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Prerna Guleria, Saumya Ranjan Mallick, Prashant Ramteke, Deepali Jain
Anaplastic Lymphoma Kinase positive Large B-cell Lymphoma (ALK+LBCL), is a rare entity, of which case reports exist in literature. It is a B-cell neoplasm with plasma-cell differentiation and displays plasmablasts/immunoblast like cells along with a peculiar immuno-histochemical profile. The cytomorphological characteristics of this entity have been described earlier, however, with the help of this case which had misleading clinical presentation, we wish to highlight certain cytological features which will act as diagnostic clues in identification of cases of ALK+LBCL in aspiration cytology...
July 14, 2018: Cytopathology: Official Journal of the British Society for Clinical Cytology
Jianzong Li, Yue Huang, Miaomiao Wu, Chuanfang Wu, Xin Li, Jinku Bao
Anaplastic lymphoma kinase (ALK) is considered as a validated molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the effectiveness of molecularly targeted therapies using ALK inhibitors is almost universally limited by drug resistance. Drug resistance to molecularly targeted therapies has now become a major obstacle to effective cancer treatment and personalized medicine. It is of particular importance to provide an improved understanding on the mechanisms of resistance of ALK inhibitors, thus rational new therapeutic strategies can be developed to combat resistance...
July 13, 2018: Scientific Reports
Anthony C Wang, David T W Jones, Isaac Joshua Abecassis, Bonnie L Cole, Sarah E S Leary, Christina M Lockwood, Lukas Chavez, David Capper, Andrey Korshunov, Aria Fallah, Shelly Wang, Chibawanye Ene, James M Olson, Russell Geyer, Eric C Holland, Amy Lee, Richard G Ellenogen, Jeffrey G Ojemann
Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n=8) diagnosed histologically as DIG/DIGA...
July 13, 2018: Molecular Cancer Research: MCR
Mohamed W Attwa, Hany W Darwish, Hassan A Alhazmi, Adnan A Kadi
Entrectinib (ENC) is a potent orally available anaplastic lymphoma kinase (ALK) inhibitor. In 10 July 2017, biotechnology company (Ignyta) announced that granted orphan drug designation approval was given by the FDA to ENC for "treatment of NTRK fusion-positive solid tumors". A validated LC-MS/MS methodology was developed for ENC quantification in human plasma matrix. The supposed method characterized by high speed, specificity and sensitivity. This established method was applied for metabolic degradation assessment of ENC...
July 10, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Cheng-Han Jiang, Chong-Xian Huang, Ya-Jyun Chen, Yu-Chung Chuang, Bo-Yen Huang, Chia-Ning Yang
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in various cancers. In its basal state, the structure of ALK is in an autoinhibitory form stabilized by its A-loop, which runs from the N-lobe to the C-lobe of the kinase. Specifically, the A-loop adopts an inhibitory pose with its proximal A-loop helix (αAL-helix) to anchor the αC-helix orientation in an inactive form in the N-lobe; the distal portion of the A-loop is packed against the C-lobe to block the peptide substrate from binding...
July 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Merrida A Childress, Stephen M Himmelberg, Huiqin Chen, Wanleng Deng, Michael A Davies, Christine M Lovly
Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5' fusion partners have been reported, treatment of ALK-rearranged cancers is generally decided without regard to which 5' partner is present. There is little data addressing how the 5' partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKIs). Based on the hypothesis that the 5' partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs; clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated...
July 12, 2018: Molecular Cancer Research: MCR
Jing Tu, Li Ting Song, Hong Lin Zhai, Juan Wang, Xiao Yun Zhang
As an attractive therapeutic target for non-small-cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) has got increased attention, and the selectivity of ALK inhibitors is an enormous challenge. Recently, 2,4-Diarylaminopyrimidines with high inhibitory activity over InsR/IGF1R were reported as ALK inhibitors, which harboring phosphine oxide moiety. In this work, it is the first time to reveal that the incorporation of dimethylphosphine oxide moiety and the smaller active pocket of ALK is key factor in the selectivity of inhibitor 11q toward ALK over IGF1R/InsR...
