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Gaurav Narula, Nirmalaya D Pradhan, Brijesh Arora, Sripad D Banavali
BACKGROUND: Involvement of risk-organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance-similarly augmented for RO+, and retrospectively analyzed its impact. PROCEDURE: LCH patients from 2009 through 2014 were included...
March 7, 2018: Pediatric Blood & Cancer
Nikki A Evensen, P Pallavi Madhusoodhan, Julia Meyer, Jason Saliba, Ashfiyah Chowdhury, David J Araten, Jacob Nersting, Teena Bhatla, Tiffaney L Vincent, David Teachey, Stephen P Hunger, Jun Yang, Kjeld Schmiegelow, William L Carroll
Survival of children with relapsed acute lymphoblastic leukemia is poor and understanding mechanisms underlying resistance is essential in developing new therapy. Relapse-specific heterozygous deletions in MSH6, a crucial part of DNA Mismatch Repair, are frequently detected. Our aim was to determine whether MSH6 deletion results in a hypermutator phenotype associated with generation of secondary mutations involved in drug resistance or leads to a failure to initiate apoptosis directly in response to chemotherapeutic agents...
February 15, 2018: Haematologica
Joshua C Berkowitz, Joanna Stein-Fishbein, Sundas Khan, Richard Furie, Keith S Sultan
AIM: To describe trends of combination therapy (CT) of infliximab (IFX) and immunomodulator (IMM) for inflammatory bowel disease (IBD) in the community setting. METHODS: A retrospective study was conducted of all IBD patients referred for IFX infusion to our community infusion center between 04/01/01 and 12/31/14. CT was defined as use of IFX with either azathioprine, 6-mercaptopurine, or methotrexate. We analyzed trends of CT usage overall, for Crohn's disease (CD) and ulcerative colitis (UC), and for the subgroups of induction patients...
February 6, 2018: World Journal of Gastrointestinal Pharmacology and Therapeutics
Tina Gerbek, Maria Ebbesen, Jacob Nersting, Thomas L Frandsen, Malin Lindqvist Appell, Kjeld Schmiegelow
PURPOSE: To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. METHODS: Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen...
February 1, 2018: Cancer Chemotherapy and Pharmacology
Mervat Alsous, Al-Motassem Yousef, Mariam Abdel Jalil, Mohammed Zawiah, Shorouq Yacoub, Deema Momani, Alia Gharabli, Suha Omar, Rawad Rihani
Background and Aims: It has been demonstrated that homozygote and heterozygote mutant allele carriers for thiopurine S-methyltransferase (TPMT) are at high risk of developing myelosuppression after receiving standard doses of 6-mercaptopurine (6-MP). The aim of this study was to determine the frequency of TPMT deficient alleles in children with acute lymphoblastic leukemia (ALL) in Jordan and to compare it with other ethnic groups. Methods: We included 52 ALL childhood cases from King Hussein Cancer Research Center in Jordan...
January 27, 2018: Asian Pacific Journal of Cancer Prevention: APJCP
Perry K Pratt, Nunes David, Horst C Weber, Frédéric F Little, Themistoklis Kourkoumpetis, Gregory J Patts, Janice Weinberg, Francis A Farraye
Background: Studies have demonstrated an association between anti-TNF/immunomodulator agents used in inflammatory bowel disease (IBD) and impaired hepatitis B virus (HBV) vaccine immunogenicity, but little data exist on whether specific medication types affect protective HBsAb titers. Our aim was to analyze this association. Methods: This is a retrospective cohort study. Inclusion criteria: age ≥18, diagnosis of Crohn's disease (CD) or ulcerative colitis (UC), previous HBV vaccination series and/or ≥1 positive HBsAb, and record of IBD therapy in 6 months before titer level...
January 18, 2018: Inflammatory Bowel Diseases
Hagop Kantarjian, Farhad Ravandi, Nicholas J Short, Xuelin Huang, Nitin Jain, Koji Sasaki, Naval Daver, Naveen Pemmaraju, Joseph D Khoury, Jeffrey Jorgensen, Yesid Alvarado, Marina Konopleva, Guillermo Garcia-Manero, Tapan Kadia, Musa Yilmaz, Gautam Bortakhur, Jan Burger, Steven Kornblau, William Wierda, Courtney DiNardo, Alessandra Ferrajoli, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Elias Jabbour
BACKGROUND: Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to a toxin, calicheamicin, has shown single-agent activity in relapsed or refractory acute lymphoblastic leukaemia. We aimed to assess the activity and safety of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with acute lymphoblastic leukaemia. METHODS: We did a single-arm, phase 2 study at the MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, acute lymphoblastic leukaemia, and an Eastern Cooperative Oncology Group performance status of 3 or lower...
January 15, 2018: Lancet Oncology
Gannie Tzoneva, Chelsea L Dieck, Koichi Oshima, Alberto Ambesi-Impiombato, Marta Sánchez-Martín, Chioma J Madubata, Hossein Khiabanian, Jiangyan Yu, Esme Waanders, Ilaria Iacobucci, Maria Luisa Sulis, Motohiro Kato, Katsuyoshi Koh, Maddalena Paganin, Giuseppe Basso, Julie M Gastier-Foster, Mignon L Loh, Renate Kirschner-Schwabe, Charles G Mullighan, Raul Rabadan, Adolfo A Ferrando
Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity...
