tbuckley/cabot-search huggingface dataset:
90Y Ibritumomab Tiuxetan (Zevalin®; 90YZ) Doses Higher Than .4 mCi/kg May Be Safely Combined with High-Dose Beam and Autotransplant: The Role for Dosimetry.
Authors: Jane N. Winter, David J. Inwards, Stewart Spies, Gregory Wiseman, David Patton, William Erwin, Alfred Rademaker, Stephanie F. Williams, Martin S. Tallman, Ivana Micallef, Jayesh Mehta, Seema Singhal, Michael Zimmer, Arturo Molina, Christine White, Leo I. Gordon
Journal: Blood (2004)
Abstract 4418: Identification and characterization of patient-derived PREX2 mutation in HCC
Authors: Yen-Fu A. Chen, Kuo-Jui Lee, Yi-Hsiung Lin, Chung-Hsien Li, Chia-Hung Yen, Hui-Kuan Lin, Yi-Ming Chen
Journal: Cancer Research (2016)

Abstract Phosphatidylinositol 3,4,5-trisphosphate Rac exchange factor 2 (PREX2), a highly distributed GEF, is abundant in human cancer cells. Also, PREX2 is frequently mutated in melanoma, stomach, colorectal, and lung cancers. Recently, we identified HectH9 (homologous to E6AP carboxyl terminus homologous protein 9) is the E3 ligase of PREX2 and mediates its degradation. We found that PREX2 was overexpressed in HCC and associated with the following clinical characteristics: viral infection (P = 0.004), tumor size (P = 0.03) and AFP levels (P = 0.04). Results from multivariate logistic regression analysis indicated that PREX2 expression profoundly correlated with hepatitis B virus infection (odds ratio = 14.07, P = 0.01). Moreover, high-expression level of PREX2 in the tumor tissues was associated with poor survival (P = 0.02). In addition, we performed HaloPlex sequencing to analyze the PREX2 genome among tumorous, tumor-adjacent tissues and peripheral blood mononuclear cells from 68 HCC patients. Thirteen non-silent point mutations were detected in PREX2. Compared to wild-type PREX2, the S113R mutant displayed a weaker interaction with HectH9, a reduced ubiquitination level and prolonged half-life. Moreover, the S1113R mutant further enhanced AKT activation and cell proliferation. These results reveal a novel mechanism through which GNMT restrains AKT signaling and HCC tumorigenesis. Citation Format: Yen-Fu A. Chen, Kuo-Jui Lee, Yi-Hsiung Lin, Chung-Hsien Li, Chia-Hung Yen, Hui-Kuan Lin, Yi-Ming Chen. Identification and characterization of patient-derived PREX2 mutation in HCC. [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 4418.
Abstract LB-082: Endoplasmic reticulum stress induces secretion of high mobility group (HMG) proteins and is associated with tumor-infiltrating lymphocytes in triple-negative breast cancer
Authors: Sun-Hee Heo, In Ah Park, Hee Jin Lee, Young-Ae Kim, Gyungyub Gong
Journal: Cancer Research (2016)

