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https://www.readbyqxmd.com/read/29243224/palbociclib-synergizes-with-braf-and-mek-inhibitors-in-treatment-na%C3%A3-ve-melanoma-but-not-after-the-development-of-braf-inhibitor-resistance
#1
Claire A Martin, Carleen Cullinane, Laura Kirby, Shatha Abuhammad, Emily J Lelliott, Kelly Waldeck, Richard J Young, Natalie Brajanovski, Donald P Cameron, Rachael Walker, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Richard B Pearson, Rodney J Hicks, Grant A McArthur, Karen E Sheppard
Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination were assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors...
December 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29242895/comparison-of-laboratory-developed-tests-and-fda-approved-assays-for-braf-egfr-and-kras-testing
#2
Annette S Kim, Angela N Bartley, Julia A Bridge, Suzanne Kamel-Reid, Alexander J Lazar, Neal I Lindeman, Thomas A Long, Jason D Merker, Alex J Rai, David L Rimm, Paul G Rothberg, Patricia Vasalos, Joel T Moncur
Importance: The debate about the role of the Food and Drug Administration (FDA) in the regulation of laboratory-developed tests (LDTs) has focused attention on the analytical performance of all clinical laboratory testing. This study provides data comparing the performance of LDTs and FDA-approved companion diagnostics (FDA-CDs) in proficiency testing (PT) provided by the College of American Pathologists Molecular Oncology Committee. Objective: To compare the analytical performance of LDTs and FDA-CDs on well-characterized PT samples and to compare the practice characteristics of laboratories using these assays...
December 14, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29241739/braf-and-kras-mutations-in-tubular-apocrine-adenoma-and-papillary-eccrine-adenoma-of-the-skin
#3
Jau-Yu Liau, Jia-Huei Tsai, Wen-Chang Huang, Jui Lan, Jin-Bon Hong, Chang-Tsu Yuan
Tubular apocrine adenoma (TAA) and papillary eccrine adenoma (PEA) are benign sweat gland tumors. Their names imply that they exhibit apocrine and eccrine differentiation, respectively. However, morphologically they are very similar and are often indistinguishable. The molecular pathogenesis of either tumor is poorly understood at present. On the basis of an index case of nipple adenoma that was morphologically reminiscent of cutaneous TAA/PEA and harbored a BRAFV600E mutation, we investigated whether a similar genetic change is also present in TAA/PEA...
December 11, 2017: Human Pathology
https://www.readbyqxmd.com/read/29232304/rapid-braf-mutation-tests-in-patients-with-advanced-melanoma-comparison-of-immunohistochemistry-droplet-digital-pcr-and-the-idylla-mutation-platform
#4
Cornelis Bisschop, Arja Ter Elst, Lisette J Bosman, Inge Platteel, Mathilde Jalving, Anke van den Berg, Arjan Diepstra, Bettien van Hemel, Gilles F H Diercks, Geke A P Hospers, Ed Schuuring
BRAF mutational testing has become a common practice in the diagnostic process of patients with advanced melanoma. Although time-consuming, DNA sequencing techniques are the current gold standard for mutational testing. However, in certain clinical situations, a rapid test result is required. In this study, the performance of three rapid BRAF mutation tests was compared. Thirty-nine formalin-fixed paraffin-embedded melanoma tissue samples collected between 2007 and 2014 at a single center were included. These samples were analyzed by immunohistochemistry using the anti-BRAF-V600E (VE1) mouse monocolonal antibody (BRAF-VE1 IHC), a V600E-specific Droplet Digital PCR Test, and the Idylla BRAF- Mutation Test (Idylla)...
December 11, 2017: Melanoma Research
https://www.readbyqxmd.com/read/29227915/novel-1-2-4-triazole-derivatives-as-potential-anticancer-agents-design-synthesis-molecular-docking-and-mechanistic-studies
#5
Hany A M El-Sherief, Bahaa G M Youssif, Syed Nasir Abbas Bukhari, Mohamed Abdel-Aziz, Hamdy M Abdel-Rahman
A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g with the least IC50 values in MTT assay were tested against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and were also observed to be strong Tubulin inhibitors...
December 5, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29227119/-molecular-pathology-of-lung-cancer-in-routine-diagnostic-practice-2017-update
#6
Radoslav Matěj, Zdeněk Rohan, Kristýna Němejcová, Pavel Dundr
The group of non-small cell lung carcinomas includes tumors that are variable at the clinical, histopathological and molecular levels. Advances in the understanding of molecular pathology of lung adenocarcinomas in particular led to changes in their histopathological classification and treatment. Patients diagnosed with lung adenocarcinoma harboring specific mutations benefit from the administration of specific targeted therapy. Analysis of EGFR gene mutations and ALK rearrangement in lung adenocarcinomas are already routinely performed and are closely related to the indication for the administration of tyrosinkinase inhibitors...
