tbuckley/cabot-search huggingface dataset:
A dual tyrosine kinase inhibitor lapatinib and overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer.
Authors: Chyong-Huey Lai, Chiao-Yun Lin, Angel Chao, Tzu-Hao Wang, Huei-Jean Huang
Journal: Journal of Clinical Oncology (2014)

e16543 Background: As analogous totriple-negative breast cancer (TNBC), TN endometrial cancers (TNEC) may have poor prognosis. TNBCs have been sequenced and TP53 mutations are the most frequent, followed by PIKCA. Epidermal groth factor receptor (EGFR) was found to be overexpressed in 70-78% basal-like TNBC. TP53-targeting agents are not available in the market, while AKT/PIKCA/mTOR pathway targeting drugs are available. We aim to investigate the therapeutic effects and molecular mechanisms underlying treatment of lapatinib (GlaxoSmithKline) and everolimus (Novartis) in TNEC cells. Methods: Affymetrix oligonucleotide microarrays were used to screen the differential gene expression of EC cells treated with lapatinib or everolimus. The significantly differentially expressed genes were confirmed in 58 clinical specimens of EC and 30 normal endometrial tissues by IHC. EC cell lines were cultured for performing RT-qPCR, western blot, promoter assay, proliferation and cell apoptosis analysis. Results: Among the 58 EC specimens, 13 were TN. Patients with TNEC (6/13) were associated with increased cancer-specific death than non-TNEC (8/45) (p = 0.035). IGFBP2 was downregulated in lapatinib and everolimus treated TNEC cell lines (late-passage of RL95-2 and Ishikawa cells). Combination of lapatinib and everolimus had synergistic effects on phosphorylation of ribosomal protein pS6, cell viability and apoptosis in both EC cells. Promoter assay showed that site is required for lapatinib and everolimus-repressed IGFBP2. IGFBP2 was significantly higher in the TNEC than normal endometrial tissues in IHC analysis (p < 0.0001). Cell cytotoxicity was greater in combined shIGFBP2 and paclitaxel than the group with paclitaxel alone or a control shIGFBP2 in the TNEC cell lines. Conclusions: Synergistic effect of everolimus and lapatinib in endometrial cancer cells was observed via targeting IGFBP2. The combined treatment may provide a potential treatment option for patients with TNEC and restore the drug sensitivity of resistant TNEC to conventional chemotherapeutic agents.
ASSOCIATION OF CHRONIC RENAL INSUFFICIENCY WITH IN-HOSPITAL OUTCOMES OF TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Tanush Gupta, Dhaval Kolte, Sahil Khera, Pedro Villablanca, Kashish Goel, Wilbert Aronow, Anna Bortnick, David Slovut, Cynthia Taub, Jorge Kizer, J. Abbott, Charanjit Rihal, Gregg Fonarow, Robert Pyo, Deepak Bhatt, Mario Garcia
Journal: Journal of the American College of Cardiology (2017)
Advanced NSCLC: Finding the right prescription for oncologist education.
