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https://www.readbyqxmd.com/read/29768959/challenges-of-dispensing-costly-tablets-with-short-shelf-life
#1
Mário L de Lemos, Brittney Mathers, Nadine Badry, Linda Hamata, Kelly Lo
Afatinib, trametinib and regorafenib are three costly oral oncology drugs with a short shelf-life after the original container has been opened. Their short shelf-lives are due to degradation on exposure to moisture. Therefore, manufacturers recommend them to be dispensed in the original packaging with the desiccant. However, the prescribed quantities do not always match the quantities in the original packaging, usually because of dose modifications for toxicities. This leads to potentially significant drug wastage and financial losses...
January 1, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29768711/clinical-resistance-associated-with-a-novel-map2k1-mutation-in-a-patient-with-langerhans-cell-histiocytosis
#2
David O Azorsa, David W Lee, Daniel H Wai, Ranjan Bista, Apurvi R Patel, Eiman Aleem, Michael M Henry, Robert J Arceci
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p...
May 16, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29742076/update-on-hairy-cell-leukemia
#3
Robert J Kreitman, Evgeny Arons
Hairy cell leukemia (HCL) is a chronic B-cell malignancy with multiple treatment options, including several that are investigational. Patients present with pancytopenia and splenomegaly, owing to the infiltration of leukemic cells expressing CD22, CD25, CD20, CD103, tartrate-resistant acid phosphatase (TRAP), annexin A1 (ANXA1), and the BRAF V600E mutation. A variant lacking CD25, ANXA1, TRAP, and the BRAF V600E mutation, called HCLv, is more aggressive and is classified as a separate disease. A molecularly defined variant expressing unmutated immunoglobulin heavy variable 4-34 (IGHV4-34) is also aggressive, lacks the BRAF V600E mutation, and has a phenotype of HCL or HCLv...
March 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29741568/hemophagocytic-lymphohistiocytosis-associated-with-dabrafenib-and-trametinib-combination-therapy-following-pembrolizumab-administration-for-advanced-melanoma
#4
K Sasaki, J Uehara, S Iinuma, H Doi, M Honma, Y Toki, A Ishida-Yamamoto
No abstract text is available yet for this article.
May 7, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29736211/therapeutic-effects-of-targeting-ras-erk-signaling-in-giant-congenital-melanocytic-nevi
#5
Qingxiong Yu, Min Wu, Lingling Sheng, Qingfeng Li, Feng Xie
Most giant congenital melanocytic nevi (GCMN) exhibit an activating mutation in NRAS. Constitutive activation of the RAS-ERK signaling pathway induces proliferation in nevus cells and plays a pivotal role in melanoma development. In this study, we studied the efficacy of RAS-ERK pathway targeted therapy in GCMN. We isolated nevus cells from GCMN (GNCs) and compared the morphology of GNCs with normal melanocytes and the A375 melanoma cell line. Proliferation curves of GNCs and A375 cells were determined using Cell Counting Kit-8 assays...
2018: American Journal of Translational Research
https://www.readbyqxmd.com/read/29731968/blockage-of-the-mevalonate-pathway-overcomes-the-apoptotic-resistance-to-mek-inhibitors-with-suppressing-the-activation-of-akt-in-cancer-cells
#6
Mahiro Iizuka-Ohashi, Motoki Watanabe, Mamiko Sukeno, Mie Morita, Ngoc Thi Hong Hoang, Takahiro Kuchimaru, Shinae Kizaka-Kondoh, Yoshihiro Sowa, Koichi Sakaguchi, Tetsuya Taguchi, Toshiyuki Sakai
With increasing clinical demands for MEK inhibitors in cancer treatment, overcoming the resistance to MEK inhibitors is an urgent problem to be solved. Numerous reports have shown that MEK inhibition results in the activation of PI3K-Akt signaling, which may confer apoptotic resistance to MEK inhibitors. We here demonstrate that the blockade of the mevalonate pathway using the antilipidemic drug statins represses Akt activation following MEK inhibition and induces significant apoptosis when co-treated with CH5126766 or trametinib...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29729495/braf-in-non-small-cell-lung-cancer-nsclc-pickaxing-another-brick-in-the-wall
#7
REVIEW
Alessandro Leonetti, Francesco Facchinetti, Giulio Rossi, Roberta Minari, Antonia Conti, Luc Friboulet, Marcello Tiseo, David Planchard
Molecular characterization of non-small cell lung cancer (NSCLC) marked an historical turning point for the treatment of lung tumors harboring kinase alterations suitable for specific targeted drugs inhibition, translating into major clinical improvements. Besides EGFR, ALK and ROS1, BRAF represents a novel therapeutic target for the treatment of advanced NSCLC. BRAF mutations, found in 1.5-3.5% of NSCLC, are responsible of the constitutive activation of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway...
