tbuckley/cabot-search huggingface dataset:
A phase II study to evaluate the safety and efficacy of RAD001 plus erlotinib in patients with well-differentiated neuroendocrine tumors (NET).
Authors: Emily K. Bergsland, Lindsey Watt, Andrew H. Ko, Margaret A. Tempero, Wolfgang Michael Korn, Robin Katie Kelley, Thomas Weber, Iche Siah, Jimmy Hwang, Eric K. Nakakura, Alan Paul Venook
Journal: Journal of Clinical Oncology (2012)

285 Background: Building on strong preclinical data, we hypothesized that concomitantly targeting mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) signaling pathways will inhibit neuroendocrine tumors (NET) more effectively than targeting either pathway alone (thus improving likelihood of shrinkage). We initiated a prospective, phase II study to assess the safety and efficacy of RAD001 plus erlotinib in patients (pts) with advanced NET. Methods: Pts with well-differentiated NET were enrolled using a Simon 2-stage design with 2 groups: pancreatic NET (PNET) and other low-grade NET/ carcinoid (CARC). Eligibility criteria included histological diagnosis of a well- to moderately-differentiated NET and no prior mTOR- or EGFR-inhibitor. Pts treated with RAD001 5 mg PO QD and erlotinib 100 mg PO QD without scheduled breaks (1 cycle = 28 d). Pts followed for toxicity and radiographic response, with first planned analysis after 8 evaluable pt/group. Results: Since 6/09, 17 pt enrolled: M/F 9/8; PNET/CARC 8/9. Pts on octreotide remained on drug. All pt had PD at enrollment. Median # cycles: 12 in CARC (range 2-20); 5.5 (to date) in PNET (range 0.5-18). Excessive toxicity in first 7 pts prompted reduction in starting erlotinib dose from 150 to 100 mg/d, resulting in improved tolerability: Gr 3 stomatitis in 3/7 initial pts (43%) vs 1/10 (10%) after new starting dose. Overall, the most common side effects include diarrhea, stomatitis, rash, anorexia, and fatigue. Enrollment to CARC cohort stopped after first stage due to insufficient efficacy (7/9 SD, 2/9 PD; 0 PR). Conclusions: RAD001 plus erlotinib appears to be associated with radiographic stability, but not shrinkage, in CARC. Combining the two agents has proven challenging; toxicity precludes administration of either agent at full dose. Interim efficacy analysis for PNET stratum pending. Correlation with expression of mTOR pathway components in archived tissue planned.
Designing an intervention program for cancer survivors and work.
Authors: Dawn Aubel
Journal: Journal of Clinical Oncology (2017)

23 Background: Nearly two-thirds of cancer survivors return to work after their diagnosis, experiencing unique challenges as they strive to maintain health and career goals. Keeping the workforce healthy through innovative solutions is essential for employers and society. The purpose of this study was to describe the needs of cancer survivors who continue to work and to improve a navigation program designed to optimize well-being. The conceptual framework of the Cancer Survivorship and Work Model by Mehnert, de Boer, &amp; Feuerstein (2013) was used to guide program development and outcomes measurement. Methods: Participants included cancer survivors who were employed at a company where a navigation-based program was offered. Two study groups included individuals who used the intervention program and non-users. There were a total of 7 participants in the intervention group and 17 participants in the non-user group. A mixed-methods design was used. Self-efficacy, emotional support, and informational support were evaluated using validated patient-reported outcome (PRO) instruments. Patient satisfaction with the navigator relationship among program users was assessed. Open-ended questions were asked to gain a richer understanding regarding a supportive work intervention. Results: Among participants, there were deficits in self-efficacy and social support. There was no significant difference between groups. There was high satisfaction with the navigator relationship. Qualitative themes included a desire to maintain privacy, and the struggle to integrate health-related needs and high work demands. Conclusions: Population health challenges associated with cancer survivorship should be addressed by relevant interventions and further research. A dedicated work program is appropriate for work success. The navigation design should be further developed and available to employers aiming for a culture of health. Future research should include intervention evaluation using PROs, qualitative inquiry of cancer survivors regarding privacy and work, and applications to other chronic diseases.
The Novel PIEZO1 Mutation p.L2023V Is Causal for Hereditary Xerocytosis Resulting in Delayed Channel Inactivation and a Dehydrated Red Blood Cell Phenotype
Authors: Mary A Risinger, Edyta Glogowska, Amber Hogart Begtrup, Neha Dagaonkar, Satheesh Chonat, Clinton H Joiner, Charles T. Quinn, Theodosia A. Kalfa, Patrick G Gallagher
Journal: Blood (2014)
Ovarian suppression with luteinizing hormone-releasing hormone agonists during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients: a systematic review and meta-analysis of randomized studies
Authors: F. Poggio, M. Lambertini, M. Ceppi, D. Ugolini, A. Levaggi, S. Giraudi, A. D'Alonzo, C. Bighin, M. Vaglica, G. Rossi, E. Blondeaux, S. Pastorino, A. Abate, G. Iacono, P. Pronzato, L. Del Mastro
Journal: Annals of Oncology (2015)
Phase 1, first-in-human, open label, dose escalation ctudy of MGD009, a humanized B7-H3 x CD3 dual-affinity re-targeting (DART) protein in patients with B7-H3-expressing neoplasms or B7-H3 expressing tumor vasculature.
Authors: Anthony W. Tolcher, Evan W. Alley, Guru Chichili, Jan E. Baughman, Paul A. Moore, Ezio Bonvini, James Robert Vasselli, Jon M. Wigginton, John D. Powderly
Journal: Journal of Clinical Oncology (2016)

