tbuckley/cabot-search huggingface dataset:
The effect of a tamoxifen dose increase from 20 mg to 40 mg in patients with at least one inactive CYP2D6 variant allele and/or concomitant use of a CYP2D6 inhibitor.
Authors: M. E. B. Welzen, V. O. Dezentje, R. H. N. van Schaik, E. P. H. Colbers, H. Guchelaar, J. den Hartigh, D. M. Burger, H. Van Laarhoven
Journal: Journal of Clinical Oncology (2011)

584 Background: Genetic polymorphisms leading to reduced CYP2D6 activity and the use of CYP2D6 inhibitors both influence the formation of endoxifen (active metabolite of tamoxifen (TAM)). CYP2D6 genotyping is not part of the standard clinical management of patients treated with TAM and there are no formal recommendations for dose adjustments in patients using TAM and a CYP2D6 inhibitor. We hypothesized that in patients who are either a CYP2D6 intermediate or poor metabolizer and/or are treated with a CYP2D6 inhibitor a dose adjustment of TAM compensates for reduced formation of endoxifen. Methods: Female breast cancer patients treated with TAM 20mg QD for at least 4 weeks were included. They were genotyped for CYP2D6 variant alleles (inactive alleles *3, *4, *5, *6 and decreased activity alleles *10, *41). Patients with at least one inactive allele, two decreased CYP2D6 activity alleles, and/or concomitant use of a CYP2D6 inhibitor received a dose increase of TAM to 40mg QD for 4 weeks. TAM, 4-OH-TAM, N-desmethylTAM and endoxifen levels were determined with LC-MS in blood samples at screening and after 4 weeks. Results: 40 patients with median age 55 (range 37-81) years were enrolled of which 22 extensive (EM), 15 intermediate (IM) and 3 poor metabolizers (PM) for CYP2D6. Three EMs concomitantly used a CYP2D6 inhibitor (paroxetine, escitalopram or citalopram) and were categorized as PM. Mean (SD) endoxifen levels in EMs, IMs, and PMs were 11.4 (5.2), 8.7 (4.6) and 4.1 (1.4) ng/mL, respectively (one-way ANOVA: p=0.007). Three patients were genotyped as *4/*41 or *41/*41, and by consensus classified as IMs; their endoxifen levels (1.9; 3.4; 3.7 ng/mL, respectively) were, however, not different from those observed in PMs. 10 patients have completed the 4 week dose increase (8 IMs, 2 PMs). Mean endoxifen level for the IMs increased from 10.3 to 17.0 ng/mL and from 3.0 to 5.4 ng/mL in the PMs. No serious adverse events occurred after the dose increase. Conclusions: Increasing the dose of TAM from 20 mg to 40 mg QD can compensate for the reduced endoxifen level in CYP2D6 IMs. In contrast, a dose increase to 40mg QD in PMs does not appear to be sufficient to reach endoxifen levels seen in EMs.
Phase I study of polyphenon E (P) in addition to erlotinib (E) in advanced non-small cell lung cancer (NSCLC).