Abstract Purpose: Even though prognostic and predictive significance of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC) have been demonstrated widely, the cause of TIL influx is not clear. High mobility group (HMG) N1, one of the three subtypes of HMGs which are nucleosome-binding proteins is recently known as a potent alarmin that binds to TLR4 and induces Th1 immune responses. The mechanisms which involve transportation of HMGN1 are not identified. We, in this study, suggest that extracellular secretion of HMGN1 might be associated with influx of TILs and subsequent formation of TLSs, as well as dendritic cell maturation and activation in human TNBC. Experimental Design: We reviewed the hematoxylin and eosin (H&amp;E)-stained slides of 767 patients with TNBC and evaluated the degree of TILs. We also measured the degree of expression of HMGs (HMGB1 and HMGN1) and several endoplasmic reticulum stress (ERS)-associated molecules (PERK, p-eIF2a, and XBP1) by immunohistochemical (IHC) staining in tissue microarrays of the patients. The hypothesis that HMGN1 migrates from nucleus to cytoplasm and extracellular space as the cell gets variable ER stresses was confirmed by Western blot analyses using human TNBC cell lines and pharmacological ER stress inducers. Results: On IHC staining, high cytoplasmic expression of HMGB1, HMGN1, PERK, p-eIF2a, and XBP1 were identified in 43.1%, 25.7%, 45.9%, 46.9%, and 41.8% of TNBCs, respectively. Cytoplasmic expression of HMGB1 was significantly correlated with cytoplasmic expression of HMGN1, amount of TILs, expression of PERK and XBP1 (p&amp;lt;0.001∼0.039). Cytoplasmic expression of HMGN1 was also significantly correlated with amount of TILs, expression of p-eIF2a and XBP1 (p&amp;lt;0.001∼0.004). Higher nuclear expression of both HMGB1 (p&amp;lt;0.001) and HMGN1 (p&amp;lt;0.001) showed significant association with ER stress. On Western blot analyses using TBNC cell lines, treatment of a ERS inducer resulted in the secretion of HMG proteins to the extracellular space. Conclusions: To the best of our knowledge, it is the first study that elucidated the associations among ERS, extracellular secretion of HMGs, and degree of TILs in TNBCs. Understanding the mechanisms of TIL influx will help to develop effective immunotherapeutic agents for treatment of TNBC. Citation Format: Sun-Hee Heo, In Ah Park, Hee Jin Lee, Young-Ae Kim, Gyungyub Gong. Endoplasmic reticulum stress induces secretion of high mobility group (HMG) proteins and is associated with tumor-infiltrating lymphocytes in triple-negative 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 LB-082.
Phase Ib study of axitinib in combination with crizotinib in patients with advanced solid tumors.
Authors: Dale Randall Shepard, Justine Yang Bruce, Ignacio Garrido-Laguna, Brad Rosbrook, Jean-Francois Martini, Yazdi K. Pithavala, Olga Valota, M Dror Michaelson
Journal: Journal of Clinical Oncology (2014)

TPS4596 Background: Antiangiogenic therapy is proven to be effective in the treatment of multiple advanced solid tumors, including renal cell carcinoma (RCC), colorectal cancer, and non-small cell lung cancer. However, the majority of patients treated with vascular endothelial growth factor (VEGF)-pathway inhibitors ultimately develop resistance to such treatments. Overexpression of mesenchymal-epithelial transition factor (c-MET), with or without upregulation of its ligand hepatocyte growth factor, has been implicated in tumor resistance to VEGF-pathway inhibitors. Results from preclinical models suggest that combining c-MET and VEGF receptor (VEGFR) inhibition provides added benefit compared with VEGF-pathway inhibition alone (Ciamporcero et al, AACR 2013:Abstr 1618). This study is evaluating axitinib (highly specific tyrosine kinase inhibitor of VEGFRs 1–3) in combination with crizotinib (c-MET/anaplastic lymphoma kinase [ALK] inhibitor). Methods: This ongoing, multicenter, phase Ib study (NCT01999972) employs a dose escalation phase exploring oral administration of axitinib (starting dose 3 mg twice daily [BID]; range 2–5 mg BID) plus crizotinib (starting dose 200 mg BID; range 250 mg once daily–250 mg BID) on a continuous schedule to ~25 patients with advanced solid tumors resistant to standard therapy or for which no standard therapy is available. Dose escalation/de-escalation decisions are based on the modified toxicity probability interval (mTPI) design. Following determination of the maximum tolerated dose (MTD) of the combination treatment, patients with advanced clear cell RCC will be enrolled in two cohorts of ~20 patients each (cohort 1: no prior systemic therapy; cohort 2: 1–2 prior systemic therapies) in a dose expansion phase. The primary study objective is to assess the tolerability of the combination treatment in order to determine the MTD and select the recommended phase II dose. Other objectives include characterization of pharmacokinetics and antitumor activity. Correlative biomarker studies on blood and tumor tissue (archival tissue and de novo biopsies) will be performed and will include evaluation of c-MET expression. Enrollment in the dose escalation phase began in Jan 2014. Clinical trial information: NCT01999972.
Abstract 3324: Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via inhibition of STAT3 activation in triple-negative breast cancer cells
Authors: Ji Young Kim, Hyunsook An, Eunhye Oh, Youngkwan Cho, Nahyun Lee, Jae Hong Seo
Journal: Cancer Research (2016)