January 17, 2018: Nature
Zlatko Djurić, Ljiljana Šaranac, Ivana Budić, Voja Pavlović, Jelena Djordjević
The main role of therapy in Crohn's disease is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in Crohn's disease include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate. Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines independently or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of methotrexate in children suffering from Crohn's disease...
January 16, 2018: Bosnian Journal of Basic Medical Sciences
Joshua W Hagen, Melissa A Pugliano-Mauro
BACKGROUND: Azathioprine and 6-mercaptopurine (thiopurines) are common adjunct treatments for inflammatory bowel disease (IBD). Although thiopurine therapy in organ transplant recipients is known to increase nonmelanoma skin cancers (NMSCs), dermatologic literature yields less data regarding NMSC risk of thiopurine use in IBD. OBJECTIVE: The aim of this study was to systematically review current literature on NMSC risk in patients with IBD using thiopurine therapy...
January 8, 2018: Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]
Yaruo Xiao, Enqi Zhang, Ailing Fu
Much effort has been devoted to the discovery of effective biomaterials for nerve regeneration. Here, we reported a novel application of gold nanoparticles (AuNPs) modified with 6-mercaptopurine (6MP) and a neuron-penetrating peptide (RDP) as a neurophic agent to promote proliferation and neurite growth of human neuroblastoma (SH-SY5Y) cells. When the cells were treated with 6MP-AuNPs-RDP conjugates, they showed higher metabolic activity than the control. Moreover, SH-SY5Y cells were transplanted onto the surface coated with 6MP-AuNPs-RDP to examine the effect of neurite development...
December 29, 2017: Nanoscale Research Letters
Amani Mahbub, Christine Le Maitre, Sarah Haywood-Small, Neil Cross, Nicola Jordan-Mahy
Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6-mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis. Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines...
December 1, 2017: Oncotarget
Amporn Atsawarungruangkit, Fernando Dominguez, Gustavo Borda, Nikolaos Mavrogiorgos
Listeria monocytogenes is a gram-positive bacterium that causes listeriosis. Brain abscess is a very uncommon manifestation of listeriosis and has not been reported to be associated with adalimumab (humira), one of the approved medications for treating Crohn's disease. A 45-year-old female with Crohn's disease presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She was on prednisone and 6-mercaptopurine. She had started taking adalimumab 17 days prior to admission...
September 2017: Case Reports in Gastroenterology
Dimple Garg, Akansha Mehta, Amit Mishra, Soumen Basu
Presently, the combination of carbon quantum dots (CQDs) and metal oxide nanostructures in one frame are being considered for the sensing of purine compounds. In this work, a combined system of CQDs and MnO2 nanostructures was used for the detection of anticancer drugs, 6-Thioguanine (6-TG) and 6-Mercaptopurine (6-MP). The CQDs were synthesized through microwave synthesizer and the MnO2 nanostructures (nanoflowers and nanosheets) were synthesized using facile hydrothermal technique. The CQDs exhibited excellent fluorescence emission at 420nm when excited at 320nm wavelength...
March 5, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Geoffrey C Wall, Hamid Muktar, Cassandra Effken, Pramod B Mahajan
Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease...
February 2018: Pharmacotherapy
Hannah Rieger, Patrik Schmidt, Elke Schaeffeler, Manabu Abe, Mira Schiffhauer, Matthias Schwab, Nicolas von Ahsen, Gabriela Zurek, Hartmut Kirchherr, Maria Shipkova, Eberhard Wieland
BACKGROUND: Variation in metabolism, toxicity and therapeutic efficacy of thiopurine drugs is largely influenced by genetic polymorphisms in the thiopurine S-methyltransferase (TPMT) gene. Determination of TPMT activity is routinely performed in patients to adjust drug therapy. METHODS: We further optimized a previously established high-performance liquid chromatography (HPLC) method by measuring TPMT activity in whole blood instead of isolated erythrocytes, which is based on conversion of 6-mercaptopurine to 6-methylmercaptopurine using S-adenosyl-methionine as methyl donor...
December 1, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa
The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations...
February 2018: Journal of Gastroenterology
Yelena P Wu, David D Stenehjem, Lauri A Linder, Bin Yu, Bridget Grahmann Parsons, Ryan Mooney, Mark N Fluchel
Adherence to oral medications during maintenance therapy is essential for pediatric patients with acute lymphoblastic leukemia. Self-reported or electronic monitoring of adherence indicate suboptimal adherence, particularly among particular sociodemographic groups. This study used medication refill records to examine adherence among a national sample of pediatric patients with acute lymphoblastic leukemia. Patients in a national claims database, aged 0 to 21 years with a diagnosis of acute lymphoblastic leukemia and in the maintenance phase of treatment, were included...
March 2018: Journal of Pediatric Oncology Nursing: Official Journal of the Association of Pediatric Oncology Nurses
Marwa H El-Wakil, Hayam M Ashour, Manal N Saudi, Ahmed M Hassan, Ibrahim M Labouta
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its "double-drug" antitumor effect...
February 2018: Bioorganic Chemistry
Brigitte Moreau, Pierre Clement, Yves Theoret, Ernest G Seidman
Background: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD...
November 2017: Therapeutic Advances in Gastroenterology
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