Authors: H. B. Illum, S. H. R. Jafri, J. Mclarty, G. M. Mills, J. Dowell, A. Sharma, D. H. Wang, M. Lowery Nordberg, J. Cardelli
Journal: Journal of Clinical Oncology (2011)

e18050 Background: E is an oral tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR). Polyphenon E is a green tea extract containing mainly epigallocatechin gallate (EGCG) which inhibits c-met and vascular endothelial growth factor (VEGF) signaling. In vitro studies and in vivo tumor models have demonstrated synergism from EGCG when to added E . This phase I study evaluated safety and tolerability of P and E in patients (pts) with advanced NSCLC. Methods: Pts with stage IV NSCLC who had progressed after first or second line chemotherapy were included in the study. Pts were enrolled in cohorts of 3 with increasing dose of P (200mg, 400mg and 800mg PO once daily). E was given at 150mg/day continuously in 28 day cycles. End points were safety, tolerability and maximum tolerated dose (MTD) of P in combination with E. Results: Between April 2008 and Nov 2010 a total of 11 pts were enrolled. Two pts were not included in the final analysis as they discontinued therapy due to progression or worsening of performance status prior to completing the required minimum of 4 weeks of treatment. Median age was 64.6 years (range 57-75). All pts were male and all were current or former smokers. Seven patients had squamous cell histology and two had adenocarcinoma. There were no serious adverse events. Four pts developed acneiform rash (2 – grade 2 and 2 – grade 1). One patient developed herpes zoster deemed unrelated to treatment. One patient in the 400mg cohort developed grade 2 transaminitis which resolved after temporarily holding E and P. MTD of P in combination with E was not reached. Nine patients were assessed for tumor response, 6 patients had stable disease and 3 had progression of disease. The median progression-free survival for the entire group was 3 months. Conclusions: The combination of P and E was well-tolerated with no dose limiting toxicity observed at the maximum planned dose of P of 800mg. Preliminary efficacy data suggest a progression-free survival that is modestly better than that reported with E alone. This is the first reported trial evaluating the addition of P to E in NSCLC. Larger prospective studies are required to better define the role of this combination as second-line therapy in advanced NSCLC.
Phase I Study of Cladribine, Cytarabine (Ara-C), Granulocyte Colony Stimulating Factor (G-CSF) (CLAG Regimen) and Simultaneous Escalating Doses of Imatinib Mesylate (Gleevec) in Relapsed/Refractory AML.
Authors: Camille N. Abboud, Alison Walker, Rami S. Komrokji, Jainulabdeen J. Ifthikharuddin, Connie Sparks, Kelly Likly, Patti Messina, Deborah Mulford, Jonathan Friedberg, Michael W. Becker, Faith Young, Steven H. Bernstein, August J. Salvado, Gordon L. Phillips, Jane L. Liesveld
Journal: Blood (2006)
New and Comprehensive Cytogenetic Prognostication and Categorization in MDS.
Authors: Detlef Haase, Ulrich Germing, Julie Schanz, Michael Pfeilstoecker, Thomas Noesslinger, Barbara Hildebrandt, Andrea Kuendgen, Michael Luebbert, Aristoteles Giagounidis, Carlo Aul, Lorenz Truemper, Thomas Mueller, Peter Valent, Christa Fonatsch, Christian Steidl
Journal: Blood (2006)
Abstract 5225: Endothelial-specific Jagged1 blockade prevents solid tumor growth in pre-clinical models
Authors: Antonio Duarte, Ana-Rita Pedrosa, Alexandre Trindade, Catarina Carvalho, José Graça, Sandra Carvalho, Maria C. Peleteiro, Ralf H. Adams
Journal: Cancer Research (2015)