TPS3105 Background: MGD009 is a B7-H3 x CD3 Dual Affinity Re-Targeting (DART) protein. DART proteins are bispecific, antibody-based molecules that can bind two distinct antigens simultaneously. MGD009 is designed to redirect T cells to eliminate B7-H3-expressing target cells through co-engagement of B7-H3 on the target cell and CD3 on the T cell, each in a monovalent binding manner. MGD009 contains a mutated human IgG1 Fc domain to reduce / eliminate effector function via binding to Fc gamma receptors (FcγRs) and complement, but retains binding to the neonatal Fc receptor (FcRn) enabling use of the IgG salvage pathway to prolong circulating its half-life. B7-H3 protein expression is extremely limited in normal human tissues but is overexpressed in a broad range of tumor types, including melanoma (M), NSCLC (LC), SCCHN (HN), mesothelioma (MESO) and urothelial cancer (UC). By binding to B7-H3 on tumor cells and CD3 on T lymphocytes, MGD009 can recruit cytotoxic T cells, irrespective of their ability to recognize cancer cells, and trigger T-cell activation, expansion, and T-cell mediated killing of B7-H3- expressing tumors. The limited expression of B7-H3 on normal cells should restrict the potential for cytolytic activity directed at normal tissues, and unintended toxicity in patients treated with MGD009. Methods: This multi-center, open-label trial is a Phase 1 dose escalation / cohort expansion study (NCT02628535). All patients must have advanced B7-H3+ tumors. Prior checkpoint inhibitor therapy will be allowed. Dose escalation uses a 3+3+3 design, with patients treated every 2 weeks with escalating doses of IV MGD009 (starting dose 0.3 ug/kg). Cohort expansions (N = 16/cohort) treated at the maximum tolerated dose will include patients with M, HN, MESO, UC and LC. Major objectives include characterization of the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of MGD009 in this ongoing study. Clinical trial information: NCT02628535.
A phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of CHIR-258, a novel oral multiple receptor tyrosine kinase (RTK) inhibitor
Authors: D. Sarker, J. Evans, M. Hardie, R. Molife, C. Marriott, R. Morrison, F. Garzon, C. Heise, G. Michelson, J. De-Bono
Journal: Journal of Clinical Oncology (2006)