April 24, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29727601/trametinib-downregulates-survivin-expression-in-rb1-positive-kras-mutant-lung-adenocarcinoma-cells
#8
Toshiyuki Sumi, Sachie Hirai, Miki Yamaguchi, Yusuke Tanaka, Makoto Tada, Toshiro Niki, Hiroki Takahashi, Yuji Sakuma
High expression levels of survivin in KRAS-mutant lung adenocarcinomas are linked with unfavorable patient outcomes, suggesting that survivin is a promising target for tumor treatment. We found that trametinib, a MEK inhibitor, downregulates survivin expression in the RB1-positive KRAS-mutant lung adenocarcinoma cell lines H358 and H441. In these cell lines, trametinib treatment induced p21 expression and dephosphorylated RB1, leading to sustained suppression of survivin. Knockdown of p21 or RB1 restored survivin expression in trametinib-treated cells, at least partially, which supports the contribution of these molecules to trametinib-mediated survivin suppression...
May 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29720369/genomic-status-of-met-potentiates-sensitivity-to-met-and-mek-inhibition-in-nf1-related-malignant-peripheral-nerve-sheath-tumors
#9
Jacqueline D Peacock, Matthew G Pridgeon, Elizabeth A Tovar, Curt J Essenburg, Megan J Bowman, Zachary B Madaj, Julie Koeman, Elissa A Boguslawski, Jamie Grit, Rebecca D Dodd, Vadim Khachaturov, Diana M Cardona, Mark Chen, David G Kirsch, Flavio Maina, Rosanna Dono, Mary E Winn, Carrie R Graveel, Matthew R Steensma
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1 MET)...
May 2, 2018: Cancer Research
https://www.readbyqxmd.com/read/29717260/a-modified-gene-trap-approach-for-improved-high-throughput-cancer-drug-discovery
#10
Shelli M Morris, Andrew J Mhyre, Savanna S Carmack, Carrie H Myers, Connor Burns, Wenjuan Ye, Marc Ferrer, James M Olson, Richard A Klinghoffer
While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development of robust cell-based assays in relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present a modified gene trap approach to efficiently generate pathway-specific reporters that result in a robust "on" signal when the pathway of interest is inhibited. In this proof-of-concept study, we used vemurafenib and trametinib to identify traps that specifically detect inhibition of the mitogen-activated protein kinase (MAPK) pathway in a model of BRAFV600E driven human malignant melanoma...
May 2, 2018: Oncogene
https://www.readbyqxmd.com/read/29694792/response-to-trametinib-of-a-pulmonary-langerhans-cell-histiocytosis-harboring-a-map2k1-deletion
#11
Gwenaël Lorillon, Fanelie Jouenne, Barouyr Baroudjian, Constance de Margerie-Mellon, Laetitia Vercellino, Véronique Meignin, Celeste Lebbe, Robert Vassallo, Samia Mourah, Abdellatif Tazi
No abstract text is available yet for this article.
April 25, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29690649/responses-to-the-selective-bruton-s-tyrosine-kinase-btk-inhibitor-tirabrutinib-ono-gs-4059-in-diffuse-large-b-cell-lymphoma-cell-lines
#12
Ryohei Kozaki, Meike Vogler, Harriet S Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J S Dyer, Toshio Yoshizawa
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines...
April 23, 2018: Cancers
https://www.readbyqxmd.com/read/29683947/encephalocraniocutaneous-lipomatosis
#13
Abhishek Bavle, Rikin Shah, Naina Gross, Theresa Gavula, Alejandro Ruiz-Elizalde, Klaas Wierenga, Rene McNall-Knapp
A 5-year-old boy presented with worsening headaches for 3 months. On examination, he was found to have a hairless fatty tissue nevus of the scalp (nevus psiloliparus), subcutaneous soft tissue masses on the right side of his face, neck, mandible and right buttock and epibulbar dermoid of the right eye (choristoma) (Figs. 1A, B). Magnetic resonance imaging revealed a large suprasellar mass, which was debulked and found to be a pilocytic astrocytoma. Testing was not performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation...