Abstract Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development. Although its role as a pro-angiogenic ligand has been thoroughly studied in developmental contexts, the real contribution of this Notch ligand to tumor angiogenesis remains unknown. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). We show that the tumor vasculature of eJag1OE mutants presents increased vessel density, branching, and perivascular maturation, causing increased tumor perfusion. Ultimately, this leads to increased proliferation and survival of tumor cells, and increased epithelial-to-mesenchymal transition (EMT) resulting in increased LLC tumor growth as well as development and progression of prostate adenocarcinoma in mice. In contrast, in eJag1cKO mutants the vasculature is characterized by decreased vessel density, branching, and perivascular maturation, which restricts tumor vascular perfusion and increases vascular extravasation. This vascular phenotype leads to decreased proliferation and increased death of tumor cells, reduced EMT culminating in decreased LLC growth as well as inhibited development and progression of prostate adenocarcinoma in mice. Therefore, endothelial Jagged1 may constitute a novel promising target for solid cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Antonio Duarte, Ana-Rita Pedrosa, Alexandre Trindade, Catarina Carvalho, José Graça, Sandra Carvalho, Maria C. Peleteiro, Ralf H. Adams. Endothelial-specific Jagged1 blockade prevents solid tumor growth in pre-clinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5225. doi:10.1158/1538-7445.AM2015-5225
404. Development of Human Artificial Chromosomes for Gene Cell Therapy of Muscular Dystrophies
Authors: Artur A. Isaev, Ilya I. Eremin, Andrey A. Pulin, Roman V. Deev, Alexey N. Tomilin, Michail A. Liskovykh, Vladimir Larionov, Natalia Kouprina, Kseniya Iur'eva, Vadim L. Zorin, Ilya Ya Bozo, Konstantin V. Kotenko
Journal: Molecular Therapy (2015)

Muscular dystrophies are clinically heterogeneous group of muscle diseases related to different genes defects. The results of defects impair myogenic differentiation and histophysiology of skeletal muscles. One of major forms of disease – limb-girdle muscular dystrophy 2B (LGMD2B), caused by dysferlin gene mutations. Both big size of gene and wide variety of mutations complicate development of genetically engineered drugs. Human artificial chromosomes (HAC) could be used as alternative approach. This vector can contain unlimitedly large DNA region for transfer, is retained during cell division, and does not have carcinogenic and immunogenic properties. HAC matrix was developed earlier by Larionov V. et al. (http://www.ncbi.nlm.nih.gov/pubmed/22123967). Optimized DYSF gene sequence (optDYSF) from pAd/CMV/V5-DEST vector (kindly provided by A.A. Rizvanov) was transferred into backbone vector also containing loxP sites for further transfer into HAC. Transfer correctness confirmed by sequencing. After that Chinese hamster ovary cells carrying HAC were transfected by backbone vector containing optDYSF. Selection performed in HAT medium. 7 clones were selected and analyzed at day 10. Expression of optDYSF observed in all obtained clones. Episomal HAC localization determined using fluorescent hybridization in sity by colocalization of label at optDYSF and a-satellite DNA. Episomal localization of HAC determined only in 2 clones from 7. Dysferlin production observed in all clones. On other hand described vector requires somatic myogenic vector cell. Human myoblasts could be successfully used for this purpose. The major source of myoblasts – skeletal muscle tissue is not optimal due to limited proliferative potential, especially in patients with muscular dystrophies. Our team revealed presence of myoblasts in gingival mucosa specimens and developed new method of myoblasts obtainment from it. Primary cultures of multipotent mesenchymal stromal cells (MSC) were derived from gingiva biopsy samples. The cells expressed typical mesenchymal stem cells markers and had ability for 3-way differentiation. Myogenic induction of gingiva derived MSC in culture was demonstrated. Gingiva derived MSC are capable to express markers of myogenic differentiation (skeletal actin, sceletal myosin, MyoD1) and form multicellular elongated fibers – myotubes. Ability of gingiva derived MSC cultures to differentiate in myogenic direction was preserved during up to 10th passage. Such features make this cell source attractive for using in treatment of inherited muscular degenerative diseases. In our future research we are planning to transfer HAC containing optDYSF gene into clonogenic gingiva derived MSC using microcell-mediated chromosome transfer. This method could be used for further development of gene cell therapy of LGMD2B.