Abstract Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Triple-negative breast cancer (TNBC) is an aggressive tumor subtype with an enriched CD44+/CD24- stem-like population. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. The objective of the present study was to investigate the effect of salinomycin on cell death, migration, and invasion, as well as CSC-like properties in TNBC. Salinomycin significantly induced anoikis-sensitivity, accompanied by caspase-3 and caspase-8 activation and PARP cleavage, during anchorage-independent growth. Salinomycin treatment also caused a marked suppression of cell migration and invasion with concomitant downregulation of MMP-9 and MMP-2 mRNA levels. Notably, salinomycin inhibited the formation of mammospheres and effectively reduced the CD44+/CD24- stem-like population during anchorage-independent growth. These observations were associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, interleukin-6 (IL-6)-induced STAT3 activation was strongly suppressed by salinomycin challenge. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of CD44, ALDH1 and phopspho-STAT3 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on triple-negative breast cancer stem cells. Citation Format: Ji Young Kim, Hyunsook An, Eunhye Oh, Youngkwan Cho, Nahyun Lee, Jae Hong Seo. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via inhibition of STAT3 activation in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3324.
Abstract 3653: Mutational analysis of PARK2, a regulator of cyclin D1 stability, in sporadic parathyroid adenoma
Authors: Kelly Brewer, Jessica Costa-Guda, Andrew Arnold
Journal: Cancer Research (2016)

Abstract The molecular mechanisms underlying the pathogenesis of sporadic parathyroid adenomas are incompletely understood. The oncoprotein cyclin D1 is overexpressed in 20-40% of sporadic parathyroid adenomas; however, known aberrations in the gene that encodes cyclin D1, CCND1, account for less than half of these cases. Genetic alterations of PARK2, which encodes the E3 ubiquitin ligase responsible for targeting cyclin D1 for degradation, have been identified as a frequent finding in a variety of human tumors. Interestingly, genetic abnormalities of PARK2 were mutually exclusive of cyclin D1 gene alterations, suggesting a common pathway in tumorigenesis. We postulate that inactivating mutations in PARK2 lead to increased stability of cyclin D1 and thereby may contribute to the development of sporadic parathyroid adenoma. We therefore sought to identify PARK2 coding region mutations in a series of sporadic parathyroid adenomas by direct DNA sequencing. The entire coding region and intron-exon boundaries of PARK2 were examined in a cohort of eighty typically presenting, sporadic parathyroid adenomas. Six known polymorphisms were identified in several of the adenomas in this series; however, none of the polymorphisms are associated with cancer, and no other cancer-associated mutations were found. The absence of intragenic mutations in PARK2 suggests that such mutations do not commonly contribute to the development of sporadic parathyroid adenoma. However, because such intragenic mutations could be rare and limited to only those samples in which overexpression of cyclin D1 cannot be explained by genetic abnormalities in the CCND1 gene, a significant role for cyclin D1 accumulation in parathyroid tumor formation due intragenic inactivating mutations of PARK2 cannot be ruled out. Further research must be conducted in order to elucidate the mechanism(s) of cyclin D1 accumulation in parathyroid adenomas in which CCND1 aberrations are not present. . Citation Format: Kelly Brewer, Jessica Costa-Guda, Andrew Arnold. Mutational analysis of PARK2, a regulator of cyclin D1 stability, in sporadic parathyroid adenoma. [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 3653.
ZEB1 drives epithelial-to-mesenchymal transition in lung cancer
Authors: Jill E. Larsen, Vaishnavi Nathan, Jihan K. Osborne, Rebecca K. Farrow, Dhruba Deb, James P. Sullivan, Patrick D. Dospoy, Alexander Augustyn, Suzie K. Hight, Mitsuo Sato, Luc Girard, Carmen Behrens, Ignacio I. Wistuba, Adi F. Gazdar, Nicholas K. Hayward, John D. Minna
Journal: Journal of Clinical Investigation (2016)

Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-β) or oncogenetic (MYC) factors. Both TGF-β– and MYC-induced EMT required ZEB1, but engaged distinct TGF-β–dependent and vitamin D receptor–dependent (VDR-dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non–small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-β and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC.
Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.
Authors: Antoni Ribas, Caroline Robert, Adil Daud, F. Stephen Hodi, Jedd D. Wolchok, Richard Kefford, Amita Patnaik, Wen-Jen Hwu, Jeffrey S. Weber, Anthony Joshua, Peter Hersey, Tara C. Gangadhar, Richard Wayne Joseph, Roxana Stefania Dronca, Hassane M. Zarour, Scot Ebbinghaus, Kevin Gergich, Xiaoyun (Nicole) Li, Soonmo Peter Kang, Omid Hamid
Journal: Journal of Clinical Oncology (2013)

9009 Background: Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor that may lead to suppression of antitumor immunity. Lambrolizumab is a humanized monoclonal IgG4 antibody against PD-1. This study explored the safety and clinical activity of lambrolizumab in patients (pts) with advanced melanoma (MEL). Methods: In this ongoing phase 1b expansion study of MEL pts with or without previous ipilimumab (IPI) treatment, lambrolizumab was administered IV every 2 or 3 weeks until disease progression or unacceptable toxicity. Tumor response was assessed every 12 weeks by independent, central, blinded radiographic review per immune-related response criteria and RECIST 1.1. Results: As of December 1, 2012, 294 pts with MEL were enrolled, including 179 IPI-naive and 115 IPI-pretreated. Pts received lambrolizumab 10 mg/kg (n = 183) or 2 mg/kg (n = 111). Preliminary data from the first 85 consecutive pts dosed before April 25, 2012, who had independent radiologic review available as of December 3, 2012, indicate a confirmed overall response rate per RECIST 1.1 of greater than 35%, pooled across all doses and schedules and including both IPI-naive and IPI-pretreated patients. The median duration of response has not been reached as only 2 pts who had initial response discontinued due to disease progression, but the duration of confirmed responses range from 28+ to 240+ days (up to 8+ months). Among 133 pts who were dosed with lambrolizumab before July 31, 2012, and evaluable for adverse events (AEs) as of September 28, 2012, fatigue (22%), rash (18%), and pruritus (14%) were the most common drug-related AEs (mostly grade 1/2). The incidence of drug-related grade 3/4 AEs was 10% (24% regardless of attribution). Four drug-related cases of pneumonitis were reported, all of grade 1/2. Grade 3/4 drug-related hypothyroidism (n = 1) and hyperthyroidism (n = 1) were noted. Conclusions: Preliminary data suggest that lambrolizumab has significant antitumor activity and is well tolerated with manageable side effects in both IPI-naive and IPI-pretreated MEL pts. These data have led to an ongoing, international, randomized study of lambrolizumab versus chemotherapy in IPI-pretreated MEL. Clinical trial information: NCT01295827.
Alemtuzumab Is Effective in Patients with Advanced, Pretreated B-Cell Chronic Lymphocytic Leukemia: A Nationwide Study of Routine Use in Austria.
Authors: Michael Fiegl, Andreas Falkner, Georg Hopfinger, Stefan Brugger, August Zabernigg, Ferdinand Haslbauer, Johannes Andel, Josef Thaler, Michael Fridrik, Franz Bauer, Michael Mian, Georg Tatzreiter, Niklas Zojer, Dita Demirtas, Gerhard Postner, Jutta Auberger, Günther Gastl, Richard Greil
Journal: Blood (2005)
The Importance of Fostering Ownership During Medical Training: Working 9–5 Isn't the Only Issue
Authors: Katie Greenzang, Jennifer Kesselheim
Journal: The American Journal of Bioethics (2016)