July 2, 2018: International Journal of Biological Macromolecules
Jarish N Cohen, Iwei Yeh, Richard C Jordan, Rebecca J Wolsky, Andrew E Horvai, Timothy H McCalmont, Philip E LeBoit
Non-neural granular cell tumor (NNGCT; also known as primitive polypoid granular cell tumor) is a rare neoplasm composed of large ovoid cells with abundant granular cytoplasm, variable nuclear pleomorphism, and the potential for regional lymph node spread. In contrast to conventional granular cell tumor (GCT), NNGCT lacks S100 expression and can exhibit greater nuclear atypia and mitotic activity. Therefore, we investigated clinicopathologic features of 12 NNGCT, and also used next-generation sequencing to identify potential driver events in a subset of NNGCT and 6 GCT...
July 11, 2018: American Journal of Surgical Pathology
Wen-Xian Wang, Chun-Wei Xu, Yan-Ping Chen, Wei Liu, Li-Hua Zhong, Fang-Fang Chen, Wu Zhuang, Yun-Jian Huang, Zhang-Zhou Huang, Rong-Rong Chen, Yan-Fang Guan, Xin Yi, Tang-Feng Lv, Wei-Feng Zhu, Jian-Ping Lu, Xiao-Jiang Wang, Yi Shi, Xian-Dong Lin, Gang Chen, Yong Song
Background: Advanced non-small cell lung cancer (NSCLC) patients who harbor anaplastic lymphoma kinase ( ALK ) rearrangement are sensitive to an ALK inhibitor (crizotinib), but not all ALK -positive patients benefit equally from crizotinib treatment. We analyze the impact of TP53 mutations on response to crizotinib in patients with ALK rearrangement NSCLC. Methods: Sixty-six ALK rearrangement NSCLC patients receiving crizotinib were analyzed. 21 cases were detected successfully by the next generation sequencing validation FFPE before crizotinib...
May 2018: Journal of Thoracic Disease
Tangfeng Lv, Qian Zou, Zhengbo Song, Hongbing Liu, Qiming Wang, Yong Song
Background: Non-small cell lung cancer (NSCLC) patients with EML4-ALK fusion exhibited various durations of response to crizotinib. Molecular heterogeneity is also one of the factors associated with resistance to crizotinib. This study investigated the relevance of molecular heterogeneity to the clinical efficacy of crizotinib using next-generation sequencing (NGS). Methods: A total of 52 ALK-positive advanced NSCLC patients were enrolled. The genetic variation was revealed by NGS...
May 2018: Journal of Thoracic Disease
Liping Liu, Di Shao, Qiuhua Deng, Hailing Tang, Jingjing Wang, Jilong Liu, Fengming Guo, Yongping Lin, Zhiyu Peng, Mao Mao, Karsten Kristiansen, Mingzhi Ye, Jianxing He
Background: Molecular profiling of non-small cell lung cancer (NSCLC) is essential for therapeutic decision-making. Pleural effusion obtained by a non-invasive, repeatable procedure may provide an opportunity for molecular profiling and thereby possibly provide information enabling targeted therapy. In this study, we aimed to evaluate the diagnostic performance of pleural effusion as a specimen for molecular analysis. Methods: Thirty patients with paired malignant pleural effusion and thoracic biopsy specimens were included...
May 2018: Journal of Thoracic Disease
Po-Ru Loh, Giulio Genovese, Robert E Handsaker, Hilary K Finucane, Yakir A Reshef, Pier Francesco Palamara, Brenda M Birmann, Michael E Talkowski, Samuel F Bakhoum, Steven A McCarroll, Alkes L Price
The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%)...
July 11, 2018: Nature
Matilde Calanchini, Ahmad Moolla, Jeremy W Tomlinson, Jeremy F Cobbold, Ashley Grossman, Andrea Fabbri, Helen E Turner
OBJECTIVE: Abnormal liver function tests (LFTs) are frequent in Turner syndrome (TS). The causes and clinical significance are unclear. AIMS: to investigate the prevalence of elevated LFTs in adult TS; secondly, to analyse the associations between elevated LFTs, TS-karyotypes, and TS-related conditions; and thirdly, to evaluate liver stiffness and histological assessment. METHODS: 125 TS women were retrospectively studied. Karyotypes, clinical and biochemical details and aortic measurements were recorded...