2017: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/29226425/intraventricular-melanocytoma-diagnosis-confirmed-by-gene-mutation-profile
#7
Ulrich J Knappe, Iris Tischoff, Andrea Tannapfel, Wolf-Dieter Reinbold, Inga Möller, Antje Sucker, Dirk Schadendorf, Klaus G Griewank, Johannes A P van de Nes
Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i...
December 11, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/29221650/-immunohistochemistry-using-clone-ve1-is-an-economic-specific-and-sensitive-method-for-detecting-the-presence-of-brafv600e-mutations-in-melanoma
#8
M Etienne, F Oca, D Prunier-Mirebeau, A Croué, L Martin
BACKGROUND: Determination of BRAF mutation status is mandatory in the management of patients with inoperable stage IIIC or stage IV melanoma. Currently, molecular biology (MB) has been validated for detecting the presence of BRAF mutations. OBJECTIVE: To compare the sensitivity, specificity and cost of immunohistochemistry (IHC) (clone VE1) versus BM methods (qPCR and Sanger sequencing). PATIENTS AND METHODS: All the samples for which BRAF mutation status was requested between March 2013 and February 2015 at the cellular and molecular analysis laboratory of the Angers Hospital were included retrospectively and consecutively...
December 5, 2017: Annales de Dermatologie et de Vénéréologie
https://www.readbyqxmd.com/read/29221192/tumor-suppressive-function-of-unc5d-in-papillary-thyroid-cancer
#9
Man-Man Zhang, Feng Sun, Bing Cui, Le-Le Zhang, Ya Fang, Yan Li, Rui-Jia Zhang, Xiao-Ping Ye, Yu-Ru Ma, Bing Han, Huai-Dong Song
Background: Studies have shown an association of the UNC5D gene with kidney and bladder cancer and neuroblastoma. We investigated whether UNC5D acts as a tumor suppressor in papillary thyroid carcinoma (PTC). Methods: Primary PTC tumors and matched normal thyroid tissues were obtained from 112 patients to detect UNC5D mRNA by real-time PCR. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. The association between UNC5D expression and clinicopathological data from PTC patients was reviewed retrospectively...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29221145/subependymal-giant-cell-astrocytomas-in-tuberous-sclerosis-complex-have-consistent-tsc1-tsc2-biallelic-inactivation-and-no-braf-mutations
#10
Anika Bongaarts, Krinio Giannikou, Roy J Reinten, Jasper J Anink, James D Mills, Floor E Jansen, G M Wim Spliet, Willfred F A den Dunnen, Roland Coras, Ingmar Blümcke, Werner Paulus, Theresa Scholl, Martha Feucht, Katarzyna Kotulska, Sergiusz Jozwiak, Anna Maria Buccoliero, Chiara Caporalini, Flavio Giordano, Lorenzo Genitori, Figen Söylemezoğlu, José Pimentel, Mark Nellist, Antoinette Y N Schouten-van Meeteren, Anwesha Nag, Angelika Mühlebner, David J Kwiatkowski, Eleonora Aronica
Subependymal giant cell astrocytomas (SEGAs) are rare, low-grade glioneuronal brain tumors that occur almost exclusively in patients with tuberous sclerosis complex (TSC). Though histologically benign, SEGAs can lead to serious neurological complications, including hydrocephalus, intractable seizures and death. Previous studies in a limited number of SEGAs have provided evidence for a biallelic two-hit inactivation of either TSC1 or TSC2, resulting in constitutive activation of the mechanistic target of rapamycin complex 1 pathway...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29217530/the-impact-of-smoking-and-tp53-mutations-in-lung-adenocarcinoma-patients-with-targetable-mutations-the-lung-cancer-mutation-consortium-lcmc2
#11
Dara L Aisner, Lynette M Sholl, Lynne Berry, Michael Rossi, Heidi Chen, Junya Fujimoto, Andre L Moreira, Suresh Ramalingam, Liza C Villaruz, Gregory A Otterson, Eric B Haura, Katerina Politi, Bonnie S Glisson, Jeremy Cetnar, Edward Garon, Joan Schiller, Saiama Waqar, Lecia V Sequist, Julie R Brahmer, Yu Shyr, Kelly Kugler, Ignacio Ivan Wistuba, Bruce E Johnson, John D Minna, Mark G Kris, Paul A Bunn, David J Kwiatkowski
PURPOSE Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. PATIENTS AND METHODS Sixteen U.S. institutions enrolled 1367 lung cancer patients in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and immunohistochemistry...
December 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29213343/exome-sequencing-characterizes-the-somatic-mutation-spectrum-of-early-serrated-lesions-in-a-patient-with-serrated-polyposis-syndrome-sps
#12
Sukanya Horpaopan, Jutta Kirfel, Sophia Peters, Michael Kloth, Robert Hüneburg, Janine Altmüller, Dmitriy Drichel, Margarete Odenthal, Glen Kristiansen, Christian Strassburg, Jacob Nattermann, Per Hoffmann, Peter Nürnberg, Reinhard Büttner, Holger Thiele, Philip Kahl, Isabel Spier, Stefan Aretz
Background: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified...
