: Kuancan Liu, Fuan Xie, Anding Gao, Rui Zhang, Long Zhang, Zhangwu Xiao, Qiong Hu, Weifeng Huang, Qiaojia Huang, Baoshun Lin, Jian Zhu, Haikun Wang, Jianwen Que, Xiaopeng Lan
Journal: Molecular Cancer (2017)

High levels of SOX2 protein are correlated with increased dissemination of breast cancer. However, the underlying molecular mechanisms are not fully understood. In this study we investigate the role of SOX2 in breast cancer metastasis using multiple in vitro and in vivo assays including cell culture, shRNA-mediated knockdown, wound healing, colony formation, transwell chamber, xenograft and tail vein injection. Moreover, western blot, immunostaining, microarray and real-time PCR were used to determine the change of protein and miRNA levels. Luciferase assays were also used to evaluate activity which TUSC3 is a target of miR-181a-5p and miR-30e-5p, and the clinical survival relevance was analyzed by Kaplan-Meier analysis. We identified a novel pathway involving SOX2 regulation of microRNAs to control the proliferation and migration of breast cancer cells. shRNA-mediated knockdown of SOX2 inhibits breast cancer cell expansion and migration. More importantly, we found that these changes are accompanied by significant reduction in the levels of two microRNAs, miR-181a-5p and miR-30e-5p. Overexpression of these two microRNAs leads to reduced protein levels of Tumor Suppressor Candidate 3 (TUSC3) in breast cancer cells; mutations of the potential binding sites in the 3’-UTR of TUSC3 abrogate the inhibitory effects of the microRNAs. We further found that upregulation of TUSC3 expression leads to reduced proliferation and migration of breast cancer cells. In human breast cancer samples the levels of TUSC3 protein are inversely correlated with those of SOX2 protein. Taken together, our work reveals a novel SOX2-mediated regulatory axis that plays critical roles in the proliferation, migration and invasiveness of breast cancer cells. Targeting this axis may provide beneficial effect in the treatment of breast cancer.
Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment
Authors: Liliana E. Lucca, David A. Hafler
Journal: Journal of Clinical Investigation (2017)

Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor. They show that the oncometabolite 2-hydroxyglutarate (2HG), generated by mutated forms of isocitrate dehydrogenase (IDH1 and IDH2), reduces the expression of STAT1, thereby limiting the production of the chemokines CXCL9 and CXCL10. As a result, IDH1-mutated tumors are less effectively infiltrated by CD8+ T cells, contributing to tumor escape. Finally, in mice harboring syngeneic gliomas, an inhibitor of 2HG synthesis complemented vaccination to ameliorate tumor control. Understanding how to increase immune infiltration of gliomas represents a key first step in achieving tumor destruction through immunotherapy.
Trastuzumab and pertuzumab-based versus other therapy as second-line therapy in HER2-positive metastatic breast cancer: A retrospective study from single center.
Authors: Daniel Fontes Santos De Teive E Argolo, Lillian Mary Smyth, Neil M. Iyengar, Sujata Patil, Larry Norton, Jose Baselga, Clifford A. Hudis, Chau T. Dang
Journal: Journal of Clinical Oncology (2015)