July 10, 2018: Clinical Endocrinology
Jessica Corean, K David Li
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a very rare and aggressive subtype of diffuse large B-cell lymphoma characterized by ALK rearrangement. Immunophenotypically, the tumor cells are typically negative for common B-cell markers, T-cell markers, and CD30; however, they express markers of terminally differentiated B cells/plasma cells such as CD38, CD138, and MUM-1/IRF4. The diagnosis of ALK+ LBCL can be challenging, and often a large panel of immunostains is required to exclude other hematopoietic and nonhematopoietic neoplasms...
2018: Case Reports in Hematology
Claudio Sini, Alessandro Tuzi, Giovanni Rossi, Alessandro Russo, Aldo Pezzuto
The advance of tyrosine kinase inhibitors has profoundly changed the therapeutic algorithm of non-small-cell lung cancer in molecularly selected patients. However, benefit from these agents is often transient and usually most patients progress within 12 months from treatment. Novel and more potent and selective tyrosine kinase inhibitors have been developed to overcome acquired resistance; however, these agents are once again associated with only temporary benefit and patients frequently develop secondary resistance, a heterogeneous phenomenon that involves different molecular mechanisms simultaneously...
June 2018: Future Oncology
Silvia Vecchiarelli, Chiara Bennati
Lung cancer is the leading cause of cancer mortality worldwide. Activating mutations in the EGFR and rearrangements in the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genes have been identified as oncogenic drivers in non-small-cell lung cancer. Development of specific small-molecule tyrosine kinase inhibitors, able to interfere with tumor growth and metastatic spread, dramatically changed the natural history of oncogene-addicted non-small-cell lung cancer. However, despite advances in targeted therapies, all patients inevitably develop acquired resistance to tyrosine kinase inhibitors...
June 2018: Future Oncology
Yasser M Omar, Hajjaj H M Abdu-Allah, Samia G Abdel-Moty
Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame...
July 3, 2018: Bioorganic Chemistry
Hajime Sasano, Akimasa Sekine, Toru Hirata, Keisuke Iwamoto, Yuhei Itou, Hidetoshi Itani, Shigeto Kondou, Toshiya Tokui, Motoaki Tanigawa
We herein report a 37-year-old woman with lung adenocarcinoma with brain metastases and an asymptomatic ovarian tumor. Immunohistochemistry and a fluorescent in situ hybridization analysis of the biopsied lung tumor revealed ALK gene rearrangement. Although the origin of the ovarian tumor remained unclear, alectinib administration was initiated, and radiological responses were observed in all lesions, which confirmed that the ovarian tumor was a metastasis from lung cancer. Although differentiating the origin of an ovarian tumor is difficult in lung cancer patients due to the rarity of ovarian metastases, alectinib therapy can replace an invasive biopsy, especially in ALK-rearranged lung cancer patients...
July 6, 2018: Internal Medicine
Tejas Patil, Derek E Smith, Paul A Bunn, Dara L Aisner, Anh T Le, Mark Hancock, William T Purcell, Daniel W Bowles, D Ross Camidge, Robert C Doebele
INTRODUCTION: Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in stage IV ROS1+ non-small cell lung cancer (NSCLC) and rate of CNS progression on crizotinib. METHODS: A retrospective review of 579 patients with stage IV NSCLC between June 2008 to December 2017 was performed. Brain metastases and oncogene status (ROS1, ALK, EGFR, KRAS, BRAF, and other) were recorded...
July 5, 2018: Journal of Thoracic Oncology
Kartik Sehgal, Mary Linton B Peters, Paul A VanderLaan, Deepa Rangachari, Susumu S Kobayashi, Daniel B Costa
No abstract text is available yet for this article.
July 5, 2018: Journal of Thoracic Oncology
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