2017: Hereditary Cancer in Clinical Practice
https://www.readbyqxmd.com/read/29212029/melk-promotes-melanoma-growth-by-stimulating-the-nf-%C3%AE%C2%BAb-pathway
#13
Radoslav Janostiak, Navin Rauniyar, TuKiet T Lam, Jianhong Ou, Lihua J Zhu, Michael R Green, Narendra Wajapeyee
Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29211306/telomerase-reverse-transcriptase-promoter-alterations-across-cancer-types-as-detected-by-next-generation-sequencing-a-clinical-and-molecular-analysis-of-423-patients
#14
Maria Schwaederle, Nithya Krishnamurthy, Gregory A Daniels, David E Piccioni, Santosh Kesari, Paul T Fanta, Richard B Schwab, Sandip P Patel, Barbara A Parker, Razelle Kurzrock
BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015...
December 6, 2017: Cancer
https://www.readbyqxmd.com/read/29198052/melanoma-brain-metastases-harboring-braf-v600k-or-nras-mutations-are-associated-with-an-increased-local-failure-rate-following-conventional-therapy
#15
Penny Fang, Nicholas S Boehling, Eugene J Koay, Amanda D Bucheit, John A Jakob, Stephen H Settle, Paul D Brown, Michael A Davies, Erik P Sulman
Studies on melanoma brain metastases (MBM) with regard to mutational status are lacking. We investigated the outcomes of MBM in molecularly characterized patients for BRAF and NRAS mutations receiving conventional treatment. We investigated associations between outcomes [competing risk of local and distant brain failure (LF, DF) and overall survival (OS)] and clinical/pathological features of patients with known mutation status following initial treatment of MBM. Competing risk analysis was performed using the methods of Fine and Gray...
December 2, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29198034/population-level-effect-of-molecular-testing-and-targeted-therapy-in-patients-with-advanced-pulmonary-adenocarcinoma-a-prospective-cohort-study
#16
Christine Schwegler, Dinu Kaufmann, David Pfeiffer, Stefan Aebi, Joachim Diebold, Oliver Gautschi
Large cancer centres in the USA demonstrated that molecular diagnosis and targeted therapy improved overall survival of patients with advanced pulmonary adenocarcinoma. We validated this finding in a rural area of Switzerland, served by private practices, community hospitals and a tertiary referral centre. We conducted a prospective cohort study with the Cancer Registry of Central Switzerland, covering 4 cantons and 517,000 inhabitants. All residents newly diagnosed with stage IV pulmonary adenocarcinoma from 2010 to 2014 were enrolled...
December 2, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29192649/the-histopathology-of-erdheim-chester-disease-a-comprehensive-review-of-a-molecularly-characterized-cohort
#17
Neval Ozkaya, Marc K Rosenblum, Benjamin H Durham, Janine D Pichardo, Omar Abdel-Wahab, Meera R Hameed, Klaus J Busam, William D Travis, Eli L Diamond, Ahmet Dogan
Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series...
December 1, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29192597/circulating-tumour-dna-analytical-aspects-and-clinical-applications-for-metastatic-melanoma-patients
#18
Guillaume Herbreteau, Audrey Vallée, Anne-Chantal Knol, Sandrine Théoleyre, Gaëlle Quéreux, Amir Khammari, Brigitte Dréno, Marc G Denis
The management of metastatic melanoma has evolved since the onset of treatments with BRAF inhibitors. In order to predict which patients are likely to respond to these treatments, the therapeutic strategy is now conditioned by the search for the activating mutations of the BRAF gene. Tumor genotyping is routinely performed from DNA extracted from tissue or cellular specimens from the primary tumor, metastases, or neoplastic effusions. Due to their invasiveness, these specimens are rarely repeated during the management...
December 1, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/29191620/genetic-alterations-in-primary-acral-melanoma-and-acral-melanocytic-nevus-in-korea-common-mutated-genes-show-distinct-cytomorphological-features
#19
Ki Rang Moon, Yoo Duk Choi, Jung Min Kim, Suna Jin, Min-Ho Shin, Hyun-Jeong Shim, Jee-Bum Lee, Sook Jung Yun
Acral melanoma occurring on the palms, soles, and nails is the most common subtype of cutaneous melanoma in Asians. Genetic alterations in acral melanoma and acral melanocytic nevus are not well known. We performed next-generation sequencing and evaluated the correlations between genetic information and the clinicopathologic characteristicsfrom 85 Korean patients with acral melanocytic neoplasms. Of the 64 patients with acral melanoma, most had ≥ T2 stage, and the heel was the most common anatomical site of melanoma (n = 34, 53...
November 27, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29187213/jmjd6-promotes-melanoma-carcinogenesis-through-regulation-of-the-alternative-splicing-of-pak1-a-key-mapk-signaling-component
#20
Xujun Liu, Wenzhe Si, Xinhua Liu, Lin He, Jie Ren, Ziran Yang, Jianguo Yang, Wanjin Li, Shumeng Liu, Fei Pei, Xiaohan Yang, Luyang Sun
BACKGROUND: Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. METHODS: We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis...
November 29, 2017: Molecular Cancer
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