616 Background: First line treatment with dual anti-HER2 therapy (Rx) with trastuzumab plus pertuzumab (HP), and a taxane led to significant improvement in outcomes for patients (pts) with HER2+ metastatic breast cancer (MBC). In 2nd line, data on HP-based Rx are limited. We conducted a retrospective analysis of pts with HER2+ MBC who had progressive disease after 1st line treatment. Methods: Pts diagnosed with HER2+ MBC evaluated at MSKCC between 1-1-2011 and 6-30-2014 and who progressed on 1st line Rx were eligible. Pts who received ≥ 2 lines of Rxs were classified in two groups: pts treated with HP-based Rx (Group 1) and with other Rxs (Group 2). Primary endpoint was progression-free survival (PFS) in the 2nd line setting. Results: 103 pts were identified (Group 1: 24, Group 2: 79). The baseline characteristics and treatments of each group are summarized in table 1. With a median follow-up of 10.9 months (mo) (range 0.32-42.4), median PFS was 11.5 mo (95% CI, 6.5-NR) in Group 1 and 5 mo (95% CI, 3.75-7.25) in Group 2 (p=0.0027). Conclusions: In this retrospective analysis, HP-based Rx appeared to be associated with a longer PFS when compared with other Rx in the 2nd line setting. Baseline characteristics and treatments. Group 1 (n=24) Age (years) Median 54.46 Range 34-86 Hormone Receptor Status (n) (%) ER and/or PR positive 16 66.7 ER and PR negative 8 33.3 Prior Adj/Neoadjuvant Rx No 11 45.8 Yes 13 54.2 Trastuzumab 11 45.8 First-line Rx One prior line of therapy 24 100 Anti-HER2-based 18 75 HP-based 6 25 Other 6 25 Second-line Rx Chemotherapy + HP 18 75 Endocrine therapy + HP 5 20.8 Other + HP 1 4.2 Group 2 (n=79) Age (years) Median 53.42 Range 25-87 Hormone Receptor Status (n) (%) ER and/or PR positive 49 62.0 ER and PR negative 30 38.0 Prior Adj/Neoadjuvant Rx Unknown 1 1.3 No 34 43.0 Yes 44 55.7 Trastuzumab 35 44.3 First-line Rx One prior line of therapy 79 100.0 Anti-HER2-based 66 83.5 HP-based 19 24.1 Other 13 16.5 Second-line Rx Trastuzumab-based 35 44.3 T-DM1-based 17 21.5 Lapatinib-based 5 6.3 Trastuzumab+Lapatinib-based 9 11.4 Non anti-HER2-based 13 16.5
PERIPHERAL ARTERY DISEASE AND TRANSCATHETER AORTIC VALVE REPLACEMENT OUTCOMES: A REPORT FROM THE STS/TVT REGISTRY
Authors: Alexander C. Fanaroff, Pratik Manandhar, David Holmes, David Cohen, J. Kevin Harrison, G. Chad Hughes, Vinod Thourani, Michael Mack, William Jones, Sreekanth Vemulapalli
Journal: Journal of the American College of Cardiology (2017)
IN-STENT RESTENOSIS OF DRUG-ELUTING STENTS: INCIDENCE, LESION CHARACTERISTICS AND OUTCOMES IN CONTEMPORARY PRACTICE OVER THE LAST DECADE – HOW ARE THEY DIFFERENT FROM DE NOVO LESIONS?
Authors: Ron Waksman, Kyle Buchanan, M. Chadi Alraies, Arie Steinvil, Toby Rogers, Edward Koifman, Jiaxiang Gai, Rebecca Torguson, Itsik Ben-Dor, Augusto Pichard, Lowell Satler
Journal: Journal of the American College of Cardiology (2017)
Natural History, Risk Factors and Prognostic Impact of Graft-Versus-Host Disease Classified According to the National Institute of Health Criteria in Patients Receiving Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia
Authors: Theis H Terwey, Arturo Vega-Ruiz, Philipp G. Hemmati, Peter Martus, Ekkehart Dietz, Lam G Vuong, Philipp D le Coutre, Bernd Dörken, Renate Arnold
Journal: Blood (2010)
The ING tumor suppressor genes and their specific role in the pathogenesis of renal cell carcinoma
Authors: E. Nichiporuk, T. Lebedeva, M. Gasser, F. Hillig, J. Lutz, M. Grimm, B. Kneitz, U. Heemann, H. Riedmiller, A. Waaga-Gasser
Journal: Journal of Clinical Oncology (2006)