PTU-042 Ratio of methylated metabolites to thioguanine nucleotides predicts hepatotoxicity and non-response to thiopurine therapy
Authors: M A Smith, A M Marinaki, M Arenas, E Escuredo, P Irving, J D Sanderson
Journal: Gut (2010)

<h3>Introduction</h3> Azathioprine (AZA) and 6-mercaptopurine (6MP) are the immunomodulators of choice for inflammatory bowel disease (IBD). There are two main problems with these therapies: lack of response and toxicity. These problems conflict, making dosage decisions difficult, especially as the complex metabolism of thiopurines is subject to inter-individual variation such that patients on the recommended dose are at risk of either non-response or toxicity. Therapeutic monitoring of thioguanine nucleotides (TGNs), the active metabolic end-product of AZA and 6MP, is thought to predict both response to treatment and toxicity, and is the subject of ongoing research. TGN levels can be used to detect non-adherence, under- and over-dosing, as well as treatment resistance. TGNs are measured alongside methylated metabolite levels (MeMP) and there are previous reports in small cohorts that the ratio of these two metabolites predicts non-response to treatment and hepatotoxicity with a cut off of 11. <h3>Methods</h3> MeMP/TGN measurements taken on a series of 190 patients attending IBD clinics at Guy9s and St Thomas Hospitals on AZA or 6MP were reviewed. In particular we noted incidences of hepatotoxicity and looked for any association between MeMP/TGN ratio and non-response to treatment. Associations were tested for significance using the 2-sided Fisher9s exact test. The relationship between MeMP/TGN ratio and TPMT was analysed using linear regression analysis. <h3>Results</h3> Twelve patients were found to be non-compliant with both metabolite levels &lt;10 pmol/8×10<sup>8</sup> RBC, and were excluded from further analysis. Eight patients developed abnormal LFTs that were thought to relate to thiopurine treatment. One was diagnosed with genetic haemochromatosis and was excluded from further analysis. Of the remaining seven patients, six had MeMP/TGN ratios ≥11, (compared to 15 of the 147 without hepatotoxicity) p&lt;0.0001. A MeMP/TGN ratio of ≥11 was also associated with non-response (104/134 responders with ratio &lt;11 vs 8/19 with ratio ≥11, p=0.001). The MeMP/TGN ratio did not correlate with TPMT activity (r<sup>2</sup>=0.02). <h3>Conclusion</h3> Our results confirm in a large cohort, that the ratio of MeMP/TGN is a useful predictor of non-response to thiopurines and the development of thiopurine-related hepatotoxicity. This is particularly important, since by adding allopurinol to thiopurines at 25–50% of usual target dose, both these problems can be easily circumvented without losing thiopurines as a treatment option. The lack of relationship to TPMT is interesting and could relate to dosing differences as reported in other cohorts.
Interaction of Human Platelets with Enterohemorrhagic E. coli O111, Induces an Increase in the Procoagulant Activity, Thrombin Generation and Adhesion to Endothelial Cells
Authors: Valeria Matus, José Guillermo Valenzuela, Claudia G Sáez, Patricia Hidalgo, Karla Pereira, Jaime Pereira, Diego Mezzano
Journal: Blood (2014)
Abstract 4127: Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks
Authors: Michalis Mastri, Amanda Tracz, Li Shen, Roberto Pili, John M.L. Ebos
Journal: Cancer Research (2015)

Abstract Preclinical and clinical studies have suggested that stopping antiangiogenic therapy may lead to rapid revascularization and rebound tumor growth in certain instances. However, the implications for these findings remain unclear. It is possible that treatment rebounds may impact disease progression following neoadjuvant therapy, where drugs are administered for short periods and then halted prior to surgical removal of a primary tumor. Indeed, recent retrospective clinical studies have suggested that neoadjuvant antiangiogenic treatment discontinuation increases vascular proliferation and, in turn, might increase post-surgical disease progression and metastasis. However, this hypothesis has not been studied experimentally in clinically relevant mouse models of metastatic disease. We examined the effect of treatment discontinuation in the neoadjuvant setting using approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) such as sunitinib. Our studies utilized models of spontaneous metastatic