Authors: Tara Herrmann, Ramaswamy Govindan, Daniel Morgensztern, Pamela M. Peters, Evan Rhodes, James C. Williamson
Journal: Journal of Clinical Oncology (2014)

8115 Background: Lung cancer is the leading cause of cancer related death in the United States. The objective of this study was to evaluate the impact of a personalized education curriculum on narrowing gaps in clinical practices of oncologists who care for patients with advanced NSCLC. Methods: A pre-education assessment tool designed to identify relevant knowledge and practice gaps in individual oncologist learners was made available online to healthcare providers without monetary compensation or charge. The assessment consisted of 10 knowledge and case-based multiple-choice questions. Upon completion of the survey, each oncologist learner was directed to a personalized learning plan, which included up to 5 distinct activities. Confidentiality of survey respondents was maintained and responses were de-identified and aggregated prior to analyses. The case vignettes and questions were based on current standards of care and evidence-base in the treatment of advanced NSCLC. The pre-assessment survey and corresponding activities launched on January 31, 2013 and participant responses were collected over the following 6 months. Results: In total, 92 oncologists completed their individualized educational curriculum. The intervention was associated with an effect size of 0.70, exceeding the recognized medium effect size standard of 0.45-0.50. After the education activity, there was a significant increase in the number of oncologists able to identify the rationale for determining the histological subtype of NSCLC (68% at baseline to 81% post education), prevalence of specific genetic abnormalities (76% to 97%, P = 0.04), and awareness of who should be considered for maintenance therapy (55% to 86%, P = 0.01). There was also a significant improvement in the identification of the most appropriate treatment regimen for squamous cell carcinoma (19% increase, P = 0.003) and adenocarcinoma (44% increase, P< 0.001). Conclusions: Our study demonstrates the feasibility of a personalized, targeted educational intervention for improving practice patterns of oncologists treating patients with advanced NSCLC. Novel personalized educational programs need to be developed to improve physician learning experience in an era of personalized medicine.
TRANSCATHETER MITRAL VALVE REPAIR (MITRACLIP) IN UNITED STATES: ETIOLOGIES AND PREDICTORS OF READMISSION AND IN-HOSPITAL MORTALITY FROM THE NATIONWIDE READMISSION DATABASE
Authors: Sidakpal Panaich, Shilpkumar Arora, Elad Maor, Claire Raphael, Nilay Patel, Harshil Shah, Varun Kumar, Apurva Badheka, Abhishek Deshmukh, Mackram Eleid, Rajvee Patel, Charanjit Rihal
Journal: Journal of the American College of Cardiology (2017)
ASSOCIATION OF TOTAL TESTOSTERONE WITH PROGRESSION OF CAROTID ATHEROSCLEROSIS AND CORONARY ARTERY CALCIUM SCORE: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS
Authors: Indre Ceponiene, Rebekah Young, Richard Kronmal, James Stein, Dhananjay Vaidya, Adam Gepner, Nathan Wong, Ronald S. Swerdloff, Christina Wang, Jonas Ceponis, Rine Nakanishi, Negin Nezarat, Mitsuru Kanisawa, Kazuhiro Osawa, Sina Rahmani, Matthew Tattersall, Claudia Korcarz, Matthew Budoff
Journal: Journal of the American College of Cardiology (2017)
C6-ceramide to restore sensitivity to cetuximab in KRAS-mutant colorectal cancer.
Authors: Alvaro G. Menendez, Daniel J. Curzake, LuGuang Luo, Harold J. Wanebo
Journal: Journal of Clinical Oncology (2015)

e13562 Background: Management of patients with metastatic colorectal cancer (mCRC) depends on extent of disease and whether the tumor expresses KRAS mutation among others. Chemotherapy remains the mainstay of treatment for advanced disease with occasional options for salvage surgery. Cetuximab (Cet), a monoclonal antibody that inhibits EGFR, was approved as first-line treatment in combination with FOLFIRI for patients with mCRC. A subsequent study (CECOG/CORE2) demonstrated benefit of Cet in KRAS Wild Type (WT) CRC patients only. C6-Ceramide (C6-Cer) can induce cancer cell apoptosis and act synergistically with other chemotherapeutic drugs in several cancer types as seen in preclinical studies. The aim of this study was to compare growth inhibition percentage (GIP) of cytostatics 5-fluoruracil (5-FU), oxaliplatin (Ox) and Cet with or without C6-Cer in KRAS-defined CRC cell lines. Materials and Methods: A series of human CRC cell lines were incubated with 0.8µM of 5-FU, 0.04µM of Ox, 25 µg/mL of Cet (IC50 established earlier in the study) and C6-Cer concentrations ranging from 5 to 10 µM. GIP was assessed after 72 hours of incubation and compared to control wells. Results: C6-Cer alone increased GIP in KRAS Mutant (Mut) CRC (average of 78.3%). It was noted that the addition of C6-Cer to Ox, Cet and 5-FU also increased GIP. Concentrations of 5 and 7.5µM resulted in a doubling of GIP (75% and 86.25%, respectively vs 32.5% of 5-FU, Ox and Cet alone) (p < 0.0003). The greatest effect was observed with 10µM of C6-Cer which increased GIP to 92.5% (p < 0.0006). Same concentrations increased GIP of KRAS WT cells to 93.5%. Conclusions: C6-Cer appears to have direct inhibitory properties on KRAS Mut cells and when added to Ox, 5-FU and Cet, C6-Cer restored response of KRAS Mut cells. The underlying mechanism of this effect is unclear, however we believe our data suggests KRAS signal pathway may not play a critical role for Cet resistant CRC. We hope these results would provide a starting point for clinical studies with C6-Cer in patients with relapsing or metastatic KRAS Mut CRC in combination with standard chemotherapy plus molecular targeting agents reasonably anticipating this could translate into clinical benefit for this difficult to treat patient population.