10045 Background: The inhibitor of growth (ING) family of tumor suppressor genes is involved in cell cycle arrest, regulation of gene transcription as well as DNA repair. p33 ING1b plays an important role in the pathogenesis of certain carcinomas by modulation of p53. We analyzed p33 ING1b and p29 ING4 gene expression together with specific immune responses in patients with renal cell carcinoma (n=50) at different tumor stages. Methods: Peripheral blood lymphocytes (PBMCs) from patients (Robson stage I-IV) were stimulated with pools of synthetic overlapping peptides of the p33 ING1b or p29 ING4 sequences encompassing the full length sequence of these two genes. PBMCs and tumor specimens were further characterized (ELISPOT, FACS, immunohistology, Real Time PCR). Results: T cells from stage I/II patients expressed higher IL-10 (n=5) than IFN-γ (n=5) levels in response to p29 ING4 peptides. However, distinct residues of peptides were found that induced a Th2 type response (IL 10, n=5) in stage III/IV patients. Interestingly, distinct residues induced a Th1 (IFN-γ, n=5) response in the latter patients. Lymphocytes stimulated with p33 ING1b peptide pools expressed IFN-γ as well as IL-10, independently from the tumor stage. Remarkably, immunohistochemical staining as well as Real Time PCR analysis of tumor specimens revealed higher numbers of CD4/CD8, CD4/CD25, CD4/Foxp3, CD4/CTLA-4, and NK cells as well as IL-10, IFN-γ, and Annexin V expression at the tumor site of stage I/II patients than later tumor stages. However, stronger staining and gene expression of p33 ING1b as well as p29 ING4 together with a reduced staining and expression of p53 was observed in stage III/IV patients. A correlation between the stage and the grading of the tumor was not present. Conclusions: In order to exert its function as a growth arrest and apoptosis inducing protein, p53 needs to interact with other tumor suppressor genes like the ING gene family. Subsequently, the loss of ING function may be a potential mechanism for the inactivation of p53 function in renal cell carcinoma. The results of this study may provide the basis for immune therapeutical strategies (induction of apoptosis or of a Th1 response using a vaccination protocol in particular with p29 ING4 in the early stage of the disease) in renal cell carcinoma. No significant financial relationships to disclose.
QUANTITATION OF DEGENERATIVE MITRAL REGURGITATION: RESERVED TO THE SPECIALIZED FEW OR APPLICABLE TO ROUTINE CLINICAL PRACTICE?
Authors: Clémence Antoine. Giovanni Benfari, Hector Michelena, Joseph F. Maalouf, Vuyisile Nkomo, Maurice Enriquez-Sarano
Journal: Journal of the American College of Cardiology (2017)
High Response RATE and NO Treatment Related Mortality After Brentuximab Vedotin Salvage Therapy Followed by Reduced Intensity Conditioning Regimen Allogeneic STEM CELL Transplantation (RIC-ALLO) in Patients with CD 30+ Lymphomas
Authors: Sabine Furst, Reda Bouabdallah, Diane Coso, Roberto Crocchiolo, Jean El-Cheikh, Catherine Faucher, Angela Granata, Claire Oudin, Geoffroy Venton, Anne Marie Stoppa, Claude Lemarie, Christian Chabannon, Didier Blaise
Journal: Blood (2012)
Significance of CD44-positive and EMT phenotype on the tumorigenic properties of pancreatic cancer cells.
Authors: Katherine Wei-Lin Chang, Shujie Zhao, Lin Cao, James W Freeman
Journal: Journal of Clinical Oncology (2014)

e15210 Background: Heterogeneity of cancer cells within tumors and established cancer cell lines is well-known. The impact of this heterogeneity in regards to pathobiology and therapy has not been fully investigated. We found that CD44, a non-kinase transmembrane receptor that binds hyaluronan (HA), shows a varied level of expression in pancreatic ductal adenocarcinoma (PDAC) cell lines. Methods: In this preliminary study, cells from CFPAC-1 were sorted, by flow cytometry, on the basis of their expression level of CD44 and these cells are referred to as CD44high and CD44low. CD44high cells were characterized for changes associated with epithelial to mesenchymal transition (EMT), including changes in morphology, loss of E-cadherin, and increased expression of vimentin. In vitro tumorigenic properties were characterized by invasion assays, sensitivity to gemcitabine, and ability to form tumorspheres. In vivo analyses using an orthotopic mouse model determined whether CD44high/EMT cells showed increased tumorigenic properties, including tumor growth and desmoplasia. Results: In vitro studies showed that CD44high/EMT cells were more invasive, showed a reduced response to gemcitabine, and formed tumorspheres. Treating CD44high/EMT cells with the CD44 ligand HA, caused a transient activation of c-Met but not other phosphotyrosine kinase receptors including EGFR. All mice formed tumors as determined by optical imaging at weeks 1, 3 and 5. Mice were sacrificed at week 5. Tumors from mice implanted with CD44high/EMT cells tended to be larger than tumors from mice implanted with CD44low cells. The amount of desmoplasia measured by collagen staining also tended to be greater in tumors from PSCs group for CD44high compared to CD44low. Conclusions: CD44high cells display EMT phenotype, and found to be more highly invasive in vitro, with increased resistance to gemcitabine. Tumors implanted with CD44high cells formed larger tumors in vivo, and displayed greater amount of desmoplasia. Further studies using larger number of mice are needed to establish statistically significant differences, and to investigate the impact of these cells on pancreatic cancer pathogenesis and guide treatment options in the future.