3043 Background: CHIR-258 is a potent small molecule inhibitor of VEGF, FGF, PDGF and c-KIT RTKs with IC 50 ≤10nM that demonstrates activity in a variety of angiogenesis, tumour and metastasis models. Methods: Patients (pts) with histologically confirmed advanced solid tumors, ECOG PS 0–2 were treated in cohorts of 3–6 with CHIR-258. Treatment was as single daily doses on a repeated 7 days (d) on/7d off schedule (25–100mg), with a subsequent protocol amendment to continuous (cont) daily dosing. The objectives were to determine maximum tolerated dose (MTD) and dose limiting toxicity (DLT), evaluate PK and PD endpoints - ERK phosphorylation in PBL - and describe anti-tumour activity. Results: 35pts (median age 56.5 yrs; 15F/20M) were treated in 4 intermittent dosing cohorts (25, 50, 75, 100 mg/d) and 3 continuous dosing cohorts (100,125, 175 mg/d). The most common drug related adverse events were (grade [gr], number of pts): nausea (gr 1–3, 12); fatigue (gr 1–2, 9); headache (gr 1–3, 8); vomiting (gr 1–2, 7); anorexia (gr 1–2, 7); diarrhoea (gr 1–2, 6); dysgeusia (gr1–2, 6); anaemia (gr 2–3, 4); hypertension (gr 1–3, 3) and reversible asymptomatic drop in left ventricular ejection fraction (gr 2, 2). DLTs were gr 3 hypertension (HTN) in 1 pt with pre-existing HTN (100mg, cont); asymptomatic uncomplicated grade 2 elevation in cardiac troponin I (125mg); gr 3 anorexia/fatigue and gr 3 rise in alkaline phosphatase (both at 175mg). 3 pts have had prolonged stable disease (all 4m+; parotid, renal and imatinib-refractory GIST). The plasma PKs of CHIR-258 were linear over the dose range of 25–175 mg with respect to C max and AUC. On d1, the mean C max was 13.5(5.3) ng/mL to 109 (26) ng/mL, the mean AUC (0–24) was 224(97.4)ng*h/mL to 1740(466)ng*h/mL, and the t½ was 17h. Trough CHIR-258 concentrations at doses &gt;50 mg/d were above the concentrations known to inhibit target receptor activation in vitro. Data on evaluable samples demonstrate up to 90% inhibition of basal ERK phosphorylation. Conclusions: CHIR-258 was safely administered at continuous daily doses up to 175mg/d. Modulation of p-ERK was demonstrated. Treatment is associated with disease stabilization. [Table: see text]
Diagnostic imaging modalities for the surveillance of melanoma patients: A meta-analysis.
Authors: Y. Xing, Y. Bronstein, M. I. Ross, R. L. Askew, J. E. Lee, J. E. Gershenwald, R. Royal, J. N. Cormier
Journal: Journal of Clinical Oncology (2010)

8581 Background: Diagnostic imaging provides critical information for surveillance of cancer patients. The purpose of this meta- analysis was to compare the diagnostic accuracy of ultrasonography (US), computed tomography (CT), positron emission tomography (PET), and positron emission tomography/computed tomography(PET/CT) for post-surgical surveillance of regional and distant metastatic melanoma. Methods: A comprehensive systematic review of the literature (1990-2009) was conducted. Eligible studies included 10 or more melanoma patients, comparisons of diagnostic modalities to a gold standard, and patient-level data. Studies were rated according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) scale (0-14). A meta-analysis was conducted using Bayesian bivariate binomial models that examine pairs of observed sensitivity and specificity estimates and account for possible correlation between these two outcome variables. Additionally, diagnostic odds ratios (DOR) were determined as a single indicator of test performance. Results: A total of 74 articles satisfied the search criteria for US (n = 22), CT (n = 13), PET (n = 42), and PET/CT (n = 13). The overall mean QUADAS score was 5.8 (SD = 2.5). For indentifying regional lymph node metastasis at follow-up, US had the highest sensitivity (96%), specificity (99%), and DOR (1675) compared to CT (61%, 97% and 46), PET (87%, 98% and 391), and PET/CT (65%, 99% and 196). For identifying distant metastases, PET/CT had the highest sensitivity (86%), specificity (91%), and DOR (67) compared to CT (63%, 78% and 6) and PET alone (82%, 83% and 22). Conclusions: Among diagnostic imaging modalities, US is the best test for the detection of regional lymph node metastases, while PET/CT is the best test for the detection of distant metastases. As technology related to diagnostic imaging continues to advance, these findings provide information critical to defining evidence-based surveillance strategies. No significant financial relationships to disclose.
ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
Authors: Taru Muranen, Laura M. Selfors, Julie Hwang, Lisa L. Gallegos, Jonathan L. Coloff, Carson C. Thoreen, Seong A. Kang, David M. Sabatini, Gordon B. Mills, Joan S. Brugge
Journal: Cancer Research (2016)