Concurrent ipilimumab and radiotherapy in patients with metastatic melanoma: A retrospective analysis.
Authors: Kristian Michael Koller, Heath B. Mackley, Henry Wagner, Rogerio Izar Neves, Todd Schell, Bryan Anderson, Colette Pameijer, Carol Mallon, Joseph J. Drabick
Journal: Journal of Clinical Oncology (2015)

e20048 Background: The abscopal effect is a phenomenon in which local radiation therapy(RT) is associated with responses to malignant disease at sites outside of the radiation field, including distant metastases. The mechanism of this phenomenon is unclear, but is thought to be mediated by activation of the immune system. Ipilimumab is a monoclonal antibody used in the treatment of malignant melanoma that inhibits cytotoxic T-Lymphocyte antigen 4 (CTLA-4), an immunologic checkpoint on T cells. Published case studies of the abscopal effect have been reported with the use of ipilimumab an RT in metastatic melanoma, but systematic studies supporting these observations are limited. . Methods: We conducted a retrospective analysis to evaluate metastatic melanoma patients treated with ipilimumab for metastatic melanoma at a single institution from May 2011 to October 2013. Patients were grouped into those that had received concurrent radiation therapy while on ipilimumab treatment, and those who did not. We then evaluated the treatment response following completion of ipilimumab. Primary outcome measured was rate of complete response(CR) in both radiated and distant disease sites, measured by RECIST criteria. Secondary outcome measures included ORR, PFS, and OS. Results: A total of 48 patients received ipilimumab in the prespecified time frame. Among those patients, 22 received concurrent (RT) and 26 received Ipilimumab without concurrent RT. Among the 22 who received concurrent Ipi-RT, 5 achieved a CR response, compared to 2 out of 26 in the Ipi alone group [Odds ratio 3.53 (95%CI 0.61-20.4), p = 0.15]. This correlated with a CR rate of 29.4% in the Ipi-RT arm compared to 8.3% in the Ipi alone arm. Secondary measure will be reported in an updated analysis. Conclusions: Patients treated with concurrent ipilimumab plus radiation therapy had a higher percentage of complete responses than those treated with ipilimumab alone. Although this study was not powered to show statistical significance, we feel that the data support a general proof of concept, and look forward to the results of prospective studies addressing this question. .
Pilot study of redirected autologous T cells engineered to contain anti-CD19 attached to TCRζ and 4-1BB signaling domains in patients with chemotherapy-resistant or -refractory CD19+ leukemia and lymphoma.
Authors: Stephan A. Grupp, David L. Porter, Bruce Levine, Michael Kalos, Christine Strait, Susan R. Rheingold, Richard Aplenc, Carl H. June
Journal: Journal of Clinical Oncology (2013)

TPS10072 Background: Outcomes remain poor for patients (pts) with relapsed or refractory (r/r) B-cell malignancies such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). CD19 is an attractive therapeutic target because it is widely expressed on normal and malignant B cells throughout B-cell maturation but not on pluripotent stem cells or non–B-cell tissues. We have developed chimeric antigen receptor T cells to target CD19+ cells (CART-19 or CTL019). This approach involves patient-derived T cells that are genetically modified via lentiviral transduction to express a CD19 antigen recognition domain attached to intracellular signaling domains (TCRζ and 4-1BB) that mediate T-cell activation. A recent study in CLL showed that CART-19 therapy had potent activity with responses in 5/8 evaluable pts (3 CR, 2 PR). Pts achieving CR (two &gt; 24 months and one &gt; 5 months) remain in CR with detectable CART-19 cells (Porter et al. ASH 2012). Here we describe a study of CART-19 therapy in pediatric pts with r/r leukemia and lymphoma (NCT01626495). Methods: Pts eligible for this single-arm, open-label study are aged 1 to 24 years with r/r CD19+ B-cell malignancies, without a transplant option or having relapsed after allogeneic stem cell transplantation (ASCT). Pts will undergo leukapheresis to obtain T cells, which will be stimulated, expanded, and transduced ex vivo to express the chimeric antigen receptor. Pts may receive lymphodepleting chemotherapy prior to CART-19 infusion. Study objectives: determine the safety and feasibility of administering CART-19 therapy to pediatric pts, assess duration of in vivo survival of CART-19 cells, and measure antitumor response. There are 2 cohorts in the study: Cohort 1 includes pts who have not undergone ASCT and are not currently eligible for a transplant, and cohort 2 includes pts who relapsed after ASCT. Cells are collected from the recipient, not the donor, which allows for this approach to be used in pts s/p cord blood transplant, and which we hypothesize will reduce the risk of GVHD as a result of toleration of the T cells in the recipient. To date, 7 pts have been enrolled. Clinical trial information: NCT01626495.
Oral contraceptives and breast cancer risk: Modification by NQO1genetic polymorphisms.
Authors: Jay H. Fowke, Xiao-Ou Shu, Qi Dai, Fan Jin, Qiuyin Cai, Yu-Tang Gao, Wei Zheng
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

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Background: Oral Contraceptives (OCs) contain a potent synthetic estrogen, ethinyl estradiol (EE), possibly increasing breast cancer risk. However, prior investigations have found that little evidence of an OC and breast cancer association. OCs actually suppress endogenous E2 and are weak progenitors of reactive semi-quinone estrogen metabolites capable of damaging DNA, potentialy decreasing risk. NAD(P)H:-oxoreductase (NQO1) prevents genetic damage from reactive estrogens, but NQO1 induction also is regulated in part by the estrogen receptor (ER). Thus, the association between OC use and breast cancer may be complex, and depend on NQO1 activity and response to reactive oxygen species. Methods : A population-based case-control study in Shanghai, China. Cases were identified from the Shanghai Cancer Registry, and controls were identified using the population registry. OC history and other risk factors were assessed by questionnaire. Data from 1020 cases and 1095 controls were analyzed with logistic regression, controlling for age, BMI, and other risk factors. The NQO1 C609T polymorphism has limited activity compared to the C/C wild-type. Findings : Breast cancer was not directly associated with OC use or NQO1 genotypes. However, OC use increased postmenopausal breast cancer risk among women with the NQO1 C/C genotype (OR=2.03 (1.08, 3.80)), while a lower risk was observed with the T-allele of NQO1 (OR=0.70 (0.48, 1.04); pint <0.01). This crossover modification was stronger with OC use prior to age 30 years (C/C: OR=3.03 (1.42, 6.40)); C/T or T/T: OR=0.49 (0.29, 0.82), pint < 0.01). First OC use after age 30 years was associated with reduced premenopausal breast cancer (OR=0.52 (0.30,0.90)), and this association was restricted to women with the NQO1 T-allele (OR=0.39 (0.18, 0.82)). Interpretation : Prior research has found little consistent evidence for an association between OC use and breast cancer risk. Our results suggest that the OC and breast cancer association depends the age of OC use and NQO1 genotype, consistent with E2 suppression and the ability to invoke an adequate protective response to reactive semi-quinone estrogen metabolties previously linked with breast carcinogenesis.