"The Importance of Fostering Ownership During Medical Training: Working 9–5 Isn't the Only Issue." The American Journal of Bioethics, 16(9), pp. 17–18
Abstract 3112: HMGB1 and its isoform are sensitive and specific biomarkers to detect asbestos exposure and to identify mesothelioma patients
Authors: Andrea Napolitano, Daniel J. Antoine, Laura Pellegrini, Francine Baumann, Ian Pagano, Sandra Pastorino, Chandra M. Goparaju, Kirill Prokrym, Claudia Canino, Harvey I. Pass, Michele Carbone, Haining Yang
Journal: Cancer Research (2016)

Abstract Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. We propose total and hyper-acetylated HMGB1 as valuable biomarkers to differentiate MM patients from individuals professionally exposed to asbestos and from unexposed people. Citation Format: Andrea Napolitano, Daniel J. Antoine, Laura Pellegrini, Francine Baumann, Ian Pagano, Sandra Pastorino, Chandra M. Goparaju, Kirill Prokrym, Claudia Canino, Harvey I. Pass, Michele Carbone, Haining Yang. HMGB1 and its isoform are sensitive and specific biomarkers to detect asbestos exposure and to identify mesothelioma patients. [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 3112.
Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib.
Authors: Heather A. Wakelee, Shirish M. Gadgeel, Jonathan Wade Goldman, Karen L. Reckamp, Chris Alan Karlovich, Vladislava Melnikova, Jean-Charles Soria, Helena Alexandra Yu, Benjamin J. Solomon, Maurice Perol, Joel W. Neal, Stephen V. Liu, Mitch Raponi, Darrin Despain, Mark G. Erlander, Shannon L. Matheny, Sergey Yurasov, D. Ross Camidge, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2016)

9001 Background: Rociletinib is an oral inhibitor of mutant EGFR, including T790M. We compared EGFR mutation detection in circulating tumor DNA from blood and urine to that in matched tissue in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in pts with mutant EGFRpositive advanced NSCLC. Methods: EGFR status was assessed by the therascreen EGFR test (Qiagen) in tissue, BEAMing (Sysmex) in plasma, and a quantitative short footprint assay method that uses next-generation sequencing (Trovagene) in urine. Results: Of 417 pts in the 500 and 625 mg BID dosing groups (data cut-off date: 18 Sept 2015; pts enrolled as of 1 July 2015), 331 of 417 were T790M+ by central tissue genotyping; 189 of 242 were T790M+ by plasma genotyping; and 136 of 169 were T790M+ by urine genotyping. Confirmed investigator-assessed objective response rate (ORR) and median duration of response (mDOR) were similar regardless of sample type (Table). Four of 14 pts who were T790M+ in plasma but T790M− in tissue responded; 3 of 7 pts who were T790M+ in urine but T790M− in tissue responded. Shrinkage of target lesions correlated with higher T790M:activating mutation ratio in plasma (P=0.006). With tissue as reference, positive percent agreement for T790M status between matched plasma and tissue was 81.5% (n=195) and 83.8% (n=136) between matched urine and tissue. In both dosing groups, the most common treatment-related adverse events were hyperglycemia, diarrhea, nausea, and fatigue. Conclusions: In T790M+ pts, response was similar whether T790M status was identified by tissue, plasma or urine. Plasma and urine testing identified T790M mutations missed by biopsy due to tumor heterogeneity or inadequate sample quality. These data suggest plasma and urine EGFRanalyses complement tissue biopsies in EGFR TKI resistant NSCLC. Clinical trial information: NCT01526928. 500 mg BID 625 mg BID Tissue Plasma Urine Tissue Plasma Urine n (T790M+) 156 61 50 175 128 86 ORR, % 25.0 27.9 32.0 39.4 33.6 40.7 95% CI 18.4-32.6 17.1-40.8 19.5-46.7 32.1-47.1 25.5-42.5 30.2-51.8 mDOR, mo 9.0 9.0 9.0 7.9 6.7 8.0 95% CI 4.6-11.0 4.4-11.0 2.6-11.0 5.6-9.2 4.8-9.0 6.8-11.2 CI, confidence interval; mo, months; NR, not reached.