Abstract Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell–targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors. Cancer Res; 76(24); 7168–80. ©2016 AACR.
Elevated Apurinic/Apyrimidinic Endonuclease Activity Significantly Contributes to DNA Instability in Multiple Myeloma.
Authors: Masood A. Shammas, Robert C. Bertheau, Hemanta Koley, Paola Neri, Pierfrancesco Tassone, Ramesh B. Batchu, Nikhil C. Munshi
Journal: Blood (2006)
Outcome of Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Relapse After Tyrosine Kinase Inhibitor (TKI) Therapy
Authors: Hun Ju Lee, Susan O'Brien, Hagop M. Kantarjian, Farhad Ravandi, Stefan Faderl, Charles Koller, Marina Konopleva, Srdan Verstovsek, Tapan Kadia, Guillermo Garcia-Manero, Gautam Borthakur, William G. Wierda, Jan A. Burger, Deborah A. Thomas, Jorge E. Cortes
Journal: Blood (2011)
MAGE-A Inhibits Apoptosis In Proliferating Multiple Myeloma Cells
Authors: Tricia Nardiello, Achim A Jungbluth, Anna Mei, Maurizio DiLiberto, Xiangao Huang, Scott A Ely, Ruben Niesvizky, Morton Coleman, Roger N Pearse, David Jayabalan, Lloyd J Old, Selina Chen-Kiang, Hearn J. Cho
Journal: Blood (2010)
Effective Containment of Human Respiratory Syncytial Virus Infections in a Bone Marrow Transplantation Program Resulting from the Combined Implementation of Molecular Epidemiology, Infection Control, and Early Treatment Strategies.
Authors: Steven S. Cha, Monic J. Stuart, Susan Poutanen, Sasha Madison, Ellen Jo Baron, Dean Erdman, Janice M. Brown
Journal: Blood (2004)
<i>MDM2</i> polymorphism and recurrence-free and overall survival in early stage non-small cell lung cancer (NSCLC)
Authors: R. Suk Heist, W. Zhou, T. Cogan-Drew, G. Liu, L. Su, D. Neuberg, T. J. Lynch, J. C. Wain, D. C. Christiani
Journal: Journal of Clinical Oncology (2006)

7221 Background: MDM2 is a negative regulator of p53. A T-&gt;G polymorphism in the promoter region of MDM2 has been described, where the G/G genotype is associated with higher MDM2 mRNA and protein levels. Overexpression of MDM2 is thought to interfere with p53-mediated apoptosis and growth inhibition, leading to cancer progression. We hypothesized that the MDM2 G/G genotype may be associated with worse survival outcomes in early stage lung cancer. Methods: We evaluated the relationship between MDM2 polymorphism status and overall survival (OS) and recurrence-free survival (RFS) among 385 Stage I and II NSCLC patients treated with surgical resection at Massachusetts General Hospital from 1992 to 2000. The MDM2 polymorphism was genotyped using the 5’-nuclease assay (Taqman). Kaplan-Meier methods and the log-rank test were used to compare survival by polymorphism status. Cox proportional hazards models were used to adjust for possible confounding variables. Results: Median age was 69, and 48% were female. 52% were Stage IA, 29% Stage IB, 4% Stage IIA, and 15% Stage IIB. 49% had adenocarcinoma, 29% squamous cell, 12% BAC, and 10% other NSCLC. The genotype frequencies for the MDM2 polymorphism were: T/T 161 (42%), T/G 156 (40%), G/G 68 (18%). Genotype was not associated with age, sex, stage, histology, or smoking status. Median follow-up time was 5.79 years. After adjusting for age, sex, stage, histology, and pack-yrs of smoking, the G/G genotype appeared to be associated with worse RFS and OS (AHR 1.60 (95% CI 1.10–2.34), p = 0.01; AHR 1.56 (95% CI 1.03–2.38), p = 0.04; respectively). In subset analysis, patients with squamous cell cancer and current-smokers had significantly worse survival with the G/G genotype, while there was no significant difference by genotype among adenocarcinomas and non-current smokers. (For squamous cell, 5-yr OS for T/T 59%, T/G 52%, G/G 7%, p = 0.0001; for current smokers, 5-yr OS for T/T 67%, T/G 49%, G/G 27%, p = 0.04). Conclusions: Our findings suggest that the G/G genotype of the MDM2 polymorphism is associated with worse survival among early stage NSCLC patients, particularly those with squamous cell histology and current smokers. Supported by NIH grants CA074386, CA092824, CA090578, FAMRI Young Clinical Scientist Award, Doris Duke Foundation. [Table: see text]
RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics
Authors: Elisabeth Salzer, Deniz Cagdas, Miroslav Hons, Emily M Mace, Wojciech Garncarz, Özlem Yüce Petronczki, René Platzer, Laurène Pfajfer, Ivan Bilic, Sol A Ban, Katharina L Willmann, Malini Mukherjee, Verena Supper, Hsiang Ting Hsu, Pinaki P Banerjee, Papiya Sinha, Fabienne McClanahan, Gerhard J Zlabinger, Winfried F Pickl, John G Gribben, Hannes Stockinger, Keiryn L Bennett, Johannes B Huppa, Loïc Dupré, Özden Sanal, Ulrich Jäger, Michael Sixt, Ilhan Tezcan, Jordan S Orange, Kaan Boztug
Journal: Nature Immunology (2016)
Improved differentiation of 300 breast lesions using real-time elastography
Authors: A. Thomas, S. Kümmel, S. Landt, M. Warm, F. Fritzsche, W. Lichtenegger, T. Fischer
Journal: Journal of Clinical Oncology (2006)