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EXTERNAL VALIDATION OF DAPT SCORE IN TWO LARGE COHORTS
Authors: Yiu Tung Anthony Wong, Do-Yoon Kang, Jung-Min Ahn, Ungjeong Do, Osung Kwon, Kyusup Lee, Jung Ae Hong, Se Hun Kang, Pil Hyung Lee, Duk-Woo Park, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2017)
Emergence of <i>KRAS</i> mutation in detection of circulating tumor DNA during treatments for metastatic gastrointestinal cancer patients.
Authors: Yuji Takayama, Koichi Suzuki, Tsutomu Daito, Kosuke Ichida, Taro Fukui, Yuta Muto, Nao Kakizawa, Hirofumi Imoto, Yusuke Taniyama, Yuji Kaneda, Hiroyuki Tanaka, Fumiaki Watanabe, Takaharu Kato, Fumi Hasegawa, Masaaki Saito, Shingo Tsujinaka, Yasuyuki Miyakura, Hiroshi Noda, Fumio Konishi, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2015)

11026 Background: It has been reported that molecular alterations in KRAS status were observed during treatment in colorectal cancers. The aim of this study was to explore change in KRAS status during various treatments for metastatic gastrointestinal cancer patients. Methods: One hundred and nineteen plasma samples were collected prospectively in 2014 from 52 patients who underwent chemotherapy due to metastatic gastrointestinal cancer including 46 colorectal and 6 pancreatic cancer patients. KRAS mutant circulating tumor DNA (ctDNA) was detected by digital PCR. Less than 0.1% of positive KRAS mutant is estimated as negative. Results: KRAS assessment in tumor tissues showed 22 patients withKRAS mutation (MT), 18 without KRAS mutation (WT) and 12 patients without KRAS information (NI). Among 22 patients with MT, KRAS assessment in ctDNA displayed 10 patients with KRAS mutant ctDNA and 12 patients without mutant ctDNA. While 18 patients with WT did not show any mutant ctDNA before chemotherapy, 3 patients exhibited KRAS mutant ctDNA after treatments. They are treated with different regimens such as CapeOX+BEV, CPT+Cmab and Regorafenib, respectively. KRAS mutant ctDNA was detectable in the blood of these three patients prior to radiographic detection of disease progression (PD). Among 12 patients with NI, there were 4 patients with KRAS mutant ctDNA and 8 patients without mutant ctDNA. Concerning response to chemotherapy, poor outcome was found in patients with KRAS mutant ctDNA regardless of KRAS status in tumor tissues. Conclusions: These results indicated that blood monitoring of KRAS status could be required not only to predict outcome of treatments but also to choose optimal regimes. KRAS status Change in KRAS ststus Tumors Treatments Response Tissue ctDNA Number Colon Pancreas Chemotherapy Chemo+ BEV Chemo+ Cmab or Pmab Regorafenib CR+PR+SD (%***) PD Not determined Mutant (n = 22) Mutant 10 0 7 3* 3 6 0 1 0 (0%) 10 0 Negative 12 0 10 2* 5 7 0 0 5 (50.0%) 5 2 WILD (n = 18) Mutant 0 0 0 0 0 0 0 0 0 (0%) 0 0 Negative 18 3 (Negative→MT) 17 1* 2 7 (1**) 6 (1**) 3 (1**) 10 (58.8%) 7 1 Unknown (n = 12) Mutant 4 0 4 0 2 2 0 0 0 (0%) 2 2 Negative 8 0 8 0 1 7 0 0 2 (66.6%) 3 3 *, FOLFIRINOX; **, Negative→MT; ***, CR+PR+SD/CR+PR+SD+PD
Single agent, canfosfamide (C, TLK286) vs pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P) refractory or resistant ovarian cancer (OC): Phase 3 study results
Authors: I. Vergote, N. Finkler, J. del Campo, A. Lohr, J. Hunter, D. Matei, D. Spriggs, J. Kavanagh, J. Vermorken, G. L. Brown, S. Kaye
Journal: Journal of Clinical Oncology (2007)

LBA5528 Background: Canfosfamide (C) is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1. P resistant OC has a poor prognosis and non-P agents are used for palliation. C reported objective responses in multicenter Phase 2 OC trials. Methods: Pts with P resistant OC who progressed after D or T, measurable disease (RECIST), adequate liver/renal/bone marrow function were eligible. Randomization was stratified by prior D or T treatment, ECOG PS (0 or 1 vs 2) and presence or absence of bulky disease (= 5cm). Patients received C at 1000 mg/m 2 IV q3wks, or to D at 50 mg/m 2 IV q4wks or T at 1.5 mg/m 2 IV daily × 5 q3wks until progression. The trial had a 90% power to detect a 29% reduction in the relative risk of death. Results: 461 pts (C=232 and D or T=229) received 1052 cycles [median 3; range (r) 1–33], 699 (median 4; r 1–32), and 469 (median 5; r 1–21) for C, D and T respectively. Most common Grade 3–4 AEs for C were: nausea (31.6%), vomiting (8.7%), fatigue (6.1%), and anemia (5.6%), for D/T were: nausea (55.3%), anemia (15.2%), fatigue (6.9%), neutropenia (23.5%), thrombocytopenia (12.4%), febrile neutropenia (6%), stomatitis (6%), and PPE syndrome (6%). ORR for C was 4.3% including a CR, vs 10.9% ORR for D/T. Median survival (MS) was 8.5 mos for C, 13.6 mos for D/T (p=0.0001). Median progression-free survival was 2.3 mos for C and 4.4 mos for D/T, (p=0.0001). D/T MS was 14.2/10.8 mos, respectively. Conclusions: Canfosfamide did not meet the primary endpoint. C demonstrated single agent activity in P refractory or resistant OC and was well tolerated. C in combination with standard agents in less heavily treated OC trials are in progress. No significant financial relationships to disclose.
CARDIAC RESYNCHRONIZATION IS ASSOCIATED WITH REDUCTION IN THE RATE OF ICD THERAPIES, WHILE IMPROVES VENTRICULAR FUNCTION
Authors: Enrique Galve Basilio, Gerard Oristrell Santamaria, Gabriel Acosta, Aida Ribera, Moya Angel, Ferreira Ignacio, Perez-Rodon Jordi, Garcia-Dorado David, Enrique Galve
Journal: Journal of the American College of Cardiology (2017)
Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity
Authors: Eva Czirr, Nicholas A. Castello, Kira I. Mosher, Joseph M. Castellano, Izumi V. Hinkson, Kurt M. Lucin, Bernat Baeza-Raja, Jae Kyu Ryu, Lulin Li, Sasha N. Farina, Nadia P. Belichenko, Frank M. Longo, Katerina Akassoglou, Markus Britschgi, John R. Cirrito, Tony Wyss-Coray
Journal: The Journal of Experimental Medicine (2017)

Recent genetic evidence supports a link between microglia and the complement system in Alzheimer’s disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein–transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.
Cryptic Unbalanced Chromosomal Changes in a Case of Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Identified By Single Nucleotide Polymorphism (SNP) Microarray, but Not By Conventional Karyotyping
Authors: Peter C. Kurniali, Anas Al-Janadi, Hongyan Chai, Sainan Wei
Journal: Blood (2014)