April 20, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29682188/imaging-markers-of-response-to-combined-braf-and-mek-inhibition-in-braf-mutated-vemurafenib-sensitive-and-resistant-melanomas
#14
Stefania Acciardo, Lionel Mignion, Nicolas Joudiou, Caroline Bouzin, Jean-François Baurain, Bernard Gallez, Bénédicte F Jordan
A majority of patients with a V600x melanoma respond quickly to BRAF/MEK inhibition (BRAFi/MEKi) and have an obvious clinical benefit. Nearly all the patients after this initial phase will develop resistance. Therefore, non-invasive early markers of response/non-response are needed in order to identify those patients who, due to intrinsic or acquired resistance, do not respond to treatment and would be eligible for alternative treatments. The aim of this study was to investigate the value of magnetic resonance spectroscopy (1 H-MRS) of choline and diffusion-weighted magnetic resonance imaging (DW-MRI) as early markers of response to BRAF inhibition (BRAFi) with vemurafenib alone or in combination with MEK inhibition (MEKi) with trametinib, in BRAFi-sensitive and BRAFi-resistant melanoma xenografts...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662630/type-ii-raf-inhibitor-causes-superior-erk-pathway-suppression-compared-to-type-i-raf-inhibitor-in-cells-expressing-different-braf-mutant-types-recurrently-found-in-lung-cancer
#15
Amir Noeparast, Philippe Giron, Sylvia De Brakeleer, Carolien Eggermont, Ulrike De Ridder, Erik Teugels, Jacques De Grève
A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK signaling and can induce ERK paradoxical activation in CRAF-overexpressing cells. The present study compared the effects of Dabrafenib and a type II RAF inhibitor, AZ628, on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants, and in a non-V600 and impaired-kinase BRAF-mutant lung cancer cell line (H1666)...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662327/spotlight-on-dabrafenib-trametinib-in-the-treatment-of-non-small-cell-lung-cancer-place-in-therapy
#16
REVIEW
Thomas C Weart, Kenneth D Miller, Charles B Simone
Advanced non-small-cell lung cancer (NSCLC) remains a challenging disease. The limited utility of chemotherapy indicates the need for additional therapeutic options. Targeted therapy continues to be an important tool in the treatment of NSCLC. Mutations within the RAS-RAF-MEK-MAPK pathway, specifically the BRAF V600E mutation, have become an important target for the subset of NSCLC patients with this mutation. This paper summarizes the clinical evidence that lead to the recent approval of the combination of dabrafenib and trametinib to treat patients with advanced NSCLC who harbor a BRAF V600E mutation...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/29658816/a-mixed-treatment-comparison-of-toxicity-of-gemcitabine-combined-with-different-targeted-drugs-in-the-treatment-of-advanced-or-metastatic-pancreatic-cancer
#17
Penpa Dorjee, Zi-Wen Long
The mixed treatment comparison study was performed in order to compare the toxicities of Gemcitabine and different targeted drug combinations in the treatment of advanced/metastatic pancreatic cancer (PC). Searches were performed from the inception of PubMed and Cochrane Library databases to February 2017. This study included randomized controlled trials (RCTs) of Gemcitabine and different targeted drug combinations in the treatment of advanced/metastatic PC. Odds ratio (OR) values were calculated by direct and indirect comparisons, and the surface under the cumulative ranking curves (SUCRA) were drawn...
April 16, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29658609/survivin-knockdown-induces-senescence-in-ttf%C3%A2-1-expressing-kras-mutant-lung-adenocarcinomas
#18
Toshiyuki Sumi, Sachie Hirai, Miki Yamaguchi, Yusuke Tanaka, Makoto Tada, Gen Yamada, Tadashi Hasegawa, Yohei Miyagi, Toshiro Niki, Atsushi Watanabe, Hiroki Takahashi, Yuji Sakuma
Survivin plays a key role in regulating the cell cycle and apoptosis, and is highly expressed in the majority of malignant tumors. However, little is known about the roles of survivin in KRAS-mutant lung adenocarcinomas. In the present study, we examined 28 KRAS-mutant lung adenocarcinoma tissues and two KRAS-mutant lung adenocarcinoma cell lines, H358 and H441, in order to elucidate the potential of survivin as a therapeutic target. We found that 19 (68%) of the 28 KRAS-mutant lung adenocarcinomas were differentiated tumors expressing thyroid transcription factor‑1 (TTF‑1) and E-cadherin...
April 11, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29650281/recent-developments-and-obstacles-in-the-treatment-of-melanoma-with-braf-and-mek-inhibitors
#19
REVIEW
Mohd Wahid, Arshad Jawed, Raju K Mandal, Sajad A Dar, Naseem Akhter, Pallavi Somvanshi, Farah Khan, Mohtashim Lohani, Mohammed Y Areeshi, Shafiul Haque
Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes, lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time...
May 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29642934/correlation-of-gene-expression-and-associated-mutation-profiles-of-apobec3a-apobec3b-rev1-ung-and-fhit-with-chemosensitivity-of-cancer-cell-lines-to-drug-treatment
#20
Suleyman Vural, Richard Simon, Julia Krushkal
BACKGROUND: The APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment...
April 11, 2018: Human Genomics
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