10608 Background: Differences in tissue elasticity are useful in the diagnosis of breast tumors. With elastography the elastic properties of breast tissue can be imaged in real time by means of color-coded superimposition on the B image and then used for evaluating focal lesions. The goal of the present study was to compare the sensitivity and specificity of elastography with that of B-mode sonography. Methods: A total of 300 patients with histologically confirmed breast lesions (168 benign, 132 malignant) were included in the study. The patients’ average age was 51 years, the range 16 to 86 years. Evaluation was by means of the 3D finite-element method. The data is color-coded and superimposed on the B-mode ultrasound scan (HITACHI EUB 8500). A second examiner was employed to improve the objectivity of the method. The results were compared with histology and the data obtained by previous ultrasound investigations. Sensitivities and specificities were calculated. Results: B-mode sonography yielded a sensitivity of 95.5% and a specificity of 84%. The two examiners were almost in complete agreement in their evaluation of the elastography images (McNemar Test: weighted kappa: 0.86): elastography yielded a sensitivity of 82%, a specificity of 88%. Conclusion: The diagnostic results for elastography in breast lesions showed a higher specificity and a somewhat lower sensitivity in comparision with B-mode sonography. No significant financial relationships to disclose.
GW26-e1336 Myocardial Protection by MiR-126 Against Ischemia/Reperfusion Injury Through Suppression of GSK-3β
Authors: Qian Wang, Jianbing Zhu, Lin Wang, Wenjun Yu, Renfeng Zhang, Lihua Qiao, Xinyue Ge, Jiatao Lou
Journal: Journal of the American College of Cardiology (2015)
GW26-e2206 Phosphatidylinositol 4-Kinase β (PI4Kβ) and Phosphatidylinositol 4,5-Bisphosphate (PIP2) Modulated the Expression and Trafficking of BKCa Channels
Authors: Xiaoqiu Tan, Xiuli Cheng, Li Yan, Wengjun Huang, Tao Li, Yan Yang, Xiaorong Zeng, Jimin Cao
Journal: Journal of the American College of Cardiology (2015)
Physical Activity and Anger or Emotional Upset as Triggers of Acute Myocardial Infarction
Authors: Andrew Smyth, Martin O’Donnell, Pablo Lamelas, Koon Teo, Sumathy Rangarajan, Salim Yusuf
Journal: Circulation (2016)

Physical exertion, anger, and emotional upset are reported to trigger acute myocardial infarction (AMI). In the INTERHEART study, we explored the triggering association of acute physical activity and anger or emotional upset with AMI to quantify the importance of these potential triggers in a large, international population.INTERHEART was a case-control study of first AMI in 52 countries. In this analysis, we included only cases of AMI and used a case-crossover approach to estimate odds ratios for AMI occurring within 1 hour of triggers.Of 12 461 cases of AMI 13.6% (n=1650) engaged in physical activity and 14.4% (n=1752) were angry or emotionally upset in the case period (1 hour before symptom onset). Physical activity in the case period was associated with increased odds of AMI (odds ratio, 2.31; 99% confidence interval [CI], 1.96-2.72) with a population-attributable risk of 7.7% (99% CI, 6.3-8.8). Anger or emotional upset in the case period was associated with an increased odds of AMI (odds ratio, 2.44; 99% CI, 2.06-2.89) with a population-attributable risk of 8.5% (99% CI, 7.0-9.6). There was no effect modification by geographical region, prior cardiovascular disease, cardiovascular risk factor burden, cardiovascular prevention medications, or time of day or day of onset of AMI. Both physical activity and anger or emotional upset in the case period were associated with a further increase in the odds of AMI (odds ratio, 3.05; 99% CI, 2.29-4.07; P for interaction <0.001).Physical exertion and anger or emotional upset are triggers associated with first AMI in all regions of the world, in men and women, and in all age groups, with no significant effect modifiers.