breast, melanoma, and kidney cancer following surgical removal of orthotopically grown primary tumors. Neoadjuvant sunitinib treatment periods were 14 days in duration (60 mg/kg) with treatment breaks of 0, 3, 7, and 11 days compared. Pre-surgical molecular and cellular biomarkers were investigated as potential surrogates for post-surgical metastatic disease progression. These included tumor and vascular cell Ki67 and CD31 expression, as well as circulating tumor cells (CTCs) and myeloid derived suppressor cells (MDSCs). Our results show that VEGF RTKI neoadjuvant treatment benefits observed pre-surgically (such as reduction in primary tumor growth) did not consistently correlate with post-surgical survival and reduced metastatic recurrence. The addition of treatment breaks prior to surgery had positive or negative impact on post-surgical survival depending on the tumor model used. Interestingly, high-dose bolus (3 day) neoadjuvant sunitinib (120 mg/kg) treatment consistently improved post-surgical benefits when compared to sustained treatments, despite gaps in therapy. Finally, our results show that tumoral CD31+/Ki67+ cells, CTCs, and MDSCs may serve as surrogate markers of metastatic potential and predict the impact of treatment cessation on disease recurrence. Citation Format: Michalis Mastri, Amanda Tracz, Li Shen, Roberto Pili, John M.L. Ebos. Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2015-4127
Rash and Arthralgias in a Teenager With Autism
Authors: Amanda Jacobsen, Katherine DeNiro
Journal: JAMA Pediatrics (2017)

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Late Clonal Disorders in Patients with Aplastic Anemia
Authors: Alina Kokhno, Elena A Mikhaylova, Zalina T. Fidarova, Elena Ustinova, Vera V. Troitskaya, Andrey N. Sokolov, Larisa P. Mendeleeva, Larisa A. Kuzmina, Nina V. Tsvetaeva, Valentina N. Dvirnyk, Tatiana N. Obukhova, Alla M. Kovrigina, Elena N. Parovichnikova, Valeri Savchenko
Journal: Blood (2015)
77. Clinical Scale Zinc Finger Nuclease (ZFN)-Driven Gene-Editing of PD-1 in Tumor Infiltrating Lymphocytes (TIL) for the Potential Treatment of Metastatic Melanoma
Authors: Joal D. Beane, Gary Lee, Zhili Zheng, Nimisha Gandhi, Daniel Abate-Daga, Mini Bharathan, Mary Black, Matthew Mendel, Zhiya Yu, Sadik H. Kassim, Smita Chandran, Martin A. Giedlin, Dale Ando, Ed Rebar, Andreas Reik, Michael C. Holmes, Philip D. Gregory, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan, Steven A. Feldman
Journal: Molecular Therapy (2015)

Multiple inhibitory pathways are exploited by a number of cancers to block the body's immune response which may limit the effectiveness of adoptive cell transfer (ACT). Programmed cell death-1 (PD-1) is a member of the CD28 superfamily and is expressed on activated T cells. Importantly, its ligands, PDL-1 and PDL-2 are expressed on a variety of tumor cells, including melanoma. The binding of PD-1 to PDL-1 inhibits T cell effector function, and represents an important mechanism for PDL-1 expressing tumors to evade the host immune response to cancer. PD-1 thus represents an attractive target for gene-editing of tumor targeted T cells prior to ACT. Here we describe the elimination of PD-1 expression in tumor infiltrating lymphocytes (TIL) by genome-editing using zinc finger nucleases (ZFNs) directed against the PDCD1 gene at a scale sufficient for patient treatment. Using the MaxCyte GT Flow Transfection System to deliver mRNA encoding the PD-1 specific ZFNs, the clinical scale TIL production process yielded efficient modification of the PDCD1 gene locus (mean = 74.8% of alleles, n=3, range = 69.9 – 84.1%), which resulted in a 76% reduction in PD-1 surface-expression. Importantly, the PD-1 modified TIL products displayed an effector memory phenotype and expanded approximately 500 – 2000 fold during a rapid cell expansion. In addition, PD-1 modified and unmodified TILs showed equivalent levels of engraftment in a NSG-mouse model. PD-1 modified TILs demonstrated improved in vitro T cell effector functions relative to controls (statistically significant greater TNFα, GM-CSF and IFNγ cytokine secretion when co-cultured with MART-1+ tumor cells). Preliminary safety evaluations showed that PD-1 modified TILs maintained IL-2 dependent growth in vitro, and no tumors were observed in an NSG-mouse tumorigenicity study. These data support the further study of the efficacy and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma.